FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Quaia, C Optican, LM AF Quaia, C Optican, LM TI No "When" without "Where" SO BEHAVIORAL AND BRAIN SCIENCES LA English DT Editorial Material ID MONKEY SUPERIOR COLLICULUS; NEURONAL-ACTIVITY; EYE-MOVEMENTS; MODULATION; DISCHARGE; FIXATION; CELLS AB Deciding where to look is a very complicated process, but deciding when to look is probably much simpler. Once the brain is certain of where it wants to look, the saccade-generating pathway may simply start autonomously. Higher cognitive areas of the brain can only override this automatic start by preventing all saccades. Hence, the brain has no ability to say when to go; it can only say "go there" or "stay here." C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Quaia, C (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 9 TC 2 Z9 2 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0140-525X J9 BEHAV BRAIN SCI JI Behav. Brain Sci. PD AUG PY 1999 VL 22 IS 4 BP 696 EP + DI 10.1017/S0140525X9945215X PG 11 WC Psychology, Biological; Behavioral Sciences; Neurosciences SC Psychology; Behavioral Sciences; Neurosciences & Neurology GA 255KP UT WOS:000083668300058 ER PT J AU Resjo, S Oknianska, A Zolnierowicz, S Manganiello, V Degerman, E AF Resjo, S Oknianska, A Zolnierowicz, S Manganiello, V Degerman, E TI Phosphorylation and activation of phosphodiesterase type 3B (PDE3B) in adipocytes in response to serine/threonine phosphatase inhibitors: deactivation of PDE3B in vitro by protein phosphatase type 2A SO BIOCHEMICAL JOURNAL LA English DT Article DE calyculin A; insulin signalling; lipolysis; okadaic acid ID CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES; KM CAMP PHOSPHODIESTERASE; HORMONE-SENSITIVE LIPASE; RABBIT-SKELETAL-MUSCLE; RAT ADIPOCYTES; OKADAIC ACID; CALYCULIN-A; INSULIN-SECRETION; FAT-CELLS; KINASE AB Phosphodiesterase type 3B (PDE3B) has been shown to be activated and phosphorylated in response to insulin and hormones that increase cAMP. In order to study serine/threonine protein phosphatases involved in the regulation of rat adipocyte PDE3B, we investigated the phosphorylation and activation of PDE3B in vivo in response to phosphatase inhibitors and the dephosphorylation and deactivation of PDE3B in vitro by phosphatases purified from rat adipocyte homogenates, Okadaic acid and calyculin A induced dose- and lime-dependent activation of PDE3B, Maximal effects were obtained after 30 min using 1 mu M okadaic acid (1.8-fold activation) and 300 nM calyculin A (4-fold activation), respectively. Tautomycin and cyclosporin A did not induce activation of PDE3B. Incubation of adipocytes with 300 nM calyculin A inhibited protein phosphatase (PP) 1 and PP2A completely. Okadaic acid (1 mu M) reduced PP2A activity by approx. 50 % but did not affect PP 1 activity, and 1 mu M tautomycin reduced PP1 activity by approx. 60 % but PP2A activity by only 11 %. This indicates an important role for PP2A in the regulation of PDE3B. Furthermore, rat adipocyte PDE3B phosphatase activity co-purified with PP2A but not with PPI during MonoQ chromatography, As compared with insulin, okadaic acid and calyculin A induced phosphorylation of PDE3B by 2.8- and 14-fold respectively, whereas tautomycin and cyclosporin A had no effect. Both calyculin A and okadaic acid induced phosphorylation on serine 302, the site known to be phosphorylated on PDE3B in response to insulin and isoproterenol (isoprenaline), as well as on sites not identified previously. In summary, PP2A seems to be involved in the regulation of PDE3B in vivo and can act as a PDE3B phosphatase in vitro. In comparison with insulin, calyculin A induced a dramatic activation of PDE3B and both calyculin A and okadaic acid induced phosphorylation on additional sites, which could have a role in signalling pathways not yet identified. C1 Univ Lund, Sect Mol Signalling, Dept Cell & Mol Biol, S-22100 Lund, Sweden. MUG, UG, Intercollegiate Fac Biotechnol, PL-80211 Gdansk, Poland. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Resjo, S (reprint author), Univ Lund, Sect Mol Signalling, Dept Cell & Mol Biol, POB 94, S-22100 Lund, Sweden. NR 52 TC 45 Z9 45 U1 0 U2 3 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD AUG 1 PY 1999 VL 341 BP 839 EP 845 DI 10.1042/0264-6021:3410839 PN 3 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 223ZN UT WOS:000081871600045 PM 10417351 ER PT J AU Bondoc, FY Bao, ZP Hu, WY Gonzalez, FJ Wang, YY Yang, CS Hong, JY AF Bondoc, FY Bao, ZP Hu, WY Gonzalez, FJ Wang, YY Yang, CS Hong, JY TI Acetone catabolism by cytochrome P450 2E1: Studies with CYP2E1-null mice SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE acetone metabolism fasting; cytochrome P450 2E1; 2E1 knockout mice ID METABOLISM; RAT AB Previous experiments in vitro have suggested that cytochrome P450 2E1 (CYP2E1) is involved in acetone catabolism by converting acetone to acetol and then to methylglyoxal, both intermediates in the gluconeogenic pathway. In the present study, CYP2E1-null mice were used to demonstrate the role of CYPZE1 in acetone catabolism in vivo. The blood acetone level in male CYP2E1-null mice was 3.3 +/- 0.9 mu g/mL, which was similar to levels of their sex- and age-matched parental lineage strains C57BL/6N (2.3 +/- 0.2 mu g/mL) and 129/Sv (3.5 +/- 0.3 mu g/mL) mice (both are CYP2E1wild-type). After fasting for 48 hr, the blood acetone levels in the CYP2E1 wild-type mice were increased by 2.5- to 4.4-fold, but that in the CYP2E1-null mice increased 28-fold. These results clearly demonstrate that CYPZE1 plays a vital role in the catabolism of acetone under fasting conditions. (C) 1999 Elsevier Science Inc. C1 Rutgers State Univ, Coll Pharm, Canc Res Lab, Piscataway, NJ 08854 USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Hong, JY (reprint author), Rutgers State Univ, Coll Pharm, Canc Res Lab, 164 Frelinghuysen Rd, Piscataway, NJ 08854 USA. FU NIEHS NIH HHS [ES03938, ES05022] NR 19 TC 55 Z9 57 U1 0 U2 3 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 1999 VL 58 IS 3 BP 461 EP 463 DI 10.1016/S0006-2952(99)00111-2 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 210LH UT WOS:000081106600010 PM 10424765 ER PT J AU Grem, JL Nguyen, D Monahan, BP Kao, V Geoffroy, FJ AF Grem, JL Nguyen, D Monahan, BP Kao, V Geoffroy, FJ TI Sequence-dependent antagonism between fluorouracil and paclitaxel in human breast cancer cells SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE taxanes; fluorouracil; drug interactions; DNA damage; p53; p21; Bcl-2 ID COLON-CANCER; IN-VITRO; TUMOR-CELLS; PHASE-I; TAXOL; DNA; CYTOTOXICITY; 5-FLUOROURACIL; DOXORUBICIN; CISPLATIN AB The effects of 24-hr exposures to 5-fluorouracil (FUra) and paclitaxel in Various sequences were studied in MCF-7 breast cancer cells to determine an optimal schedule for possible clinical use. In clonogenic assays, pre-exposure to FUra followed by paclitaxel resulted in marked antagonism, while sequential paclitaxel followed by FUra was optimal. Concurrent or pre exposure to paclitaxel did not affect [H-3]FUra metabolism, [H-3]FUra-RNA incorporation, or the extent of FUra-mediated thymidylate synthase inhibition. Paclitaxel led to G(2)/M phase accumulation that persisted for up to 24 hr after drug exposure, while a 24-hr FUra exposure produced S-phase accumulation. FUra pre-exposure diminished paclitaxel-associated G(2)/M phase block, whereas subsequent exposure to FUra after paclitaxel did not. FUra exposure resulted in transient induction of p53 and p21, which returned to basal levels 24 hr after drug removal. p53 and p21 protein content also increased markedly during paclitaxel exposure, accompanied by phosphorylation of Bcl-2. Double-stranded DNA fragmentation(similar to 50 kb) was seen at 48 hr when cells were exposed to paclitaxel for an initial 24-hr period. Paclitaxel-associated DNA fragmentation was not prevented by concurrent or subsequent exposure to FUra. Thus, paclitaxel-mediated G(2)/M phase arrest appeared to be a crucial step in induction of DNA fragmentation. Since an initial 24-hr paclitaxel exposure did not interfere with subsequent FUra metabolism or thymidylate synthase inhibition, and delayed exposure to FUra did not impede either paclitaxel-mediated induction of mitotic blockade or DNA fragmentation, the sequence of paclitaxel followed by FUra is recommended for clinical trials. (C) 1999 Elsevier Science Inc. C1 USN, Natl Med Ctr, NCI, Med Branch,Dev Therapeut Dept, Bethesda, MD 20889 USA. USN, Hematol Oncol Sect, Dept Med, Natl Med Ctr, Bethesda, MD 20889 USA. RP Grem, JL (reprint author), USN, Natl Med Ctr, NCI, Med Branch,Dev Therapeut Dept, 8901 Wisconsin Ave,Bldg 8,Room 5101, Bethesda, MD 20889 USA. NR 35 TC 39 Z9 41 U1 0 U2 0 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 1999 VL 58 IS 3 BP 477 EP 486 DI 10.1016/S0006-2952(99)00099-4 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 210LH UT WOS:000081106600013 PM 10424768 ER PT J AU Kawamura, M Eisenhofer, G Kopin, IJ Kador, PF Lee, YS Tsai, JY Fujisawa, S Lizak, MJ Sinz, A Sato, S AF Kawamura, M Eisenhofer, G Kopin, IJ Kador, PF Lee, YS Tsai, JY Fujisawa, S Lizak, MJ Sinz, A Sato, S TI Aldose reductase, a key enzyme in the oxidative deamination of norepinephrine in rats SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE aldose reductase; aldehyde reductase; norepinephrine; 3,4-dihydroxymandelaldehyde; 3,4dihydroxyphenylglycol; sympathetic nervous system ID ALDEHYDE REDUCTASES; METABOLISM; INHIBITION; BRAIN; CATECHOLAMINES; EXPRESSION AB The sympathoneural neurotransmitter norepinephrine (NE) is deaminated to 3,4-dihydroxymandelaldehyde (DHMAL) and subsequently converted to either 3,4-dihydroxymandelic acid (DHMA) or 3,4- dihydroxyphenylglycol (DHPG). In this study, we investigated the relative importance of aldose reductase versus aldehyde reductase in the formation of DHPG from DHMAL. The in vitro incubation of NE with aldose reductase in the presence of monoamine oxidase (MAO) resulted in the formation of DHPG, which was confirmed by mass spectrometry. Although aldehyde reductase also generated DHPG, its activity was much lower than that of aldose reductase. With northern blotting, the expression of both aldose reductase and aldehyde reductase was detected in rat superior cervical ganglia. However, with western blotting, only aldose reductase was immunologically detectable. Treatment of rats with aldose reductase inhibitors for 3 days increased the plasma level of DHMA. There was no correlation between the selectivity of inhibitors and effects on NE metabolite levels. A significant decrease in DHPG, however, was obtained only with an extremely high dose (9 mg/kg/day) of the nonselective inhibitor AL 1576. The present study confirmed that aldose reductase generates DHPG from NE in the presence of MAO. In rat sympathetic neurons, aldose reductase appears to be more important than aldehyde reductase for the formation of DHPG. However, when aldose reductase is inhibited, it appears that aldehyde reductase can compensate for the conversion of DHMAL to DHPG, indicating redundancy in the reduction pathway. (C) 1999 Elsevier Science Inc. C1 NEI, LOT, NIH, Bethesda, MD 20892 USA. NINDS, Clin Neurosci Branch, NIH, Bethesda, MD 20892 USA. RP Sato, S (reprint author), NEI, LOT, NIH, 10-10B09,10 Ctr Dr,MSC 1850, Bethesda, MD 20892 USA. NR 31 TC 16 Z9 16 U1 0 U2 0 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 1999 VL 58 IS 3 BP 517 EP 524 DI 10.1016/S0006-2952(99)00121-5 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 210LH UT WOS:000081106600017 PM 10424772 ER PT J AU Blagosklonny, MV AF Blagosklonny, MV TI A node between proliferation, apoptosis, and growth arrest SO BIOESSAYS LA English DT Article ID CELL-CYCLE ARREST; MYC-INDUCED APOPTOSIS; C-MYC; TUMOR-SUPPRESSOR; P21(WAF1/CIP1) EXPRESSION; P53-DEPENDENT APOPTOSIS; RETINOBLASTOMA PROTEIN; HUMAN FIBROBLASTS; DNA-SYNTHESIS; E1B 19-KDA AB Paradoxically, oncogenes and growth factors can induce proliferation and promote cellular survival but can also cause apoptosis and growth arrest. What determines whether a cell decides to proliferate, arrest growth, or die? Mitogens and activators of mitogen-activated pathways initiate the simultaneous production of proliferative (cyclins) and anti-proliferative (CDK inhibitors such as p21WAF1/ CIP1) signals. Quiescent cells may respond to these signals by proliferation whereas proliferating cells may respond by growth arrest. Although pro-apoptotic oncoproteins, which constitute the downstream pathway (cyclin D, E2F, c-myc) directly induce proliferation, the activation of the upstream steps (growth factor receptors, Ras, cytoplasmic kinases) is required to prevent apoptosis. BioEssays 21,704-709, 1999. (C) 1999 John Wiley & Sons, Inc. C1 NCI, Med Branch, NIH, Bethesda, MD 20892 USA. RP Blagosklonny, MV (reprint author), NCI, Med Branch, NIH, Bldg 10,R 12N226, Bethesda, MD 20892 USA. NR 72 TC 50 Z9 52 U1 0 U2 4 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 1999 VL 21 IS 8 BP 704 EP 709 DI 10.1002/(SICI)1521-1878(199908)21:8<704::AID-BIES10>3.0.CO;2-5 PG 6 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 223ZP UT WOS:000081871700010 PM 10440867 ER PT J AU Franklin, WL Johnson, WE Sarno, RJ Iriarte, JA AF Franklin, WL Johnson, WE Sarno, RJ Iriarte, JA TI Ecology of the Patagonia puma Felis concolor patagonica in southern Chile SO BIOLOGICAL CONSERVATION LA English DT Article DE puma; ecology; human conflict; Patagonia; Chile ID SKUNK CONEPATUS-HUMBOLDTI; PAINE-NATIONAL-PARK; FEEDING ECOLOGY; AMERICA; PATTERNS; JAGUAR AB The ecology of the Patagonia puma was studied in Torres del Paine National Park, Chile. Thirteen pumas were captured from 1986 to 1989 and equipped with radio transmitters. During the winter of 1988 there was one puma per 17 km(2) in the 200 km(2) study area. Home ranges varied from 24 to 107 km(2). Female home ranges overlapped with those of other males and females extensively, but male ranges overlapped each other for only short time periods. Seven adult pumas had home ranges extending outside the park boundaries and at least three preyed on sheep. Guanacos Lama guanicoe, especially young animals, were the puma's most important prey item by biomass, but European hares Lepus capensis were preyed upon more than expected relative to available biomass. Of 731 guanaco skulls collected from 1979 to 1988, 33% showed clear evidence of having been killed by pumas. Over the past decade puma numbers are believed to have increased in the park, perhaps in response to an increase in guanaco numbers and continued protection. With decreased hunting pressure and harassment by horses and dogs, pumas have habituated to people and are being observed more often by park visitors. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 Iowa State Univ, Dept Anim Ecol, Ames, IA 50011 USA. Univ Florida, Ctr Latin Amer Studies, Gainesville, FL USA. RP Johnson, WE (reprint author), NCI, Lab Genom Divers, Frederick, MD 21702 USA. RI Johnson, Warren/D-4149-2016 OI Johnson, Warren/0000-0002-5954-186X NR 55 TC 64 Z9 72 U1 1 U2 22 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0006-3207 J9 BIOL CONSERV JI Biol. Conserv. PD AUG PY 1999 VL 90 IS 1 BP 33 EP 40 DI 10.1016/S0006-3207(99)00008-7 PG 8 WC Biodiversity Conservation; Ecology; Environmental Sciences SC Biodiversity & Conservation; Environmental Sciences & Ecology GA 196PV UT WOS:000080317500004 ER PT J AU Bachevalier, J Alvarado, MC Malkova, L AF Bachevalier, J Alvarado, MC Malkova, L TI Memory and socioemotional behavior in monkeys after hippocampal damage incurred in infancy or in adulthood SO BIOLOGICAL PSYCHIATRY LA English DT Article; Proceedings Paper CT Conference on Schizophrenia - From Molecule to Public Policy CY OCT, 1998 CL SANTA FE, NEW MEXICO SP Soc Biol Psychiat, Eli Lilly & Co DE social behavior; stereotypy; hippocampal formation; nonhuman primates ID MAGNETIC-RESONANCE SPECTROSCOPY; TEMPORAL-LOBE LESIONS; RHESUS-MONKEYS; MACACA-MULATTA; VISUAL RECOGNITION; BILATERAL DAMAGE; IMPAIRMENT; SCHIZOPHRENIA; AMYGDALA; CORTEX AB The present study reviews the long-term effects of neonatal hippocampal damage in monkeys on the development of memory functions and socioemotional behavior. The results showed that neonatal damage to the hippocampal formation impairs specific memory processes, such as those subserving automatic (as opposed to effortful) recognition memory and relational learning while sparing the abilities to acquire skills, such as object discriminations. Furthermore, the neonatal hippocampectomy led to a progressive loss of social affiliation and a protracted emergence of locomotor-stereotypies. While the memory losses following neonatal hippocampal lesions resemble those Sound after similar lesions acquired in adulthood, only the neonatal lesions resulted in a protracted emergence of abnormal behaviors. These later findings suggested that presumably, the neonatal lesions impacted on neural systems remote from the site of damage. This was confirmed by our more recent neurobiological studies, demonstrating that neonatal, but not late, lesions of the medial temporal lobe region, disrupt the normal behavioral and cognitive processes subserved by the prefrontal cortex and the caudate nucleus. All together the data support the neurodevelopmental hypothesis viewing early insult to the medial temporal region as the origin of developmental psychosis in humans, such as schizophrenia. Biol Psychiatry 1999;46:329-339 (C) 1999 Society of Biological Psychiatry. C1 Univ Texas, Hlth Sci Ctr, Dept Neurobiol & Anat, Houston, TX 77030 USA. NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. RP Bachevalier, J (reprint author), Univ Texas, Hlth Sci Ctr, Dept Neurobiol & Anat, 6431 Fannin, Houston, TX 77030 USA. FU NIMH NIH HHS [F32 MH010929, MH-10929, MH-54167, MH-58846, R01 MH058846] NR 67 TC 49 Z9 51 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 1999 VL 46 IS 3 BP 329 EP 339 DI 10.1016/S0006-3223(99)00123-7 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 220TJ UT WOS:000081683300004 PM 10435198 ER PT J AU Tariot, PN Upadhyaya, A Sunderland, T Cox, C Cohen, RM Murphy, DL Loy, R AF Tariot, PN Upadhyaya, A Sunderland, T Cox, C Cohen, RM Murphy, DL Loy, R TI Physiologic and neuroendocrine responses to intravenous naloxone in subjects with Alzheimer's disease and age-matched controls SO BIOLOGICAL PSYCHIATRY LA English DT Article DE naloxone; Alzheimer's disease; opiate antagonist; neuroendocrine; opiate receptors ID CORTICOTROPIN-RELEASING HORMONE; PITUITARY-ADRENAL AXIS; HIGH-DOSE NALOXONE; DEXAMETHASONE SUPPRESSION TEST; OPIOID RECEPTOR-BINDING; BETA-ENDORPHIN; CEREBROSPINAL-FLUID; BODY-TEMPERATURE; SENILE DEMENTIA; ADRENOCORTICOTROPIC HORMONE AB Background: Prior work showed that administration of naloxone HCl had different behavioral effects in patients with Alzheimer's disease (AD) than controls. The aim of the present study was to contrast the physiologic and neuroendocrine responses to administration of a wide range of doses of intravenous naloxone of patients with probable Alzheimer's disease to aged-matched controls. Methods: This was a double-blind, placebo-controlled, study of 12 patients with probable Alzheimer's disease and 8 age-matched normal controls who each received intravenous infusions of naloxone HCl on 3 different days in doses of 0.1 mg/kg and 2.0 mg/kg preceded by test doses of 0.5 mcg/kg, Order of treatment condition was randomized. Vital signs and plasma cortisol and prolactin were obtained at regular intervals. Results: Both groups showed increased cortisol after naloxone 0.1 mg/kg and 2.0 mg/kg (p < .0001), but the increase was significantly greater and longer lived in controls than in patients. Patients, but not controls, also experienced a significant hypothermic response after naloxone 2.0 mg/kg (p < .05). Prolactin, heart rate, and blood pressure did not change following naloxone and did nor differ between groups. Conclusions: These findings support a growing body evidence that HPA axis activity is increased in AD, and further suggest that at least part of this may be due to decreased opiatergic tonic inhibition. Bioi Psychiatry 1999;46:412-419 (C) 1999 Society of Biological Psychiatry. C1 Univ Rochester, Med Ctr, Monroe Community Hosp, Dept Psychiat,Program Neurobehav Therapeut, Rochester, NY 14620 USA. Univ Rochester, Med Ctr, Dept Psychiat, Rochester, NY 14642 USA. NIMH, Clin Neurosci Lab, Bethesda, MD USA. NIMH, Geriatr Psychiat Branch, Bethesda, MD USA. Univ Rochester, Med Ctr, Dept Biostat, Rochester, NY 14642 USA. NIMH, Cerebral Metab Lab, Bethesda, MD 20892 USA. Univ Rochester, Med Ctr, Dept Neurol, Rochester, NY 14642 USA. RP Tariot, PN (reprint author), Univ Rochester, Med Ctr, Monroe Community Hosp, Dept Psychiat,Program Neurobehav Therapeut, 435 E Henrietta Rd, Rochester, NY 14620 USA. NR 80 TC 8 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD AUG 1 PY 1999 VL 46 IS 3 BP 412 EP 419 DI 10.1016/S0006-3223(98)00329-1 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 220TJ UT WOS:000081683300014 PM 10435208 ER PT J AU Vendola, K Zhou, J Wang, J Famuyiwa, OA Bievre, M Bondy, CA AF Vendola, K Zhou, J Wang, J Famuyiwa, OA Bievre, M Bondy, CA TI Androgens promote oocyte insulin-like growth factor I expression and initiation of follicle development in the primate ovary SO BIOLOGY OF REPRODUCTION LA English DT Article ID RECEPTOR GENE-EXPRESSION; PRIMORDIAL FOLLICLES; STIMULATING-HORMONE; MALE-TRANSSEXUALS; MAMMALIAN OOCYTE; VITRO; MATURATION; LOCALIZATION; SYSTEM; FEMALE AB In the study reported here, we investigated the effect of androgens on recruitment of resting, primordial follicles into the actively growing pool. Healthy, random-cycling female rhesus monkeys were treated with testosterone, dihydrotestosterone (DHT), or vehicle for 3-10 days, after which ovaries were collected for histological analysis. The first stage of follicle growth is the formation of the primary follicle, consisting of an oocyte surrounded by a single layer of cuboidal granulosa cells. The number of primary follicles was significantly increased over time in testosterone-treated animals. In situ hybridization showed that androgen treatment resulted in an increase to 3-fold in insulin-like growth factor I (IGF-I) and to 5-fold in IGF-I receptor mRNA in primordial follicle oocytes. DHT effects were comparable to those of testosterone, showing that these are androgen receptor-mediated phenomena. These data show that androgens promote initiation of primordial follicle growth and implicate oocyte-derived IGF-I in this activation process. C1 NICHD, Sect Womens Hlth, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Bondy, CA (reprint author), NICHD, Sect Womens Hlth, Dev Endocrinol Branch, NIH, Bg 10,Rm 10N262,10 Ctr Dr 1862, Bethesda, MD 20892 USA. NR 26 TC 200 Z9 208 U1 0 U2 11 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD AUG PY 1999 VL 61 IS 2 BP 353 EP 357 DI 10.1095/biolreprod61.2.353 PG 5 WC Reproductive Biology SC Reproductive Biology GA 220DK UT WOS:000081649100003 PM 10411511 ER PT J AU Fields, PA Lee, VH Jetten, A Chang, SMT Fields, MJ AF Fields, PA Lee, VH Jetten, A Chang, SMT Fields, MJ TI B-chain sequence and in situ hybridization of the rabbit placental relaxin-like gene product SO BIOLOGY OF REPRODUCTION LA English DT Article ID PREPRORELAXIN-LIKE GENE; EPITHELIAL-CELLS; EXPRESSION; PREGNANCY; PROTEINS; SYNCYTIOTROPHOBLAST AB We reported that the nucleotide sequence of a cDNA generated from rabbit placental poly(A)(+) RNA using porcine preprorelaxin primers was identical to SQ10, a product of squamous differentiated tracheal epithelial cells. However, these results did not confirm that SQ10 was the biologically active rabbit relaxin that had been isolated previously yet not sequenced. In this study, a 7-kDa protein isolated from rabbit placentas exhibited relaxin bioactivity and cross-reacted with a porcine relaxin antiserum. A partial amino acid sequence of this protein revealed a sequence identical to that of SQ10. Although the amino acid sequence of the putative relaxin receptor-binding domain found in the B chain of relaxin was modified in SQ10 from CGRDYVR to CRNDFVR, the placental protein was bioactive. These results suggest that SQ10 is the rabbit relaxin. In situ hybridization, using an SQ10 riboprobe, indicated radiolabeling in the syncytiotrophoblast cells of the rabbit placenta. The pattern of labeling corresponded with the immunohistochemical staining for relaxin observed with use of a porcine relaxin antiserum. These results indicate that the syncytiotrophoblast cells are a site of synthesis for SQ10 and that the immunostaining is not solely the result of sequestering SQ10 through receptor-mediated endocytosis. A potential role for relaxin in implantation is discussed. C1 Univ S Alabama, Coll Med, Dept Struct & Cellular Biol, Mobile, AL 36688 USA. Texas Tech Univ, Hlth Sci Ctr, Dept Biochem & Cell Biol, Lubbock, TX 79430 USA. NIEHS, Cell Biol Sect, Pulm Pathobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Florida, Dept Anim Sci, Gainesville, FL 32611 USA. RP Fields, PA (reprint author), Univ S Alabama, Coll Med, Dept Struct & Cellular Biol, MSB 1206, Mobile, AL 36688 USA. OI Jetten, Anton/0000-0003-0954-4445 NR 24 TC 4 Z9 4 U1 0 U2 1 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD AUG PY 1999 VL 61 IS 2 BP 527 EP 532 DI 10.1095/biolreprod61.2.527 PG 6 WC Reproductive Biology SC Reproductive Biology GA 220DK UT WOS:000081649100028 PM 10411536 ER PT J AU Gamble, WR Durso, NA Fuller, RW Westergaard, CK Johnson, TR Sackett, DL Hamel, E Cardellina, JH Boyd, MR AF Gamble, WR Durso, NA Fuller, RW Westergaard, CK Johnson, TR Sackett, DL Hamel, E Cardellina, JH Boyd, MR TI Cytotoxic and tubulin-interactive hemiasterlins from Auletta sp and Siphonochalina spp. sponges SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE antitumor compounds; antimitotic agents; marine metabolites; natural products; peptides ID SIPHONELLA; PEPTIDES; CYCLODEPSIPEPTIDES; DOLASTATIN-10; TRITERPENES; BINDING; DOMAIN; SITE AB Chemical and biological investigations of extracts from the sponge genus Auletta and two collections of Siphonochalina sp. have shown these organisms to be producers of the potent hemiasterlin class of antitumor agents. In addition to the previously known hemiasterlin (1) and hemiasterlin A (2), a new analogue, hemiasterlin C (3), was isolated and identified. The structures of 1 and 2 were assigned based on comparison to literature values, and 3 was identified on the basis of H-1 NMR, C-13 NMR, COSY, HSQC, and HMBC experiments. The cytotoxic and antitubulin activities of 1-3 were evaluated. In a comparative assay for inhibition of tubulin polymerization, the hemiasterlins were more potent than dolastatin 15 and equipotent with cryptophycin 1, but were somewhat less potent than dolastatin 10. (C) 1999 Published by Elsevier Science Ltd. Printed in Great Britain. C1 NCI, Frederick Canc Res & Dev Ctr, Lab Drug Discovery Res & Dev, Dev Therapeut Program,Div Canc Treatment & Diag, Frederick, MD 21702 USA. RP Boyd, MR (reprint author), NCI, Frederick Canc Res & Dev Ctr, Lab Drug Discovery Res & Dev, Dev Therapeut Program,Div Canc Treatment & Diag, Frederick, MD 21702 USA. NR 19 TC 64 Z9 66 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 1999 VL 7 IS 8 BP 1611 EP 1615 DI 10.1016/S0968-0896(99)00089-9 PG 5 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 228LG UT WOS:000082137500014 PM 10482453 ER PT J AU Durell, SR Hao, YL Nakamura, T Bakker, EP Guy, HR AF Durell, SR Hao, YL Nakamura, T Bakker, EP Guy, HR TI Evolutionary relationship between K(+) channels and symporters SO BIOPHYSICAL JOURNAL LA English DT Article ID RECTIFYING POTASSIUM CHANNEL; ESCHERICHIA-COLI; SACCHAROMYCES-CEREVISIAE; MEMBRANE-PROTEIN; VIBRIO-ALGINOLYTICUS; UPTAKE SYSTEM; PORE DOMAINS; GENE-CLUSTER; TRK SYSTEM; TRANSPORT AB The hypothesis is presented that at least four families of putative K(+) symporter proteins, Trk and KtrAB from prokaryotes, Trk1,2 from fungi, and HKT1 from wheat, evolved from bacterial K(+) channel proteins. Details of this hypothesis are organized around the recently determined crystal structure of a bacterial K(+) channel: i.e., KcsA from Streptomyces lividans. Each of the four identical subunits of this channel has two fully transmembrane helices (designated M1 and M2), plus an intervening hairpin segment that determines the ion selectivity (designated P). The symporter sequences appear to contain four sequential M1-P-M2 motifs (MPM), which are likely to have arisen from gene duplication and fusion of the single MPM motif of a bacterial K(+) channel subunit. The homology of MPM motifs is supported by a statistical comparison of the numerical profiles derived from multiple sequence alignments formed for each protein family. Furthermore, these quantitative results indicate that the KtrAB family of symporters has remained closest to the single-MPM ancestor protein. Strong sequence evidence is also found for homology between the cytoplasmic C-terminus of numerous bacterial K(+) channels and the cytoplasm-resident TrkA and KtrA subunits of the Trk and KtrAB symporters, which in turn are homologous to known dinucleotide-binding domains of other proteins. The case for homology between bacterial K+ channels and the four families of K(+) symporters is further supported by the accompanying manuscript, in which the patterns of residue conservation are demonstrated to be similar to each other and consistent with the known 3D structure of the KcsA K(+) channel. C1 NCI, Lab Expt & Computat Biol, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Chiba Univ, Fac Pharmaceut Sci, Lab Membrane Biohem, Inage Ku, Chiba 263, Japan. Univ Osnabruck, Abt Mikrobiol, D-49069 Osnabruck, Germany. RP Guy, HR (reprint author), NCI, Lab Expt & Computat Biol, Div Basic Sci, NIH, Bldg 12B,Rm B116,12 South Dr,MSC 5677, Bethesda, MD 20892 USA. EM guy@guy.nci.nih.gov NR 63 TC 128 Z9 140 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD AUG PY 1999 VL 77 IS 2 BP 775 EP 788 PG 14 WC Biophysics SC Biophysics GA 224VK UT WOS:000081920500012 PM 10423425 ER PT J AU Durell, SR Guy, HR AF Durell, SR Guy, HR TI Structural models of the KtrB, TrkH, and Trk1,2 symporters based on the structure of the KcsA K(+) channel SO BIOPHYSICAL JOURNAL LA English DT Article ID POTASSIUM-CHANNEL; SACCHAROMYCES-CEREVISIAE; VIBRIO-ALGINOLYTICUS; CATION-TRANSPORT; ESCHERICHIA-COLI; HELIX PACKING; UPTAKE SYSTEM; GENE-CLUSTER; PROTEINS; SELECTIVITY AB Three-dimensional computer modeling is used to further investigate the hypothesis forwarded in the accompanying paper of an evolutionary relationship between four related families of K(+) sympoter proteins and the superfamily of K+ channel proteins. Atomic-scale models are developed for the transmembrane regions of one member from each of the three more distinct symporter families, i.e., a TrkH protein from Escherichia coli, a KtrB protein from Aquifex aeolicus, and a Trk1,2 protein from Schizosaccharomyces pombe. The portions of the four consecutive M1-P-M2 motifs in the symporters that can be aligned with K(+) channel sequences are modeled directly from the recently determined crystal structure of the KcsA K(+) channel from Streptomyces lividans. The remaining portions are developed using our previously accumulated theoretical modeling criteria and principles. Concurrently, the use of these criteria and principles is further supported by the now verified predictions of our previous K(+) channel modeling efforts and the degree to which they are satisfied by the known structure of the KcsA protein. Thus the observed ability of the portions of the symporter models derived from the KcsA crystal structure to also satisfy the theoretical modeling criteria provides additional support for an evolutionary link with K(+) channel proteins. Efforts to further satisfy the criteria and principles suggest that the symporter proteins from fungi and plants (i.e., Trk1,2 and HKT1) form dimeric and/or tetrameric complexes in the membrane. Furthermore, analysis of the atomic-scale models in relation to the sequence conservation within and between the protein families suggests structural details for previously proposed mechanisms for the linked symport of K(+) with Na(+) and H(+). Suggestions are also given for experiments to test these structures and hypotheses. C1 NCI, Lab Expt & Computat Biol, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Guy, HR (reprint author), NCI, Lab Expt & Computat Biol, Div Basic Sci, NIH, Bldg 12B,Rm B116,12 South Dr,MSC 5677, Bethesda, MD 20892 USA. EM guy@guy.nci.nih.gov FU NCRR NIH HHS [RR-01081] NR 43 TC 117 Z9 127 U1 2 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD AUG PY 1999 VL 77 IS 2 BP 789 EP 807 PG 19 WC Biophysics SC Biophysics GA 224VK UT WOS:000081920500013 PM 10423426 ER PT J AU Huster, D Paasche, G Dietrich, U Zschornig, O Gutberlet, T Gawrisch, K Arnold, K AF Huster, D Paasche, G Dietrich, U Zschornig, O Gutberlet, T Gawrisch, K Arnold, K TI Investigation of phospholipid area compression induced by calcium-mediated dextran sulfate interaction SO BIOPHYSICAL JOURNAL LA English DT Article ID LOW-DENSITY LIPOPROTEINS; DEUTERIUM MAGNETIC-RESONANCE; DIVALENT-CATIONS; HEPARIN-BINDING; LIPID-MEMBRANES; CHAIN-LENGTH; BILAYERS; NMR; GLYCOSAMINOGLYCANS; PLASMA AB The association of anionic polyelectrolytes such as dextran sulfate (DS) to zwitterionic phospholipid surfaces via Ca2+ bridges results in a perturbation of lipid packing at physiologically relevant Ca2+ concentrations. Lipid area compression was investigated in 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) multilamellar bilayer dispersions by H-2-NMR and in monolayer studies. Binding of DS to DMPC surfaces via Ca2+ results in denser lipid packing, as indicated by higher lipid chain order. DMPC order parameters are homogeneously increased throughout the lipid bilayer. Higher order translates into more extended hydrocarbon chains and decreased average lipid area per molecule. Area compression is reported as a function of DS concentration and molecular weight. Altering the NaCl and Ca2+ concentrations modified electrostatic interactions between DS and phospholipid. A maximal area reduction of Delta A = 2.7 Angstrom(2) per DMPC molecule is observed. The lipid main-phase transition temperature increases upon formation of DMPC/Ca2+/DS-complexes. Lipid area compression after addition of DS and Ca2+ to the subphase was also observed in monolayer experiments. A decrease in surface tension of up to 3.5 mN/m at constant molecular area was observed. DS binds to the lipid headgroups by formation of Ca2+ bridges without penetrating the hydrophobic region. We suggest that area compression is the result of an attractive electrostatic interaction between neighboring lipid molecules induced by high local Ca2+ concentration due to the presence of DS. X-ray diffraction experiments demonstrate that DS binding to apposing bilayers reduces bilayer separation. We speculate that DS binding alters the phase state of low-density lipoproteins that associate with polyelectrolytes of the arterial connective tissue in the early stages of arteriosclerosis. C1 Univ Leipzig, Inst Med Phys & Biophys, D-04103 Leipzig, Germany. NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. Univ Leipzig, Inst Expt Phys 1, Dept Phys Biomembranes, D-04103 Leipzig, Germany. RP Arnold, K (reprint author), Univ Leipzig, Inst Med Phys & Biophys, Liebigstr 27, D-04103 Leipzig, Germany. RI Gutberlet, Thomas/D-5613-2014 OI Gutberlet, Thomas/0000-0002-6194-2259 NR 62 TC 35 Z9 35 U1 2 U2 8 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 1999 VL 77 IS 2 BP 879 EP 887 PG 9 WC Biophysics SC Biophysics GA 224VK UT WOS:000081920500020 PM 10423433 ER PT J AU Puri, A Hug, P Jernigan, K Rose, P Blumenthal, R AF Puri, A Hug, P Jernigan, K Rose, P Blumenthal, R TI Role of glycosphingolipids in HIV-1 entry: requirement of globotriosylceramide (Gb3) in CD4/CXCR4-dependent fusion SO BIOSCIENCE REPORTS LA English DT Article DE HIV-1 entry/fusion; glycosphingolipids ID ENVELOPE GLYCOPROTEINS; MONOCLONAL-ANTIBODY; CELLS; 7-TRANSMEMBRANE; DOMAIN; LYMPHOCYTES; INHIBITION; RECEPTORS; CD4 AB We have recently shown that addition of human erythrocyte glycosphingolipids (GSL) to non-human CD4(+) or GSL-depleted human CD4+ cells rendered those cells susceptible to gp120-gp41-mediated cell fusion (Puri et al., BBRC, 1998). One GSL fraction (Fraction 3) isolated from human rlythrocyte GSL mixture exhibited the highest recovery of fusion following incorporation into CD4(+) non-human and GSL-depleted HeLa-CD4 cells (HeLaCD4/GSL(-)). Structural analysis of Fraction 3 showed that this GSL had identical head group as the known GSL, Gal(alpha 1 --> 4)Gal(beta 1 --> 4)Glc-Ceramide (Gb3) (Puri el al., PNAS, 1998). Here we report that presence of Gb3 in CD4(+)/CXCR4(+) cells but not CD4(+)/CXCR4(-) cells allows fusion with HIV-1(Lai)-envelope glycoprotein expressing cells (TF228). Therefore, Gb3 functions in conjunction with HIV-1 co-receptor, CXCR4 to promote fusion. We propose that Gb3 functions by recruiting CD4 and/or CXCR4 at the fusion site through structurally specific interactions. C1 NCI, Sect Membrane Struct & Funct, LECB, Div Basic Sci,NIH, Frederick, MD 21702 USA. RP Puri, A (reprint author), NCI, Sect Membrane Struct & Funct, LECB, Div Basic Sci,NIH, POB B,Bldg 469,Rm 211, Frederick, MD 21702 USA. NR 18 TC 24 Z9 27 U1 0 U2 0 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0144-8463 J9 BIOSCIENCE REP JI Biosci. Rep. PD AUG PY 1999 VL 19 IS 4 BP 317 EP 325 DI 10.1023/A:1020554509642 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 259AM UT WOS:000083871900009 PM 10589997 ER PT J AU Schlag, EM Wassarman, DA AF Schlag, EM Wassarman, DA TI Identifying mutations in Drosophila genes by direct sequencing of PCR products SO BIOTECHNIQUES LA English DT Article ID KINASE C1 NICHHD, Cell Biol & Metab Br, NIH, Bethesda, MD 20892 USA. RP Schlag, EM (reprint author), NICHHD, Cell Biol & Metab Br, NIH, Bldg 18T,Rm 101, Bethesda, MD 20892 USA. NR 5 TC 9 Z9 9 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 1999 VL 27 IS 2 BP 262 EP + PG 2 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 225MN UT WOS:000081965500009 PM 10457826 ER PT J AU Kantz, DC Lacks, GD Cannon, RE AF Kantz, DC Lacks, GD Cannon, RE TI Chemiluminescence-based method for genotyping Tg.AC responder mice SO BIOTECHNIQUES LA English DT Article ID MOUSE C1 NIEHS, Lab Environm Carcinogenesis & Mutagenesis, Res Triangle Pk, NC 27709 USA. RP Cannon, RE (reprint author), NIEHS, Lab Environm Carcinogenesis & Mutagenesis, NIEHS Mail Drop F1-05, Res Triangle Pk, NC 27709 USA. NR 4 TC 12 Z9 12 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 1999 VL 27 IS 2 BP 278 EP 280 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 225MN UT WOS:000081965500013 PM 10457830 ER PT J AU Fantuzzi, L Borghi, P Ciolli, V Pavlakis, G Belardelli, F Gessani, S AF Fantuzzi, L Borghi, P Ciolli, V Pavlakis, G Belardelli, F Gessani, S TI Loss of CCR2 expression and functional response to monocyte chemotactic protein (MCP-1) during the differentiation of human monocytes: Role of secreted MCP-1 in the regulation of the chemotactic response SO BLOOD LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CHEMOATTRACTANT PROTEIN-1; CHEMOKINE RECEPTORS; MOLECULAR-CLONING; HIV-INFECTION; HUMAN-SERUM; CYTOKINE; PURIFICATION; RECRUITMENT; MACROPHAGES AB Human peripheral blood monocytes differentiate into macrophages when cultured in vitro for a few days. In the present study, we investigated the expression of C-C chemokine and CXCR4 receptors in monocytes at different stages of differentiation. Culturing of monocytes for 7 days resulted in a progressive decrease of the mRNA that encodes for CCR2 and CCR3, whereas the expression of mRNA for other chemokine receptors (CCR1, CCR4, CCR5, and CXCR4) was not substantially affected. The loss of CCR2 mRNA expression in 7-day-cultured macrophages was associated with a strong reduction in the receptor expression at the plasma membrane, as well as in the monocyte chemotactic protein (MCP-1) binding, as compared with freshly isolated monocytes. Furthermore, the biologic response to MCP-1, as measured by intracellular calcium ions increase and chemotactic response, was lost in 7-day-cultured macrophages, Differentiation of monocytes into macrophages also resulted in an increased secretion of MCP-1 that, at least in part, was responsible for the downmodulation of its receptor (CCR2). The loss of CCR2 expression and the parallel increase of MCP-1 secretion triggered by differentiation may represent a feedback mechanism in the regulation of the chemotactic response of monocytes/macrophages. (C) 1999 by The American Society of Hematology. C1 Ist Super Sanita, Virol Lab, I-00161 Rome, Italy. Ist Ris Cesare Serono, Drug Discovery Dept, Ardea, Italy. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Human Retrovirus Sect, Frederick, MD USA. RP Gessani, S (reprint author), Ist Super Sanita, Virol Lab, Viale Regina Elena 299, I-00161 Rome, Italy. RI Conti, Lucia/C-3159-2009; Gessani, Sandra/K-5151-2016 OI Gessani, Sandra/0000-0002-8451-0758 NR 53 TC 94 Z9 94 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1200 19TH ST, NW, STE 300, WASHINGTON, DC 20036-2422 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 1999 VL 94 IS 3 BP 875 EP 883 PG 9 WC Hematology SC Hematology GA 220TN UT WOS:000081683700005 PM 10419877 ER PT J AU Sloand, EM Kumar, PN Kim, S Chaudhuri, A Weichold, FF Young, NS AF Sloand, EM Kumar, PN Kim, S Chaudhuri, A Weichold, FF Young, NS TI Human immunodeficiency virus type 1 protease inhibitor modulates activation of peripheral blood CD4(+) T cells and decreases their susceptibility to apoptosis in vitro and in vivo SO BLOOD LA English DT Article ID FAS-MEDIATED APOPTOSIS; ANTIRETROVIRAL THERAPY; CONVERTING ENZYME; HIV-1; REPLICATION; INFECTION; LIGAND; DEATH; CD95; CYTOKINES AB CD4(+) T cells from patients with human immunodeficiency virus (HIV) infection undergo apoptosis at an increased rate, which leads to their depletion during disease progression. Both the Fas-Receptor (Fas-R) and interleukin-1 beta (IL-1 beta)converting enzyme (ICE; caspase 1) appear to play a role in the mechanism of apoptosis of CD4(+) lymphocytes. Although Fas-R is upregulated on both CD4(+) and CD8(+) cells in HIV-infected patients, results from our laboratory and others indicate that, in patients with advanced disease, CD4(+) cells preferentially express ICE. Protease inhibitors have successfully halted the progression of HIV disease and increased CD4(+) T counts. In this study, We examined the effect of protease inhibitors on Fas-R (CD95), ICE (caspase I)expression, apoptosis, and cell death in CD4(+) T cells of (1) HIV-infected patients who were receiving protease inhibitors, and (2) normal and patient CD4(+) T cells cultured with a protease inhibitor in vitro. Fifteen patients with advanced HIV disease on treatment showed dramatically decreased CD4(+) T-cell ICE expression, diminished apoptosis, and increased numbers of CD4(+) cells within 6 weeks of institution of protease inhibitor therapy, and before down-modulation of Fas-R (CD95) expression was evident. To determine the role of HIV infection, we studied the effect of ritonavir, a protease inhibitor, on normal and patient cells in vitro. Stimulated and unstimulated normal CD4(+) T cells, cultured with protease inhibitor, demonstrated markedly decreased apoptosis and ICE expression (P =.01). While Fas-R expression was not significantly altered during short-term culture by such treatment, Fas-Ligand (Fas-L) membrane expression of phytohemagglutinin (PHA)-stimulated blood lymphocytes was decreased by protease inhibitor In the presence of ritonavir, CD4(+) T cells from HIV-infected patients showed similar changes in ICE intracellular levels without alteration of Fas expression. In conclusion, protease inhibitors appear to decrease CP4(+) T-cell ICE expression and apoptosis before they affect Fas-R expression in HIV-infected patients. This action was independent of HIV infection, as similar effects were seen in CD4(+) T cells from normal controls. Some of the benefit of protease inhibitors may be related to modification of programmed cell death, which increases CD4(+) T-cell number. Whether this is due to directly to the changes effected in the caspase system remains to be determined. (C) 1999 by The American Society of Hematology. C1 NHLBI, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Div Infect Dis, Washington, DC 20057 USA. Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. RP Sloand, EM (reprint author), NHLBI, NIH, 31 Ctr Dr,MSC 2490,Bldg 31,Room 4A11, Bethesda, MD 20892 USA. NR 27 TC 128 Z9 132 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1200 19TH ST, NW, STE 300, WASHINGTON, DC 20036-2422 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 1999 VL 94 IS 3 BP 1021 EP 1027 PG 7 WC Hematology SC Hematology GA 220TN UT WOS:000081683700022 PM 10419894 ER PT J AU Cavanaugh, PG Jia, LB Zou, YY Nicolson, GL AF Cavanaugh, PG Jia, LB Zou, YY Nicolson, GL TI Transferrin receptor overexpression enhances transferrin responsiveness and the metastatic growth of a rat mammary adenocarcinoma cell line SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE breast neoplasms; metastasis; transferrin; transferrin receptor ID ORGAN-DERIVED CHEMOATTRACTANTS; METASTASIZING TUMOR-CELLS; NUDE-MICE; CANCER METASTASIS; MESSENGER-RNA; LUNG-CANCER; IRON UPTAKE; T-CELLS; EXPRESSION; PURIFICATION AB We previously found that breast cancer cell transferrin receptor expression and proliferative response to transferrin often correlated with metastatic capability. To further explore this, we transfected mammary tumor cells with a cDNA coding for the transferrin receptor and examined the effects of its overexpression on various cellular properties. A human transferrin receptor expression plasmid was made by excising the cDNA for the receptor from pcDTRl and ligating it into the multiple cloning site of pcDNAlNeo. The resulting construct was transfected into the poorly metastatic rat MTLn2 line that expresses low endogenous levels of rat transferrin receptor, and transfection-induced receptor expression was ascertained using antibodies specific for the human protein. Approximately 50 of the initial geneticin-resistant transfected MTLn2 cells overexpressed human transferrin receptor protein. High expressors were further isolated by four sequential FACS sorts. The final cell population expressed approximately 3-7 times more cell surface transferrin receptor than did vector transfected controls. Both lines proliferated at the same rate in normal (medium plus 5 FBS) culture conditions. However, in serum-free conditions, the transferrin receptor overexpressor cells displayed a pronounced proliferative response to transferrin whereas the control line did not. When injected into the mammary fat pads of female nude mice, cells from both lines formed micrometastases to the lung that were specifically visualized by immunohistochemical staining of rat cytokeratin 17. This revealed that the transferrin receptor transfected line formed larger lesions of this nature than did cells from the vector transfected controls. When injected into the tail vein of female nude mice, the transferrin receptor overexpressors likewise formed gross lung metastases of remarkably greater size than did the vector only transfectants. Overexpression of cell surface human transferrin receptor on MTLn2 cells appeared to affect their invitro growth response to transferrin and their ability to grow at a secondary site in vivo. C1 Univ Texas, MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. Natl Human Genome Res Inst, NIH, Bethesda, MD USA. Inst Mol Med, Huntington Beach, CA USA. RP Cavanaugh, PG (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Canc Biol, 1515 Holcombe Blvd, Houston, TX 77030 USA. FU NCI NIH HHS [R35-CA44352] NR 55 TC 13 Z9 13 U1 0 U2 3 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD AUG PY 1999 VL 56 IS 3 BP 203 EP 217 PG 15 WC Oncology SC Oncology GA 245HP UT WOS:000083101000001 PM 10573112 ER PT J AU Silverman, DT Schiffman, M Everhart, J Goldstein, A Lillemoe, KD Swanson, GM Schwartz, AG Brown, LM Greenberg, RS Schoenberg, JB Pottern, LM Hoover, RN Fraumeni, JF AF Silverman, DT Schiffman, M Everhart, J Goldstein, A Lillemoe, KD Swanson, GM Schwartz, AG Brown, LM Greenberg, RS Schoenberg, JB Pottern, LM Hoover, RN Fraumeni, JF TI Diabetes mellitus, other medical conditions and familial history of cancer as risk factors for pancreatic cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE diabetes mellitus; cholecystectomy; allergies; family history of cancer; pancreatic neoplasm ID POPULATION-BASED COHORT; PARTIAL GASTRECTOMY; COLORECTAL-CANCER; DIRECT INTERVIEWS; GASTRIC-SURGERY; UNITED-STATES; HAMSTER MODEL; PEPTIC-ULCER; CARCINOMA; ALCOHOL AB In a population-based case-control study of pancreatic cancer conducted in three areas of the USA, 484 cases and 2099 controls were interviewed to evaluate the aetiologic role of several medical conditions/interventions, including diabetes mellitus, cholecystectomy, ulcer/gastrectomy and allergic states. We also evaluated risk associated with family history of cancer. Our findings support previous studies indicating that diabetes is a risk factor for pancreatic cancer, as well as a possible complication of the tumour. A significant positive trend in risk with increasing years prior to diagnosis of pancreatic cancer was apparent (P-value for test of trend = 0.016), with diabetics diagnosed at least 10 years prior to diagnosis having a significant 50% increased risk. Those treated with insulin had risks similar to those not treated with insulin (odds ratio (OR) = 1.6 and 1.5 respectively), and no trend in risk was associated with increasing duration of insulin treatment. Cholecystectomy also appeared to be a risk factor, as well as a consequence of the malignancy. Subjects with a cholecystectomy at least 20 years prior to the diagnosis of pancreatic cancer experienced a 70% increased risk, which was marginally significant. In contrast, subjects with a history of duodenal or gastric ulcer had little or no elevated risk (OR = 1.2, confidence interval = 0.9-1.6). Those treated by gastrectomy had the same risk as those not receiving surgery, providing little support for the hypothesis that gastrectomy is a risk factor for pancreatic cancer. A significant 40% reduced risk was associated with hay fever, a non-significant 50% decreased risk with allergies to animals, and a non-significant 40% reduced risk with allergies to dust/moulds. These associations; however, may be due to chance since no risk reductions were apparent for asthma or several other types of allergies. In addition, we observed significantly increased risks for subjects reporting a first-degree relative with cancers of the pancreas (OR = 3.2), colon (OR = 1.7) or ovary (OR = 5.3) and non-significantly increased risks for cancers of the endometrium (OR = 1.5) or breast (OR = 1.3). The pattern is consistent with the familial predisposition reported for pancreatic cancer and with the array of tumours associated with hereditary non-polyposis colon cancer. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NIDDKD, Div Digest Dis & Nutr, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21205 USA. Michigan Canc Fdn, Detroit, MI 48201 USA. Emory Univ, Sch Publ Hlth, Div Epidemiol, Atlanta, GA USA. New Jersey State Dept Hlth, Special Epidemiol Program, Trenton, NJ 08625 USA. NIH, Off Director, Bethesda, MD 20892 USA. RP Silverman, DT (reprint author), NCI, Div Canc Epidemiol & Genet, Execut Plaza S,Room 8108, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CP-51089, N01-CP-51090, N01-CP-51092] NR 60 TC 252 Z9 265 U1 1 U2 5 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 1999 VL 80 IS 11 BP 1830 EP 1837 DI 10.1038/sj.bjc.6690607 PG 8 WC Oncology SC Oncology GA 224LJ UT WOS:000081900300026 PM 10468306 ER PT J AU Yoshida, N Ishii, E Nomizu, M Yamada, Y Mohri, S Kinukawa, N Matsuzaki, A Oshima, K Hara, T Miyazaki, S AF Yoshida, N Ishii, E Nomizu, M Yamada, Y Mohri, S Kinukawa, N Matsuzaki, A Oshima, K Hara, T Miyazaki, S TI The laminin-derived peptide YIGSR (Tyr-Ile-Gly-Ser-Arg) inhibits human pre-B leukaemic cell growth and dissemination to organs in SCID mice SO BRITISH JOURNAL OF CANCER LA English DT Article DE laminin; multimeric YIGSR peptide; SCID mice; tumour metastasis; leukaemia cells ID EXPERIMENTAL METASTASIS FORMATION; SEVERE COMBINED IMMUNODEFICIENCY; ACUTE LYMPHOBLASTIC-LEUKEMIA; TUMOR-GROWTH; RECEPTOR-BINDING; ATTACHMENT; MATRIGEL; INTEGRINS; ADHESION; SEQUENCE AB The YIGSR (Tyr-Ile-Gly-Ser-Arg) laminin beta 1 chain sequence has an inhibitory effect on tumour growth and the metastasis of melanoma and fibrosarcoma cells. In the present study, we investigated whether the multimeric YIGSR peptide (Ac-Y16) has an antiproliferative effect and/or prevents the metastasis of human pre-B acute lymphoblastic leukaemia cells (NALM6) in severe combined immune deficient (SCID) mice. In in vitro studies, Ac-Y16 significantly inhibited leukaemic cell colony formation and the invasion of NALM6 cells in a Matrigel-based assay. The tumour growth and leukaemic infiltration in peripheral tissues were also analysed in SCID mice 9 weeks after NALM6, Matrigel and Ac-Y16 were subcutaneously co-injected. The weight of the subcutaneous tumours was significantly suppressed by Ac-Y16 in a dose-dependent manner. Flow cytometry analysis showed that the leukaemic infiltration was significantly inhibited in ail organs with 1.5-2.0 mg of Ac-Y16. Leukaemic infiltrations in the brain were inhibited with 0.5 mg of Ac-Y16, and those in brain and bane marrow were also inhibited with 1.0 mg of Ac-Y16. With Ac-S16, a control;scrambled peptide; the only significant inhibition of the leukaemic infiltration was observed in bone marrow at a much higher dose. These data suggest that the multimeric YIGSR peptide can inhibit the tumour growth and metastasis of leukaemic cells and may be useful as a potential therapeutic reagent for leukaemic infiltrations. C1 Hamanoumachi Hosp, Div Pediat, Chuo Ku, Fukuoka 8108539, Japan. Saga Med Sch, Dept Pediat, Saga, Japan. Kyushu Univ, Fac Med, Lab Anim Ctr, Fukuoka 812, Japan. Kyushu Univ, Fac Med, Dept Med Informat, Fukuoka 812, Japan. Kyushu Univ, Fac Med, Dept Pediat, Fukuoka 812, Japan. Fukuoka Univ, Dept Pathol, Fukuoka 81401, Japan. Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. RP Ishii, E (reprint author), Hamanoumachi Hosp, Div Pediat, Chuo Ku, 3-5-27 Maizuru, Fukuoka 8108539, Japan. NR 40 TC 20 Z9 20 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 1999 VL 80 IS 12 BP 1898 EP 1904 DI 10.1038/sj.bjc.6690618 PG 7 WC Oncology SC Oncology GA 224LK UT WOS:000081900400005 PM 10471037 ER PT J AU Panaro, NJ Popescu, NC Harris, SR Thorgeirsson, UP AF Panaro, NJ Popescu, NC Harris, SR Thorgeirsson, UP TI Flavone acetic acid induces a G2/M cell cycle arrest in mammary carcinoma cells SO BRITISH JOURNAL OF CANCER LA English DT Article DE FAA; cell cycle; mammary; rat ID FLAVONE-8-ACETIC ACID; NITRIC-OXIDE; XANTHENONE-4-ACETIC ACID; IONIZING-RADIATION; ANTITUMOR-ACTIVITY; LUNG-CARCINOMA; BLOOD-FLOW; HELA-CELLS; TUMOR; EXPRESSION AB Flavone acetic acid (FAA) is a synthetic flavonoid that demonstrated extraordinary anti-tumour properties in murine models but was not effective in clinical trials. In an effort to better understand the molecular mechanisms by which FAA asserts its tumouricidal activities, we have examined the effect of FAA on the cell cycle. We observed FAA-mediated G2/M cell cycle arrest in mammary carcinoma cells at a concentration previously demonstrated to have anti-tumour effects in rodent models. The cell cycle arrest was accompanied by an increase in the P34(cdc2) (cdc2) cyclin-dependent kinase activity. Morphological cytogenetic analysis demonstrated a colcemid-like effect of FAA on cytokinesis by causing accumulation of condensed C-metaphases of a sustained mitotic block. The cell cycle effect was blocked by the antioxidants ADPC and ascorbate, the superoxide scavenger Tiron, and the sphingosine kinase inhibitor L-cycloserine, but not by inhibitors of nitric oxide synthase. Based on these data, we propose that FAA may induce cell cycle arrest by stimulating the activity of acidic sphingomyelinase leading to the generation of reactive oxygen species. C1 NCI, Div Basic Sci, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. NCI, Div Basic Sci, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Thorgeirsson, UP (reprint author), NCI, Div Basic Sci, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. NR 38 TC 16 Z9 17 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD AUG PY 1999 VL 80 IS 12 BP 1905 EP 1911 DI 10.1038/sj.bjc.6690619 PG 7 WC Oncology SC Oncology GA 224LK UT WOS:000081900400006 PM 10471038 ER PT J AU Henson, DE AF Henson, DE TI Cancer and the Internet SO CANCER LA English DT Editorial Material ID INFORMATION C1 NCI, Div Canc Prevent, Canc Biomarkers Res Grp, Bethesda, MD 20892 USA. RP Henson, DE (reprint author), NCI, Div Canc Prevent, Canc Biomarkers Res Grp, EPN Bldg,Room 330,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 6 TC 13 Z9 13 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 1999 VL 86 IS 3 BP 373 EP 374 DI 10.1002/(SICI)1097-0142(19990801)86:3<373::AID-CNCR1>3.0.CO;2-Q PG 2 WC Oncology SC Oncology GA 218KZ UT WOS:000081552900001 PM 10430241 ER PT J AU Fisher, ER Dignam, J Tan-Chiu, E Costantino, J Fisher, B Paik, S Wolmark, N AF Fisher, ER Dignam, J Tan-Chiu, E Costantino, J Fisher, B Paik, S Wolmark, N CA NSABP Collaborating Investigators TI Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17 - Intraductal carcinoma SO CANCER LA English DT Article DE breast; intraductal carcinoma; ductal carcinoma in situ; pathology; treatment ID IN-SITU; RADIATION-THERAPY; RESIDUAL DISEASE; CLASSIFICATION; LUMPECTOMY; FAILURE; INSITU; RECURRENCE; CANCER; DCIS AB BACKGROUND. This report is an 8-year update of the authors' previous findings from National Surgical Adjuvant Breast Project (NSABP) Protocol B-17, which relates to the influence of pathologic characteristics on the natural history and treatment of intraductal carcinoma (DCIS). METHODS. Nine pathologic features observed in a pathologic subset of 623 of 814 evaluable women enrolled in this randomized clinical trial were assessed for their role in the prediction of second ipsilateral breast tumors (IBT), other events, and selection of breast irradiation (XRT) following lumpectomy. RESULTS. The frequency of subsequent IBT was reduced from 31% to 13% (P = 0.0001) by XRT. The average annual hazard rates for IBT were reduced by XRT for all pathologic features examined. Four characteristics were individually noted to be significantly related to IBT, but only moderate-to-marked and absent-to-slight comedo necrosis were found to be independent high and low risk predictors, respectively, for such an event in patients of both treatment groups. XRT effected a 7% absolute reduction at. 8 years in the low risk group. Despite a relatively high incidence (approximate to 40%) of BET consisting of invasive cancer, mortality due to breast carcinoma after DCIS for the entire cohort was found to be only 1.6% at 8 years. CONCLUSIONS. The degree of comedo necrosis in patients with DCIS appears to be sufficient for discriminating between high and low risks for IBT following lumpectomy for DCIS. Although margin status, unlike in our previous report, was found to have only a slight or borderline influence on the frequency of IBT at 8 years, excision of DCIS with free margins is advised. The low risk group exhibits a statistically significant reduction of IBT from XRT. The decision to forgo XRT in the treatment of this singular subset of patients would appear to depend on clinical considerations and the input of informed patients rather than being standard practice. (C) 1999 American Cancer Society. C1 Natl Surg Adjuvant Breast & Bowel Project, Pathol Ctr, Pittsburgh, PA USA. Natl Surg Adjuvant Breast & Bowel Project, Ctr Stat, Pittsburgh, PA USA. Natl Surg Adjuvant Breast & Bowel Project, Operat Ctr, Pittsburgh, PA USA. RP Fisher, ER (reprint author), Allegheny Univ, Allegheny Gen Hosp, Continuing Care Ctr, 5th Floor,320 East North Ave, Pittsburgh, PA 15212 USA. FU NCI NIH HHS [NCI-U10-CA-37377, NCI-U10-CA-39086, NCI-U10-CA-120270] NR 37 TC 318 Z9 334 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER JI Cancer PD AUG 1 PY 1999 VL 86 IS 3 BP 429 EP 438 DI 10.1002/(SICI)1097-0142(19990801)86:3<429::AID-CNCR11>3.0.CO;2-Y PG 10 WC Oncology SC Oncology GA 218KZ UT WOS:000081552900011 PM 10430251 ER PT J AU Persson, I Weiderpass, E Bergkvist, L Bergstrom, R Schairer, C AF Persson, I Weiderpass, E Bergkvist, L Bergstrom, R Schairer, C TI Risks of breast and endometrial cancer after estrogen and estrogen-progestin replacement SO CANCER CAUSES & CONTROL LA English DT Article DE breast neoplasms; cohort; endometrial neoplasms; estrogens; hormone replacement therapy; progestins ID EXOGENOUS HORMONE USE; POSTMENOPAUSAL WOMEN; THERAPY; COHORT; MAMMOGRAPHY; OSTEOPOROSIS; MORTALITY AB Objective: We studied the risk of breast and endometrial cancer in a cohort of 11,231 Swedish women prescribed different replacement hormone regimens. Methods: All 10,472 women at risk of developing breast cancer and 8,438 women at risk of endometrial cancer were followed up from the time of the questionnaire in 1987-88 through 1993, by record-linkages to the National Swedish Cancer Registry. Using data from a questionnaire we analyzed the relationships between hormone exposures and cancer risk, with non-compliers and users of less than 1 year as a reference group. Results: For breast cancer, women reporting use of estrogens combined with progestins had evidence of an increased risk relative to women denying intake or taking hormones for less than 1 year; relative risk (RR) = 1.4 (95% confidence interval 0.9-2.3) after 1-6 years of intake, and RR=1.7 (95% CI 1.1-2.6) after more than 6 years. This excess risk seemed confined to recent exposure. We found no association with intake of estrogens alone using non-compliers and short-term takers as the reference group. The risk of invasive endometrial cancer was increased four-fold in women using medium-potency estrogens alone for 6 years or longer, RR = 4.2 (95% CI 2.5-8.4). Women on such long-term progestin-combined treatment had a lower, non-significant, excess risk (RR = 1.4; 95% CI 0.6-3.3). Conclusions: We conclude that long-term recent use of estrogen-progestin combined replacement therapy may increase the risk of breast cancer. Exposure to estrogen alone substantially elevates the risk of endometrial cancer, an increase that can be reduced or perhaps avoided by adding progestins. C1 Karolinska Inst, Dept Med Epidemiol, Stockholm, Sweden. Univ Uppsala, Dept Stat, S-75105 Uppsala, Sweden. NCI, Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Persson, I (reprint author), Karolinska Inst, Dept Med Epidemiol, Stockholm, Sweden. RI Weiderpass, Elisabete/M-4029-2016 OI Weiderpass, Elisabete/0000-0003-2237-0128 FU NCI NIH HHS [N01-CP-85636-06] NR 34 TC 194 Z9 202 U1 1 U2 2 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 1999 VL 10 IS 4 BP 253 EP 260 DI 10.1023/A:1008909128110 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 213PL UT WOS:000081282400002 PM 10482483 ER PT J AU Marcus, PM Newman, B Moorman, PG Millikan, RC Baird, DD Qaqish, B Sternfeld, B AF Marcus, PM Newman, B Moorman, PG Millikan, RC Baird, DD Qaqish, B Sternfeld, B TI Physical activity at age 12 and adult breast cancer risk (United States) SO CANCER CAUSES & CONTROL LA English DT Article DE adolescence; breast neoplasms; epidemiology; exercise; female ID YOUNG-WOMEN; REDUCED RISK; EXERCISE; TIME; EPIDEMIOLOGY; PREVENTION; ESTROGENS; FAT AB Objectives: Some epidemiologic studies suggest that adolescent physical activity reduces subsequent breast cancer risk. To examine this question further, we analyzed data on physical activity at age 12 that had been collected as part of the Carolina Breast Cancer Study (CBCS). Methods: The CBCS is a population-based, case-control study of 527 white and 337 African-American cases and 790 controls, frequency-matched on age and race. Respondents were asked whether, and to what extent, they engaged in four specific activities at age 12 (walking to school, biking to school, competitive training, performing vigorous household chores). Results: Women who reported participation in any of the four activities had a modest reduction in breast cancer risk (odds ratio (OR): 0.8, 95% confidence interval (CI): 0.6-1.0). Using an index measuring approximate number of activity episodes per week, analyses revealed modest inverse relationships for nearly all levels of activity relative to no reported activity; a weighting of the index by metabolic equivalent scores produced similar results. Conclusions: Our findings support the hypothesis that adolescent physical activity may protect against adult breast cancer, even at moderate levels. C1 NCI, Biometry Branch, Div Canc Prevent, Bethesda, MD 20892 USA. Univ N Carolina, Chapel Hill, NC 27599 USA. Yale Univ, New Haven, CT 06520 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Kaiser Permanente Med Care Program, Div Res, Oakland, CA 94611 USA. RP Marcus, PM (reprint author), NCI, Biometry Branch, Div Canc Prevent, Execut Plaza N,Room 344,MSC 7354, Bethesda, MD 20892 USA. OI Baird, Donna/0000-0002-5544-2653 FU NCI NIH HHS [P50-CA58223, R25-CA57726, T32-CA09330] NR 35 TC 45 Z9 46 U1 0 U2 0 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 1999 VL 10 IS 4 BP 293 EP 302 DI 10.1023/A:1008971417282 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 213PL UT WOS:000081282400007 PM 10482488 ER PT J AU Vasandani, VM Burris, JA Sung, C AF Vasandani, VM Burris, JA Sung, C TI Reversible nephrotoxicity of onconase and effect of lysine pH on renal onconase uptake SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE ribonuclease; nephrotoxicity; lysine; pH; metabolic acidosis ID DISULFIDE-STABILIZED FV; SEMINAL RIBONUCLEASE; P-30 PROTEIN; INHIBITION; REABSORPTION; SUPERFAMILY; CARCINOMA; RECEPTOR; INFUSION; FRAGMENT AB Purpose: To examine the histopathology of the kidney in mice following repeated injections of the antitumor drug onconase, and to determine whether lysine, which reportedly blocks kidney uptake of other basic proteins, blocks the high renal uptake of onconase. Methods: Mice received repeated intraperitoneal onconase injections over 3 weeks. Kidneys were examined by light microscopy after 1 week, 3 weeks, and 5 weeks (2 weeks after cessation of injections) and compared to kidneys from animals receiving a similar schedule of PBS injections. Renal uptake of radioiodinated onconase was measured in animals receiving intraperitoneal injections of lysine solutions of acidic and neutral pH given at -30, 0 and +5 min relative to intravenous onconase injection. Renal onconase uptake was also measured in animals made metabolically acidotic by ingestion of ammonium chloride, arginine chloride or lysine dihydrochloride from the drinking water. Results: Onconase caused acute moderate multifocal proximal renal tubular necrosis, and this toxicity was reversed by 2 weeks after drug withdrawal. Intraperitoneal injections of lysine dihydrochloride in PBS (pH 1.5) reduced renal onconase uptake at 15 min from 67.9 +/- 13.4% to 17.0 +/- 3.8% of the injected dose without affecting the plasma concentration and also reduced the fraction of degraded onconase in the urine. However, neutral solutions of lysine dihydrochloride at pH 7.4 or lysine acetate at pH 7.1 were ineffective at blocking renal onconase uptake. Furthermore, renal onconase uptake was minimally or not affected by a state of metabolic acidosis. Conclusions: Proximal tubular toxicity of onconase was reversible. Renal onconase uptake was blocked by lysine at pH 1.5 but not at neutral pH. C1 NIH, Bioengn & Phys Sci Program, Off Res Serv, Bethesda, MD 20892 USA. NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NIH, Vet Resources Program, Bethesda, MD 20892 USA. RP Sung, C (reprint author), NIH, Bioengn & Phys Sci Program, Off Res Serv, Bldg 13,Rm 3N17, Bethesda, MD 20892 USA. NR 24 TC 28 Z9 28 U1 0 U2 3 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 1999 VL 44 IS 2 BP 164 EP 169 DI 10.1007/s002800050962 PG 6 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 210GD UT WOS:000081096000012 PM 10412952 ER PT J AU Dean, M Jacobson, LP McFarlane, G Margolick, JD Jenkins, FJ Howard, OMZ Dong, HF Goedert, JJ Buchbinder, S Gomperts, E Vlahov, D Oppenheim, JJ O'Brien, SJ Carrington, M AF Dean, M Jacobson, LP McFarlane, G Margolick, JD Jenkins, FJ Howard, OMZ Dong, HF Goedert, JJ Buchbinder, S Gomperts, E Vlahov, D Oppenheim, JJ O'Brien, SJ Carrington, M TI Reduced risk of AIDS lymphoma in individuals heterozygous for the CCR5-Delta 32 mutation SO CANCER RESEARCH LA English DT Article ID HIV-1 INFECTION; DISEASE PROGRESSION; CCR5; CHEMOKINES; RESISTANCE; RANTES; ALLELE; COHORT; PATHOGENESIS; TRANSMISSION AB Non-Hodgkin's lymphoma (NHL) has been increasing in frequency in the industrialized world, but the environmental and genetic factors that contribute to susceptibility are not known. B-cell lymphomas represent a major cause of morbidity and mortality in HIV-infected individuals. The identification of a deletion in the CCR5 chemokine receptor gene that alters the risk for infection and progression to AIDS led us to examine a potential role of this gene in AIDS Lymphoma. A matched case-control analysis was performed using all eligible NHL cases in the Multicenter AIDS Cohort Study. Patients were matched for age, study center, time AIDS-free, and slope of the CD4+ T-cell decline. The CCR5-Delta 32 allele was found to be associated with a 3-fold lower risk of NHL among individuals after controlling for time of infection and progression toward AIDS. The CCR5 gene was not associated with a difference in risk for Kaposi's sarcoma, another common malignancy in AIDS patients, or opportunistic infections. Costimulation of normal phorbol 12-myristate 13-acetate-treated B cells with the CCR5 ligand RANTES induced a proliferative response, indicating that RANTES is a mitogen for B cells. Taken together, these findings suggest that the CCR5 gene plays a role in the risk of NHL in HIV-infected patients, perhaps through a mechanism involving a decreased response of B cells to the mitogenic activity of RANTES. C1 NCI, Lab Genom Divers, Frederick, MD 21702 USA. NCI, Lab Mol Immunol, Frederick, MD 21702 USA. NCI, Viral Epidemiol Branch, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Microbiol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Mol Immunol, Baltimore, MD 21205 USA. Univ Pittsburgh, Sch Med & Publ Hlth, Dept Pathol, Pittsburgh, PA USA. Univ Pittsburgh, Sch Med & Publ Hlth, Dept Infect Dis & Microbiol, Pittsburgh, PA USA. NCI, Intramural Res Support Program, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. San Francisco Dept Publ Hlth, San Francisco, CA 94102 USA. Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. RP O'Brien, SJ (reprint author), NCI, Lab Genom Divers, Frederick, MD 21702 USA. RI Jenkins, Frank/A-8529-2009; Dean, Michael/G-8172-2012; Howard, O M Zack/B-6117-2012 OI Dean, Michael/0000-0003-2234-0631; Howard, O M Zack/0000-0002-0505-7052 FU NCI NIH HHS [N01-CO-56000] NR 29 TC 62 Z9 66 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 1 PY 1999 VL 59 IS 15 BP 3561 EP 3564 PG 4 WC Oncology SC Oncology GA 224GT UT WOS:000081890200007 PM 10446961 ER PT J AU Arbeit, JM Riley, RR Huey, B Porter, C Kelloff, G Lubet, R Ward, JM Pinkel, D AF Arbeit, JM Riley, RR Huey, B Porter, C Kelloff, G Lubet, R Ward, JM Pinkel, D TI Difluoromethylornithine chemoprevention of epidermal carcinogenesis in K14-HPV16 transgenic mice SO CANCER RESEARCH LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUG; ORNITHINE DECARBOXYLASE GENE; LABEL-RETAINING CELLS; SKIN TUMOR PROMOTION; ALPHA-DIFLUOROMETHYLORNITHINE; MOUSE SKIN; STEM-CELLS; MULTISTAGE CARCINOGENESIS; ADENOCARCINOMA XENOGRAFT; SQUAMOUS CARCINOGENESIS AB To be informative for chemoprevention, animal models must both closely emulate human disease and possess surrogate endpoint biomarkers that facilitate rapid drug screening. This study elucidated site-specific histopathological and biochemical surrogate endpoint biomarkers of spontaneous epidermal carcinogenesis in K14-HPV16 transgenic mice and demonstrated that the incidence and severity of these markers were decreased by the ornithine decarboxylase (ODC) inhibitor difluoromethylornithine (DFMO), The cumulative incidence of visible epidermal cancers in 127 untreated transgenic mice was 42% by 52 weeks of age, most frequently affecting the chest as flat lesions in association with chronic ulcers, or in the ear as protuberant masses. Microscopic malignancies were detected in 39% of 32-week-old transgenic mice and were found to emerge from precursor lesions that were of two distinct types: dysplastic sessile ear papillomas and hyperproliferative follicular/interfollicular chest dysplasias, ODC activity and tissue polyamine contents were differentially elevated in ear and chest skin during carcinogenesis, such that there was a marked elevation of both parameters of polyamine metabolism as early as 4 weeks of age in the ear, whereas in the chest, polyamine metabolism was increased significantly only in the late stages of neoplastic progression and in epidermal cancers. Administration of 1.0% DFMO in the drinking water from 4 to 32 weeks of age prevented both visible and microscopic malignancies and significantly decreased the incidence of chest and ear precursor lesions, ODC activity and tissue putrescine content were markedly diminished by DFMO chemoprevention in ear skin, whereas there was a more modest decline of these parameters in chest skin. DFMO treatment of transgenic mice from 28 to 32 weeks of age was associated with an absence of ear cancer and a marked regression of dysplastic papillomas, In contrast, the results in chest skin were complex in that the severity of chest precursors diminished, but their incidence was unchanged, and microscopic cancers were still detectable within these lesions. Collectively, this study highlights the utility of multistage epidermal carcinogenesis in K14-HPV16 transgenic mice both for the study of the biology of, and as a screening tool for, novel drugs and chemopreventive regimens. C1 Univ Calif San Francisco, Mt Zion Med Ctr, Dept Surg, San Francisco, CA 94143 USA. NCI, Div Canc Chemoprevent, Bethesda, MD 20262 USA. Roswell Pk Mem Canc Ctr, Grace Canc Drug Ctr, Buffalo, NY 14263 USA. NCI, Off Lab & Anim Sci, Vet & Tumor Pathol Sect, Frederick, MD 21702 USA. Univ Calif San Francisco, Ctr Canc, San Francisco, CA 94143 USA. RP Arbeit, JM (reprint author), Univ Calif San Francisco, Mt Zion Med Ctr, Dept Surg, 2340 Sutter St,Box 1674, San Francisco, CA 94143 USA. FU NCI NIH HHS [N01-CN-55183-MAO] NR 66 TC 39 Z9 40 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 1999 VL 59 IS 15 BP 3610 EP 3620 PG 11 WC Oncology SC Oncology GA 224GT UT WOS:000081890200017 PM 10446971 ER PT J AU Felix, K Kelliher, KA Bornkamm, GW Janz, S AF Felix, K Kelliher, KA Bornkamm, GW Janz, S TI Elevated mutant frequencies in lymphoid tissues persist throughout plasmacytoma development in BALB/c.lambda LIZ mice SO CANCER RESEARCH LA English DT Article ID IN-VIVO MUTAGENICITY; TRANSGENIC MICE; CHROMOSOMAL TRANSLOCATIONS; MUTAGENESIS ASSAY; BALB/CANPT MICE; LACI TRANSGENE; MOUSE; INDUCTION; SUSCEPTIBILITY; CELLS AB Using the phage lambda LIZ-based transgenic in vivo mutagenesis assay, the mean mutant frequencies in the target gene, lad, were found to be significantly increased in lymphoid tissues of congenic BALB/c.lambda LIZ N-5 mice in the terminal stage of a plasmacytoma induction experiment, 213-280 days after the first i.p. injection of the plasmacytomagenic agent pristane (2,6,10,14-tetramethylpentadecane). In plasmacytoma-bearing mice (n = 7), mutant frequencies in the spleens and mesenteric lymph nodes were elevated 2.46-fold and 5.35-fold, respectively, when compared with age-matched controls. In plasmacytoma-negative mice (n = Il), mutant frequencies were increased 2.30-fold (spleens) and 3.48-fold (mesenteric nodes). These results, interpreted in conjunction with our previous findings (K, Felix et at, Cancer Res., 58: 1616-1619, 1998) of approximately 3-fold elevations in pristane-induced splenic mutagenesis on day 42 postpristane, indicate that increased mutant levels in lymphoid tissues persist throughout plasmacytomagenesis in genetically susceptible BALB/c mice. C1 NIH, Genet Lab, Div Basic Sci, NCI, Bethesda, MD 20892 USA. GSF, Inst Klin & Mol Biol & Tumorgenet, D-81377 Munich, Germany. RP Felix, K (reprint author), NIH, Genet Lab, Div Basic Sci, NCI, Bldg 37,Room 2B10, Bethesda, MD 20892 USA. NR 35 TC 6 Z9 6 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 1999 VL 59 IS 15 BP 3621 EP 3626 PG 6 WC Oncology SC Oncology GA 224GT UT WOS:000081890200018 PM 10446972 ER PT J AU Tam, AS Foley, JF Devereux, TR Maronpot, RR Massey, TE AF Tam, AS Foley, JF Devereux, TR Maronpot, RR Massey, TE TI High frequency and heterogeneous distribution of p53 mutations in aflatoxin B-1-induced mouse lung tumors SO CANCER RESEARCH LA English DT Article ID DNA ADDUCT FORMATION; HUMAN BREAST-CANCER; STRAIN-A MICE; HEPATOCELLULAR-CARCINOMA; SUPPRESSOR GENE; K-RAS; MOLECULAR PATHOGENESIS; CARCINOGENESIS; ACTIVATION; CODON-249 AB Inactivation of the p53 tumor suppressor gene Is one of the most frequent genetic alterations observed in human lung cancers. However, p53 mutations are more rarely detected in chemically induced mouse lung tumors. In this study, 62 female AC3F1 (A/J x C3H/HeJ) mice were treated with anatoxin B-1 (AFB(1); 150 mg/kg i.p. divided into 24 doses over 8 weeks). At 6-14 months after dosing, mice were killed, and tumors were collected. A total of 71 AFB(1)-induced lung tumors were examined for overexpression of p53 protein by immunohistochemical staining. Positive nuclear p53 staining was observed in 79% of the AFB(1)-induced tumors, but the pattern was highly heterogeneous. In approximately 73% of the positively stained tumors, fewer than 5% of cells demonstrated positive staining; in the other 27%, between 10% and 60% of the cells stained positively, with staining localized to the periphery of the tumors in many cases. Single-strand conformational polymorphism analysis of the evolutionarily conserved regions of the p53 gene (exons 5-8) from APB(1)-induced whole lung tumor DNA revealed banding patterns consistent with point mutations in 20 of 76 (26%) tumors, with 85% of the mutations in exon 7 and 15% of the mutations in exon 6. Identification of point mutations could not be confirmed by direct sequence analysis because bands representing putative mutations appeared only weakly on autoradiograms. This was presumably due to the heterogeneous nature of the DNA analyzed. Single-strand conformational polymorphism analysis of DNA from laser capture microdissected cells of paraffin-embedded AFB(1)-induced tumor tissue sections stained for p53 produced banding patterns consistent with point mutations in 18 of 30 (60%) DNA samples. Direct sequencing of the microdissected samples revealed mutations at numerous different codons in exons 5, 6, and 7. Of 26 mutations found in microdissected regions from adenomas and carcinomas, 9 were G:C-->A:T transitions, II were A:T-->G:C transitions, and 5 were transversions (2 G:C-->T:A, 2 T:A-->A:T, and 1 A:T-->C:G), whereas 1 deletion mutation was identified. The concordance between immunostaining and molecular detection of p53 alterations was 72% when laser capture microdissection was used versus 17% based on whole tumor analysis. The high mutation frequency and heterogeneous staining pattern suggest that p53 mutations occur relatively late in APB(1)-induced mouse lung tumorigenesis and emphasize the value of analyzing different staining regions from paraffin-embedded mouse lung tumors. C1 Queens Univ, Dept Pharmacol & Toxicol, Kingston, ON K7L 3N6, Canada. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Toxicol Grp, Res Triangle Pk, NC 27709 USA. RP Massey, TE (reprint author), Queens Univ, Dept Pharmacol & Toxicol, Kingston, ON K7L 3N6, Canada. NR 59 TC 37 Z9 40 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 1999 VL 59 IS 15 BP 3634 EP 3640 PG 7 WC Oncology SC Oncology GA 224GT UT WOS:000081890200020 PM 10446974 ER PT J AU Vineis, P Crosignani, P Sacerdote, C Fontana, A Masala, G Miligi, L Nanni, O Ramazzotti, V Rodella, S Stagnaro, E Tumino, R Vigano, C Vindigni, C Costantini, AS AF Vineis, P Crosignani, P Sacerdote, C Fontana, A Masala, G Miligi, L Nanni, O Ramazzotti, V Rodella, S Stagnaro, E Tumino, R Vigano, C Vindigni, C Costantini, AS TI Hematopoietic cancer and peptic ulcer: a multicenter case-control study SO CARCINOGENESIS LA English DT Article ID HELICOBACTER-PYLORI; LYMPHOMAS; RISK AB Helicobacter pylori has been suggested as a cause of gastric carcinoma and gastric non-Hodgkin's lymphoma (NHL), In a previous cohort study, a relative risk of six for gastric NHL was reported among subjects who tested positive for anti-H,pylori antibodies, The association between peptic ulcer and NHL has been studied in a population-based case-control investigation on hemato-lymphopoietic malignancies in Italy, based on face-to-face interviews to 2671 cases and 1718 controls (refusal rates 10 and 19%, respectively). Subjects who reported a diagnosis of peptic ulcer had a relative risk of 5.6 [95% confidence interval (CI) 3.8-8.0] for gastric NHL, whereas the estimate for nongastric NHL was 1.3 (1.0-1.6). The association with recent diagnosis of ulcer was stronger, but the odds ratio (OR) was as high as 2.1 (95% CI 1.1-4.2) after greater than or equal to 20 years since such diagnosis. After exclusion of the last 2 years before the diagnosis of NHL, and of ulcers diagnosed before 1978 (when gastroscopy became common in Italy), the OR was still 5.3 (95% CI 3.0-9.2). We found a strong effect modification by educational level, with ORs for ulcer more elevated in higher social groups. Gender was an effect modifier (OR = 4.1 in males, 9.2 in females; P = 0.03 for heterogeneity), The association with other gastrointestinal pathologies was much lower and statistically not significant. Almost all gastric lymphomas were B-cell NHLs of intermediate grade according to the working formulation; the majority belonged to the mucosa-associated lymphoid tissue (MALT) type. The association with ulcer was much stronger among MALT lymphomas, but only for recent ulcer diagnoses (2-10 years). Our study shows an increased risk for gastric NHL, very similar to the estimate reported in a previous cohort study. The risk was higher among more educated subjects. C1 Osped S Giovanni, Canc Epidemiol Unit, I-10126 Turin, Italy. CPO Piemonte, I-10126 Turin, Italy. Natl Canc Inst, Epidemiol Unit, I-20133 Milan, Italy. Local Hlth Unit, Novara, Italy. Natl Canc Inst, Genoa, Italy. Ctr Oncol Prevent, Epidemiol Unit, Florence, Italy. Ist Oncol Romagnolo, Forli, Italy. Natl Canc Inst, Ist Regina Elena, Rome, Italy. Azienda Osped, Verona, Italy. Canc Registry, Ragusa, Italy. Univ Siena, Inst Pathol, I-53100 Siena, Italy. RP Vineis, P (reprint author), Osped S Giovanni, Canc Epidemiol Unit, Via Santena 7, I-10126 Turin, Italy. OI NANNI, ORIANA/0000-0001-7338-2896; Masala, Giovanna/0000-0002-5758-9069 FU NCI NIH HHS [CA51086] NR 12 TC 14 Z9 14 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 1999 VL 20 IS 8 BP 1459 EP 1463 DI 10.1093/carcin/20.8.1459 PG 5 WC Oncology SC Oncology GA 226DB UT WOS:000082004100011 PM 10426792 ER PT J AU Izzotti, A Bagnasco, M D'Agostini, F Cartiglia, C Lubet, RA Kelloff, GJ De Flora, S AF Izzotti, A Bagnasco, M D'Agostini, F Cartiglia, C Lubet, RA Kelloff, GJ De Flora, S TI Formation and persistence of nucleotide alterations in rats exposed whole-body to environmental cigarette smoke SO CARCINOGENESIS LA English DT Article ID CARCINOGEN-DNA ADDUCTS; HYDROCARBON HYDROXYLASE-ACTIVITY; PULMONARY ALVEOLAR MACROPHAGES; CHRONIC DEGENERATIVE DISEASES; N-ACETYLCYSTEINE; TOBACCO-SMOKE; LUNG; TISSUES; GLUTATHIONE; ASSAY AB The assessment of pathological effects produced by environmental tobacco smoke in humans is controversial in epidemiological studies, On the other hand, animal models are poorly sensitive to smoke carcinogenicity, We designed an experimental study assessing the tissue-selective formation and persistence of DNA adducts in smoke-exposed rats. Sprague-Dawley rats were exposed for 6 h per day, 5 days per week, to environmental smoke resulting from a mixture of sidestream and mainstream smoke generated from Kentucky 2R1 reference cigarettes. The total particulate matter was in the range of 73-93 mg/m(3), DNA adducts were measured by P-32-postlabelling in rat organs (lung, heart, liver, bladder and testis), tissues (dissected tracheal epithelium) and cells [isolated bronchoalveolar lavage (BAL) cells]. A time-related increase of P-32-post-labelled DNA modifications was detectable by autoradiography, in the form of massive diagonal radioactive zones and individual spots. Top levels were reached after 4-5 weeks of exposure. The ratio of smoke-induced DNA adducts to the background levels detected in sham-exposed rats was 11.2 in the tracheal epithelium, 10.4 in BAL cells, 7.3 in the heart, 6.3 in the lung, 5.1 in the bladder, 1.9 in the testis and 1.1 in the liver. Appearance of DNA adducts in the lung was also revealed by synchronous fluorescence spectrophotometry, Smoke-related oxidative damage was demonstrated by a significant enhancement of 8-hydroxy-2'-deoxyguanosine in lung DNA, In parallel, there was a time-related induction of lung microsomal arylhydrocarbon hydroxylase activity, an elevation in cytosolic glutathione S-transferase activity, and a moderate but progressive and significant depletion of reduced glutathione, After discontinuing exposure to environmental cigarette smoke for 1 week, DNA adduct levels significantly dropped in the lung, tracheal epithelium, heart and bladder. The decrease was evident but not statistically significant in BAL cells, and was negligible in the heart. The selective localization and the differential persistence of these promutagenic nucleotide modifications in rat organs, tissues and cells suggest that exposure to environmental cigarette smoke, at least under the high exposure regimens used in experimental studies, may pose a potential risk of developing mutation-related diseases. C1 Univ Genoa, Sect Hyg & Prevent Med, Dept Hlth Sci, I-16132 Genoa, Italy. NCI, Rockville, MD 20892 USA. RP De Flora, S (reprint author), Univ Genoa, Sect Hyg & Prevent Med, Dept Hlth Sci, Via A Pastore 1, I-16132 Genoa, Italy. OI izzotti, alberto/0000-0002-8588-0347 FU NCI NIH HHS [N01-CN-75008] NR 51 TC 54 Z9 55 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 1999 VL 20 IS 8 BP 1499 EP 1505 DI 10.1093/carcin/20.8.1499 PG 7 WC Oncology SC Oncology GA 226DB UT WOS:000082004100017 PM 10426798 ER PT J AU Anderson, LE Boorman, GA Morris, JE Sasser, LB Mann, PC Grumbein, SL Hailey, JR McNally, A Sills, RC Haseman, JK AF Anderson, LE Boorman, GA Morris, JE Sasser, LB Mann, PC Grumbein, SL Hailey, JR McNally, A Sills, RC Haseman, JK TI Effect of 13 week magnetic field exposures on DMBA-initiated mammary gland carcinomas in female Sprague-Dawley rats SO CARCINOGENESIS LA English DT Article ID MALE BREAST-CANCER; ELECTROMAGNETIC-FIELDS; CARCINOGENICITY; 50-HZ; RISK; MORTALITY; WORKERS; WOMEN AB Several studies suggest that exposure to 50 Hz magnetic fields may promote chemically induced breast cancer in rats. Groups of 100 female Sprague-Dawley rats were initiated with four weekly 5 mg gavage doses of 7,12-dimethylbenz[a]anthracene (DMBA) starting at 50 days of age. After the first weekly DMBA administration, exposure to ambient fields (sham exposed), 50 Hz magnetic fields at either 1 or 5 G field intensity or 60 Hz fields at 1 G for 18.5 h/day, 7 days/week was initiated. Exposure continued for 13 weeks. A vehicle control group without DMBA was included. In a second study, using lower doses of DMBA, groups of 100 female Sprague-Dawley rats were initiated with four weekly doses of 2 mg of DMBA starting at 50 days of age followed, after the first weekly DMBA administration, by exposure to ambient fields (sham exposed) or 50 Hz magnetic fields at either 1 or 5 G field intensity for 18.5 h/day, 7 days/week for 13 weeks. Rats were weighed and palpated meekly for the presence of tumors. There was no effect of magnetic field exposure on body weight gains or on the time of appearance of mammary tumors in either study. At the end of 13 weeks, the animals were killed and the mammary tumors counted and measured, Mammary gland masses found grossly were examined histologically. In the first 13 week study, the mammary gland carcinoma incidences were 92, 86, 96 and 96% for the DMBA controls, 1 G, 50 Hz, 5 G, 50 Hz and 1 G, 60 Hz groups, respectively. The total numbers of carcinomas were 691, 528 (P < 0.05, decrease), 561 and 692 for the DMBA controls, 1 G, 50 Hz, 5 G, 50 Hz and 1 G, 60 Hz groups, respectively. In study 2, the mammary gland carcinoma incidences mere 43, 48 and 38% for the DMBA controls, 1 G, 50 Hz and 5 G, 50 Hz groups, respectively. The total numbers of carcinomas were 102, 90 and 79 for the DMBA controls, 1 G, 50 Hz and 5 G, 50 Hz groups, respectively. There was no effect of magnetic field exposure on tumor size either by in-life palpation or by measurement at necropsy in either study. There was no evidence that 50 or 60 Hz magnetic fields promoted breast cancer in these studies in female rats. These studies do not support the hypothesis that magnetic field exposure promotes breast cancer in this DMBA rat model. C1 Pacific NW Lab, Richland, WA 99352 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Expt Pathol Lab Inc, Res Triangle Pk, NC 27709 USA. RP Boorman, GA (reprint author), Pacific NW Lab, POB 999, Richland, WA 99352 USA. NR 28 TC 27 Z9 29 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 1999 VL 20 IS 8 BP 1615 EP 1620 DI 10.1093/carcin/20.8.1615 PG 6 WC Oncology SC Oncology GA 226DB UT WOS:000082004100034 PM 10426815 ER PT J AU Bialkowski, K Bialkowska, A Kasprzak, KS AF Bialkowski, K Bialkowska, A Kasprzak, KS TI Cadmium(II), unlike nickel(II), inhibits 8-oxo-dGTPase activity and increases 8-oxo-dG level in DNA of the rat testis, a target organ for cadmium(II) carcinogenesis SO CARCINOGENESIS LA English DT Article ID METAL CARCINOGENESIS; MUTAGENIC SUBSTRATE; CELLS; DAMAGE; 8-HYDROXYDEOXYGUANOSINE; 8-HYDROXYGUANINE; 5'-TRIPHOSPHATE; GENOTOXICITY; ELIMINATION; COPPER(II) AB 8-Oxo-2'-deoxyguanosine 5'-triphosphate pyrophosphohydrolase (8-oxo-dGTPase) is an enzyme which prevents incorporation into DNA of promutagenic 8-oxo-2'-deoxyguanosine (8-oxo-dG) from a deoxynucleotide pool damaged by endogenous oxidants, Its inhibition may thus be carcinogenic. We previously found that Cd(II) inhibited 8-oxo-dGTPase in both cell free systems and cultured cells. To verify this finding in a relevant animal model, we investigated the effects of Cd(II) on cellular 8-oxo-dGTPase activity and nuclear DNA 8-oxo-dG levels in the rat testis, a target organ for Cd(II) carcinogenesis. Ni(II), which does not induce testicular tumors in rats and is a weaker in vitro inhibitor of 8-oxo-dGTPase than Cd(II), was investigated as a comparison. Male F344/NCr rats were given a single s.c. dose of 20 mu mol Cd(II) acetate, 90 mu mol Ni(II) acetate or 180 mu mol sodium acetate (controls) per kg body wt and killed 2, 8, 24 or 48 h later (three rats/time point). Cd(II) caused a gradual decrease in testicular 8-oxo-dGTPase activity with time. It became significant only after 8 h postinjection (P < 0.05) and resulted in a final 50% loss of the enzyme activity at 48 h (P < 0.01). Although the results for Ni(II) at 8 h and later were apparently lower than the controls, the decrease did not reach statistical significance, Treatment of rats with Cd(II) led to an early and progressive increase (from 130% at 2 h to 200% at 48 h versus the controls) of the 8-oxo-dG level in testicular DNA (P < 0.05 or better). NI(II) acetate also tended to raise the testicular 8-oxo-dG level, but the increase was transient, with an apparent maximum at 8 h, and did not approach statistical significance (P < 0.2), Thus, Cd(II), unlike Ni(II), is able to inhibit 8-oxo-dGTPase activity and to raise 8-oxo-dG levels in rat testicular DNA, However, the time course of both effects indicates that 8-oxo-dGTPase inhibition is most likely not the sole cause of the increase in 8-oxo-dG. C1 FCRDC, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. RP Kasprzak, KS (reprint author), NCI, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. RI Bialkowski, Karol/E-2328-2014; Bialkowska, Aneta/G-9280-2014 FU NCI NIH HHS [N01-CO-56000] NR 29 TC 27 Z9 30 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 1999 VL 20 IS 8 BP 1621 EP 1624 DI 10.1093/carcin/20.8.1621 PG 4 WC Oncology SC Oncology GA 226DB UT WOS:000082004100035 PM 10426816 ER PT J AU Reddy, BS Kawamori, T Lubet, R Steele, V Kelloff, G Rao, CV AF Reddy, BS Kawamori, T Lubet, R Steele, V Kelloff, G Rao, CV TI Chemopreventive effect of S-methylmethane thiosulfonate and sulindac administered together during the promotion/progression stages of colon carcinogenesis SO CARCINOGENESIS LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; FAMILIAL ADENOMATOUS POLYPOSIS; METHYL METHANE THIOSULFONATE; ASPIRIN USE; F344 RATS; CANCER; PIROXICAM; APOPTOSIS; MODEL; RISK AB S-methylmethane thiosulfonate (S-MMTS), isolated from cauliflower and having antiproliferative activity, and the non-steroidal anti-inflammatory drug sulindac have been shown to inhibit chemically induced colon carcinogenesis when they are administered during the initiation and/or post-initiation stages. The present study was designed to investigate the chemopreventive efficacy of 80 p.p.m. S-MMTS administered during the initiation and postinitiation stages and of S-MMTS and sulindac administered together at low doses (40 and 160 p.p.m., respectively) during the promotion/progression phases (late in the premalignant stage) of colon carcinogenesis. At 5 weeks of age, groups of male F344 rats were fed diets containing 0 (control diet) or 80 p.p.m. S-MMTS. At 7 and 8 weeks of age all rats except those in the vehicle-treated groups were given s.c. injections of 15 mg/kg body wt azoxymethane (AOM). Rats receiving the control diet and intended for the study of inhibition of colon carcinogenesis during the promotion/progression phases were continued on the control diet for 14 weeks after the second AOM treatment; they were then switched to experimental diets containing 80 p.p.m. S-MMTS, 160 p.p.m. sulindac or 40 p.p.m. S-MMTS plus 160 p.p.m. sulindac. The rats were maintained on their respective dietary regimens until 52 weeks after carcinogen treatment and were then killed. Colon tumors were evaluated histopathologically. Administration of 80 p.p.m. S-MMTS alone during the initiation and post-initiation stages and promotion/progression stages had no significant effect on colon tumor inhibition. In contrast, the administration of 160 p.p.m. sulindac during the promotion/progression stages did significantly inhibit total colon tumor multiplicity (P < 0.05). Moreover, coadministration of 40 p.p.m. S-MMTS with 160 p.p.m. sulindac during the promotion/progression stages suppressed the incidence and multiplicity of non-invasive adenocarcinomas (P < 0.05-0.01) and multiplicity of invasive and total adenocarcinomas of the colon to a significant degree (P < 0.05-0.01). These findings have potential clinical implications. C1 Amer Hlth Fdn, Div Nutr Carcinogenesis, Valhalla, NY 10595 USA. NCI, Div Canc Prevent, Chemoprevent Branch, Bethesda, MD 20892 USA. RP Reddy, BS (reprint author), Amer Hlth Fdn, Div Nutr Carcinogenesis, 1 Dana Rd, Valhalla, NY 10595 USA. RI Chinthalapally, Rao/B-3633-2010; Kawamori, Toshihiko/G-7636-2012 FU NCI NIH HHS [CA-17613, CN-55150] NR 20 TC 13 Z9 13 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 1999 VL 20 IS 8 BP 1645 EP 1648 DI 10.1093/carcin/20.8.1645 PG 4 WC Oncology SC Oncology GA 226DB UT WOS:000082004100041 PM 10426822 ER PT J AU Ribadeau-Dumas, A Brady, M Boateng, SY Schwartz, K Boheler, KR AF Ribadeau-Dumas, A Brady, M Boateng, SY Schwartz, K Boheler, KR TI Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) gene products are regulated post-transcriptionally during rat cardiac development SO CARDIOVASCULAR RESEARCH LA English DT Article DE sarco(endo)plasmic reticulum Ca2+-ATPase; heart development; rat; gene transcription; RNA ID MUSCLE SARCOPLASMIC-RETICULUM; MESSENGER-RNA; CA-2+-ATPASE GENE; THYROID-HORMONE; MYOCARDIAL-CONTRACTILITY; HEART-FAILURE; EXPRESSION; PHOSPHOLAMBAN; HYPERTROPHY; RELAXATION AB Objective: The Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) plays a major role in the contraction-relaxation cycle and is responsible for transporting calcium into the lumen of the sarcoplasmic reticulum. This study was pet-formed to determine if the increase in SERCA2 messenger RNA (mRNA) abundance during the perinatal period is regulated transcriptionally. Methods: Transcriptional activity was determined by nuclear run-on assays and mRNA and protein abundances were determined during late fetal and early neonatal cardiac development in rat. Results: From nuclear run-on assays, SERCA2 gene transcription at 17/18 embryonic days (139+/-41 parts per million (ppm), n=7) did not differ from that at 20 neonatal days (139+/-37 ppm, n=6) after birth. No increase in transcriptional activity could be demonstrated during the time frame examined. In contrast, both alpha and beta myosin heavy chains showed significant changes in measured transcriptional activity. SERCA2 mRNA normalized to 18S RNA levels are very low in the fetus (9.8+/-1.9 to 13.4+/-4.9 arbitrary units (A.U.) from 17/18 to 19/20 embryonic days) and significantly increase from birth (15+/-3.8 A.U.) to reach a maximum at 20 days of age (29.1+/-9.5 to 48.3+/-7.0 in 15 to 20 neonatal days rats respectively). Similarly, SR Ca2+-ATPase protein levels are less abundant in the fetus (0.82+/-0.08 to 1.13+/-0.13 A.U./mu g total protein) and reach a maximum at 15-20 neonatal days (3.08+/-0.58 to 2.98+/-0.17). Ca2+ uptake in the fetal heart is about one sixth the level seen in the adult, reaches the highest observed value at 5 days after birth (6.05+/-0.77 pmole Ca2+ per mu g/min) and remains relatively constant over the next 15 days. The activity increases even though phospholamban protein increases in abundance. Conclusions: Since the transcriptional activity of this gene is unchanged whereas the mRNA, protein abundance and activity increase, we conclude that the abundance of SERCA2 gene products is regulated primarily through post-transcriptional mechanisms during the perinatal period. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. Grp Hosp Pitie Salpetriere, Inst Myol, INSERM, Unite UR 153, F-75634 Paris, France. NIA, NIH, Baltimore, MD 21224 USA. RP Boheler, KR (reprint author), Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. NR 42 TC 20 Z9 22 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD AUG 1 PY 1999 VL 43 IS 2 BP 426 EP 436 DI 10.1016/S0008-6363(99)00120-0 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 221VJ UT WOS:000081747400023 PM 10536673 ER PT J AU Kawane, K Fukuyama, H Adachi, M Sakahira, H Copeland, NG Gilbert, DJ Jenkin, NA Nagata, S AF Kawane, K Fukuyama, H Adachi, M Sakahira, H Copeland, NG Gilbert, DJ Jenkin, NA Nagata, S TI Structure and promoter analysis of murine CAD and ICAD genes SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE apoptosis; CAD; ICAD; alternative splicing; expression; promoter ID DNA FRAGMENTATION FACTOR; CASPASE-ACTIVATED DNASE; CELL-DEATH; MOLECULAR-CLONING; APOPTOSIS; ORGANIZATION; INHIBITOR; EXPRESSION; SUBUNIT; PROTEIN AB Caspase-activated DNase (CAD) degrades chromosomal DNA during apoptosis, whereas ICAD (inhibitor of CAD) inhibits the CAD's DNase by binding to it. Here, we describe the assignment of murine CAD and ICAD genes to the distal part of murine chromosome 4, Molecular cloning and structural analysis indicated that CAD and ICAD genes are comprised of 7 and 6 exons, respectively. Two different ICAD mRNAs coding for two forms of ICAD proteins (ICAD-S and ICAD-L) were found to be produced by alternative splicing of intron 5. The CAD and ICAD mRNAs were detected ubiquitously in various murine tissues. Analyses of the promoter activity with a series of deletion mutants of their 5' flanking regions indicated that a 190-bp 5' flanking region of the CAD gene was sufficient to promote the transcription. Whereas, a 120-bp flanking region of ICAD gene was required to promote its transcription. These regions do not show similarity between CAD and ICAD genes, suggesting that expression of CAD and ICAD genes is regulated by different mechanisms. C1 Osaka Univ, Med Sch B3, Dept Genet, Osaka 5650871, Japan. Japan Sci & Technol Corp, Core Res Evolut Sci & Technol, Osaka 5650871, Japan. NCI, Mammalian Genet Lab, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Nagata, S (reprint author), Osaka Univ, Med Sch B3, Dept Genet, 2-2 Yamada Oka, Osaka 5650871, Japan. NR 29 TC 24 Z9 25 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD AUG PY 1999 VL 6 IS 8 BP 745 EP 752 DI 10.1038/sj.cdd.4400547 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 229WQ UT WOS:000082219100005 PM 10467348 ER PT J AU Yang, YL Hong, JS Eder, A Ashwell, JD AF Yang, YL Hong, JS Eder, A Ashwell, JD TI Bacterial death induced by expression of the intracellular portion of human Fas SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE Fas; CD95; bacteria; programmed cell death ID PROGRAMMED CELL-DEATH; TUMOR-NECROSIS-FACTOR; PROTEIN-TYROSINE-PHOSPHATASE; ESCHERICHIA-COLI; MEDIATED APOPTOSIS; SURFACE ANTIGEN; CPP32-LIKE PROTEASES; MONOCLONAL-ANTIBODY; GROWTH-INHIBITION; MOLECULAR-CLONING AB In attempting to produce the intracellular portion of human Fas (IC175 - 319) as a GST-fusion protein we found that expression of GST-IC175 - 319, but not GST alone or GST-IC231 - 298 (containing the Fas death domain), rapidly caused the death of host E. coli cells. Expression of GST-IC175 - 319 with a single amino acid substitution (V238N) corresponding to the mouse Ipr(cg) mutation, or E245A, which abolishes the ability of Fas to self-associate, did not kill bacteria. Deletional analysis identified a 20-amino acids region (Asp(210) - Lys(230)) as essential for the killing activity, and introduction of a single amino acid substitution (T225P) in this 20 amino acid region markedly decreased the ability of Fas- IC175 - 319 to cause bacterial death. These data indicate that Fas can deliver a death signal in prokaryotic organisms by a means that shares some features with eukaryotic cells, and raise the possibility that certain mechanisms leading to programmed cell death may be conserved from bacteria to mammalian cells. C1 NCI, Lab Immune Cell Biol, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Ashwell, JD (reprint author), NCI, Lab Immune Cell Biol, Div Basic Sci, NIH, Bldg 10,Room 1B-40, Bethesda, MD 20892 USA. NR 53 TC 5 Z9 5 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD AUG PY 1999 VL 6 IS 8 BP 805 EP 812 DI 10.1038/sj.cdd.4400555 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 229WQ UT WOS:000082219100012 PM 10467355 ER PT J AU Ketter, TA Frye, MA Cora-Locatelli, G Kimbrell, TA Post, RM AF Ketter, TA Frye, MA Cora-Locatelli, G Kimbrell, TA Post, RM TI Metabolism and excretion of mood stabilizers and new anticonvulsants SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Review DE bipolar disorder; mood disorders; metabolism; excretion; drug-drug interactions; mood stabilizers; anticonvulsants; lithium; carbamazepine; valproate; felbamate; gabapentin; lamotrigine; topiramate; tiagabine ID MAGNETIC-RESONANCE SPECTROSCOPY; INDUCED CARBAMAZEPINE TOXICITY; IMPORTANT DRUG-INTERACTIONS; VALPROIC ACID; CYTOCHROME-P450 3A; EPILEPTIC PATIENTS; BIPOLAR DISORDER; PHARMACOKINETIC PROPERTIES; CLINICAL PHARMACOKINETICS; LITHIUM CONCENTRATIONS AB 1. The mood stabilizers lithium, carbamazepine (CBZ), and valproate (VPA), have differing pharmacokinetics, structures, mechanisms of action, efficacy spectra, and adverse effects. Lithium has a low therapeutic index and is renally excreted and hence has renally-mediated but not hepatically-mediated drug-drug interactions. 2. CBZ has multiple problematic drug-drug interactions due to its low therapeutic index, metabolism primarily by a single isoform (CYP3A3/4), active epoxide metabolite, susceptibility to CYP3A3/4 or epoxide hydrolase inhibitors, and ability to induce drug metabolism (via both cytochrome P450 oxidation and conjugation). In contrast, VPA has less prominent neurotoxicity and three principal metabolic pathways, rendering it less susceptible to toxicity due to inhibition of its metabolism. However, VPA can increase plasma concentrations of some drugs by inhibiting metabolism and increase free fractions of certain medications by displacing them from plasma proteins. 3. Older anticonvulsants such as phenobarbital and phenytoin induce hepatic metabolism, may produce toxicity due to inhibition of their metabolism, and have not gained general acceptance in the treatment of primary psychiatric disorders. 4. The newer anticonvulsants felbamate, lamotrigine, topiramate, and tiagabine have different hepatically-mediated drug-drug interactions, while the renally excreted gabapentin lacks hepatic drug-drug interactions but may have reduced bioavailability at higher doses. 5. Investigational anticonvulsants such as oxcarbazepine, vigabatrin, and zonisamide appear to have improved pharmacokinetic profiles compared to older agents. 6. Thus, several of the newer anticonvulsants lack the problematic drug-drug interactions seen with older agents, and some may even (based on their mechanisms of action and preliminary preclinical and clinical data) ultimately prove to have novel psychotropic effects. C1 Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. RP Ketter, TA (reprint author), Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, 401 Quarry Rd,Room 2124, Stanford, CA 94305 USA. NR 133 TC 42 Z9 43 U1 3 U2 7 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD AUG PY 1999 VL 19 IS 4 BP 511 EP 532 DI 10.1023/A:1006990925122 PG 22 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 204RF UT WOS:000080777400005 PM 10379423 ER PT J AU Nystrom, FH Quon, MJ AF Nystrom, FH Quon, MJ TI Insulin signalling: Metabolic pathways and mechanisms for specificity SO CELLULAR SIGNALLING LA English DT Review DE signal transduction; signal specificity; GLUT4; insulin resistance ID PROTEIN-TYROSINE-PHOSPHATASE; RAT ADIPOSE-CELLS; SRC HOMOLOGY-2 DOMAINS; STIMULATED GLUT4 TRANSLOCATION; 60-KDA PHOSPHOTYROSINE PROTEIN; GLYCOGEN-SYNTHASE KINASE-3; GLUCOSE-TRANSPORT ACTIVITY; RECEPTOR SUBSTRATE FAMILY; GROWTH-FACTOR RECEPTORS; SMOOTH-MUSCLE CELLS AB Biological actions of insulin are mediated by the insulin receptor, a member of a large family of receptor tyrosine kinases (RTK). Signal transduction by the insulin receptor follows a paradigm for RTK signalling Many intracellular signalling molecules contain multiple modular domains that mediate protein-protein interactions and participate in the formation of signalling complexes. Phosphorylation cascades are also a prominent feature of RTK signalling. Distal pathways are difficult to dissect because branching paths emerge from downstream effecters and several upstream inputs converge upon single branch points. Thus, insulin action is determined by complicated signalling networks rather than simple linear pathways. Interestingly, many signalling molecules downstream from the insulin receptor are also activated by a plethora of RTKs. Therefore, mechanisms that generate specificity are required. In this review we discuss recent advances in the elucidation of specific metabolic insulin signalling pathways related to glucose transport, one of the most distinctive biological actions of insulin. We also present examples of potential mechanisms underlying specificity in insulin signalling including interactions between multiple branching pathways, subcellular compartmentalization, tissue-specific expression of key effectors and modulation of signal frequency and amplitude. CELL SIGNAL 11;8:563-574, 1999. (C) 1999 Elsevier Science Inc. C1 NHLBI, Hypertens Endocrine Branch, NIH, Bethesda, MD 20892 USA. RP Quon, MJ (reprint author), NHLBI, Hypertens Endocrine Branch, NIH, Bldg 10,Room 8C-103,10 Ctr Dr MSC 1754, Bethesda, MD 20892 USA. RI Quon, Michael/B-1970-2008; OI Quon, Michael/0000-0002-9601-9915; Nystrom, Fredrik/0000-0002-1680-1000; Quon , Michael /0000-0002-5289-3707 NR 158 TC 122 Z9 125 U1 2 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0898-6568 J9 CELL SIGNAL JI Cell. Signal. PD AUG PY 1999 VL 11 IS 8 BP 563 EP 574 DI 10.1016/S0898-6568(99)00025-X PG 12 WC Cell Biology SC Cell Biology GA 207DF UT WOS:000080919600003 PM 10433517 ER PT J AU Okada, Y Fukumizu, A Takahashi, M Yokoi, T Tsuda, Y Bryant, SD Lazarus, LH AF Okada, Y Fukumizu, A Takahashi, M Yokoi, T Tsuda, Y Bryant, SD Lazarus, LH TI Synthesis of pyrazinone ring-containing opioid mimetics and examination of their opioid receptor-binding activity SO CHEMICAL & PHARMACEUTICAL BULLETIN LA English DT Letter DE peptide mimetic; opioid mimetic; pyrazinone ring; enkephalin sequence; receptor-binding activity; mu-selective ID AMINO-ACIDS; PEPTIDES; ENKEPHALIN; ANALOGS; BRAIN AB Cyclization of dipeptidyl chloromethyl ketones gave 6-(4-aminobutyl)3-carboxyethyl-5-methyl-2(1H)-pyrazinone, 3-(4-aminobutyl)-6-carboxyethyl-5-methyl-2(1H)-pyrazinone, and 3,6-bis(4-aminobutyl)-5-methyl-2(1H)-pyrazinone, which were inserted into the enkephalin sequence to give opioid mimetics, Thus, it was confirmed that a pyrazinone ring can be easily inserted into a peptide sequence in order to evaluate structural components required for biologically active peptides. C1 Kobe Gakuin Univ, Fac Pharmaceut Sci, Nishi Ku, Kobe, Hyogo 6512180, Japan. Natl Inst Environm Hlth Sci, LCBRA, Res Triangle Pk, NC 27709 USA. RP Okada, Y (reprint author), Kobe Gakuin Univ, Fac Pharmaceut Sci, Nishi Ku, Kobe, Hyogo 6512180, Japan. EM okada@pharm.kobegakuin.ac.jp NR 11 TC 5 Z9 5 U1 0 U2 0 PU PHARMACEUTICAL SOC JAPAN PI TOKYO PA 2-12-15 SHIBUYA, SHIBUYA-KU, TOKYO, 150-0002, JAPAN SN 0009-2363 J9 CHEM PHARM BULL JI Chem. Pharm. Bull. PD AUG PY 1999 VL 47 IS 8 BP 1193 EP 1195 PG 3 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 228XY UT WOS:000082163800030 PM 10478476 ER PT J AU Fubini, B Zanetti, G Altilia, S Tiozzo, R Lison, D Saffiotti, U AF Fubini, B Zanetti, G Altilia, S Tiozzo, R Lison, D Saffiotti, U TI Relationship between surface properties and cellular responses to crystalline silica: Studies with heat-treated cristobalite SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID ALVEOLAR MACROPHAGES; QUARTZ HAZARD; II CELLS; INFLAMMATION; PARTICLES; EXPOSURE; LUNG; RAT; REACTIVITY; TOXICITY AB A fibrogenic sample of cristobalite dust, CRIS (crystalline silica of mineral origin), was heated to 1300 degrees C (CRIS-1300) to relate induced physicochemical modifications to cytotoxicity. Heating did not affect dust micromorphology and crystallinity, except for limited sintering and decreased surface area of CRIS-1300. Thermal treatments deeply affected surface properties. Electron paramagnetic resonance showed surface radicals progressively annealed by heating, mostly disappearing at greater than or equal to 800 degrees C. Surface hydrophilicity or hydrophobicity, evaluated with water vapor adsorption, still showed some hydrophilic patches in CRIS-800, but CRIS-1300 was fully hydrophobic. Heating modified the biological activity of cristobalite. Cytotoxicity, tested on proliferating cells of the mouse monocyte macrophage cell line J774, showed that CRIS was cytotoxic and CRIS-800 was still cytotoxic, but CRIS-1300 was substantially inert. Cytotoxicity of CRIS to the rat lung alveolar epithelial cell line, AE6, as measured by colony forming efficiency, was greatly reduced for CRIS-800 and eliminated for CRIS-1300. The rate of lactate dehydrogenase release by rat alveolar macrophages was lowered for CRIS-800, and release was completely inactivated for CRIS-1300. The absence of surface radicals and the onset of hydrophobicity may both account for the loss of cytotoxicity upon heating. Differences observed between CRIS-800 and CRIS-1300, both fully deprived of surface radicals, indicate that hydrophobicity is at least one of the surface properties determining the cytotoxic potential of a dust. C1 Univ Turin, Dipartimento Chim Inorgan Chim Fis & Chim Mat, Fac Farm, I-10125 Turin, Italy. Univ Modena, Fac Med, Sezione Patol Gen, Dipartimento Sci Biomed, I-41100 Modena, Italy. Univ Catholique Louvain, Ind Toxicol & Occupat Med unit, B-1200 Brussels, Belgium. NCI, Lab Expt Pathol, NIH, Bethesda, MD 20892 USA. RP Fubini, B (reprint author), Univ Turin, Dipartimento Chim Inorgan Chim Fis & Chim Mat, Fac Farm, Via Pietro Giuria 7, I-10125 Turin, Italy. NR 39 TC 75 Z9 76 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 1999 VL 12 IS 8 BP 737 EP 745 DI 10.1021/tx980261a PG 9 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 228KH UT WOS:000082135300008 PM 10458708 ER PT J AU Allegra, CJ AF Allegra, CJ TI Dihydropyrimidine dehydrogenase activity: Prognostic partner of 5-fluorouracil? SO CLINICAL CANCER RESEARCH LA English DT Editorial Material ID FAMILIAL PYRIMIDINEMIA; CANCER-PATIENTS; TOXICITY; CHEMOTHERAPY; DEFICIENCY; POPULATION; GENE C1 NCI, Med Branch, Bethesda, MD 20892 USA. RP Allegra, CJ (reprint author), NCI, Med Branch, Bldg 10,Room 12N226,10 Ctr Dr,MSC 1906, Bethesda, MD 20892 USA. NR 25 TC 28 Z9 29 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 1999 VL 5 IS 8 BP 1947 EP 1949 PG 3 WC Oncology SC Oncology GA 228KL UT WOS:000082135600001 PM 10473070 ER PT J AU Kopreski, MS Benko, FA Kwak, LW Gocke, CD AF Kopreski, MS Benko, FA Kwak, LW Gocke, CD TI Detection of tumor messenger RNA in the serum of patients with malignant melanoma SO CLINICAL CANCER RESEARCH LA English DT Article ID POLYMERASE CHAIN-REACTION; K-RAS MUTATIONS; COLORECTAL-CANCER; REVERSE-TRANSCRIPTASE; SENSITIVE DETECTION; PANCREATIC-CANCER; PERIPHERAL-BLOOD; RT-PCR; CELLS; PLASMA AB Serum RNases are known to be elevated in patients with cancer, Consequently, it is not clear whether human mRNA with sufficient integrity as to permit reverse transcription-PCR (RT-PCR) amplification is detectable in serum. We examined serum from six patients with malignant melanoma for human tyrosinase mRNA using RT-PCR. Serum from 20 normal volunteers served as controls. Tyrosinase mRNA could be demonstrated in serum from four of the six melanoma patients with detection by gel electrophoresis and confirmation by blotting amplified product to a tyrosinase-specific probe. The serum remained tyrosinase mRNA positive, even if passed through a 0.45 mu m filter prior to RNA extraction, indicating that the mRNA was extracellular at the time of extraction. Tyrosinase mRNA could not be detected in any control serum (0 of 20 individuals). The presence and integrity of amplifiable RNA was confirmed in all serum specimens (patients and controls) by RT-PCR amplification of c-abl mRNA, Amplifiable RNA could be demonstrated regardless of whether serum was freshly drawn or stored frozen for several years. We conclude that human mRNA can be extracted and amplified from serum, The ability to amplify tumor mRNA from serum may have important utility in cancer diagnostics and monitoring. C1 OncoMEDx Inc, Columbia, MD USA. NCI, Bethesda, MD 20892 USA. Penn State Univ, Milton S Hershey Med Ctr, Hershey, PA 17033 USA. RP Kopreski, MS (reprint author), Pharmacia & Upjohn Inc, 1015-298-163,7000 Portage Rd, Kalamazoo, MI 49001 USA. NR 31 TC 226 Z9 244 U1 0 U2 10 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 1999 VL 5 IS 8 BP 1961 EP 1965 PG 5 WC Oncology SC Oncology GA 228KL UT WOS:000082135600003 PM 10473072 ER PT J AU Schraml, P Kononen, J Bubendorf, L Moch, H Bissig, H Nocito, A Mihatsch, MJ Kallioniemi, OP Sauter, G AF Schraml, P Kononen, J Bubendorf, L Moch, H Bissig, H Nocito, A Mihatsch, MJ Kallioniemi, OP Sauter, G TI Tissue microarrays for gene amplification surveys in many different tumor types SO CLINICAL CANCER RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMA; IN-SITU HYBRIDIZATION; C-MYC ONCOGENE; CYCLIN D1 OVEREXPRESSION; HUMAN GASTRIC CARCINOMAS; GROWTH-FACTOR RECEPTOR; POLYMERASE CHAIN-REACTION; LYMPH-NODE METASTASIS; BREAST-CANCER; LUNG-CANCER AB Gene amplifications are common in many different tumor types and may confer diagnostic, prognostic, or therapeutic information for patient management. Tedious experiments are often required to determine which tumor types have amplifications of a specific oncogene, To facilitate rapid screening for molecular alterations in many different malignancies, a tissue microarray consisting of samples from 17 different tumor types was generated. Altogether, 397 individual tumors were arrayed in a single paraffin block. To determine whether results from the literature can be reproduced on minute tissue samples (diameter, 0.6 mm), amplification of three extensively studied oncogenes (CCND1, CMYC, and ERBB2) was analyzed in three fluorescence in situ hybridization experiments from consecutive sections cut from the tissue microarray. Amplification of CCND1 was found in breast, lung, head and neck, and bladder cancer, as well as in melanoma, ERBB2 was amplified in bladder, breast, colon, stomach, testis, and lung cancer. CMYC was amplified in breast, colon, kidney, lung, ovary, bladder, head and neck, and endometrial cancer. These results confirm and even extend existing data in the literature on such amplifications. In summary, we applied three fluorescence in situ hybridization experiments to analyze amplifications of three oncogenes in three x 397 tumors within a week. This demonstrates the power of using minute arrayed tissue specimens for tumor screening. C1 Univ Basel, Inst Pathol, CH-4003 Basel, Switzerland. NHGRI, Canc Genet Lab, NIH, Bethesda, MD 20892 USA. RP Schraml, P (reprint author), Univ Basel, Inst Pathol, Schoenbeinstr 40, CH-4003 Basel, Switzerland. RI 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 NR 98 TC 361 Z9 406 U1 1 U2 8 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 1999 VL 5 IS 8 BP 1966 EP 1975 PG 10 WC Oncology SC Oncology GA 228KL UT WOS:000082135600004 PM 10473073 ER PT J AU Garry, PJ Baumgartner, RN Brodie, SG Montoya, GD Liang, HC Lindeman, RD Williams, TM AF Garry, PJ Baumgartner, RN Brodie, SG Montoya, GD Liang, HC Lindeman, RD Williams, TM TI Estrogen replacement therapy, serum lipids, and polymorphism of the apolipoprotein E gene SO CLINICAL CHEMISTRY LA English DT Article ID CORONARY HEART-DISEASE; DENSITY-LIPOPROTEIN CHOLESTEROL; HEALTHY ELDERLY POPULATION; POSTMENOPAUSAL WOMEN; PLASMA-LIPOPROTEINS; ARTERY DISEASE; METABOLISM; LIPASE; ATHEROSCLEROSIS; ASSOCIATION AB Background: Pharmacogenomics, the study of genetic loci that modulate drug responsiveness, may help to explain why estrogen replacement therapy (ERT) has differential effects on serum lipid and lipoprotein concentrations hn postmenopausal women who inherit distinct alleles of the apolipoprotein E gene (APOE). Methods: We compared total-cholesterol, triglyceride, and lipoprotein (LDL and HDL) concentrations in 66 postmenopausal women receiving ERT ([+]ERT) with 174 postmenopausal women not receiving ERT ([-]ERT), controlling for three APOE genotypes divided into three groups: E2 (epsilon 2/epsilon 3, n = 31), E3 (epsilon 3/epsilon 3, n = 160), and E4 (epsilon 3/epsilon 4 + epsilon 4/epsilon 4, n = 49). Results: Mean total-cholesterol concentrations were lower in all three [+]ERT groups compared with their [-]ERT counterparts but were statistically significant only for women in group E4 (P = 0.014). The mean LDL-cholesterol concentrations were significantly lower in all three [+]ERT groups compared with their [-]ERT counterparts (P less than or equal to 0.005). Although all three groups of [+]ERT women fended to have higher mean HDL-cholesterol concentrations compared with their [-]ERT counterparts, the differences were not statistically significant. [+]ERT women in groups E2 and E3 had significantly higher (P <0.05) triglyceride concentrations than their [-]ERT counterparts, In [+]ERT women, the ratios of total and LDL-cholesterol to HDL-cholesterol were significantly higher in group E3 and E4 women compared with E2 women (P<0.006). Group E4 [+]ERT women had ratios of total and LDL-cholesterol to HDL-cholesterol that were comparable to group E2 [-]ERT women. Conclusions: Triglyceride concentrations in group E2 [+]ERT women may need to be monitored more closely than those in E3 or E4 [+]ERT women. Group E4 women should probably be targeted for ERT. Results suggest that APOE genotypes have a differential effect on serum lipids and lipoproteins in [+]ERT postmenopausal women. (C) 1999 American Association for Clinical Chemistry. C1 Univ New Mexico, Hlth Sci Ctr, Dept Pathol, Albuquerque, NM 87131 USA. Univ New Mexico, Hlth Sci Ctr, Dept Med, Albuquerque, NM 87131 USA. Univ New Mexico, Hlth Sci Ctr, Clin Nutr Program, Albuquerque, NM 87131 USA. NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Garry, PJ (reprint author), Univ New Mexico, Hlth Sci Ctr, Dept Pathol, Room 215,Surge Bldg,2701 Frontier Pl NE, Albuquerque, NM 87131 USA. FU NCRR NIH HHS [MO1RR00977]; NIA NIH HHS [R01AG10149, R37AG02049] NR 30 TC 25 Z9 32 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD AUG PY 1999 VL 45 IS 8 BP 1214 EP 1223 PN 1 PG 10 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 224FV UT WOS:000081887500014 PM 10430787 ER PT J AU Vgontzas, AN Mastorakos, G Bixler, EO Kales, A Gold, PW Chrousos, GP AF Vgontzas, AN Mastorakos, G Bixler, EO Kales, A Gold, PW Chrousos, GP TI Sleep deprivation effects on the activity of the hypothalamic-pituitary-adrenal and growth axes: potential clinical implications SO CLINICAL ENDOCRINOLOGY LA English DT Article ID HORMONE-SECRETION; BIOCHEMICAL MANIFESTATIONS; URINARY CORTISOL; STRESS SYSTEM; DEPRESSION; TIME; NEUROBIOLOGY; HUMANS; PEAKS AB OBJECTIVES Although several studies have shown that sleep deprivation is associated with increased slow wave sleep during the recovery night, the effects of sleep deprivation on cortisol and growth hormone (GH) secretion the next day and recovery night have not been assessed systematically. We hypothesized that increased slow wave sleep postsleep deprivation is associated with decreased cortisol levels and that the enhanced GH secretion is driven by the decreased activity of the HPA axis. DESIGN AND SUBJECTS After four consecutive nights in the Sleep Laboratory, 10 healthy young men were totally deprived of sleep during the fifth night, and then allowed to sleep again on nights six and seven. Twenty-four hour blood sampling was performed serially every 30 minutes on the fourth day, immediately following the previous night of sleep and on the sixth day, immediately after sleep deprivation. MEASUREMENT Eight-hour sleep laboratory recording, including electroencephologram, electro-oculogram and electromyogram. plasma cortisol and GH levels using specific immunoassay techniques. RESULTS Mean plasma and time-integrated (AUC) cortisol levels were lower during the postdeprivation nighttime period than on the fourth night (P<0.05). Pulsatile analysis showed significant reduction of both the 24 h and daytime peak area (P<0.05) and of the pulse amplitude (P<0.01), but not of the pulse frequency. Also, the amount of time-integrated GH was significantly higher for the first 4 h of the postdeprivation night compared to the predeprivation night (P<0.05). Cross-correlation analyses between the absolute values of the time-series of each hormone value and percentage of each sleep stage per half hour revealed that stow wave sleep was negatively correlated with cortisol and positively correlated with GH with slow wave sleep preceding the secretion of these hormones. In contrast, indices of sleep disturbance, i.e. wake and stage 1 sleep, were positively correlated with cortisol and negatively correlated with GH. CONCLUSION We conclude that steep deprivation results in a significant reduction of cortisol secretion the next day and this reduction appears to be, to a large extent, driven by the increase of stow wave sleep during the recovery night. We propose that reduction of CRH and cortisol secretion may be the mechanism through which sleep deprivation relieves depression temporarily. Furthermore, deep sleep has an inhibitory effect on the HPA axis while it enhances the activity of the GH axis. In contrast, sleep disturbance has a stimulatory effect on the HPA axis and a suppressive effect on the GH axis. These results are consistent with the observed hypocortisolism in idiopathic hypersomnia and HPA axis relative activation in chronic insomnia. Finally, our findings support previous hypotheses about the restitution and immunoenhancement role of slow wave (deep) sleep. C1 Penn State Univ, Coll Med, Dept Psychiat, Sleep Res & Treatment Ctr, Hershey, PA 17033 USA. Univ Athens, Evgenidon Hosp, Endocrine Unit, Athens, Greece. NIMH, Clin Neuroendocrinol Branch, Bethesda, MD 20892 USA. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Vgontzas, AN (reprint author), Penn State Univ, Coll Med, Dept Psychiat, Sleep Res & Treatment Ctr, 500 Univ Dr, Hershey, PA 17033 USA. NR 37 TC 130 Z9 137 U1 1 U2 4 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0300-0664 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD AUG PY 1999 VL 51 IS 2 BP 205 EP 215 DI 10.1046/j.1365-2265.1999.00763.x PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 226MK UT WOS:000082023600013 PM 10468992 ER PT J AU Nagaraju, K Raben, N Villalba, ML Danning, C Loeffler, LA Lee, E Tresser, N Abati, A Fetsch, P Plotz, PH AF Nagaraju, K Raben, N Villalba, ML Danning, C Loeffler, LA Lee, E Tresser, N Abati, A Fetsch, P Plotz, PH TI Costimulatory markers in muscle of patients with idiopathic inflammatory myopathies and in cultured muscle cells SO CLINICAL IMMUNOLOGY LA English DT Article DE myositis; human skeletal muscle cells; costimulatory molecules; CD28; CTLA4; CD86; CD40; CD154 ID EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; MULTIORGAN TISSUE DESTRUCTION; TRANSFER RNA-SYNTHETASES; T-CELLS; MURINE LUPUS; MEDIATED-IMMUNITY; CLASS-I; EXPRESSION; CTLA-4; CD28 AB In an attempt to understand the mechanisms of cell injury in the inflammatory myopathies, we analyzed the expression of costimulatory molecules, CTLA4, CD28, CD86, CD40, and CD154 as well as HLA class I, HLA class II, and ICAM-I in normal muscle and in muscle biopsies from patients with polymyositis (PM) or dermatomyositis (DM). By immunohistochemical staining, DM and PM: biopsies showed the presence of CTLA4, CD28, CD86, and CD40 on inflammatory cells. More strikingly, however, low levels of CTLA4 and CD28 were observed on muscle cells. The expression of CTLA4 and CD28 on nonlymphoid cells has not been previously reported. These unexpected findings were confirmed in cultured normal human myoblasts: various proinflammatory cytokines induced the expression of CTLA4 and CD28 on normal human muscle cells. The sequences of the cDNAs were found to be identical to the sequences for these molecules in T cells. The data suggest a novel complexity in the network of cellular interactions between the infiltrated immune cells and the muscle cells in which the normal relationship between infiltrating inflammatory cells and target tissue is under a previously unrecognized set of controls. C1 NIAMSD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. NINDS, NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. RP Nagaraju, K (reprint author), NIAMSD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. NR 52 TC 50 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD AUG PY 1999 VL 92 IS 2 BP 161 EP 169 DI 10.1006/clim.1999.4743 PG 9 WC Immunology SC Immunology GA 222EF UT WOS:000081769900005 PM 10444360 ER PT J AU Gerber, MA Marcy, SM AF Gerber, MA Marcy, SM TI Editorial response: Judicious use of antimicrobial agents for respiratory tract infections in children - Why are the pediatricians in Toronto doing so well? SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID RESISTANT STREPTOCOCCUS-PNEUMONIAE; OTITIS-MEDIA; ANTIBIOTICS; PHYSICIANS; BACTERIA; PENICILLIN; PREVALENCE; COUGH; COLDS C1 NIAID, DMID, CRAB, NIH, Bethesda, MD 20892 USA. Kaiser Fdn Hosp, Panorama City, CA USA. RP Gerber, MA (reprint author), NIAID, DMID, CRAB, NIH, 6700-B Rockledge Dr,Room 3104, Bethesda, MD 20892 USA. NR 32 TC 1 Z9 1 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG PY 1999 VL 29 IS 2 BP 318 EP 320 DI 10.1086/520208 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 227YE UT WOS:000082106900019 PM 10476735 ER PT J AU Burns, DN FitzGerald, G Semba, R Hershow, R Zorrilla, C Pitt, J Hammill, H Cooper, ER Fowler, MG Landesman, S AF Burns, DN FitzGerald, G Semba, R Hershow, R Zorrilla, C Pitt, J Hammill, H Cooper, ER Fowler, MG Landesman, S CA Women Infants Transmission Study Grp TI Vitamin A deficiency and other nutritional indices during pregnancy in human immunodeficiency virus infection: Prevalence, clinical correlates, and outcome SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID MOTHER-TO-CHILD; EXPERIMENTAL PULMONARY TUBERCULOSIS; FEMALE GENITAL-TRACT; A-DEFICIENCY; PERINATAL TRANSMISSION; IMMUNE ACTIVATION; 1-INFECTED CELLS; HIV-1 INFECTION; RISK-FACTORS; DRUG-USE AB Vitamin A levels in plasma and other nutritional indices were measured during pregnancy for 449 women enrolled in a multicenter cohort study of mother-to-infant transmission of human immuno deficiency virus type 1 (HIV-1). During the third trimester, 29.6% of the women had low (20 to <30 mu g/dL) and 11.1% had very low (<20 mu g/dL) vitamin A levels. Vitamin A and body mass index, serum albumin levels, and hemoglobin levels were weakly correlated. After adjustment for other covariates, women with low and very low vitamin A levels before the third trimester were more likely to deliver infants with low birth weight (<2500 g) than were those with higher levels (odds ratio [OR], 4.58; 95% confidence interval [CI], 1.57-13.4; and OR, 6.99; 95% CI, 1.09-45.0, respectively). However, there was no statistically significant association between vitamin a level and mother-to-infant transmission of HIV-1, Anemia and low body mass index before the third trimester were associated with an increased risk of transmission in univariate analyses but not in multivariate analyses. C1 NICHHD, Ctr Res Mothers & Children, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD 20892 USA. NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. New England Res Inst, Watertown, MA 02172 USA. Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Ocular Immunol Serv, Baltimore, MD USA. Univ Illinois, Sch Publ Hlth, Div Epidemiol & Biostat, Chicago, IL USA. Univ Puerto Rico, Sch Med, Dept Obstet & Gynecol, San Juan, PR 00936 USA. Columbia Univ, Coll Phys & Surg, Dept Pediat, New York, NY USA. Baylor Coll Med, Dept Pediat, Houston, TX USA. Baylor Coll Med, Dept Family & Community Med, Houston, TX USA. Boston Univ, Dept Pediat, Sch Med, Boston, MA 02215 USA. Boston Med Ctr, Boston, MA USA. SUNY Hlth Sci Ctr, Dept Med, Brooklyn, NY 11203 USA. RP Burns, DN (reprint author), NICHHD, Ctr Res Mothers & Children, Pediat Adolescent & Maternal AIDS Branch, 6100 Execut Blvd,Room 4B11, Bethesda, MD 20892 USA. FU NIAID NIH HHS [AI-34841, AI-34840, AI-34842] NR 54 TC 30 Z9 30 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG PY 1999 VL 29 IS 2 BP 328 EP 334 DI 10.1086/520210 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 227YE UT WOS:000082106900021 PM 10476737 ER PT J AU Lehrnbecher, T Venzon, D de Haas, M Chanock, SJ Kuhl, J AF Lehrnbecher, T Venzon, D de Haas, M Chanock, SJ Kuhl, J TI Assessment of measuring circulating levels of interleukin-6, interleukin-8, C-reactive protein, soluble Fc gamma receptor type III, and mannose-binding protein in febrile children with cancer and neutropenia SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID TUMOR-NECROSIS-FACTOR; ACUTE-PHASE REACTANT; BACTEREMIC PATIENTS; PLASMA ENDOTOXIN; FACTOR-ALPHA; FEVER; SERUM; INFECTION; RISK; MANAGEMENT AB Circulating levels of interleukin (IL)-6, IL-8, soluble Fc gamma receptor type III (sFc gamma RIII), mannose-binding protein (MBP), and C-reactive protein (CrP) were assessed among febrile children with cancer and neutropenia. Levels of IL-6, IL-8, sFc gamma RIII, MBP, and CrP were measured in serum from 56 pediatric cancer patients at the time of admission for 121 episodes of febrile neutropenia (88 febrile episodes without identifiable source, 5 clinically documented infections, 20 episodes of bacteremia due to gram-positive and 5 due to gram-negative organisms, and 3 fungal infections). IL-6 and IL-8 levels were higher in patients with either bacteremia due to gram-negative organisms or fungal infections than in patients with febrile episodes without an identifiable source (P < .00001 for each). IL-6 and IL-8 levels were higher in children with bacteremia due to gram-negative organisms than in those with bacteremia due to gram-positive organisms (P = .0011 and P = .0003, respectively). The measured levels of CrP, MBP, and sFc gamma RIII were not useful for identifying the type of infection. These preliminary results show the potential usefulness of IL-6 and IL-8 as early indicators for life-threatening infections in febrile cancer patients with neutropenia. C1 Univ Wurzburg, Kinderklin & Poliklin, Dept Pediat, D-97080 Wurzburg, Germany. NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Data Management Sect, NIH, Bethesda, MD 20892 USA. Cent Lab Blood Transfus, Amsterdam, Netherlands. RP Lehrnbecher, T (reprint author), Univ Wurzburg, Kinderklin & Poliklin, Dept Pediat, Josef Schneider Str 2, D-97080 Wurzburg, Germany. RI Venzon, David/B-3078-2008 NR 43 TC 65 Z9 68 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG PY 1999 VL 29 IS 2 BP 414 EP 419 DI 10.1086/520224 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 227YE UT WOS:000082106900035 PM 10476751 ER PT J AU Boumpas, DT Tassiulas, IO Fleisher, TA Vaughan, E Piscitelli, S Kim, Y Pucino, F Balow, JE Austin, HA AF Boumpas, DT Tassiulas, IO Fleisher, TA Vaughan, E Piscitelli, S Kim, Y Pucino, F Balow, JE Austin, HA TI A pilot study of low-dose fludarabine in membranous nephropathy refractory to therapy SO CLINICAL NEPHROLOGY LA English DT Article DE lymphopenia; regeneration; pharmacokinetics ID HEYMANN NEPHRITIS; GLOMERULONEPHRITIS; REGENERATION; INJURY AB Background: Lymphocytes are believed to play a role in the induction and perpetuation of membranous nephropathy. Fludarabine is a purine nucleoside analog with selective activity against both dividing and resting lymphocytes. We evaluated the tolerance, toxicity, pharmacokinetics, immunologic, and clinical effects of fludarabine in patients with membranous nephropathy in an single arm pilot study. Patients and methods: Eight patients with idiopathic (n = 7) or lupus (n = 1) membranous nephropathy who had failed high-dose prednisone (n = 8) and/or alkylating agents (n = 2), or cyclosporine (n = 1) were treated with 6-monthly cycles of fludarabine (cycles 1 - 2, 20 mg/m(2)/day x 2 days, cycles 3 - 6, 20 mg/m(2)/day x 3 days). Mean proteinuria was 9 g/day with a mean duration of disease of 25 months (range 12 - 48). Proteinuria, GFR and effective renal plasma flow were compared before and after completing the treatment. Results: Seven patients completed the protocol. CD3, CD4, CD8 and B cell counts decreased by 53%, 46%, 61% and 84%, respectively, at the end of treatment and remained at lower than pretreatment levels 6 months after completing the trial. Despite lymphopenia, serum immunoglobulin levels remained unchanged. Both naive (CD45RA+) and memory CD4+ T cells (CD45RO+) were reduced (naive > memory). Proteinuria decreased by greater than or equal to 50% in 5 out of 7 patients (p = 0.11). Filtration fraction improved in all patients with decreased filtration fraction at baseline. The only side-effect observed was one episode of acute bacterial sinusitis that responded promptly to antibiotic therapy. Conclusion: We conclude that low-dose fludarabine treatment in patients with membranous nephropathy is well tolerated and results in significant lymphopenia involving B more than T cells. In this pilot study improvement in proteinuria and filtration rate were observed. Additional studies are required to determine the optimal dose and clinical efficacy of fludarabine. C1 NIAMSD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Clin Immunol, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Pharm, Bethesda, MD 20892 USA. RP Boumpas, DT (reprint author), NIH, Clin Invest Sect, 9000 Rockville Pike,Bldg 10,Room 93205, Bethesda, MD 20892 USA. NR 24 TC 36 Z9 38 U1 0 U2 1 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 1999 VL 52 IS 2 BP 67 EP 75 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 226YH UT WOS:000082050400001 PM 10480216 ER PT J AU Norel, R Wolfson, HJ Nussinov, R AF Norel, R Wolfson, HJ Nussinov, R TI Small molecule recognition: Solid angles surface representation and molecular shape complementarity SO COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING LA English DT Article ID PROTEIN-PROTEIN INTERFACES; DOCKING PROBLEM; ALGORITHM; BINDING; SEARCH; SITES AB Here we examine the recognition of small molecules by their protein and DNA receptors. We focus on two questions: First, how well does the solid angle molecular surface representation perform in fitting together the surfaces of small ligands, such as drugs and cofactors to their corresponding receptors; And second, in particular, to what extent does the shape complementarity play a role in the matching (recognition) process of such small molecules. Both questions have been investigated in protein-protein binding: "Critical Points" based on solid angle calculations have been shown to perform well in the matching of large protein molecules. They are robust, may be few in numbers, and capture satisfactorily the molecular shape. Shape complementarity has been shown to be a critical factor in protein-protein recognition, but has not been examined in drug-receptor recognition. To probe these questions, here we dock 185 receptor-small ligand molecule pairs. We find that such a representation performs adequately for the smaller ligands too, and that shape complementarity is also observed. These issues are important, given the large databases of drugs that routinely have to be scanned to find candidate, lead compounds. We have been able to carry out such large scale docking experiments owing to our efficient, computer-vision based docking algorithms. Its fast CPU matching times, on the order of minutes on a PC, allows such large scale docking experiments. C1 NCI, Lab Expt & Computat Biol, SAIC, FCRDC, Frederick, MD 21702 USA. Tel Aviv Univ, Sch Math Sci, Dept Comp Sci, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Fac Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Lab Expt & Computat Biol, SAIC, FCRDC, Bldg 469,Rm 151, Frederick, MD 21702 USA. RI Wolfson, Haim/A-1837-2011; OI Norel, Raquel/0000-0001-7737-4172 NR 31 TC 12 Z9 13 U1 0 U2 0 PU BENTHAM SCIENCE PUBL BV PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 1386-2073 J9 COMB CHEM HIGH T SCR JI Comb. Chem. High Throughput Screen PD AUG PY 1999 VL 2 IS 4 BP 223 EP 236 PG 14 WC Biochemical Research Methods; Chemistry, Applied; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA 240ZF UT WOS:000082856100004 PM 10469882 ER PT J AU Berger, VW Exner, DV AF Berger, VW Exner, DV TI Detecting selection bias in randomized clinical trials SO CONTROLLED CLINICAL TRIALS LA English DT Article DE allocation concealment; blocking; treatment allocation ID FOLLOW-UP; STRATEGIES; CHALLENGES; QUALITY AB Lack of concealment of allocation in randomized clinical trials can invite selection bias, which is the preferential enrollment of specific patients into one treatment group over another. For example, patients more likely to respond may be enrolled only when the next treatment to be assigned is known to be the active treatment, and patients less likely to respond may be enrolled only when the next treatment to be assigned is known to be the control. Despite the fact that selection bias can compromise both the internal and external validity of trials, little methodology has been developed for its detection. An investigator may test the success of the randomization by comparing baseline characteristics across treatment groups, but such test is limited by the potential inability of the measured baseline variables to predict response. A new method for detecting selections bias, based on response data only, is developed for the case in which a small block size, and either unmasking of treatment codes or an open-label design, have compromised the concealment of allocation. This new method complements baseline comparisons, and is sensitive to detect selection bias even in situations in which baseline comparisons are not. Control Clin Trials 1999;20:319-327 (C) Elsevier Science Inc. 1999. C1 NHLBI, Clin Trials Res Grp, Bethesda, MD 20892 USA. RP Berger, VW (reprint author), US FDA, CBER, HFM-215,1401 Rockville Pike,Suite 200S, Rockville, MD 20852 USA. NR 25 TC 88 Z9 88 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD AUG PY 1999 VL 20 IS 4 BP 319 EP 327 DI 10.1016/S0197-2456(99)00014-8 PG 9 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 218MG UT WOS:000081555900002 PM 10440559 ER PT J AU Willy, ME Henderson, DK Magnuson, WG AF Willy, ME Henderson, DK Magnuson, WG TI Bacteremia in the intensive care unit: A predicament propagated by progress SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE bacteremias; intensive care units; nosocomial infections ID NOSOCOMIAL INFECTION; TRENDS; STATES C1 US FDA, Off Postmkt Drug Risk Assessment, Bethesda, MD 20014 USA. NIH, Warren G Magnuson Clin Ctr, Off Deputy Director Clin Care, Bethesda, MD 20892 USA. RP Willy, ME (reprint author), US FDA, Off Postmkt Drug Risk Assessment, Bethesda, MD 20014 USA. NR 12 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD AUG PY 1999 VL 27 IS 8 BP 1648 EP 1650 DI 10.1097/00003246-199908000-00048 PG 3 WC Critical Care Medicine SC General & Internal Medicine GA 229WG UT WOS:000082218300038 PM 10470780 ER PT J AU Slonim, AD Walker, LK AF Slonim, AD Walker, LK TI Assessing new technology, another chapter: Lung volume reduction surgery/recombinant human growth hormone SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE technological assessment; recombinant human growth hormone; respiratory failure; lung volume reduction surgery; emphysema, chronic obstructive pulmonary disease; outcomes ID PROTEIN-SYNTHESIS; OPERATION; NUTRITION; DISEASE; SURGERY C1 NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. George Washington Univ, Sch Med, Childrens Natl Med Ctr, Washington, DC USA. RP Slonim, AD (reprint author), Childrens Natl Med Ctr, Dept Crit Care Med, 111 Michigan Ave NW, Washington, DC 20010 USA. NR 15 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD AUG PY 1999 VL 27 IS 8 BP 1687 EP 1689 DI 10.1097/00003246-199908000-00069 PG 3 WC Critical Care Medicine SC General & Internal Medicine GA 229WG UT WOS:000082218300059 PM 10470801 ER PT J AU Baum, BJ O'Connell, BC AF Baum, BJ O'Connell, BC TI In vivo gene transfer to salivary glands SO CRITICAL REVIEWS IN ORAL BIOLOGY & MEDICINE LA English DT Review DE salivary glands; gene transfer; recombinant viruses; therapy; therapeutics ID RAT SUBMANDIBULAR GLANDS; HUMAN TISSUE KALLIKREIN; IN-VIVO; GROWTH-HORMONE; RECOMBINANT ADENOVIRUS; EXPRESSION; SECRETION; THERAPY; PROTEINS; CELLS AB Considerable progress has occurred recently in transferring foreign genes to different tissues in vivo. Gene transfer to salivary glands has mirrored progress in the general field. Most salivary studies have utilized replication-deficient, recombinant adenoviruses as gene transfer vectors in rat models, These vectors are able to transduce almost all rat salivary epithelial cell types and lead to relatively high levels of transgene expression. Additionally, successful, though quite modest, gene transfer to salivary glands has been achieved with retroviral vectors and with different plasmid conjugates (liposomes: nonrecombinant adenoviruses). Salivary gland gene transfer has been used for two potential clinical goals: (i) the repair of hypofunctional gland parenchyma, and (ii) the production of secretory transgene products for either systemic or upper gastrointestinal tract pharmaceutical use. Gene transfer can also be used as a powerful tool to alter cellular phenotype in vivo and probe cell biological questions. The current spectrum of studies demonstrates the potential broad and profound influence gene transfer can make on salivary physiology and pathophysiology. C1 NIDCR, CTTB, NIH, Bethesda, MD 20892 USA. RP Baum, BJ (reprint author), NIDCR, CTTB, NIH, 10 Ctr Dr,MSC 1190,Bldg 10,Room 1N113, Bethesda, MD 20892 USA. OI O'Connell, Brian/0000-0003-4529-7664 NR 37 TC 20 Z9 21 U1 0 U2 0 PU INT AMER ASSOC DENTAL RESEARCH PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 1045-4411 J9 CRIT REV ORAL BIOL M JI Crit. Rev. Oral Biol. Med. PD AUG PY 1999 VL 10 IS 3 BP 276 EP 283 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 291MV UT WOS:000085741400003 PM 10759409 ER PT J AU Spriggs, MK Sher, A AF Spriggs, MK Sher, A TI New lessons for immunology at the host-pathogen interface SO CURRENT OPINION IN IMMUNOLOGY LA English DT Editorial Material C1 Immunex Corp, Dept Mol Biol, Seattle, WA 98101 USA. NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Spriggs, MK (reprint author), Immunex Corp, Dept Mol Biol, 51 Univ St, Seattle, WA 98101 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD AUG PY 1999 VL 11 IS 4 BP 363 EP 364 DI 10.1016/S0952-7915(99)80061-2 PG 2 WC Immunology SC Immunology GA 223EU UT WOS:000081828600001 PM 10448149 ER PT J AU Cohen, JI AF Cohen, JI TI The biology of Epstein-Barr virus: lessons learned from the virus and the host SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID CYTOTOXIC T-LYMPHOCYTES; NF-KAPPA-B; LATENT MEMBRANE-PROTEIN-1; IN-VIVO; SIGNALING PROTEINS; HODGKINS-DISEASE; EBV PERSISTENCE; ENCODING GENE; CELLS; RECEPTOR AB Recent studies indicate that a large proportion of cytotoxic T cells are directed towards the Epstein-Barr virus (EBV) during both acute infection and convalescence. The virus, in turn, has usurped cellular pathways to promote proliferation of infected cells and has pirated cellular genes into its genome to modulate the immune system to allow lifelong infection of humans. Analysis of the immune response to the virus is leading to novel therapies for EBV-associated malignancies, including the use of virus-specific cytotoxic T cell infusions. C1 NIH, Med Virol Sect, Clin Invest Lab, Bethesda, MD 20892 USA. RP Cohen, JI (reprint author), NIH, Med Virol Sect, Clin Invest Lab, Bldg 10,Room 11N214, Bethesda, MD 20892 USA. NR 51 TC 41 Z9 43 U1 0 U2 2 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD AUG PY 1999 VL 11 IS 4 BP 365 EP 370 DI 10.1016/S0952-7915(99)80062-4 PG 6 WC Immunology SC Immunology GA 223EU UT WOS:000081828600002 PM 10448133 ER PT J AU Sousa, CRE Sher, A Kaye, P AF Sousa, CRE Sher, A Kaye, P TI The role of dendritic cells in the induction and regulation of immunity to microbial infection SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; EPIDERMAL LANGERHANS CELLS; COLONY-STIMULATING FACTOR; TUMOR-NECROSIS-FACTOR; ANTIGEN-PRESENTING CELLS; T-CELLS; IN-VIVO; MYCOBACTERIUM-TUBERCULOSIS; EFFICIENT PRESENTATION; PROTECTIVE IMMUNITY AB Dendritic cells (DCs) play a critical role in the initiation and regulation of immune responses. Recent advances have begun to uncover the nature and diversity of DC-pathogen interactions and the modulation of DC function by microbial stimuli. Antigen pulsed DCs have also been shown in several infection models to induce high levels of protective immunity and to display immunotherapeutic potential. The study of the function of DCs in the response to infection is thus an exciting and rapidly expanding field with important implications for both fundamental and clinical immunology. C1 Imperial Canc Res Fund, Immunobiol Lab, London WC2A 3PX, England. NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Univ London London Sch Hyg & Trop Med, Immunol Unit, London WC1E 7HT, England. RP Sousa, CRE (reprint author), Imperial Canc Res Fund, Immunobiol Lab, 44 Lincolns Inn Fields, London WC2A 3PX, England. EM caetano@icrf.icnet.uk NR 76 TC 158 Z9 160 U1 0 U2 2 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD AUG PY 1999 VL 11 IS 4 BP 392 EP 399 PG 8 WC Immunology SC Immunology GA 223EU UT WOS:000081828600006 ER PT J AU Finkelman, FD Wynn, TA Donaldson, DD Urban, JF AF Finkelman, FD Wynn, TA Donaldson, DD Urban, JF TI The role of IL-13 in helminth-induced inflammation and protective immunity against nematode infections SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID INTERLEUKIN-2 RECEPTOR-GAMMA; T-CELLS; ENDOTHELIAL-CELLS; INTERLEUKIN-4/INTERLEUKIN-13 RECEPTOR; SIGNAL-TRANSDUCTION; JANUS KINASE; TYROSINE PHOSPHORYLATION; AIRWAY HYPERREACTIVITY; CYTOKINE PRODUCTION; BINDING SUBUNIT AB Helminth infections induce the production of type 2 cytokines, which contribute both to expulsion of the worms and inflammatory responses that can either protect or damage the host. Although IL-4 has been considered the most critical cytokine for both inflammation and protective immunity, recent observations indicate that IL-13 - a related cytokine - can have equal or even greater importance than IL-4 in inflammatory responses and host protection against infection. C1 Univ Cincinnati, Coll Med, Div Immunol, Cincinnati, OH 45267 USA. Vet Adm Med Ctr, Res Serv 151, Cincinnati, OH 45220 USA. NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. Genet Inst, Cambridge, MA 02140 USA. ARS, Immunol Dis Resistance Lab, Inst Livestock & Poultry Sci, USDA,Beltsville Agr Res Ctr E, Beltsville, MD 20705 USA. RP Finkelman, FD (reprint author), Univ Cincinnati, Coll Med, Div Immunol, POB 670563, Cincinnati, OH 45267 USA. RI Wynn, Thomas/C-2797-2011; OI Urban, Joseph/0000-0002-1590-8869 FU NIAID NIH HHS [R01 AI35987] NR 85 TC 98 Z9 100 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD AUG PY 1999 VL 11 IS 4 BP 420 EP 426 DI 10.1016/S0952-7915(99)80070-3 PG 7 WC Immunology SC Immunology GA 223EU UT WOS:000081828600010 PM 10448138 ER PT J AU Wellems, TE Su, XZ Ferdig, M Fidock, DA AF Wellems, TE Su, XZ Ferdig, M Fidock, DA TI Genome projects, genetic analysis, and the changing landscape of malaria research SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID PARASITE PLASMODIUM-FALCIPARUM; YEAST ARTIFICIAL CHROMOSOMES; SEQUENCE TAGS; DNA FRAGMENTS; PROTEIN; TRANSFECTION; INHIBITION; CYCLOPHILIN; SPOROZOITES; EXPRESSION AB Genome analysis of the Plasmodium falciparum malaria parasite already is identifying genes relevant to therapeutic and vaccine-related research. The genetic blueprint of P. falciparum will ultimately need to be understood at multiple levels of an integrated system and will provide a detailed account of the life processes of the parasite and of the devastating disease it causes. C1 NIAID, Malaria Genet Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP NIAID, Malaria Genet Sect, Parasit Dis Lab, NIH, Bldg 4,Room 126,4 Ctr Dr,MSC 0425, Bethesda, MD 20892 USA. EM tew@helix.nih.gov RI Ferdig, Michael/C-6627-2016; OI Fidock, David/0000-0001-6753-8938; Su, Xinzhuan/0000-0003-3246-3248 NR 53 TC 10 Z9 10 U1 0 U2 1 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 EI 1879-0364 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD AUG PY 1999 VL 2 IS 4 BP 415 EP 419 DI 10.1016/S1369-5274(99)80073-3 PG 5 WC Microbiology SC Microbiology GA 223XE UT WOS:000081866200014 PM 10458983 ER PT J AU McDowell, MA Sacks, DL AF McDowell, MA Sacks, DL TI Inhibition of host cell signal transduction by Leishmania: observations relevant to the selective impairment of IL-12 responses SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID PROTEIN-KINASE-C; NF-KAPPA-B; HUMAN-IMMUNODEFICIENCY-VIRUS; SEQUENCE-BINDING PROTEIN; NECROSIS-FACTOR-ALPHA; IFN-GAMMA; INTRACELLULAR INFECTION; INTERLEUKIN-12 PRODUCTION; MONONUCLEAR PHAGOCYTES; MURINE LEISHMANIASIS AB Leishmania parasites are able to delay the onset of cell-mediated immunity by selectively impairing the ability of infected macrophages to produce interleukin (IL)-12. Leishmania infection arrests the JAK/STAT-mediated signal transduction involved in activation of the IL-12 p40 promoter; the phosphorylation defects may be initiated by ligation of the phagocyte receptors used by these organisms to gain entry into the host cell. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP McDowell, MA (reprint author), NIAID, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 67 TC 29 Z9 29 U1 0 U2 1 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD AUG PY 1999 VL 2 IS 4 BP 438 EP 443 DI 10.1016/S1369-5274(99)80077-0 PG 6 WC Microbiology SC Microbiology GA 223XE UT WOS:000081866200018 PM 10458990 ER PT J AU Statham, VS Morgan, RA AF Statham, VS Morgan, RA TI Gene therapy clinical trials for HIV SO CURRENT OPINION IN MOLECULAR THERAPEUTICS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; TRANSDOMINANT NEGATIVE FORM; SINGLE-CHAIN INTRABODIES; INFECTED IDENTICAL-TWINS; CYTOTOXIC T-LYMPHOCYTES; RETROVIRAL VECTORS; BONE-MARROW; REV PROTEIN; INTRACELLULAR ANTIBODIES; HIV-1-INFECTED DONORS AB Despite advances in drug treatment for human immunodeficiency virus (HIV), new therapeutics are needed for sustained treatment of this infection. Gene therapy has great potential for HIV due to its specificity for viral targets and prolonged expression of therapeutics. In this review, the various approaches that current gene therapy clinical trials are using to treat HIV disease are described. Results reported from these trials indicate that the approaches tested appear to be safe and confer some benefit to the genetically-modified cell. However, technical improvements must be made in order for gene therapy to realize its true potential. C1 NIH, Clin Gene Therapy Branch, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. RP Statham, VS (reprint author), NIH, Clin Gene Therapy Branch, Natl Human Genome Res Inst, Bldg 10, Bethesda, MD 20892 USA. NR 61 TC 5 Z9 6 U1 0 U2 0 PU PHARMAPRESS LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1P 6LB, ENGLAND SN 1464-8431 J9 CURR OPIN MOL THER JI Curr. Opin. Mol. Ther. PD AUG PY 1999 VL 1 IS 4 BP 430 EP 436 PG 7 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 342HG UT WOS:000088638700003 ER PT J AU Dalakas, MC AF Dalakas, MC TI Advances in chronic inflammatory demyelinating polyneuropathy: disease variants and inflammatory response mediators and modifiers SO CURRENT OPINION IN NEUROLOGY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE NEURITIS; NECROSIS-FACTOR-ALPHA; UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY; INTERFERON-BETA; MULTIPLE-SCLEROSIS; PLASMA-EXCHANGE; HUMAN-MELANOMA; DOUBLE-BLIND; CROSS-OVER AB Available data on the immunopathogenesis of chronic inflammatory demyelinating polyneuropathy remain still fragmentary and insufficient for a unified hypothesis, Macrophage-mediated demyelination appears to play a fundamental role and cytokines, especially tumour necrosis factor-alpha, participate in this process, The nature of antigen presenting cells, T-cell receptors, adhesion molecules between inflammatory cells and myelinated fibers and the apparent predominance of T helper cell 1-related cytokines need to be explored to design more specific immunotherapies. In chronic cases of chronic inflammatory demyelinating polyneuropathy, a concomitant axonal loss secondary to primary demyelination is common and should be taken into consideration in the design of future therapeutic strategies. Curr Opin Neurol 12:403-409. (C) 1999 Lippincott Williams & Wilkins. C1 NINCDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), NINCDS, Neuromuscular Dis Sect, NIH, Bldg 10,Room 4N248,10 Ctr Dr MSC 1382, Bethesda, MD 20892 USA. NR 56 TC 37 Z9 38 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1350-7540 J9 CURR OPIN NEUROL JI Curr. Opin. Neurol. PD AUG PY 1999 VL 12 IS 4 BP 403 EP 409 DI 10.1097/00019052-199908000-00006 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 267EA UT WOS:000084342900006 PM 10555828 ER PT J AU Litvan, I AF Litvan, I TI Recent advances in atypical parkinsonian disorders SO CURRENT OPINION IN NEUROLOGY LA English DT Article ID PROGRESSIVE SUPRANUCLEAR PALSY; MULTIPLE-SYSTEM ATROPHY; CORTICOBASAL DEGENERATION; ALPHA-SYNUCLEIN; LEWY BODIES; PHARMACOLOGICAL THERAPY; CYTOPLASMIC INCLUSIONS; AUTONOMIC FAILURE; DISEASE; DEMENTIA AB Recent advances in epidemiologic, diagnostic, pathologic, and management aspects of atypical parkinsonian disorders are reviewed and placed in perspective. The implications of considering progressive supranuclear palsy and corticobasal degeneration as tauopathies, and multiple system atrophy and dementia with Lewy bodies as alpha-synucleopathies are discussed. Curr Opin Neurol 11:441-446. (C) 1999 Lippincott Williams & Wilkins. C1 NINCDS, NIH, Bethesda, MD 20892 USA. Def & Vet Head Injury Program, Neuropharmacol Unit, Bethesda, MD USA. RP Litvan, I (reprint author), Fed Bldg,Room 714, Bethesda, MD 20892 USA. OI Litvan, Irene/0000-0002-3485-3445 NR 55 TC 27 Z9 28 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1350-7540 J9 CURR OPIN NEUROL JI Curr. Opin. Neurol. PD AUG PY 1999 VL 12 IS 4 BP 441 EP 446 DI 10.1097/00019052-199908000-00011 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 267EA UT WOS:000084342900011 PM 10555833 ER PT J AU Subramaniam, S AF Subramaniam, S TI The structure of bacteriorhodopsin: an emerging consensus SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Article ID LIPIDIC CUBIC PHASES; PROTON-TRANSFER; M-INTERMEDIATE; RESOLUTION; MODEL; CRYSTAL; TRANSLOCATION; PHOTOCYCLE; PROTEINS; RELEASE AB Six different sets of coordinates have been recently published for bacteriorhodopsin, with reported resolutions ranging from 3.5 Angstrom to 2.3 Angstrom. Three of these are the result of electron crystallographic investigations of two-dimensional crystals of bacteriorhodopsin, whereas the others are from X-ray crystallographic studies of three-dimensional crystals of bacteriorhodopsin. How similar are these models? Are the structure determinations using X-ray diffraction data more accurate than those determined by electron crystallography? Is any one of these coordinate sets closer to the 'real' structure of bacteriorhodopsin than the others? Does the availability of newer models bring us closer to understanding how bacteriorhodopsin really works? These questions, as well as some related issues, are currently being explored. 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 29 TC 37 Z9 37 U1 0 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD AUG PY 1999 VL 9 IS 4 BP 462 EP 468 DI 10.1016/S0959-440X(99)80065-7 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 223WZ UT WOS:000081865700008 PM 10449372 ER PT J AU Cerretti, DP Poindexter, K Castner, BJ Means, G Copeland, NG Gilbert, DJ Jenkins, NA Black, RA Nelson, N AF Cerretti, DP Poindexter, K Castner, BJ Means, G Copeland, NG Gilbert, DJ Jenkins, NA Black, RA Nelson, N TI Characterization of the cDNA and gene for mouse tumour necrosis factor alpha converting enzyme (TACE/ADAM17) and its location to mouse chromosome 12 and human chromosome 2p25 SO CYTOKINE LA English DT Article DE zinc metalloprotease; disintegrin; TNF-alpha; converting enzyme ID RNA POLYMERASE-II; ADAM FAMILY PROTEIN; HUMAN FERTILIN-BETA; SPERM-EGG FUSION; TNF-ALPHA; FACTOR RECEPTOR; DISINTEGRIN; ORGANIZATION; EXPRESSION; SEQUENCE AB Numerous proteins are cleaved or "shed" from their membrane-bound form. One such protein, tumour necrosis factor alpha (TNF-alpha), is synthesized as a type 2 transmembrane protein. Recently, a human protease responsible for this shedding, the TNF-alpha converting enzyme (TACE/ADAM17), was isolated. TACE/ADAM17 is a member of the adamalysin class of zinc-binding metalloproteases or ADAM (a disintegrin and metalloprotease). We report the isolation and characterization of the mouse TACE/ADAM17 cDNA and gene, Mouse TACE/ADAM17 has a 92% amino-acid identity with the human protein and was ubiquitously expressed. A recombinant form of the protease is found to cleave a peptide representing the cleavage site of precursor mouse TNF-alpha.An alternatively spliced form of mouse TACE/ADAM17 was found that would produce a soluble protein. The gene for TACE/ADAM17 is approximately 50 kb and contains 19 exons, Chromosomal mapping places TACE/ADAM17 on mouse chromosome 12 and human chromosome 2p25. (C) 1999 Academic Press. C1 Immunex Corp, Seattle, WA 98101 USA. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Mammalian Genet Lab, Frederick, MD 21702 USA. RP Cerretti, DP (reprint author), Immunex Corp, 51 Univ St, Seattle, WA 98101 USA. NR 53 TC 19 Z9 25 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 1043-4666 J9 CYTOKINE JI Cytokine PD AUG PY 1999 VL 11 IS 8 BP 541 EP 551 DI 10.1006/cyto.1998.0466 PG 11 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 223QA UT WOS:000081850700001 PM 10433800 ER PT J AU Johnson, NJ Sorlie, PD Backlund, E AF Johnson, NJ Sorlie, PD Backlund, E TI The impact of specific occupation on mortality in the US National Longitudinal Mortality Study SO DEMOGRAPHY LA English DT Article ID DEATH-INDEX; UNITED-STATES; ASCERTAINMENT; DRIVERS; CANCER; RISK AB We compare mortality differences for specific and general categories of occupations using a national cohort of approximately 380,000 persons aged 25-64 from the U.S. National Longitudinal Mortality Study. Based on comparisons of relative risk obtained from Cox proportional-hazards model analyses, higher risk is observed in moving across the occupational spectrum from the technical, highly skilled occupations to less-skilled and generally more labor-intensive occupations. Mortality differences obtained for social status groups of specific occupations are almost completely accounted for by adjustments for income and education. Important differences are shown to exist for selected specific occupations beyond those accounted for by social status, income, and education. Highrisk specific occupations include taxi drivers, cooks, longshoremen, and transportation operatives. Low-risk specific occupations include lawyers, natural scientists, teachers, farmers, and a variety of engineers. C1 US Bur Census, Demog Stat Methods Div, Washington, DC 20233 USA. NHLBI, Bethesda, MD 20892 USA. RP Johnson, NJ (reprint author), US Bur Census, Demog Stat Methods Div, Room 3725-3, Washington, DC 20233 USA. NR 57 TC 34 Z9 35 U1 0 U2 3 PU POPULATION ASSN AMER PI WASHINGTON PA 1722 N ST NW, WASHINGTON, DC 20036 USA SN 0070-3370 J9 DEMOGRAPHY JI Demography PD AUG PY 1999 VL 36 IS 3 BP 355 EP 367 DI 10.2307/2648058 PG 13 WC Demography SC Demography GA 228TC UT WOS:000082150900006 PM 10472499 ER PT J AU Sussel, L Marin, O Kimura, S Rubenstein, JLR AF Sussel, L Marin, O Kimura, S Rubenstein, JLR TI Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal molecular respecification within the basal telencephalon: evidence for a transformation of the pallidum into the striatum SO DEVELOPMENT LA English DT Article DE Nkx2.1; telencephalon; regionalization; mouse ID CENTRAL-NERVOUS-SYSTEM; EMBRYONIC MOUSE FOREBRAIN; VERTEBRATE FOREBRAIN; MIGRATING NEURONS; COLUMN IDENTITY; NEURAL PLATE; FLOOR PLATE; DLX GENES; EXPRESSION; HEDGEHOG AB The telencephalon is organized into distinct longitudinal domains: the cerebral cortex and the basal ganglia. The basal ganglia primarily consists of a dorsal region (striatum) and a ventral region (pallidum). Within the telencephalon, the anlage of the pallidum expresses the Nkx2.1 homeobox gene. A mouse deficient in Nkx2.1 function does not form pallidal structures, lacks basal forebrain TrkA-positive neurons (probable cholinergic neurons) and has reduced numbers of cortical cells expressing GABA, DLX2 and calbindin that migrate from the pallidum through the striatum and into the cortex. We present evidence that these phenotypes result from a ventral-to-dorsal transformation of the pallidal primordium into a striatal-like anlage. C1 Univ Calif San Francisco, Dept Psychiat, Ctr Neurobiol & Psychiat, Nina Ireland Lab Dev Neurobiol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Neurosci Program, San Francisco, CA 94143 USA. Univ Calif San Francisco, Program Dev Biol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Program Biomed Sci, San Francisco, CA 94143 USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Rubenstein, JLR (reprint author), Univ Calif San Francisco, Dept Psychiat, Ctr Neurobiol & Psychiat, Nina Ireland Lab Dev Neurobiol, 401 Parnassus Ave, San Francisco, CA 94143 USA. RI Marin, Oscar/F-3856-2012 OI Marin, Oscar/0000-0001-6264-7027 FU NIMH NIH HHS [K02 MH01046-01] NR 54 TC 553 Z9 558 U1 2 U2 12 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD AUG PY 1999 VL 126 IS 15 BP 3359 EP 3370 PG 12 WC Developmental Biology SC Developmental Biology GA 228EA UT WOS:000082123100010 PM 10393115 ER PT J AU Dunbar, ME Dann, PR Robinson, GW Hennighausen, L Zhang, JP Wysolmerski, JJ AF Dunbar, ME Dann, PR Robinson, GW Hennighausen, L Zhang, JP Wysolmerski, JJ TI Parathyroid hormone-related protein signaling is necessary for sexual dimorphism during embryonic mammary development SO DEVELOPMENT LA English DT Article DE androgen receptor; tenascin C; epithelial-mesenchymal interaction; apoptosis; PTH/PTHrP receptor; mouse ID MESENCHYMAL-EPITHELIAL INTERACTIONS; GLAND DEVELOPMENT; EXTRACELLULAR-MATRIX; ANDROGEN RECEPTOR; TENASCIN; MORPHOGENESIS; EXPRESSION; PEPTIDE; TOOTH; FETAL AB Male mice lack mammary glands due to the interaction of circulating androgens with local epithelial-mesenchymal signaling in the developing mammary bud, Mammary epithelial cells induce androgen receptor (AR) within the mammary mesenchyme and, in response to androgens, the mesenchyme condenses around the epithelial bud, destroying it, We show that this process involves apoptosis and that, in the absence of parathyroid hormone-related protein (PTHrP) or its receptor, the PTH/PTHrP receptor (PPR1), it fails due to a lack of mesenchymal AR expression. In addition, the expression of tenascin C, another marker of the mammary mesenchyme, is also dependent on PTHrP. PTHrP expression is initiated on E11 and, within the ventral epidermis, is restricted to the forming mammary epithelial bud, In contrast, PPR1 expression is not limited to the mammary bud, but is found generally within the subepidermal mesenchyme. Finally, transgenic overexpression of PTHrP within the basal epidermis induces AR and tenasin C expression within the ventral dermis, suggesting that ectopic expression of PTHrP can induce the ventral mesenchyme to express mammary mesenchyme markers, We propose that PTHrP expression specifically within the developing epithelial bud acts as a dominant signal participating in cell fate decisions leading to a specialized mammary mesenchyme. C1 Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06520 USA. NIDDKD, Lab Genet & Physiol, Natl Inst Diabet, NIH, Bethesda, MD 20892 USA. RP Wysolmerski, JJ (reprint author), Yale Univ, Sch Med, Dept Internal Med, 333 Cedar St, New Haven, CT 06520 USA. RI Robinson, Gertraud/I-2136-2012 FU NCI NIH HHS [CA60498]; NIDDK NIH HHS [5-P30-DK45735] NR 43 TC 69 Z9 69 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD AUG PY 1999 VL 126 IS 16 BP 3485 EP 3493 PG 9 WC Developmental Biology SC Developmental Biology GA 234QY UT WOS:000082496900002 PM 10409496 ER PT J AU Fantl, V Edwards, PAW Steel, JH Vonderhaar, BK Dickson, C AF Fantl, V Edwards, PAW Steel, JH Vonderhaar, BK Dickson, C TI Impaired mammary gland development in Cyl-1(-/-) mice during pregnancy and lactation is epithelial cell autonomous SO DEVELOPMENTAL BIOLOGY LA English DT Article ID HUMAN BREAST-CANCER; CYCLIN-DEPENDENT KINASES; ESTROGEN-RECEPTOR; PROGESTERONE RECEPTORS; C/EBP-BETA; MOUSE; D1; GENE; DIFFERENTIATION; TRANSCRIPTION AB A specific defect of mice lacking cyclin D1 (Cyl-1(-/-)) is impaired development of the mammary gland during pregnancy. Here we show that when tissue from Cyl-1(-/-) mammary gland was transplanted into empty mammary fat pad of wild-type mice, the abnormal phenotype was maintained, indicating that it is epithelial cell autonomous. Nevertheless, in pregnancy the early proliferative response, which is characterized by extensive side branching, still occurs in the absence of cyclin D1. However, the response is atypical due to a marked reduction in the formation of accompanying alveoli. This reduction and delay in alveolar development persists throughout pregnancy. Moreover, although prolactin synthesis and release appear to be normal, lactogenesis is severely compromised. Consistent with the appearance of numerous side branches, progesterone receptor expression was readily detected in the mammary tissue of pregnant Cyl-1(-/-) mice, although there was a significant change in the ratio of the two (A and B) receptor isoforms. In Cyl-1(-/-) mammary glands during late pregnancy there was a decrease in the abundance of total and phosphorylated Stat5a, as well as delayed onset and substantial diminution of milk protein expression. The biochemical analysis suggests that there is a cumulative delay in growth and differentiation of the mammary gland during pregnancy that results in a severely compromised gland when, at parturition, further development is curtailed by the abrupt change in hormonal milieu. (C) 1999 Academic Press. C1 Imperial Canc Res Fund, Viral Carcinogenesis Lab, London WC2A 3PX, England. Imperial Canc Res Fund, Histopathol Unit, London WC2A 3PX, England. Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. NCI, Tumor Immunol & Biol Lab, Mol & Cellular Endocrinol Sect, Bethesda, MD 20892 USA. RP Fantl, V (reprint author), Imperial Canc Res Fund, Viral Carcinogenesis Lab, 44 Lincolns Inn Fields, London WC2A 3PX, England. RI Edwards, Paul/M-8291-2014; Steel, Jennifer/B-4737-2013 OI Steel, Jennifer/0000-0003-4439-0090 NR 44 TC 67 Z9 69 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD AUG 1 PY 1999 VL 212 IS 1 BP 1 EP 11 DI 10.1006/dbio.1999.9329 PG 11 WC Developmental Biology SC Developmental Biology GA 223MH UT WOS:000081844500001 PM 10419681 ER PT J AU Weyer, C Bogardus, C Pratley, RE AF Weyer, C Bogardus, C Pratley, RE TI Metabolic factors contributing to increased resting metabolic rate and decreased insulin-induced thermogenesis during the development of type 2 diabetes SO DIABETES LA English DT Article ID GLUCOSE-INDUCED THERMOGENESIS; 24-HOUR ENERGY-EXPENDITURE; OBESE SUBJECTS; PIMA-INDIANS; POSTPRANDIAL THERMOGENESIS; ORAL GLUCOSE; BODY-FAT; MELLITUS; WOMEN; RESISTANCE AB Previous studies have indicated that individuals with type 2 diabetes have an increased resting metabolic rate (BMR) but decreased insulin-induced thermogenesis (IIT) compared with those with normal glucose tolerance (NGT). When and by which mechanisms these abnormalities occur during the development of diabetes remain unknown. In 560 Pima Indians, sleeping metabolic rate (respiratory chamber) was higher not only in subjects with diabetes (+4.9%, P < 0.001) but also in those with impaired glucose tolerance (IGT) (+2.7%, P < 0.01) compared with subjects with NGT Longitudinally, RMR (ventilated hood) increased progressively in 17 subjects in whom glucose tolerance deteriorated from NGT to IGT (+4.2%) to diabetes (+2.6%) over 5.1 +/- 1.4 years (P < 0.05 for trend). In parallel, IIT (% increase in metabolic rate during an insulin/glucose infusion) decreased during the transition from NGT (11.7%) to IGT (7.3%) to diabetes (6.5%) (P < 0.05 for trend). In 151 subjects, basal endogenous glucose output (3-H-3-glucose), fasting insulin and free fatty acid concentrations, and glucose disposal (hyperinsulinemic clamp) were significant determinants of RMR, independent of body composition, age, and sex. Nonoxidative and oxidative glucose disposal, RMR, and fasting insulin and glucose concentrations were determinants of IIT. Differences in RMR and IIT between glucose tolerance groups decreased after adjusting for these factors. These findings indicate that increases in RMR and decreases in IIT occur early in the development of type 2 diabetes, and that both changes are related to the progressive metabolic abnormalities that occur during the development of the disease. C1 NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. RP Weyer, C (reprint author), NIDDKD, Clin Diabet & Nutr Sect, NIH, 4212 N 16Th St,Room 5-41, Phoenix, AZ 85016 USA. NR 61 TC 41 Z9 42 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD AUG PY 1999 VL 48 IS 8 BP 1607 EP 1614 DI 10.2337/diabetes.48.8.1607 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 218XB UT WOS:000081577400016 PM 10426380 ER PT J AU Rodriguez, BL Lau, N Burchfiel, CM Abbott, RD Sharp, DS Yano, K Curb, JD AF Rodriguez, BL Lau, N Burchfiel, CM Abbott, RD Sharp, DS Yano, K Curb, JD TI Glucose intolerance and 23-year risk of coronary heart disease and total mortality - The Honolulu Heart Program SO DIABETES CARE LA English DT Article ID DIABETES-MELLITUS; MEN; TOLERANCE; STROKE AB OBJECTIVE - The associations between glucose intolerance measured at the study entry date and the 23-year incidence of coronary heart disease (CHD), CHD mortality, and total mortality were examined at the Honolulu Heart Program. RESEARCH DESIGN AND METHODS - This prospective study followed a cohort of 8,006 Japanese-American men who were 45-68 years old and living on the island of Oahu, HI, in 1965. Baseline glucose was measured in a nonfasting state 1 h after a 50-g glucose load. History and use of medication for diabetes was obtained during an interview The cohort was divided into four categories of glucose tolerance: low-normal, high-normal, asymptomatic hyperglycemia, and known diabetes. RESULTS - During the 23 years of follow-up, 864 incident cases of CHD, 384 deaths from CHD, and 2,166 total deaths occurred. The relative risks (RRs) were obtained using Cox proportional hazards modeling, with the low-normal category as a reference. The RRs were adjusted for age only, as well as for age, BMI, hypertension, cholesterol, triglycerides, smoking, alcohol, and a Japanese diet index. The age-adjusted and risk factor-adjusted RRs for all outcomes were significant for the asymptomatic hyperglycemic and known diabetes groups (P < 0.05). The age-adjusted RRs for CHD incidence and total mortality were marginally significant in the high-normal group, but the RRs were not significant when adjusted for risk factors. CONCLUSIONS - These results suggest a dose-response relation of glucose intolerance at baseline with CHD incidence, CND mortality, and total mortality, independent of other risk factors, in this cohort of middle-aged and older Japanese-American men. C1 Univ Hawaii Manoa, Div Clin Epidemiol, Honolulu, HI 96822 USA. Univ Hawaii Manoa, Dept Geriatr Med, Honolulu, HI 96822 USA. Univ Hawaii Manoa, Dept Med, Honolulu, HI 96822 USA. Univ Hawaii Manoa, Dept Family Practice & Community Hlth, Honolulu, HI 96822 USA. Honolulu Heart Program, Honolulu, HI USA. Kuakini Med Ctr, Honolulu, HI USA. NHLBI, Honolulu Epidemiol Res Sect, Honolulu, HI USA. NHLBI, Epidemiol & Biometry Program, Honolulu, HI USA. Univ Virginia, Sch Med, Div Biostat, Charlottesville, VA USA. RP Rodriguez, BL (reprint author), Hawaii Ctr Hlth Res, 846 S Hotel St,Suite 306, Honolulu, HI 96813 USA. FU NHLBI NIH HHS [N01-HC-05102, U01HL56274]; NIA NIH HHS [N01-AG-42149] NR 20 TC 121 Z9 125 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD AUG PY 1999 VL 22 IS 8 BP 1262 EP 1265 DI 10.2337/diacare.22.8.1262 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 218QF UT WOS:000081562600006 PM 10480768 ER PT J AU Egan, JM Clocquet, AR Elahi, D AF Egan, JM Clocquet, AR Elahi, D TI Insulinotropic effect of exendin-4 in humans SO DIABETOLOGIA LA English DT Meeting Abstract C1 NIA, Baltimore, MD 21224 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 1999 VL 42 SU 1 MA 148 BP A41 EP A41 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 225CC UT WOS:000081937600148 ER PT J AU Elahi, D Stoffers, DA Clocquet, AR Muller, DC Wideman, L Chin, GA Clarke, WL Hanks, JB Habener, JF Egan, JM AF Elahi, D Stoffers, DA Clocquet, AR Muller, DC Wideman, L Chin, GA Clarke, WL Hanks, JB Habener, JF Egan, JM TI Impaired insulin secretion and sensitivity in MODY4. SO DIABETOLOGIA LA English DT Meeting Abstract C1 NIA, NIH, Baltimore, MD 21224 USA. UVA, Charlottesville, VA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 1999 VL 42 SU 1 MA 279 BP A77 EP A77 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 225CC UT WOS:000081937600279 ER PT J AU Gautier, JF Wilson, C Weyer, C Mott, D Knowler, WC Polonsky, K Bogardus, C Pratley, RE AF Gautier, JF Wilson, C Weyer, C Mott, D Knowler, WC Polonsky, K Bogardus, C Pratley, RE TI Insulin secretion in glucose tolerant offspring correlates with age of onset of type 2 diabetes in the parents. SO DIABETOLOGIA LA English DT Meeting Abstract C1 NIDDK, NIH, Phoenix, AZ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 1999 VL 42 SU 1 MA 281 BP A78 EP A78 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 225CC UT WOS:000081937600282 ER PT J AU Malik, RA Paniagua, O Shaw, L Austin, C Heagerty, AM AF Malik, RA Paniagua, O Shaw, L Austin, C Heagerty, AM TI Resistance vessel function and structure in normotensive patients with type 1 diabetes. SO DIABETOLOGIA LA English DT Meeting Abstract C1 NIH, Div Cardiovasc Med, Bethesda, MD USA. Dept Med, Manchester, Lancs, England. NR 0 TC 6 Z9 6 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 1999 VL 42 SU 1 MA 271 BP A75 EP A75 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 225CC UT WOS:000081937600271 ER PT J AU Mei, J Rahn-Landstrom, T Brindley, D Manganiello, V Degerman, E AF Mei, J Rahn-Landstrom, T Brindley, D Manganiello, V Degerman, E TI TNF-alpha and cell-permeable ceramide stimulate lipolysis tn 3T3-L1 adipocytes by downregulation of PDE3B. SO DIABETOLOGIA LA English DT Meeting Abstract C1 Univ Lund, Dept Cell & Mol Biol, Sect Mol Signalling, S-22100 Lund, Sweden. Univ Alberta, Dept Biochem, Edmonton, AB T6G 2M7, Canada. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 1999 VL 42 SU 1 MA 654 BP A175 EP A175 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 225CC UT WOS:000081937600653 ER PT J AU Tack, CJ Goldstein, DS AF Tack, CJ Goldstein, DS TI Regional sympathetic denervation in patients with painful diabetic neuropathy SO DIABETOLOGIA LA English DT Meeting Abstract C1 Univ Nijmegen Hosp, Div Gen Internal Med, NL-6500 HB Nijmegen, Netherlands. NINDS, Clin Neurochem Sect, NIH, Bethesda, MD 20892 USA. RI Tack, Cees/A-2368-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 1999 VL 42 SU 1 MA 153 BP A42 EP A42 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 225CC UT WOS:000081937600153 ER PT J AU Abati, A AF Abati, A TI To count or not to count? A review of the issue of adequacy in breast FNA SO DIAGNOSTIC CYTOPATHOLOGY LA English DT Article ID FINE-NEEDLE ASPIRATION; SPECIMEN ADEQUACY; CYTOLOGY; BIOPSY; CONSTITUTES; MASSES; MALIGNANCIES; MANAGEMENT; PATHOLOGY; DIAGNOSIS C1 NCI, Pathol Lab, Sect Cytopathol, NIH, Bethesda, MD 20892 USA. RP Abati, A (reprint author), NCI, Pathol Lab, Sect Cytopathol, NIH, 10 Ctr Dr,Bldg 10,Room 2A19, Bethesda, MD 20892 USA. NR 32 TC 7 Z9 7 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 8755-1039 J9 DIAGN CYTOPATHOL JI Diagn. Cytopathol. PD AUG PY 1999 VL 21 IS 2 BP 142 EP 147 DI 10.1002/(SICI)1097-0339(199908)21:2<142::AID-DC12>3.0.CO;2-Z PG 6 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 221DW UT WOS:000081709600012 PM 10425054 ER PT J AU Langlois, JA Norton, R Campbell, AJ Leveille, S AF Langlois, JA Norton, R Campbell, AJ Leveille, S TI Characteristics and behaviours associated with difficulty in performing activities of daily living among older New Zealand women SO DISABILITY AND REHABILITATION LA English DT Article ID BODY-MASS INDEX; PHYSICAL-ACTIVITY; MAINTAINING MOBILITY; GRIP STRENGTH; RISK-FACTORS; LATE-LIFE; NHANES-I; DISABILITY; DECLINE; ADULTS AB Purpose: The objective of this cross-sectional study was to determine the prevalence of self-reported difficulty in perfoming activities of daily living (ADLs) and the associated characteristics and behaviours among older women in Auckland, New Zealand. Methods: A sample of 569 community dwelling women aged 65 years and older were studied. Logistic regression was used to calculate odds ratios and 95% confidence intervals for the association of participant characteristics and behaviours with reported difficulty in performing greater than or equal to 1 of five basic ADLs. Results: An age adjusted prevalence of 4.6% was found for reported ADL difficulty. Age greater than or equal to 85 years (odds ratio [OR] 5.9; 95% confidence interval [CI] 1.1-30.2), history of stroke (OR 9.8, 95% CI 4.1-23.3), history of greater than or equal to 1 fall in the past year (OR 3.4; 95% CI 1.6-7.4), low body mass index (OR 2.8; 95% CI 1.2-6.4), and low grip strength (OR 2.6; 95% CI 1.2-5.5) were significantly and independently associated with ADL difficulty. Among women with ADL difficulty, the prevalence of adaptive equipment use was high (> 90%). Conclusions: Several characteristics, medical conditions, and behaviours, some of which may be preventable, are associated with physical disability in older New Zealand women. Studies like this are an important step toward the development of interventions to reduce or delay disability and improve health and quality of life. C1 Natl Ctr Injury Prevent & Control, Atlanta, GA 30333 USA. Univ Auckland, Injury Prevent Res Ctr, Auckland 1, New Zealand. Univ Otago, Sch Med, Dunedin, New Zealand. NIA, Bethesda, MD 20892 USA. RP Langlois, JA (reprint author), Natl Ctr Injury Prevent & Control, Atlanta, GA 30333 USA. NR 41 TC 4 Z9 4 U1 0 U2 3 PU TAYLOR & FRANCIS LTD PI LONDON PA ONE GUNPOWDER SQUARE, LONDON EC4A 3DE, ENGLAND SN 0963-8288 J9 DISABIL REHABIL JI Disabil. Rehabil. PD AUG PY 1999 VL 21 IS 8 BP 365 EP 371 PG 7 WC Rehabilitation SC Rehabilitation GA 238UD UT WOS:000082729900002 PM 10503977 ER PT J AU Kim, YC Karton, Y Ji, XD Melman, N Linden, J Jacobson, KA AF Kim, YC Karton, Y Ji, XD Melman, N Linden, J Jacobson, KA TI Acyl-hydrazide derivatives of a xanthine carboxylic congener (XCC) as selective antagonists at human A(2B) adenosine receptors SO DRUG DEVELOPMENT RESEARCH LA English DT Article DE G protein-coupled receptors; radioligand; alkylxanthines; structure-activity relationships; purines; adenylyl cyclase ID A(2A)-ADENOSINE RECEPTORS; A(3) RECEPTOR; RAT-BRAIN; PROTEIN; EFFICIENT; CELLS AB The structure-activity relationships (SAR) of 8-phenyl-1,3-dipropylxanthine derivatives in binding to recombinant human A(2B) adenosine receptors were explored, in order to identify selective antagonists. Based on the finding of receptor selectivity in MRS 1204, containing an N-hydroxysuccinimide ester attached through the p-position of the 8-phenyl substituent [Jacobson et at. (1999): Drug Dev. Res., 47:45-53], a hydrazide and its more stable imide derivatives were synthesized. The hydrazide of XCC (8-[4-[[[carboxy]methyl]oxy]phenyl]-1,3-dipropylxanthine) was acylated with a variety of mono- and dicarboxylic acids. K-i values were determined in the adenosine receptor binding assays. At recombinant human A(2B) receptors expressed in membranes of HEK-293 cells, antagonist radioligands used were the xanthine I-125-ABOPX (I-125-3-(4-amino-3-iodobenzyl)-8-oxyacetate-1-propyl-xanthine) and the nonxanthine antagonist [H-3]ZM 241385 ([H-3]4-(2-[7-amino-2-(furyl)(1,2,4)triazolo(2,3-a)(1,3,5)triazin-5-ylamino-ethyl)phenol). The initial screening utilized rat A(1)/A(2A) receptors and human A(3) receptors, and selected compounds were examined at the human A(1)/A(2A) subtypes. A 1,2-dimethylmaleimide derivative, 14 (MRS 1595), bound to human A(2B) receptors with a K-i of 19 nM and proved to be selective vs. human A(1)/A(2A)/A(3) receptors by 160-, 100-, and 35-fold, respectively. Enprofylline (3-propylxanthine) is slightly selective for A(2B) receptors, suggesting removal of the 1-propyl group; however, combination of the 1-H-3-Pr and 8-phenyl substituents eliminated the selectivity. Other potent and moderately selective A(2B) antagonists were a tetrahydrophthaloyl derivative 18b (MRS 1614, K-i value 10 nM) and amino acid conjugates of the XCC-hydrazide, i.e., the glutarimide 24b (MRS 1626, K-i value 13 nM), and protected dipeptide 27 (MRS 1615, K-i value 11 nM). Published 1999 Wiley-Liss, Inc.(dagger) C1 NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Israel Inst Biol Res, Dept Chem, IL-70450 Ness Ziona, Israel. Univ Virginia, Hlth Sci Ctr, Dept Internal Med & Mol Physiol & Biol Phys, Charlottesville, VA USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 27 TC 29 Z9 30 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 0272-4391 J9 DRUG DEVELOP RES JI Drug Dev. Res. PD AUG PY 1999 VL 47 IS 4 BP 178 EP 188 DI 10.1002/(SICI)1098-2299(199908)47:4<178::AID-DDR4>3.0.CO;2-L PG 11 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 239WN UT WOS:000082793000004 ER PT J AU Lee, BL Yoo, MJ Kim, WH Hwang, DH Lee, SK Kleinman, HK AF Lee, BL Yoo, MJ Kim, WH Hwang, DH Lee, SK Kleinman, HK TI Reconstituted basement membrane reduces proliferation and increases prolactin expression of GH(3) cells SO ENDOCRINE JOURNAL LA English DT Article DE GH(3) cells; Matrigel; cell proliferation; prolactin expression ID EXTRACELLULAR-MATRIX; PITUITARY-CELLS; MESSENGER-RNA; GH3 CELLS; INVITRO; SECRETION; PHENOTYPE; CULTURE; LAMININ; GROWTH AB This study investigated the effects of reconstituted basement membrane Matrigel on the proliferation and prolactin expression of GH(3) cells in culture for 6 days. When cells were cultured on Matrigel, the initial attachment was increased but the cell number was not changed with time whereas rapid increase in cell number was observed in cultures on plastic. Bromodeoxyuridine (BrdU)-labeling showed that BrdU incorporation ratio of GH, cells cultured on Matrigel was about one half of that observed with cells cultured on plastic (9.7+/-0.7% vs. 18.7+/-1.2%). Immunocytochemistry revealed that the ratio of the prolactin-immunoreactive GH(3) cells was about 3.6 times (58.4+/-2.9% on Matrigel vs. 16.2+/-1.4% on plastic), which was compatible with the results of Western blot analysis. In situ hybridization demonstrated that prolactin mRNA-positive cells were identified more frequently when cells were cultured on Matrigel compared to cultures on plastic. These findings indicate that Matrigel is a proper culture substrate for the long-term culture of GH(3) pituitary cells due to the inhibition of overgrowth and promotion of prolactin expression. C1 Seoul Natl Univ, Coll Med, Dept Anat, Chongno Gu, Seoul 110799, South Korea. Seoul Natl Univ, Coll Med, Dept Pathol, Chongno Gu, Seoul 110799, South Korea. Kangnung Natl Univ, Dept Oral Pathol, Coll Dent, JeeByeun 210702, Kangnung, South Korea. NIDR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. RP Lee, BL (reprint author), Seoul Natl Univ, Coll Med, Dept Anat, Chongno Gu, 28 Yongon Dong, Seoul 110799, South Korea. RI Kim, Wooho/G-3703-2011; Seoul National University, Pathology/B-6702-2012; Lee, Byung Lan/J-5577-2012 NR 17 TC 1 Z9 1 U1 0 U2 0 PU JAPAN ENDOCRINE SOCIETY PI TOKYO PA C/O DEPT VETERINARY PHYSIOL, VET MED SCI, UNIV TOKYO, 1-1-1 YAYOI, BUNKYO-KU, TOKYO, 113, JAPAN SN 0918-8959 J9 ENDOCR J JI Endocr. J. PD AUG PY 1999 VL 46 IS 4 BP 597 EP 604 DI 10.1507/endocrj.46.597 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232ML UT WOS:000082374500016 PM 10580754 ER PT J AU McKay, LI Cidlowski, JA AF McKay, LI Cidlowski, JA TI Molecular control of immune/inflammatory responses: Interactions between nuclear factor-kappa B and steroid receptor-signaling pathways SO ENDOCRINE REVIEWS LA English DT Review ID HUMAN GLUCOCORTICOID-RECEPTOR; NECROSIS-FACTOR-ALPHA; CREB-BINDING-PROTEIN; MESSENGER-RNA LEVELS; ACTIVATION IN-VITRO; MEDIATES TRANSCRIPTIONAL ACTIVATION; ANGIOTENSINOGEN GENE-TRANSCRIPTION; INTERCELLULAR-ADHESION MOLECULE-1; UBIQUITIN-PROTEASOME PATHWAY; HUMAN-IMMUNODEFICIENCY-VIRUS C1 NIEHS, Lab Signal Transduct, Mol Endocrinol Grp, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, Mol Endocrinol Grp, NIH, POB 12233,MD E2-O2,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM Cidlowski@NIEHS.NIH.gov NR 271 TC 560 Z9 580 U1 6 U2 27 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0163-769X EI 1945-7189 J9 ENDOCR REV JI Endocr. Rev. PD AUG PY 1999 VL 20 IS 4 BP 435 EP 459 DI 10.1210/er.20.4.435 PG 25 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 226LF UT WOS:000082020900001 PM 10453354 ER PT J AU Tsai-Morris, CH Khanum, A Tang, PZ Dufau, ML AF Tsai-Morris, CH Khanum, A Tang, PZ Dufau, ML TI The rat 17 beta-hydroxysteroid dehydrogenase type III: Molecular cloning and gonadotropin regulation SO ENDOCRINOLOGY LA English DT Article ID DESENSITIZED LEYDIG-CELLS; 3-BETA-HYDROXYSTEROID DEHYDROGENASE; HYDROXYSTEROID DEHYDROGENASES; TISSUE DISTRIBUTION; EXPRESSION CLONING; MUTATIONS; SEQUENCE; ENZYMES; GENE AB 17 beta-Hydroxysteroid dehydrogenase (17 beta HSD), the enzyme that catalyzes the final step of testosterone biosynthesis in the testis, was cloned from a rat Leydig cell complementary DNA library to gain insights into the functional requirements, activation mechanisms, and molecular regulation. The 17 beta HSD complementary DNA encoded 306 amino acids (molecular mass of 33.7 kDa) and displayed 75% and 85% amino acid sequence homology to the human and mouse 17 beta HSD type III enzymes, respectively. Northern analysis revealed a single 1.4-kb messenger RNA (mRNA) species in rat Leydig cells, whereas ovarian mRNA was detected only by RT-PCR amplification. The cloned 17 beta HSD expressed in mammalian cell lines specifically catalyzed the reductive reaction in androgen formation with androstenedione as the preferred substrate. This reaction was significantly reduced in the absence of glucose. Expression of the endogenous 17 beta HSD gene in rat Leydig cells was inhibited by a single dose of hCG in vivo, with maximum reduction of steady state mRNA levels at 24 h and recovery at 9 days. Such agonist-induced down-regulation of 17 beta HSD expression, which preceded the marked reduction of LH receptors, resulted from changes at the transcriptional level and was accompanied by loss of enzymatic activity. These studies have demonstrated a glucose requirement for optimal activity of the enzyme in vitro and for a role of gonadotropin in regulating the expression of 17 beta HSD gene in vivo. Cloning of the 17 beta HSD type III enzyme from rat Leydig cells will facilitate further investigation of the molecular regulation of its activity in the testis. C1 NICHHD, Sect Mol Endocrinol, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP NICHHD, Sect Mol Endocrinol, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Room 6A-36,49 Convent Rd, Bethesda, MD 20892 USA. EM dufau@heliu.nih.gov NR 31 TC 33 Z9 33 U1 0 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD AUG PY 1999 VL 140 IS 8 BP 3534 EP 3542 DI 10.1210/en.140.8.3534 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 218CV UT WOS:000081536400018 PM 10433209 ER PT J AU Ma, XM Lightman, SL Aguilera, G AF Ma, XM Lightman, SL Aguilera, G TI Vasopressin and corticotropin-releasing hormone gene responses to novel stress in rats adapted to repeated restraint SO ENDOCRINOLOGY LA English DT Article ID PARVOCELLULAR NEUROSECRETORY NEURONS; HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; HYPERTONIC SALINE INJECTION; MESSENGER-RNA LEVELS; ARGININE-VASOPRESSIN; HETERONUCLEAR RNA; TRANSCRIPTIONAL ACTIVATION; HYBRIDIZATION ANALYSIS; ENHANCES VASOPRESSIN; SUPRAOPTIC NUCLEI AB Stress-responsive neurons of the hypothalamic paraventricular nucleus (PVN) show functional plasticity and adapt to repeated restraint (RR) stress. To investigate whether neuronal adaptation to the homotypic stress also affects their response to a heterotypic stressor, we used in situ hybridization with intronic and exonic probes to measure primary transcript (hnRNA) and messenger RNA (mRNA) levels for CRH and vasopressin (VP) in the PVN of control and RR rats after the heterotypic stress of ip hypertonic saline injection (ipHS). Two weeks of daily restraint blunted plasma corticosterone and parvocellular CRH, but not VP, transcript responses to a further restraint episode. IpHS increased circulating corticosterone in both groups, but levels were higher in RR rats. CRH hnRNA increased within 15 min and returned to baseline by 1 h in both naive and RR rats. CRH mRNA increased more slowly in both groups, peaking at 2 h, with RR rats showing greater responses at this time. Parvocellular VP hnRNA reached a peak 2 h after ipHS in naive rats, but more rapidly (1 h) and to higher levels in RR rats. The number of parvocellular neurons expressing VP hnRNA increased approximately 5-fold after ipHS in both groups. Basal VP mRNA levels and the number of parvocellular cells expressing VP mRNA were elevated in RR rats. Both ipHS and naive rats showed an increase in VP mRNA transcripts after ipHS, with RR rats showing greater levels at 2 and 4 h. Magnocellular cells in both PVN and supraoptic nuclei showed increases in VP hnRNA within 15 min. The data demonstrate VP responses in parvocellular neurons of both control and RR rats, whereas profound inhibition of CRH transcription is selective for the homotypic stressor with CRH responsiveness to the heterotypic stress preserved or increased. C1 NICHHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Univ Bristol, Dorothy Crowfoot Hodgkin Labs, Dept Med, Bristol BS2 8HW, Avon, England. RP Aguilera, G (reprint author), NICHHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. EM greti@helix.nih.gov NR 49 TC 140 Z9 142 U1 0 U2 5 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD AUG PY 1999 VL 140 IS 8 BP 3623 EP 3632 DI 10.1210/en.140.8.3623 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 218CV UT WOS:000081536400029 PM 10433220 ER PT J AU Tong, ZB Nelson, LM AF Tong, ZB Nelson, LM TI A mouse gene encoding an oocyte antigen associated with autoimmune premature ovarian failure SO ENDOCRINOLOGY LA English DT Article ID GLUTAMIC-ACID DECARBOXYLASE; ZONA-PELLUCIDA; CIRCULATING ANTIBODIES; NEONATAL THYMECTOMY; IN-VITRO; OOPHORITIS; CELLS; MICE; EXPRESSION; WOMEN AB Autoimmune premature ovarian failure causes young women to develop menopausal symptoms and infertility. A similar syndrome appears in mice with postthymectomy autoimmune premature ovarian failure. We demonstrate that these mice develop antibodies against a 125-kDa protein located in the oocyte cytoplasm (ooplasm). By screening a mouse ovarian complementary DNA expression library with autoimmune serum, we have identified a novel mouse gene with a 3.75-kb ovarian transcript, the expression of which is restricted to the oocyte. The longest open reading frame (3333 bp) encodes an oocyte-specific protein, designated OP1 (ooplasm-specific protein 1). The protein is composed of 1111 amino acids with a predicted molecular mass of 125,502 Da. Based on its primary structure, it appears to be novel and has no motifs to suggest a localization other than in the cytoplasm. The ability of immune serum from mice with ovarian autoimmunity to react specifically with recombinant OP1 raises the possibility that OP1 as an antigen may play a role in murine autoimmune premature ovarian failure. C1 NICHHD, Sect Womens Hlth Res, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Dept Pediat, Washington, DC 20007 USA. RP Nelson, LM (reprint author), NICHHD, Sect Womens Hlth Res, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N262, Bethesda, MD 20892 USA. EM nelsonl@cc1.nichd.nih.gov NR 43 TC 73 Z9 81 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD AUG PY 1999 VL 140 IS 8 BP 3720 EP 3726 DI 10.1210/en.140.8.3720 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 218CV UT WOS:000081536400041 PM 10433232 ER PT J AU Mitra, SW Mezey, E Hunyady, B Chamberlain, L Hayes, E Foor, F Wang, YN Schonbrunn, A Schaeffer, JM AF Mitra, SW Mezey, E Hunyady, B Chamberlain, L Hayes, E Foor, F Wang, YN Schonbrunn, A Schaeffer, JM TI Colocalization of somatostatin receptor sst5 and insulin in rat pancreatic beta-cells SO ENDOCRINOLOGY LA English DT Article ID IMMUNOHISTOCHEMICAL LOCALIZATION; FUNCTIONAL-CHARACTERIZATION; SUBTYPES; EXPRESSION; ANTIBODIES; ANALOGS; IDENTIFICATION; POLYPEPTIDE; RELEASE; COMPLEX AB Somatostatin, also known as somatotropin release-inhibiting factor (SRIF), is secreted by pancreatic delta-cells and inhibits the secretion of both insulin and glucagon. SRIF initiates its actions by binding to a family of six G protein-coupled receptors (sst1, -2A, -2B, -3, -4, and -5) encoded by five genes. Messenger RNA for both sst2 and sst5 have been reported in the rat pancreas, and the sst2A receptor protein has been localized to rat pancreatic a and pancreatic polypeptide-secreting cells in the islets as well as to pancreatic acinar cells. In this study we have used double immunostaining to show that the sst5 protein is expressed exclusively in the beta-cells of rat pancreatic islets and localizes with insulin-secreting alpha-cells. The sst5 receptor is not colocalized with sst2A. Thus, in the rat SRIF inhibits pancreatic insulin and glucagon secretion via different sst receptor subtypes. C1 Merck Res Labs, Dept Endocrinol & Chem Biol, Rahway, NJ 07065 USA. NINDS, Basic Neurosci Program, NIH, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, Dept Integrat Biol & Pharmacol, Houston, TX 77030 USA. RP Mitra, SW (reprint author), Merck Res Labs, Dept Endocrinol & Chem Biol, R80Y-310,POB 2000, Rahway, NJ 07065 USA. EM sudha_mitra@merck.com NR 30 TC 70 Z9 72 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD AUG PY 1999 VL 140 IS 8 BP 3790 EP 3796 DI 10.1210/en.140.8.3790 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 218CV UT WOS:000081536400049 PM 10433240 ER PT J AU Gold, LS Manley, NB Slone, TH Rohrbach, L AF Gold, LS Manley, NB Slone, TH Rohrbach, L TI Supplement to the Carcinogenic Potency Database (CPDB): Results of animal bioassays published in the general literature in 1993 to 1994 and by the National Toxicology Program in 1995 to 1996 SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review DE animal cancer test; carcinogenic potency; database; human carcinogen; monkey neoplasm; TD50 ID SPRAGUE-DAWLEY RATS; BUTYL ETHER MTBE; MALE F344 RATS; HEPATOCELLULAR-CARCINOMA; B6C3F1 MICE; CHRONIC TOXICITY; PEROXISOME PROLIFERATOR; CELL-PROLIFERATION; FISCHER-344 RATS; INDUCED HEPATOCARCINOGENESIS AB The Carcinogenic Potency Database (CPDB) is a systematic and unifying analysis of results of chronic, long-term cancer tests. This paper presents a supplemental plot of the CPDB, including 513 experiments on 157 test compounds published in the general literature in 1993 and 1994 and in Technical Reports of the National Toxicology Program in 1995 and 1996. The plot standardizes the experimental results (whether positive or negative for carcinogenicity), including qualitative data on strain, sex, route of compound administration, target organ, histopathology, and author's opinion and reference to the published paper, as well as quantitative data on carcinogenic potency, statistical significance, tumor incidence, dose-response curve shape, length of experiment, duration of dosing, and dose rate. A numerical description of carcinogenic potency, the TD50 is estimated for each set of tumor incidence data reported. When added to the data published earlier, the CPDB now includes results of 5,620 experiments on 1,372 chemicals that have been reported in 1,250 published papers and 414 National Cancer Institute/National Toxicology Program Technical Reports. The plot presented here includes detailed analyses of 25 chemicals tested in monkeys for up to 32 years by the National Cancer Institute. Half the rodent carcinogens that were tested in monkeys were not carcinogenic, despite usually strong evidence of carcinogenicity in rodents and/or humans. Our analysis of possible explanatory factors indicates that this result is due in pari to the fact that the monkey studies lacked power to detect an effect compared to standard rodent bioassays. Factors that contributed to the lack of power are the small number of animals on test; a stop-exposure protocol for model rodent carcinogens; in a few cases, toxic doses that resulted in stoppage of dosing or termination of the experiment; and in a few cases, low doses administered to monkeys or early termination of the experiment even though the doses were not toxic. Among chemicals carcinogenic in both monkeys and rodents, there is some support for target site concordance, but it is primarily restricted to liver tumors. Potency values are highly correlated between rodents and monkeys. The plot in this paper can be used in conjunction with the earlier results published in the CRC Handbook of Carcinogenic Potency and Genotoxicity Databases [Gold LS, Zeiger E, eds. Boca Raton FL:CRC Press, 1997] and with our web site (http;//potency.Berkeley edu), which includes a guide to the plot of the database, a complete description of the numerical index of carcinogenic potency (TD50), and a discussion of the sources of data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature Two summary tables permit easy access to the literature of animal cancer tests by target organ and by chemical. For readers using the CPDB extensively, a combined plot on diskette or other format is available from the first author. It includes all results published earlier and in this paper, ordered alphabetically by chemical. A SAS database is also available. C1 Univ Calif Berkeley, NIEHS Ctr, Div Biochem & Mol Biol, Berkeley, CA 94720 USA. EO Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA USA. RP Gold, LS (reprint author), Univ Calif Berkeley, NIEHS Ctr, Div Biochem & Mol Biol, 401 Barker Hall, Berkeley, CA 94720 USA. FU NIEHS NIH HHS [ESO1896] NR 181 TC 36 Z9 36 U1 1 U2 3 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD AUG PY 1999 VL 107 SU 4 BP 527 EP + PG 73 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 227RU UT WOS:000082094400001 PM 10421768 ER PT J AU Melnick, RL AF Melnick, RL TI Introduction - Workshop on characterizing the effects of endocrine disrupters on human health at environmental exposure levels SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Melnick, RL (reprint author), Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. NR 0 TC 13 Z9 14 U1 0 U2 0 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD AUG PY 1999 VL 107 SU 4 BP 603 EP 604 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 227RU UT WOS:000082094400002 PM 10421769 ER PT J AU Ben-Jonathan, N Cooper, RL Foster, P Hughes, CL Hoyer, PB Klotz, D Kohn, M Lamb, DJ Stancel, GM AF Ben-Jonathan, N Cooper, RL Foster, P Hughes, CL Hoyer, PB Klotz, D Kohn, M Lamb, DJ Stancel, GM TI An approach to the development of quantitative models to assess the effects of exposure to environmentally relevant levels of endocrine disrupters on homeostasis in adults SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE androgen; estrogens; endocrine disrupters; homeostasis; spermatogenesis; testicular steroidogenesis; thyroid hormones ID ESTROGEN-RECEPTOR; BREAST-CANCER; BISPHENOL; OVULATION; GROWTH; RAT AB The workshop "Characterizing the Effects of Endocrine Disrupters on Human Health at Environmental Exposure Levels" was held to provide a forum for discussions and recommendations of methods and data needed to improve risk assessments of endocrine disrupters. This article was produced by a working group charged with determining the basic mechanistic information that should be considered when designing models to quantitatively assess potential risks of environmental endocrine disrupters in adults. To reach this goal, we initially identified a set of potential organ system toxicities in males and females on the basis of known and/or suspected effects of endocrine disrupters on estrogen, androgen. and thryoid hormone systems. We used this integrated, systems-level approach because endocrine disrupters have the potential to exert toxicities at many levels and by many molecular mechanisms. Because a detailed analysis of all these untoward effects was beyond the scope of this workshop, we selected the specific end point of testicular function for a more detailed analysis. The goal was to identify the information required to develop a quantitative model(s) of the effects of endocrine disrupters on this system while focusing on spermatogenesis, sperm characteristics, and testicular steroidogenesis as specific markers. Testicular function was selected because it is a prototypical integrated end point that can be affected adversely by individual endocrine disruptors or chemical mixtures acting at one specific site or at multiple sites. Our specific objective was to gather the information needed to develop models in the adult organism containing functional homeostatic mechanisms, and for this reason we did not consider possible developmental toxicities. Homeostatic mechanisms have the potential to ameliorate or lessen the effects of endocrine disrupters, but these pathways are also potential target sites for the actions of these chemicals. C1 Univ Texas, Sch Med, Dept Integrat Biol Pharmacol & Physiol, Houston, TX 77225 USA. Univ Cincinnati, Dept Cell Biol, Cincinnati, OH USA. US EPA, Natl Hlth Effects & Environm Res Lab, Res Triangle Pk, NC 27711 USA. Chem Ind Inst Toxicol, Res Triangle Pk, NC 27709 USA. Cedars Sinai Med Ctr, Ctr Womens Hlth, Los Angeles, CA 90048 USA. Univ Arizona, Hlth Sci Ctr, Dept Physiol, Tucson, AZ USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. Baylor Coll Med, Dept Urol, Houston, TX 77030 USA. RP Stancel, GM (reprint author), Univ Texas, Sch Med, Dept Integrat Biol Pharmacol & Physiol, POB 20708, Houston, TX 77225 USA. NR 25 TC 6 Z9 6 U1 2 U2 4 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD AUG PY 1999 VL 107 SU 4 BP 605 EP 611 DI 10.2307/3434552 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 227RU UT WOS:000082094400003 PM 10421770 ER PT J AU Bigsby, R Chapin, RE Daston, GP Davis, BJ Gorski, J Gray, LE Howdeshell, KL Zoeller, RT vom Saal, FS AF Bigsby, R Chapin, RE Daston, GP Davis, BJ Gorski, J Gray, LE Howdeshell, KL Zoeller, RT vom Saal, FS TI Evaluating the effects of endocrine disrupters on endocrine function during development SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article; Proceedings Paper CT Workshop on Characterizing the Effects of Endocrine Disruptors on Human Health at Environmental Exposure Levels CY MAY 11-13, 1998 CL RALEIGH, NC DE androgen; development; embryo; endocrine disrupters; estrogens; fetus; thyroid ID MALE REPRODUCTIVE-ORGANS; RECEPTOR EXPRESSION; ANDROGEN-BINDING; ESTROGEN; DIETHYLSTILBESTROL; ESTRADIOL; MOUSE; SERUM; MICE; MECHANISMS AB The major concerns with endocrine disrupters in the environment are based mostly on effects that have been observed on the developing embryo and fetus. The focus of the present manuscript is on disruption of three hormonal systems: estrogens, androgens, and thyroid hormones. These three hormonal systems have been well characterized with regard to their roles in normal development, and their actions during development are known to be perturbed by endocrine-disrupting chemicals. During development, organs are especially sensitive to low concentrations of the sex steroids and thyroid hormones. Changes induced by exposure to these hormones during development are often irreversible, in contrast with the reversible changes induced by transient hormone exposure in the adult. Although it is known that there are differences in embryonic/fetal/neonatal versus adult endocrine responses, minimal experimental information is available to aid in characterizing the risk of endocrine disrupters with regard to a number of issues. Issues discussed here include the hypothesis of greater sensitivity of embryos/fetuses to endocrine disrupters, irreversible consequences of exposure before maturation of homeostatic systems and during periods of genetic imprinting, and quantitative information related to the shape of the dose-response curve for specific developmental phenomena. C1 Univ Missouri, Div Biol Sci, Columbia, MO 65211 USA. Indiana Univ, Sch Med, Indianapolis, IN USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. Procter & Gamble Co, Cincinnati, OH USA. Univ Wisconsin, Madison, WI USA. US EPA, Res Triangle Pk, NC 27711 USA. RP vom Saal, FS (reprint author), Univ Missouri, Div Biol Sci, 114 Lefevre Hall, Columbia, MO 65211 USA. EM vomsaai@missouri.edu OI Chapin, Robert/0000-0002-5997-1261; gray jr, leon earl/0000-0002-1111-4754 NR 49 TC 111 Z9 117 U1 1 U2 8 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD AUG PY 1999 VL 107 SU 4 BP 613 EP 618 DI 10.2307/3434553 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 227RU UT WOS:000082094400004 PM 10421771 ER PT J AU Walker, C Ahmed, SA Brown, T Ho, SM Hodges, L Lucier, G Russo, J Weigel, N Weise, T Vandenbergh, J AF Walker, C Ahmed, SA Brown, T Ho, SM Hodges, L Lucier, G Russo, J Weigel, N Weise, T Vandenbergh, J TI Species, interindividual, and tissue specificity in endocrine signaling SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article; Proceedings Paper CT Workshop on Characterizing the Effects of Endocrine Disruptors on Human Health at Environmental Exposure Levels CY MAY 11-13, 1998 CL RALEIGH, NORTH CAROLINA DE animal models; endocrine disruptor; metabolizing enzymes; p450; polymorphisms; reproductive tract; steroid hormone receptors; susceptibility ID REPRODUCTIVE-TRACT LEIOMYOMATA; PROSTATE ANDROGEN RECEPTOR; HORMONE-BINDING GLOBULIN; BREAST-CANCER; RODENT MODEL; IN-VITRO; TRANSCRIPTIONAL ACTIVITY; INDEPENDENT ACTIVATION; PROGESTERONE-RECEPTOR; STEROID-RECEPTORS AB The activity of endocrine-active agents exhibits specificity at many levels. Differential responsiveness to these agents has been observed between different species and extends to interindividual differences within a species and between different tissues as well. In cases where they have been identified, the biologic and molecular mechanisms underlying this specificity are quite diverse. Determinants of species specificity include differences that exist in receptor binding, gene transcription, and cellular responses to endocrine-active compounds between species. Interindividual differences in responsiveness may be determined at the level of genetic polymorphisms in hormone-metabolizing enzymes, hormone receptors, and in those genes that are transactivated by these receptors, as well as during changing windows of susceptibility that occur as a function of age, such as prenatal and postmenopausal exposures. Extrinsic factors such as diet can also impact individual susceptibility to endocrine-active agents. Tissue-specific determinants of susceptibility are well documented, but little is known regarding the mechanisms underlying these different responses. Differences in the expression of accessory proteins for steroid hormone receptors and different patterns of receptor expression, estrogen receptor a and estrogen receptor beta for example, may contribute to tissue specificity as may differences in the pattern of expression of other genes such as hormone-metabolizing enzymes. The use of animal model systems and development of appropriate mathematical models has the potential to yield additional valuable information for elucidating the role of these determinants of specificity at low-dose exposures and for improved risk assessments for the adverse health effects of endocrine-active compounds. C1 Univ Texas, MD Anderson Canc Ctr, Div Sci Pk Res, Smithville, TX 78957 USA. Virginia Polytech Inst & State Univ, Blacksburg, VA 24061 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Tufts Univ, Medford, MA 02155 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. Fox Chase Canc Ctr, Philadelphia, PA USA. Baylor Coll Med, Houston, TX 77030 USA. US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. N Carolina State Univ, Raleigh, NC 27695 USA. RP Walker, C (reprint author), Univ Texas, MD Anderson Canc Ctr, Div Sci Pk Res, Pk Rd 1C, Smithville, TX 78957 USA. NR 39 TC 11 Z9 13 U1 0 U2 0 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD AUG PY 1999 VL 107 SU 4 BP 619 EP 624 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 227RU UT WOS:000082094400005 PM 10421772 ER PT J AU Cunha, GR Forsberg, JG Golden, R Haney, A Iguchi, T Newbold, R Swan, S Welshons, W AF Cunha, GR Forsberg, JG Golden, R Haney, A Iguchi, T Newbold, R Swan, S Welshons, W TI New approaches for estimating risk from exposure to diethylstilbestrol SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article; Proceedings Paper CT Workshop on Characterizing the Effects of Endocrine Disruptors on Human Health at Environmental Exposure Levels CY MAY 11-13, 1998 CL RALEIGH, NORTH CAROLINA DE carcinogenesis; clear cell carcinoma; diethylstilbestrol (DES); genital tract; human; teratogenesis ID REPRODUCTIVE-TRACT; ESTROGEN-RECEPTOR; MOUSE UTERUS; ENVIRONMENTAL ESTROGENS; MESSENGER-RNA; IN-UTERO; EXPRESSION; PROSTATE; WOMEN; DES AB subgroup from a National Institute of Environmental Health Sciences, workshop concerned with characterizing the effects of endocrine disrupters on human health at environmental exposure levels considered the question, If diethylstilbestrol (DES) were introduced into the market for human use today and likely to result in low-dose exposure of the human fetus, what would be required to assess risk! On the basis of an analysis of the quality of data on human DES exposure, the critical times and doses for inducing genital tract malformations and cancer must be determined. This would be facilitated through analysis of the ontogeny of estrogen receptor expression in the developing human genital tract. Models of low-dose estrogenic effects will have to be developed for human and rodent genital tract development. Mouse models offer many advantages over other potential animal models because of the wealth of the earlier literature, the availability of sensitive end points, the availability of mutant lines, and the possibility of generating genetically engineered model systems. Through multidisciplinary approaches, it should be possible to elucidate the cellular and molecular mechanisms of endocrine disruption elicited by estrogens during development and facilitate an assessment of risk to humans. C1 Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Ctr Reprod Endocrinol, San Francisco, CA 94143 USA. Tornblad Inst, Lund, Sweden. ToxLog, Potomac, MD USA. Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. Yokohama City Univ, Dept Biol, Yokohama, Kanagawa 236, Japan. Yokohama City Univ, Grad Sch Integrated Sci, Yokohama, Kanagawa 236, Japan. Natl Inst Environm Hlth Sci, Toxicol Lab, Environm Toxicol Program, Res Triangle Pk, NC USA. Univ Missouri, Dept Family & Community Med, Columbia, MO USA. Univ Missouri, Dept Vet Biomed Sci, Columbia, MO USA. RP Cunha, GR (reprint author), Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. FU NIDDK NIH HHS [DK02397, DK45861, DK51101] NR 53 TC 7 Z9 8 U1 0 U2 0 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD AUG PY 1999 VL 107 SU 4 BP 625 EP 630 DI 10.2307/3434555 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 227RU UT WOS:000082094400006 PM 10421773 ER PT J AU Andersen, ME Conolly, RB Faustman, EM Kavlock, RJ Portier, CJ Sheehan, DM Wier, PJ Ziese, L AF Andersen, ME Conolly, RB Faustman, EM Kavlock, RJ Portier, CJ Sheehan, DM Wier, PJ Ziese, L TI Quantitative mechanistically based dose-response modeling with endocrine-active compounds SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article; Proceedings Paper CT Workshop on Characterizing the Effects of Endocrine Disruptors on Human Health at Environmental Exposure Levels CY MAY 11-13, 1998 CL RALEIGH, NORTH CAROLINA DE endocrine-active compounds; endocrine disruptors; linkage models mechanistic dose-response modeling; pharmacodynamics; pharmacokinetics; risk assessment extrapolations ID DEPENDENT SEX DETERMINATION; RISK ASSESSMENT; DEVELOPMENTAL TOXICITY; POLYCHLORINATED-BIPHENYLS; STRUCTURAL INFORMATION; PHARMACOKINETIC MODELS; METHYLENE-CHLORIDE; GENE-TRANSCRIPTION; ESTROGEN-RECEPTOR; EXPOSURE AB A wide range of toxicity lest methods is used or is being developed for assessing the impact of endocrine-active compounds (EACs) on human hearth. Interpretation of these data and their quantitative use in human and ecologic risk assessment will be enhanced by the availability of mechanistically based dose-response (MBDR) models to assist tow-dose, interspecies, and in vitro to in vivo extrapolations. A quantitative dose-response modeling work group examined the state of the art for developing MBDR models for EACs and the near-term needs to develop, validate, and apply these models for risk assessments. Major aspects of this report relate to current status of these models, the objectives/goals in MBDR model development for EACs, low-dose extrapolation issues, regulatory inertia impeding acceptance of these approaches, and resource/data needs to accelerate model development and model acceptance by the research and the regulatory community. C1 Colorado State Univ, Dept Environm Hlth, Ft Collins, CO 80523 USA. Chem Ind Inst Toxicol, Res Triangle Pk, NC 27709 USA. Univ Washington, Dept Environm Hlth, Seattle, WA 98195 USA. US EPA, Natl Hlth & Environm Effects Res Labs, Res Triangle Pk, NC 27711 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. SmithKline Beecham Pharmaceut, King Of Prussia, PA 19406 USA. Calif Protect Agcy, RCHAS, Off Environm Hlth Hazard Assoc, Berkeley, CA USA. RP Andersen, ME (reprint author), KS Crump Grp Inc, 3200 Chapel Hill,Nelson Highway,Suite 101,POB 143, Res Triangle Pk, NC 27709 USA. RI Portier, Christopher/A-3160-2010; OI Portier, Christopher/0000-0002-0954-0279; Andersen, Melvin/0000-0002-3894-4811 NR 55 TC 15 Z9 16 U1 0 U2 1 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD AUG PY 1999 VL 107 SU 4 BP 631 EP 638 DI 10.2307/3434556 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 227RU UT WOS:000082094400007 PM 10421774 ER PT J AU Brouwer, A Longnecker, MP Birnbaum, LS Cogliano, J Kostyniak, P Moore, J Schantz, S Winneke, G AF Brouwer, A Longnecker, MP Birnbaum, LS Cogliano, J Kostyniak, P Moore, J Schantz, S Winneke, G TI Characterization of potential endocrine-related health effects at low-dose levels of exposure to PCBs SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article; Proceedings Paper CT Workshop on Characterizing the Effects of Endocrine Disruptors on Human Health at Environmental Exposure Levels CY MAY 11-13, 1998 CL RALEIGH, NC DE endocrine; estrogen; health; human; low dose; PCBs; risk; thyroid ID POLYCHLORINATED-BIPHENYLS PCBS; THYROID-HORMONE CONCENTRATIONS; DIBENZO-P-DIOXINS; CROSS-SPECIES COMPARISONS; IN-VITRO INHIBITION; BREAST-CANCER; DICHLORODIPHENYL DICHLOROETHENE; POSTNATAL EXPOSURE; FEMALE RATS; GREAT-LAKES AB This article addresses issues related to the characterization of endocrine-related health effects resulting from low-level exposures to polychlorinated biphenyis (PCBs). it is not intended to be a comprehensive review of the literature but reflects workshop discussions. "The Characterizing the Effects of Endocrine Disrupters on Human Health at Environmental Exposure Levels," workshop provided a forum to discuss the methods and data needed to improve risk assessments of endocrine disrupters. This article contains an overview of endocrine-related (estrogen and thyroid system) interactions and other low-dose effects of PCBs. The data set on endocrine effects includes results obtained from mechanistic methods/ and models (receptor based, metabolism based, and transport protein based), as well as from in vivo models, including studies with experimental animals and wildlife species. Other low-dose effects induced by PCBs, such as neurodevelopmental and reproductive effects and endocrine-sensitive tumors, have been evaluated with respect to a possible causative linkage with PCB-induced alterations in endocrine systems. In addition. studies of low-dose exposure and effects in human populations are presented and critically evaluated. A list of conclusions and recommendations is included. C1 Wageningen Univ Agr & Res Ctr, Div Toxicol, Dept Food Technol & Nutr Sci, NL-6700 EA Wageningen, Netherlands. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. US EPA, Expt Toxicol Div, Natl Hlth & Environm Effects Res Labs, Res Triangle Pk, NC 27711 USA. US EPA, Natl Ctr Environm Assessment, Washington, DC 20460 USA. Univ Buffalo, Toxicol Res Ctr, Sch Med & Biomed Sci, Buffalo, NY USA. Inst Evaluating Hlth Risks, Washington, DC USA. Univ Illinois, Coll Vet Med, Urbana, IL 61801 USA. Univ Dusseldorf, D-4000 Dusseldorf, Germany. RP Wageningen Univ Agr & Res Ctr, Div Toxicol, Dept Food Technol & Nutr Sci, POB 8000, NL-6700 EA Wageningen, Netherlands. EM bram.brouwer@algemeen.tox.wau.nl OI Longnecker, Matthew/0000-0001-6073-5322 NR 128 TC 200 Z9 212 U1 6 U2 43 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD AUG PY 1999 VL 107 SU 4 BP 639 EP 649 DI 10.2307/3434557 PG 11 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 227RU UT WOS:000082094400008 PM 10421775 ER PT J AU Bucher, JR AF Bucher, JR TI Environmental tobacco smoke epidemiology SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Letter C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Bucher, JR (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD AUG PY 1999 VL 107 IS 8 BP A395 EP A395 DI 10.2307/3434438 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 258MM UT WOS:000083843000006 PM 10523130 ER PT J AU Tennant, R AF Tennant, R TI What is a tumor promoter? SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Tennant, R (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 0 TC 8 Z9 8 U1 0 U2 0 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD AUG PY 1999 VL 107 IS 8 BP A390 EP A391 DI 10.2307/3434433 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 258MM UT WOS:000083843000001 PM 10417370 ER PT J AU Butkiewicz, D Cole, KJ Phillips, DH Harris, CC Chorazy, M AF Butkiewicz, D Cole, KJ Phillips, DH Harris, CC Chorazy, M TI GSTM1, GSTP1, CYP1A1 and CYP2D6 polymorphisms in lung cancer patients from an environmentally polluted region of Poland: correlation with lung DNA adduct levels SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Article DE GST and CYP polymorphism; lung cancer; PAH-DNA adduct levels ID GLUTATHIONE-S-TRANSFERASE; WHITE BLOOD-CELLS; GENETIC POLYMORPHISMS; TOBACCO-SMOKE; NULL GENOTYPE; CARCINOGEN METABOLISM; MESSENGER-RNA; SUSCEPTIBILITY; RISK; HUMANS AB The CYP and GST genetic polymorphisms, controlling metabolism of xenobiotics, are considered to influence an individual's susceptibility to environmental and occupational carcinogens and predisposition to cancer. In the study, the effect of the GSTM1, GSTP1, CYB1A1 and CYP2D6 polymorphisms was investigated in relation to PAH-DNA adduct levels in non-tumourous lung tissue from non-small cell lung cancer (NSCLC) patients living in the industrialized region of Upper Silesia, Poland. The level of adducts among smokers was significantly elevated when compared to non-smokers (P = 0.0005). Adduct levels correlated inversely with age of patients (P = 0.00001). The GSTP1 and CYP2D6 polymorphisms had no influence on DNA adduct levels. There was a significant relationship between high adduct levels and the combined GSTM1 (null)/CYP1A1-Ile-Val genotype in the squamous cell carcinoma group (P = 0.028). An elevated number of adducts was found in patients with the GSTM1 (null)/CYP1A1-Ile/Val genotype compared to the GSTM1 (null)/CYP1A1-Ile/Ile carriers (P = 0.043). A higher frequency of the CYP1A1-Ile/Val and GSTM1 (null)/CYP1A1-Ile/Val genotypes was observed in patients dth high adduct levels (P = 0.05 and P = 0.009, respectively). A significant prevalence of the GSTM1 (null)/CYP1A1-Ile/Val carriers in the adenocarcinoma group was found (P = 0.003). Thus, our findings imply that the GSTM1 and CYP1A1 exon 7 polymorphisms may influence PAH-DNA adduct levels in target tissue from NSCLC patients, especially in the squamous cell carcinoma group. Moreover, individuals carrying the GSTM1 (null)/CYP1A1-Ile/Val genotype might exhibit a greater predisposition to a peripheral type of lung cancer. (C) 1999 Lippincott Williams & Wilkins. C1 Ctr Oncol, Dept Tumor Biol, PL-44100 Gliwice, Poland. Haddow Labs, Canc Res Inst, Sect Mol Carcinogenesis, Surrey, England. NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Butkiewicz, D (reprint author), Ctr Oncol, Dept Tumor Biol, PL-44100 Gliwice, Poland. NR 43 TC 48 Z9 51 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-8278 J9 EUR J CANCER PREV JI Eur. J. Cancer Prev. PD AUG PY 1999 VL 8 IS 4 BP 315 EP 323 DI 10.1097/00008469-199908000-00008 PG 9 WC Oncology SC Oncology GA 232JC UT WOS:000082366700008 PM 10493307 ER PT J AU Benfield, TL Lundgren, B Shelhamer, JH Lundgren, JD AF Benfield, TL Lundgren, B Shelhamer, JH Lundgren, JD TI Pneumocystis carinii major surface glycoprotein induces interleukin-8 and monocyte chemoattractant protein-I release from a human alveolar epithelial cell line SO EUROPEAN JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE alvedar epithelium; IL-8; MCP-1; Pneumocystis carinii ID NECROSIS-FACTOR-ALPHA; CULTURED LUNG-CELLS; PNEUMONIA; AIDS; MACROPHAGES; CORTICOSTEROIDS; INFLAMMATION; ATTACHMENT; CYTOKINES; MECHANISM AB Background The major surface glycoprotein (MSG) is an abundant, immunogenic glycoprotein located on the surface of Pneumocystis carinii. Little is known about the proinflammatory effects of MSG. Design We have investigated the effect of human MSG on the secretion of the chemokines interleukin 8 (IL-8) and monocyte chemoattractant protein-1 (MCF-1) from an alveolar epithelial cell line (A549). Results Incubation of A549 cells with MSG in concentrations from 0.4 to 10 mu g mL(-1) for 24 h caused dose-dependent increases in IL-8 release (3.4-fold above control, P < 0.01). Time course experiments showed increases in IL-8 release at 4 h, 8 h and 24 h compared with control cultures (all P < 0.01). There was a minor (13%) dose- and time-related increase in MCP-1 release at 24 h (P = 0.02). Co-incubation of MSG with mannan or beta-glucan decreased IL-8 release by 48% and 42% respectively, suggesting that MSG stimulates A549 cells in part through carbohydrate moieties. Dexamethasone significantly inhibited MSG-induced IL-8 release in concentrations of 10(-6)-10(-8) mol L-1 compared with control experiments (P < 0.01). Ribonuclease protection assays for steady-state IL-8 mRNA showed that increases in response to MSG stimulation occurred by 4h and persisted throughout 8 h of stimulation. Conclusion These findings suggest that MSG can alter alveolar epithelial cytokine release and may be capable of modulating the local inflammatory response in this manner. C1 Univ Copenhagen, Hvidovre Hosp, Dept Infect Dis 144, DK-2650 Hvidovre, Denmark. Univ Copenhagen, Herlev Hosp, Dept Clin Microbiol, DK-2730 Herlev, Denmark. Natl Inst Hlth, Dept Crit Care Med, Bethesda, MD USA. RP Benfield, TL (reprint author), Univ Copenhagen, Hvidovre Hosp, Dept Infect Dis 144, DK-2650 Hvidovre, Denmark. NR 35 TC 28 Z9 29 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0014-2972 J9 EUR J CLIN INVEST JI Eur. J. Clin. Invest. PD AUG PY 1999 VL 29 IS 8 BP 717 EP 722 PG 6 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 222XX UT WOS:000081811600012 PM 10457157 ER PT J AU Papadopoulos, EJ Sassetti, C Saeki, H Yamada, N Kawamura, T Fitzhugh, DJ Saraf, MA Schall, T Blauvelt, A Rosen, SD Hwang, ST AF Papadopoulos, EJ Sassetti, C Saeki, H Yamada, N Kawamura, T Fitzhugh, DJ Saraf, MA Schall, T Blauvelt, A Rosen, SD Hwang, ST TI Fractalkine, a CX3C chemokine, is expressed by dendritic cells and is up-regulated upon dendritic cell maturation SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE chemokine; dendritic cell; skin ID COLONY-STIMULATING FACTOR; NECROSIS-FACTOR-ALPHA; LANGERHANS CELLS; LEUKOCYTE MIGRATION; RECEPTOR EXPRESSION; HUMAN BLOOD; T-CELLS; CD40; CX(3)CR1; ANTIGEN AB The lone CX3C chemokine, fractalkine (FK), is expressed in a membrane-bound form on activated endothelial cells and mediates attachment and firm adhesion of T cells, monocytes and NK cells. We now show that FK is associated with dendritic cells (DC) in epidermis and lymphoid organs. In normal human skin, dual-color fluorescence microscopy cc-localized FK expression with Langerhans cells expressing CD1a. In tonsil, FK-positive DC expressed CD83, a marker for mature DC. Human and murine cultured DC up-regulated FK mRNA expression with maturation. Furthermore, CD40 ligation, but not TNF-alpha or lipopolysaccharide treatment, of activated, migratory DC that had migrated from skin explants resulted in a 2.5-fold increase of surface expression of FK without significant alterations of expression of CD80, CD86, CD54 or MHC class II. Since FK mediates adhesion of T cells to activated endothelial cells, the increased expression of FK during DC maturation (and particularly by CD40 ligation) may play a role in the ability of T cells and mature DC to form conjugates and engage in cell-cell communication. C1 NCI, Dermatol Branch, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Anat, Program Immunol, San Francisco, CA 94143 USA. Chemocentryx, San Carlos, CA USA. RP Hwang, ST (reprint author), NCI, Dermatol Branch, Bldg 10,Rm 12N246,10 Ctr Dr MSC 1908, Bethesda, MD 20892 USA. NR 36 TC 115 Z9 121 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD AUG PY 1999 VL 29 IS 8 BP 2551 EP 2559 DI 10.1002/(SICI)1521-4141(199908)29:08<2551::AID-IMMU2551>3.0.CO;2-T PG 9 WC Immunology SC Immunology GA 226VE UT WOS:000082042500023 PM 10458770 ER PT J AU Grimaldi, M Cavallaro, S AF Grimaldi, M Cavallaro, S TI Functional and molecular diversity of PACAP/VIP receptors in cortical neurons and type I astrocytes SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE astrocyte; calcium; inositol phosphates; neuron; PACAP; VIP ID CYCLASE-ACTIVATING POLYPEPTIDE; VASOACTIVE-INTESTINAL-PEPTIDE; STIMULATE INTERLEUKIN-6 PRODUCTION; INTRACELLULAR CALCIUM RISE; ADENYLATE-CYCLASE; CYCLIC-AMP; TISSUE DISTRIBUTION; VIP RECEPTOR; CLONING; EXPRESSION AB In the present study we determined the mRNA-expression of pituitary adenylate cyclase activating polypeptide (PACAP)/vasoactive intestinal peptide (VIP) receptors in primary cultures of rat cortical neurons and type I astrocytes, and investigated the effects of PACAP38 on adenylyl cyclase, inositol phospholipid hydrolysis and intracellular calcium homeostasis. PACAP38 elicited a concentration-dependent (1 nM-100 nM) increase in inositol phosphate levels and [Ca2+](i) in neurons but not in type I astrocytes. The PACAP-induced increase of intracellular calcium concentration, [Ca2+](i), was characterized by a spike, compatible with inositol trisphosphate (IP3)-induced calcium mobilization from intracellular stores, and a plateau phase, sustained by activation of capacitative calcium entry triggered by depletion of IP3-sensitive calcium stores. In the absence of extracellular calcium, only the spike phase was present while the plateau phase was clearly reduced. In addition, thapsigargin pretreatment abolished the PACAP38-induced [Ca2+](i) rise. Treatment with 1 mM VIP did not affect [Ca2+](i) in either neurons or type I astrocytes, clearly indicating the coupling of PAC(1)-HOP subtype to phospholipase-C in neurons. In addition, as previously reported, PACAP38 stimulated cAMP formation in both neurons and type I astrocytes. Using the reverse transcription polymerase chain reaction, we found mRNA-expression of PAC(1) (PACAP-HOP variant) and VPAC(2) in neurons, PAC(1) (PACAP-R variant), VPAC(1) and VPAC(2) in astrocytes. These data indicate both a functional and molecular diversity of PACAP and VIP receptors in these cell types and support the view that the PAC(1)-HOP variant may be responsible for phospholipase-C activation and [Ca2+](i) elevation in cortical neurons. C1 NINDS, Lab Adapt Syst, NIH, Bethesda, MD 20892 USA. Italian Natl Res Council, Inst Bioimaging & Pathophysiol Cent Nervous Syst, Catania, Italy. Oasi Inst Res Mental Retardat & Brain Ageing, IRCCS, Troina, EN, Italy. RP Grimaldi, M (reprint author), NINDS, Lab Adapt Syst, NIH, Room 4 A22 Bldg 36,36 Convent Dr, Bethesda, MD 20892 USA. RI Cavallaro, Sebastiano/F-3104-2010; OI Cavallaro, Sebastiano/0000-0001-7590-1792; Grimaldi, Maurizio/0000-0002-7331-7055 NR 41 TC 55 Z9 56 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD AUG PY 1999 VL 11 IS 8 BP 2767 EP 2772 DI 10.1046/j.1460-9568.1999.00693.x PG 6 WC Neurosciences SC Neurosciences & Neurology GA 226UZ UT WOS:000082042000015 PM 10457173 ER PT J AU Newlin, DB Thomson, JB AF Newlin, DB Thomson, JB TI Chronic tolerance and sensitization to alcohol in sons of alcoholics: II. Replication and reanalysis SO EXPERIMENTAL AND CLINICAL PSYCHOPHARMACOLOGY LA English DT Article ID TIME-DEPENDENT SENSITIZATION; CHEMICAL ODOR INTOLERANCE; D-AMPHETAMINE CHALLENGE; PRE-EJECTION PERIOD; HEART-RATE; BEHAVIORAL SENSITIZATION; EXTRACELLULAR DOPAMINE; ENHANCED RESPONSE; BLOOD-PRESSURE; COCAINE AB Data from D. B. Newlin and J. B. Thomson (1991) were reanalyzed, and data from an independent replication study were analyzed, relative to tonic (baseline) and phasic (response to alcohol challenge) aspects of drinking alcohol administered at the same dose on several occasions. Among the high-risk men (sons of alcoholic fathers), linear trends across days for resting (predrinking) baselines were opposite to alcohol-evoked changes for finger pulse amplitude, finger temperature, and skin conductance in Study 1 and for pulse transit time and body sway (static ataxia) in Study 2. In contrast, the structure of the low-risk men's (sons of nonalcoholic parents) data was precisely the opposite. Results are discussed in terms of sensitization as a potential mechanism that relates vulnerability to final manifestation of addictive behavior. C1 NIDA, Intramural Res Program, Baltimore, MD 21224 USA. Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. RP Newlin, DB (reprint author), NIDA, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. FU NIAAA NIH HHS [AA06433] NR 29 TC 68 Z9 68 U1 0 U2 0 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1064-1297 J9 EXP CLIN PSYCHOPHARM JI Exp. Clin. Psychopharmacol. PD AUG PY 1999 VL 7 IS 3 BP 234 EP 243 DI 10.1037/1064-1297.7.3.234 PG 10 WC Psychology, Biological; Psychology, Clinical; Pharmacology & Pharmacy; Psychiatry SC Psychology; Pharmacology & Pharmacy; Psychiatry GA 228UW UT WOS:000082154900006 PM 10472511 ER PT J AU Sawaki, L Okita, T Fujiwara, M Mizuno, K AF Sawaki, L Okita, T Fujiwara, M Mizuno, K TI Specific and non-specific effects of transcranial magnetic stimulation on simple and go/no-go reaction time SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE transcranial magnetic stimulation; reaction time; movement-related potential; motor preparation; human ID SOMATOSENSORY STIMULI; BRAIN-STIMULATION; SAFETY; MOVEMENT; CORTEX AB The effects of subthreshold transcranial magnetic stimulation (TMS) on simple and go/no-go reaction time (RT) tasks were studied in seven healthy volunteers. Subjects were asked to respond by abducting the thumb in a warning-imperative signal paradigm. TMS was randomly delivered at variable delays to the imperative signal (IS). Simple RT was significantly shortened when TMS was delivered to the left motor cortex and parietal regions simultaneously with IS. In the go/no-go paradigm, a similar trend to shorter RT was seen at a delay of 0 ms. Additionally, a significant shortening was observed at a delay of 90 ms with TMS over the contralateral motor cortex only. Movement-related potentials (MRPs) in the two paradigms showed a predominantly contralateral negativity approximately 80 ms preceding EMG onset. Our findings support the existence of two differentiated effects of TMS on RT: (1) one non-specific effect, evidenced in both the simple and go/no-go paradigms at a 0 ms delay, which can be at least partially explained by intersensory facilitation; and (2) a motor-specific effect of TMS, unveiled in the go/no-go paradigm at a 90 ms delay. C1 NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. Hyogo Coll Med, Dept Behav Sci, Nishinomiya, Hyogo, Japan. Hyogo Coll Med, Dept Rehabil Med, Nishinomiya, Hyogo, Japan. Kobe Univ, Sch Med, Dept Orthoped Surg, Kobe, Hyogo 650, Japan. RP Sawaki, L (reprint author), NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. NR 24 TC 34 Z9 35 U1 0 U2 5 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0014-4819 J9 EXP BRAIN RES JI Exp. Brain Res. PD AUG PY 1999 VL 127 IS 4 BP 402 EP 408 DI 10.1007/s002210050808 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 229NQ UT WOS:000082201000006 PM 10480275 ER PT J AU Tosetti, F Campelli, F Levi, G AF Tosetti, F Campelli, F Levi, G TI Studies on the cellular uptake of retinol binding protein and retinol SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE HepG2; Caki-1; Hela; retinol recycling; endocytosis; serum albumin ID MEMBRANE-RECEPTOR; SERUM-ALBUMIN; PIGMENT EPITHELIUM; STELLATE CELLS; HUMAN-PLASMA; RAT-LIVER; TRANSPORT; MECHANISM; INTERNALIZATION; TRANSTHYRETIN AB The uptake and release of I-125-RBP and of holoRBP labeled with [H-3]retinol (H-3-ROH) were studied in two cell lines which synthesize and secrete REP, the HepG2 hepatocarcinoma cell line and the Caki-1 kidney adenocarcinoma cell line, and in HeLa cells that do not express the endogenous REP gene In all three cell lines a part of endocytosed I-125-RBP is recycled to the extracellular medium and part is degraded. Nonspecific endocytosis of I-125-RBP was estimated to be approximately 10% of total endocytosed I-125-RBP. In HepG2 cells the H-3-ROH from the [H-3]retinol-RBP complex (H-3-ROH-RBP) is recycled bound to REP into serum-free chase medium. This H-3-ROH recycling is blocked in HepG2 cells by cyclohexymide and by brefeldin A, an inhibitor of protein export from the main secretory route, and is absent in HeLa cells, which do not synthesize REP. These data suggest that at least part of retinol taken up from exogenous holoRBP is delivered to newly synthesized REP. H-3-ROH recycled by HeLa cells is bound to serum albumin, as is a portion of that recycled by HepG2 cells. Transfer of H-3-ROH from REP to serum albumin does not occur in the absence of cells. We conclude that REP is endocytosed through a specific pathway and that the RBP-associated retinol is transferred to newly synthesized RBP or to serum albumin. (C) 1999 Academic Press. C1 Natl Canc Inst, Adv Biotechnol Ctr, Mol Biol Lab, I-16132 Genoa, Italy. Museum Natl Hist Nat, CNRS, URA 90, F-75231 Paris, France. RP Tosetti, F (reprint author), Natl Canc Inst, Adv Biotechnol Ctr, Mol Biol Lab, Largo Rosanna Benzi 10, I-16132 Genoa, Italy. RI Tosetti, Francesca/I-7866-2012; Levi, Giovanni/B-4416-2013 NR 43 TC 6 Z9 8 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 1 PY 1999 VL 250 IS 2 BP 423 EP 433 DI 10.1006/excr.1999.4520 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 222GM UT WOS:000081775900014 PM 10413596 ER PT J AU Ruhl, M Johannsen, M Atkinson, J Manski, D Sahin, E Somasundaram, R Riecken, EO Schuppan, D AF Ruhl, M Johannsen, M Atkinson, J Manski, D Sahin, E Somasundaram, R Riecken, EO Schuppan, D TI Soluble collagen VI induces tyrosine phosphorylation of paxillin and focal adhesion kinase and activates the MAP kinase Erk2 in fibroblasts SO EXPERIMENTAL CELL RESEARCH LA English DT Article ID EXTRACELLULAR-MATRIX; SIGNAL-TRANSDUCTION; CELL-ADHESION; IN-VITRO; BINDING; INTEGRIN; PROTEOGLYCAN; PP125(FAK); PROLIFERATION; ASSOCIATION AB Signals from the extracellular matrix can modulate cellular differentiation and gene expression. We have shown previously that in contrast to other extracellular matrix molecules pepsin-solubilized collagen VI (CVI) can stimulate DNA synthesis of various mesenchymal cell types, apparently independent of integrin-mediated signal transduction. In order to further elucidate collagen VI-induced signaling events, we exposed mouse 3T3 fibroblasts and human HT1080 fibrosarcoma cells to soluble CVI. CVI induced tyrosine phosphorylation of proteins that associate with focal adhesions, such as paxillin, focal adhesion kinase (FAK), and p130CAS. Furthermore, it activated the mitogen-activated protein kinase, erk2. Kinetic analysis showed that these phosphorylations were transient, reaching a maximum after 5 min for transformed HT1080 cells and 30 min for 3T3 fibroblasts. These effects were partly inhibited by a beta(1)-integrin function blocking antibody and by single chains of CVI. Our results indicate that soluble fragments of native collagen VI, a ubiquitous component of the interstitial extracellular matrix, can mediate stimulation of DNA synthesis via tyrosine phosphorylation of paxillin, FAK, p130CAS, and erk2 in the absence of classical growth factors. Thus, CVI may serve as a matrix-derived sensor that allows for rapid reconstitution of a tissue defect by activating nearby mesenchymal cells. (C) 1999 Academic Press. C1 Univ Erlangen Nurnberg, Med Klin 1, Dept Med 1, D-91054 Erlangen, Germany. Free Univ Berlin, Klinikum Benjamin Franklin, Dept Med 1, D-12200 Berlin, Germany. NIDR, Dept Hlth & Human Serv, Publ Hlth Serv, NIH,GIIB, Bethesda, MD 20892 USA. RP Schuppan, D (reprint author), Univ Erlangen Nurnberg, Med Klin 1, Dept Med 1, Krankenhausstr 12, D-91054 Erlangen, Germany. NR 39 TC 33 Z9 34 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 1 PY 1999 VL 250 IS 2 BP 548 EP 557 DI 10.1006/excr.1999.4540 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 222GM UT WOS:000081775900025 PM 10413607 ER PT J AU Tatusova, TA Madden, TL AF Tatusova, TA Madden, TL TI BLAST 2 SEQUENCES, a new tool for comparing protein and nucleotide sequences (vol 174, pg 247, 1999) SO FEMS MICROBIOLOGY LETTERS LA English DT Correction C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Tatusova, TA (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. NR 1 TC 54 Z9 57 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1097 J9 FEMS MICROBIOL LETT JI FEMS Microbiol. Lett. PD AUG 1 PY 1999 VL 177 IS 1 BP 187 EP 188 DI 10.1016/S0378-1097(99)00277-3 PG 2 WC Microbiology SC Microbiology GA 222HC UT WOS:000081777600026 ER PT J AU Tsuchiya, K Jiang, JJ Yoshizumi, M Tamaki, T Houchi, H Minakuchi, K Fukuzawa, K Mason, RP AF Tsuchiya, K Jiang, JJ Yoshizumi, M Tamaki, T Houchi, H Minakuchi, K Fukuzawa, K Mason, RP TI Nitric oxide-forming reactions of the water-soluble nitric oxide spin-trapping agent, MGD SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE EPR; DMPO; 5,5-dimethyl-1-pyrroline N-oxide; free radical; MGD; N-methyl-D-glucamine dithiocarbamate; nitric oxide; reactive oxygen species; hydroxyurea ID FREE-RADICAL FORMATION; VIVO EPR DETECTION; RELAXING FACTOR; FENTON REACTION; NO; HYDROXYUREA; SUPEROXIDE; SYSTEMS; OXYGEN; AUTOXIDATION AB The objective of this study was to elucidate the nitric oxide-forming reactions of the iron-N-methyl-D-glucamine dithiocarbamate (Fe-MGD) complex from the nitrogen-containing compound hydroxyurea. The Fe2+(MGD)(2) complex is commonly used in electron paramagnetic resonance (EPR) spectroscopic detection of NO both in vivo and in vitro. The reaction of Fe2+(MGD)(2) with NO yields the resultant NO-Fe2+(DETC)(2) complex, which has a characteristic triplet EPR signal. It is widely believed that only NO reacts with Fe2+(MGD)(2) to form the NO-Fe2+(MGD)(2) complex. In this report, the mechanism leading to the formation of NO-Fe2+(MGD)(2) was investigated using oxygen-uptake studies in conjunction with the EPR spin-trapping technique. We found that the air oxidation of Fe2+(MGD)(2) complex results in the formation of the Fe3+(MGD)(3) complex, presumably concomitantly with superoxide (O-2(.-)). Dismutation of superoxide forms hydrogen peroxide, which can subsequently reduce Fe3+(MGD)(3) back to Fe2+(MGD)(2). The addition of NO to the Fe3+(MGD)(3), complex resulted in the formation of the NO-Fe2+(MGD)(2) complex. Hydroxyurea is not considered to be;a spontaneous NO donor, but has to be oxidized in order to form NO. We present data showing that in the presence of oxygen, Fe2+(MCD)(2) can oxidize hydroxyurea to yield the stable NO-Fe2+(MGD)(2) complex. These results imply that hydroxyurea can be oxidized by reactive oxygen species that are formed from the air oxidation of the Fe2+(MGD)(2) complex. Formation of the NO-Fe2+(MGD)(2) complex in this case could erroneously be interpreted as spontaneous formation of NO from hydroxyurea. The chemistry of the Fe2+(MGD)(2) complexes in aerobic conditions must be taken into account in order to avoid erroneous conclusions. In addition, the use of these complexes may contribute to the overall oxidative stress of the system under investigation. (C) 1999 Elsevier Science Inc. C1 NIEHS, Free Rad Metabolite Sect, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. Bruker Instruments Inc, Billerica, MA 01821 USA. Univ Tokushima, Sch Med, Dept Pharmacol, Tokushima 770, Japan. Univ Tokushima, Sch Med, Dept Pharm, Tokushima 770, Japan. Univ Tokushima, Fac Pharmaceut Sci, Tokushima 770, Japan. RP Tsuchiya, K (reprint author), NIEHS, Free Rad Metabolite Sect, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 47 TC 36 Z9 39 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD AUG PY 1999 VL 27 IS 3-4 BP 347 EP 355 DI 10.1016/S0891-5849(99)00062-3 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 227YL UT WOS:000082107500014 PM 10468208 ER PT J AU Anson, RM Senturker, S Dizdaroglu, M Bohr, VA AF Anson, RM Senturker, S Dizdaroglu, M Bohr, VA TI Measurement of oxidatively induced base lesions in liver from Wistar rats of different ages SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE oxidative DNA damage; GC/MS; mitochondrial DNA; aging; free radicals ID CHROMATOGRAPHY MASS-SPECTROMETRY; FORMAMIDOPYRIMIDINE DNA GLYCOSYLASE; HUMAN MITOCHONDRIAL-DNA; MAMMALIAN CHROMATIN; IONIZING-RADIATION; HYDROGEN-PEROXIDE; NUCLEAR-DNA; DAMAGE; REPAIR; OXYGEN AB Mitochondrial and nuclear DNA were isolated from the livers of young (6-7 month) and old (23-24 month) Wistar rats and the levels of 10 different oxidatively induced lesions were analyzed by gas chromatography/mass spectrometry. This is the first study to measure several different oxidatively induced base lesions in both mitochondrial and nuclear DNA as a function of age. No significant age effects were observed for any lesion. Furthermore, contrary to expectations, we did not observe elevated levels of oxidatively induced base lesions in mitochondrial DNA. This contrasts with 50-fold differences reported for several lesions between mitochondrial and nuclear DNA from porcine liver (Zastawny et al., Free Radic. Biol. Med. 24:722-725, 1998). The fact that different lesion levels are observed even when similar techniques are employed emphasizes that the role of oxidative mitochondrial DNA damage and its repair in aging must continue to be the subject of intense investigation. Questions concerning endogenous levels of damage should be revisited as existing methods are improved and new methods become available. (C) 1999 Elsevier Science Inc. C1 NIA, Gerontol Res Ctr, Mol Genet Lab, NIH, Baltimore, MD 21224 USA. Natl Inst Stand & Technol, Chem Sci & Technol Lab, Gaithersburg, MD 20899 USA. RP Bohr, VA (reprint author), NIA, Gerontol Res Ctr, Mol Genet Lab, NIH, 5600 Nathan Shock Dr,Box 01, Baltimore, MD 21224 USA. NR 30 TC 48 Z9 48 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD AUG PY 1999 VL 27 IS 3-4 BP 456 EP 462 DI 10.1016/S0891-5849(99)00091-X PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 227YL UT WOS:000082107500028 PM 10468222 ER PT J AU Wolf, NG Abdul-Karim, FW Farver, C Schrock, E du Manoir, S Schwartz, S AF Wolf, NG Abdul-Karim, FW Farver, C Schrock, E du Manoir, S Schwartz, S TI Analysis of ovarian borderline tumors using comparative genomic hybridization and fluorescence in situ hybridization SO GENES CHROMOSOMES & CANCER LA English DT Article ID MOLECULAR CYTOGENETIC ANALYSIS; MICROSATELLITE INSTABILITY; CHROMOSOME-ABNORMALITIES; CARCINOMAS; BENIGN; ABERRATIONS; CANCER; LOSSES; GAINS; OVERREPRESENTATION AB It is unclear whether ovarian borderline tumors (tumors of low malignant potential) are independent entities or whether they are part of a continuum of tumor progression that culminates in ovarian carcinoma. Little is known about genetic abnormalities in borderline tumors because of the difficulty of growing them in culture for chromosome studies, and because the low ratio of tumor to nontumor cells can interfere with molecular genetic examination. To circumvent these problems, we performed comparative genomic hybridization (CGH) on 10 serous borderline tumors from nine patients, using microdissection to enrich the samples for tumor DNA and reduce contamination from stromal and inflammatory cells. CGH analysis revealed that three of the tumors had detectable chromosomal imbalances, whereas seven were in a balanced state. In those tumors with imbalances, the number of abnormalities ranged from 3-6 per tumor. Additional studies by fluorescence in situ hybridization (FISH) on disaggregated nuclei confirmed the imbalances detected by CCH, revealed one tumor to be hypeptriploid, and indicated that the remaining tumors were diploid and in a balanced state. All abnormalities observed in the aneuploid cases are consistent with chromosomal aberrations previously reported for ovarian carinomas, providing further evidence that some borderline tumors are part of a continuum of tumor progression. These results also suggest that there may be different mechanisms leading to borderline tumor formation, including one associated with multiple chromosomal imbalances, and others that do not involve imbalances detectable by CGH, Genes Chromosomes Cancer 25:307-315, 1999. (C) 1999 Wiley-Liss, Inc. C1 Case Western Reserve Univ, Dept Genet, Cleveland, OH 44124 USA. Case Western Reserve Univ, Ctr Human Genet, Cleveland, OH 44124 USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. Case Western Reserve Univ, Inst Pathol, Cleveland, OH 44124 USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. NIH, Natl Human Genome Res Inst, Bethesda, MD USA. RP Schwartz, S (reprint author), Case Western Reserve Univ, Dept Genet, 10900 Euclid Ave, Cleveland, OH 44124 USA. FU NCI NIH HHS [CA-67515] NR 43 TC 37 Z9 37 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD AUG PY 1999 VL 25 IS 4 BP 307 EP 315 DI 10.1002/(SICI)1098-2264(199908)25:4<307::AID-GCC1>3.0.CO;2-1 PG 9 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 214ZU UT WOS:000081358100001 PM 10398423 ER PT J AU Michaelson, JS Bader, D Kuo, F Kozak, C Leder, P AF Michaelson, JS Bader, D Kuo, F Kozak, C Leder, P TI Loss of Daxx, a promiscuously interacting protein, results in extensive apoptosis in early mouse development SO GENES & DEVELOPMENT LA English DT Article DE Daxx; yeast two-hybrid; apoptosis; Fas ID EMBRYONIC LETHALITY; DEATH DOMAIN; CELL-DEATH; TARGETED DISRUPTION; BINDING PROTEIN; GENE; FAS; MICE; MUTATION; FADD AB The mammalian Daxx gene has been identified in a diverse set of yeast interaction trap experiments. Although a facilitating role for Darn in Fas-induced apoptosis has been suggested, Daxx's physiologic function remains unknown. To elucidate the in vivo role of Daxx, we have generated Daxx-deficient mice. Surprisingly, rather than a hyperproliferative disorder expected from the loss of a pro-apoptotic gene, mutation of Daxx results in extensive apoptosis and embryonic lethality. These findings argue against a role for Daxx in promoting Fas-induced cell death and suggest that Daxx either directly or indirectly suppresses apoptosis in the early embryo. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Genet, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Leder, P (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. NR 27 TC 161 Z9 169 U1 0 U2 2 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD AUG 1 PY 1999 VL 13 IS 15 BP 1918 EP 1923 DI 10.1101/gad.13.15.1918 PG 6 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 225QH UT WOS:000081971900003 PM 10444590 ER PT J AU Cohen-Fix, O Koshland, D AF Cohen-Fix, O Koshland, D TI Pds1p of budding yeast has dual roles: inhibition of anaphase initiation and regulation of mitotic exit SO GENES & DEVELOPMENT LA English DT Article DE budding yeast; metaphase-to-anaphase transition; mitosis; cyclin degradation ID SISTER-CHROMATID SEPARATION; SACCHAROMYCES-CEREVISIAE; PROMOTING COMPLEX; CYCLIN PROTEOLYSIS; FISSION YEAST; DEPENDENT PROTEOLYSIS; CUT2 PROTEOLYSIS; METAPHASE; APC; TRANSITION AB Progression through mitosis is controlled by protein degradation that is mediated by the anaphase-promoting complex/cyclosome (APC/C) and its associated specificity factors. In budding yeast, ApC/C-Cds20 promotes the degradation of the Pds1p anaphase inhibitor at the metaphase-to-anaphase transition, whereas APC/C-Cdh1 promotes the degradation of the mitotic cyclins at the exit from mitosis. Here we show that Pds1p has a novel activity as an inhibitor of mitotic cyclin destruction, apparently by preventing the activation of APC/C-Cdh1 This activity of Pds1p is independent of its activity as an anaphase inhibitor. We propose that the dual role of Pds1p as an inhibitor of anaphase and of cyclin degradation allows the cell to couple the exit from mitosis to the prior completion of anaphase, Finally, these observations provide a novel regulatory paradigm in which the sequential degradation of two substrates is determined by the substrates themselves, such that an early substrate inhibits the degradation of a later one. C1 NIDDKD, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. Carnegie Inst Washington, Howard Hughes Med Inst, Baltimore, MD 21210 USA. RP Cohen-Fix, O (reprint author), NIDDKD, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. FU NIGMS NIH HHS [GM1718, F32 GM018382, GM18382] NR 36 TC 101 Z9 103 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD AUG 1 PY 1999 VL 13 IS 15 BP 1950 EP 1959 DI 10.1101/gad.13.15.1950 PG 10 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 225QH UT WOS:000081971900006 PM 10444593 ER PT J AU Lewis, LK Westmoreland, JW Resnick, MA AF Lewis, LK Westmoreland, JW Resnick, MA TI Repair of endonuclease-induced double-strand breaks, in Saccharomyces cervisiae: Essential role for genes associated with nonhomologous end-joining SO GENETICS LA English DT Review ID REPLICATION PROTEIN-A; CELL-CYCLE ARREST; DNA-REPAIR; HOMOLOGOUS RECOMBINATION; MAMMALIAN-CELLS; CEREVISIAE DNA; RAD51 PROTEIN; INTRACHROMOSOMAL RECOMBINATION; ILLEGITIMATE RECOMBINATION; CHROMOSOMAL-ABERRATIONS AB Repair of double-strand breaks (DSBs) in chromosomal DNA by nonhomologous end-joining (NHEJ) is not well characterized in the yeast Saccharomyces cerevisiae. Here we demonstrate that several genes associated with NHEJ perform essential functions in the repair of endonuclease-induced DSBs in vivo. Galactose-induced expression of EcoRI endonuclease in rad50 nrel1, or xrs2 mutants, which are deficient in plasmid DSB end-joining and some forms of recombination, resulted in G2 arrest and rapid cell killing. Endonuclease synthesis also produced moderate cell killing in sir4 strains. In contrast, EcoRI caused prolonged cell-cycle arrest of recombination-defective rad51, rad52, rad54, md55, and rad57 mutants, bur cells remained viable. Cell-cycle progression was inhibited in excision repair-defective rad1 mutants, but not in rad2 cells, indicating a role for Rad1 processing of the DSB ends. Phenotypic responses of additional mutants, including exo1, srs2, rad5, and rdh54 strains, suggest roles in recombinational repair, but not in NHEJ. Interestingly, the rapid cell killing in haploid rad50 and mrel1 strains was largely eliminated in diploids, suggesting that the cohesive-ended DSBs could be efficiently repaired by homologous recombination throughout the cell cycle in the diploid mutants. These results demonstrate essential but separable roles for NHEJ pathway genes in the repair of chromosomal DSBs that are structurally similar to those occurring during cellular development. C1 NIEHS, Genet Mol Lab, Res Triangle Pk, NC 27709 USA. RP NIEHS, Genet Mol Lab, 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM resnick@niehs.nih.gov NR 122 TC 44 Z9 44 U1 0 U2 0 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 EI 1943-2631 J9 GENETICS JI Genetics PD AUG PY 1999 VL 152 IS 4 BP 1513 EP 1529 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA 224GL UT WOS:000081889600027 PM 10430580 ER PT J AU Huttley, GA Smith, MW Carrington, M O'Brien, SJ AF Huttley, GA Smith, MW Carrington, M O'Brien, SJ TI A scan for linkage disequilibrium across the human genome SO GENETICS LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; CLASS-II REGION; HUMAN-POPULATIONS; HUMAN ORIGINS; MAP; SELECTION; GENES; MICROSATELLITES; RECOMBINATION; POLYMORPHISM AB Linkage disequilibrium (LD), the tendency for alleles of linked loci to co-occur nonrandomly on chromosomal haplotypes, is an increasingly useful phenomenon for (1) revealing historic perturbation of populations including founder effects, admixture, or incomplete selective sweeps; (2) estimating elapsed time since such events based on time-dependent decay of LD; and (3) disease and phenotype mapping, particularly for traits not amenable to traditional pedigree analysis. Because few descriptions of LD for most regions of the human genome exist, we searched the human genome for the amount and extent of LD among 5048 autosomal short tandem repeat polymorphism (STRP) loci ascertained as specific haplotypes in the European CEPH mapping families. Evidence is presented indicating that similar to 4% of STRP loci separated by <4.0 cM are in LD. The fraction of locus pairs within these intervals that display small Fisher's exact test (FET) probabilities is directly proportional to the inverse of recombination distance between them (1/cM). The distribution of LD is nonuniform on a chromosomal scale and in a marker density-independent fashion, with chromosomes 2, 15, and 18 being significantly different from the genome average. Furthermore, a stepwise (locus-by-locus) 5-cM sliding-window analysis across 22 autosomes revealed nine genomic regions (2.2-6.4 cM), where the frequency of small FET probabilities among loci was greater than or equal to that presented by the HLA on chromosome 6, a region known to have extensive LD. Although the spatial heterogeneity of LD we detect in Europeans is consistent with the operation of natural selection, absence of a formal test for such genomic scale data prevents eliminating neutral processes as the evolutionary origin of the LD. C1 NCI, Lab Genome Divers, Frederick, MD 21702 USA. SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. RP Huttley, GA (reprint author), Australian Natl Univ, John Curtin Sch Med Res, Human Genet Grp, Canberra, ACT 0200, Australia. RI Smith, Michael/B-5341-2012; Huttley, Gavin/G-5169-2015 OI Huttley, Gavin/0000-0001-7224-2074 FU NCI NIH HHS [N01-CO-56000] NR 55 TC 138 Z9 138 U1 1 U2 2 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD AUG PY 1999 VL 152 IS 4 BP 1711 EP 1722 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 224GL UT WOS:000081889600042 PM 10430595 ER PT J AU Sherry, ST Ward, MH Sirotkin, K AF Sherry, ST Ward, MH Sirotkin, K TI dbSNP - Database for single nucleotide polymorphisms and other classes of minor genetic variation SO GENOME RESEARCH LA English DT Editorial Material C1 NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Sherry, ST (reprint author), NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. NR 9 TC 189 Z9 193 U1 0 U2 9 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD AUG PY 1999 VL 9 IS 8 BP 677 EP 679 PG 3 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 227DL UT WOS:000082063000002 PM 10447503 ER PT J AU Wolf, YI Aravind, L Grishin, NV Koonin, EV AF Wolf, YI Aravind, L Grishin, NV Koonin, EV TI Evolution of aminoacyl-tRNA synthetases - Analysis of unique domain architectures and phylogenetic trees reveals a complex history of horizontal gene transfer events SO GENOME RESEARCH LA English DT Article ID TRANSFER-RNA-SYNTHETASE; ACTIVATING POLYPEPTIDE-II; METHIONYL-TRANSFER-RNA; ESCHERICHIA-COLI; THERMUS-THERMOPHILUS; PROTEIN SEQUENCES; CRYSTAL-STRUCTURE; BINDING-SITE; PSI-BLAST; SUPERFAMILY AB Phylogenetic analysis of aminoacyl-tRNA synthetases (aaRSs) of all 20 specificities from completely sequenced bacterial, archaeal, and eukaryotic genomes reveals a complex evolutionary picture. Detailed examination of the domain architecture of aaRSs using sequence profile searches delineated a network of partially conserved domains that is even more elaborate than previously suspected. Several unexpected evolutionary connections were identified, including the apparent origin of the \beta-subunit of bacterial GlyRS from the HD superfamily of hydrolases, a domain shared by bacterial AspRS and the B subunit of archaeal glutamyl-tRNA amidotransferases, and another previously undetected domain that is conserved in a subset of ThrRS, guanosine polyphosphate hydrolases and synthetases, and a family of GTPases. Comparison of domain architectures and multiple alignments resulted in the delineation of synapomorphies-shared derived characters, such as extra domains or inserts-for most of the aaRSs specificities. These synapomorphies partition sets of aaRSs with the same specificity into two or more distinct and apparently monophyletic groups. In conjunction with cluster analysis and a modification of the midpoint-rooting procedure, this partitioning was used to infer the likely root position in phylogenetic trees. The topologies of the resulting rooted trees for most of the aaRSs specificities are compatible with the evolutionary "standard model" whereby the earliest radiation event separated bacteria from the common ancestor of archaea and eukaryotes as opposed to the two other possible evolutionary scenarios for the three major divisions of life. For almost all aaRSs specificities, however, this simple scheme is confounded by displacement of some of the bacterial aaRSs by their eukaryotic or, less frequently, archaeal counterparts. Displacement of ancestral eukaryotic aaRS genes by bacterial ones, presumably of mitochondrial origin, was observed for three aaRSs. In contrast, there was no convincing evidence of displacement of archaeal aaRSs by bacterial ones. Displacement of aaRS genes by eukaryotic counterparts is most common among parasitic and symbiotic bacteria, particularly the spirochaetes, in which 10 of the 19 aaRSs seem to have been displaced by the respective eukaryotic genes and two by the archaeal counterpart. Unlike the primary radiation events between the three main divisions of life, that were readily traceable through the phylogenetic analysis of aaRSs, no consistent large-scale bacterial phylogeny could be established. In part, this may be due to additional gene displacement events among bacterial lineages. Argument is presented that, although lineage-specific gene loss might have contributed to the evolution of some of the aaRSs, this is not a viable alternative to horizontal gene transfer as the principal evolutionary phenomenon in this gene class. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. Russian Acad Sci, Inst Cytol & Genet, Novosibirsk 630090, Russia. Texas A&M Univ, Dept Biol, College Stn, TX USA. RP NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov NR 75 TC 270 Z9 275 U1 9 U2 33 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD AUG PY 1999 VL 9 IS 8 BP 689 EP 710 PG 22 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 227DL UT WOS:000082063000004 PM 10447505 ER PT J AU Wolfsberg, TG Gabrielian, AE Campbell, MJ Cho, RJ Spouge, JL Landsman, D AF Wolfsberg, TG Gabrielian, AE Campbell, MJ Cho, RJ Spouge, JL Landsman, D TI Candidate regulatory sequence elements for cell cycle-dependent transcription in Saccharomyces cerevisiae SO GENOME RESEARCH LA English DT Article ID GENOMIC SCALE; BUDDING YEAST; GENES; EXPRESSION; BINDING AB Recent developments in genome-wide transcript monitoring have led to a rapid accumulation of data from gene expression studies. Such projects highlight the need for methods to predict the molecular basis of transcriptional coregulation. A microarray project identified the 420 yeast transcripts whose synthesis displays cell cycle-dependent periodicity. We present here a statistical technique we developed to identify the sequence elements that may be responsible for this cell cycle regulation. Because most gene regulatory sites contain a short string of highly conserved nucleotides, any such strings that are involved in gene regulation will occur frequently in the upstream regions of the genes that they regulate, and rarely in the upstream regions of other genes. Our strategy therefore utilizes statistical procedures to identify short oligomers, five or six nucleotides in length, that are over-represented in upstream regions of genes whose expression peaks at the same phase of the cell cycle. We report, with a high level of confidence, that 9 hexamers and 12 pentamers are over-represented in the upstream regions of genes whose expression peaks at the early G(1), late G(1), S, G(2), or M phase of the cell cycle. Some of these sequence elements show a preference for a particular orientation, and others, through a separate statistical test, for a particular position upstream of the ATC start codon. The finding that the majority of the statistically significant sequence elements are located in late G(1) upstream regions correlates with other experiments that identified the late G(1)/early S boundary as a vital cell cycle control point. Our results highlight the importance of MCB, an element implicated previously in late G(1)/early S gene regulation, as most of the late G(1) oligomers contain the MCB sequence or variations thereof. It is striking that most MCB-like sequences localize to a specific region upstream of the ATG start codon. Additional sequences that we have identified may be important for regulation at other phases of the cell cycle. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. Mol Applicat Grp, Palo Alto, CA 94304 USA. Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA. RP Landsman, D (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RI Landsman, David/C-5923-2009; OI Landsman, David/0000-0002-9819-6675 NR 29 TC 68 Z9 70 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD AUG PY 1999 VL 9 IS 8 BP 775 EP 792 PG 18 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 227DL UT WOS:000082063000011 PM 10447512 ER PT J AU Butler, RN Ferdinand, KC Roccella, EJ August, P Phillips, KC AF Butler, RN Ferdinand, KC Roccella, EJ August, P Phillips, KC TI Hypertension: How comorbid disease influences the choice of therapy - Part four of a roundtable discussion SO GERIATRICS LA English DT Editorial Material ID CONGESTIVE-HEART-FAILURE; PROGRESSION AB Two categories of-comorbid conditions affect the choice of therapy for hypertension: compelling indications, where outcomes data show improved survival, and indications where therapies may be beneficial but do not affect survival. In patients with diabetes, low-dose diuretics effectively lower blood pressure, but metabolic derangements may occur. A diuretic may exacerbate urinary incontinence and therefore may not be a first-choice therapy for some older women. Monotherapy is not effective in controlling blood pressures in patients with renal insufficiency. In patients with a history of MI, even. those age 85 and older benefit fi om beta blockade. Lowering blood pressure over a 3- to 5-year period is effective in preventing left ventricular hypertrophy and congestive heart failure. C1 Mt Sinai Med Ctr, Dept Geriatr & Adult Dev, New York, NY 10029 USA. Cornell Univ, Coll Med, Ithaca, NY 14853 USA. Cornell Univ, Med Ctr, New York Hosp, Div Hypertens, New York, NY 10021 USA. Xavier Univ, Coll Pharm, New Orleans, LA 70125 USA. Heartbeats Life Ctr, New Orleans, LA USA. Mt Sinai Sch Med, New York, NY USA. Mt Sinai Med Ctr, Hypertens & Cardiac Hlth Program, Zena & Michael A Wiener Cardiovasc Inst, New York, NY 10029 USA. NHLBI, Natl High Blood Pressure Educ Program, NIH, Bethesda, MD 20892 USA. RP Butler, RN (reprint author), Mt Sinai Med Ctr, Dept Geriatr & Adult Dev, New York, NY 10029 USA. NR 15 TC 3 Z9 3 U1 0 U2 0 PU ADVANSTAR COMMUNICATIONS PI DULUTH PA 131 W FIRST ST, DULUTH, MN 55802 USA SN 0016-867X J9 GERIATRICS JI Geriatrics PD AUG PY 1999 VL 54 IS 8 BP 34 EP + PG 6 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 224ZD UT WOS:000081929100010 PM 10451646 ER PT J AU Gangaidzo, IT Moyo, VM Saungweme, T Khumalo, H Charakupa, RM Gomo, ZAR Loyevsky, M Stearman, R La Vaute, T Enquist, EG Rouault, TA Gordeuk, VR AF Gangaidzo, IT Moyo, VM Saungweme, T Khumalo, H Charakupa, RM Gomo, ZAR Loyevsky, M Stearman, R La Vaute, T Enquist, EG Rouault, TA Gordeuk, VR TI Iron overload in urban Africans in the 1990s SO GUT LA English DT Article DE haemosiderosis; cirrhosis; iron; liver; Africa; haemochromatosis ID HEPATOCELLULAR-CARCINOMA; IDIOPATHIC HEMOCHROMATOSIS; HEREDITARY HEMOCHROMATOSIS; HEMOSIDEROSIS; CONSUMPTION; INDEX; GENE AB Background-In a previously described model, heterozygotes for an African iron loading locus develop iron overload only when dietary iron is high, but homozygotes may do so with normal dietary iron. If an iron loading gene is common, then homozygotes with iron overload will be found even in an urban population where traditional beer, the source of iron, is uncommon. Aims-To determine whether iron overload and the C282Y mutation characteristic of hereditary haemochromatosis are readily identifiable in an urban African population. Methods-Histological assessment, hepatocellular iron grading, and dry weight non-haem iron concentration were determined in post mortem tissue from liver, spleen, heart, lungs, and skin. DNA of subjects with elevated hepatic iron indexes was analysed for the C282Y mutation. Iron concentrations in other tissues were compared. Results-A moderate increase (>30 mu mol/g) in hepatic iron concentrations was found in 31 subjects (23%; 95% confidence interval 15.9 to 30.1%), and they were considerably elevated (>180 mu mol/g) in seven subjects (5.2%; 95% confidence interval 1.5 to 8.9%). Appreciably elevated hepatic iron concentrations were associated with heavy iron deposition in both hepatocytes and macrophages, and either portal fibrosis or cirrhosis. All were negative for the C282Y mutation. Very high concentrations were uncommon in subjects dying in hospital. Concentrations of iron in spleen, heart, lung, and skin were significantly higher in subjects with elevated hepatic iron. Conclusions-Iron overload is readily identified among urban Africans and is associated with hepatic damage and iron loading of several tissues. The condition is unrelated to the genetic mutation found in hereditary haemochromatosis. C1 Univ Zimbabwe, Sch Med, Dept Med, Harare, Zimbabwe. NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. George Washington Univ, Med Ctr, Dept Med, Washington, DC 20037 USA. RP Gangaidzo, IT (reprint author), Univ Zimbabwe, Sch Med, Dept Med, Box A178, Harare, Zimbabwe. FU NICHD NIH HHS [1 HD 3-3196] NR 35 TC 29 Z9 30 U1 0 U2 1 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 J9 GUT JI Gut PD AUG PY 1999 VL 45 IS 2 BP 278 EP 283 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 219EN UT WOS:000081595100023 PM 10403742 ER PT J AU Sun, ZT Lu, PX Gail, MH Pee, D Zhang, QN Ming, LH Wang, JB Wu, Y Liu, GT Wu, YY Zhu, YR AF Sun, ZT Lu, PX Gail, MH Pee, D Zhang, QN Ming, LH Wang, JB Wu, Y Liu, GT Wu, YY Zhu, YR TI Increased risk of hepatocellular carcinoma in male hepatitis B surface antigen carriers with chronic hepatitis who have detectable urinary aflatoxin metabolite M1 SO HEPATOLOGY LA English DT Article ID CARCINOGENESIS; EXPOSURE; CHINA; GENE AB We followed 145 men with chronic hepatitis B virus (HBV) hepatitis for 10 years to determine whether exposure to aflatoxin, or concomitant exposure to hepatitis C virus (HCV), or family history of hepatocellular carcinoma (HCC) increased the risk of developing HCC. We collected 8 monthly urine samples before beginning follow-up and pooled them to detect aflatoxin metabolite M1 (AFM1), AFM1 was detected in 78 (54%) of the subjects. The risk of HCC was increased 3.3-fold (with a 95% confidence interval of 1.2-8.7) in those with detectable AFM1 (above 3.6 ng/L), This relative risk was adjusted for age and for HCV status. The attributable risk from exposure to detectable AFM1 was 0.553 (0.087, 0.94). The relative risk of fatal cirrhosis for those with elevated AFM1 was 2.8 (0.6, 14.3), and the odds of having a persistently elevated alanine transaminase (ALT) were 2.5-fold greater in those with detectable AFM1 (P =.007). Concomitant infection with HCV increased the risk of HCC 5.8-fold (2.0-17), adjusted for age and AFM1 status. A family history of HCC increased the risk of HCC 5.6-fold, adjusted for age and AFM1. Four men with detectable AFM1 and HCC all had missense mutation in codon 249 of the p53 gene in cancer tissues. This study shows that exposure to AFM1 can account for a substantial part of the risk of HCC in men with chronic HBV hepatitis and adds importantly to the evidence that HCV and family history of HCC increase the risk of HCC in men with chronic HBV hepatitis. C1 Chinese Acad Med Sci, Inst Canc, Natl Lab Mol Oncol, Beijing 100021, Peoples R China. Liver Canc Inst, Jiangsu, Peoples R China. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Informat Management Serv, Rockville, MD USA. RP Sun, ZT (reprint author), Chinese Acad Med Sci, Inst Canc, Natl Lab Mol Oncol, Beijing 100021, Peoples R China. NR 15 TC 115 Z9 124 U1 0 U2 5 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD AUG PY 1999 VL 30 IS 2 BP 379 EP 383 DI 10.1002/hep.510300204 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 221ER UT WOS:000081711500004 PM 10421643 ER PT J AU Lau, DTY Doo, E Park, Y Kleiner, DE Schmid, P Kuhns, MC Hoofnagle, JH AF Lau, DTY Doo, E Park, Y Kleiner, DE Schmid, P Kuhns, MC Hoofnagle, JH TI Lamivudine for chronic delta hepatitis SO HEPATOLOGY LA English DT Article ID B SURFACE-ANTIGEN; VIRUS-INFECTION; INTERFERON-ALPHA; TRIAL; REPLICATION; MULTICENTER; CARRIERS; ANALOGS; THERAPY; DISEASE AB Chronic delta hepatitis is a severe form of chronic liver disease caused by hepatitis delta virus (HDV) infection superimposed on chronic hepatitis B or the hepatitis B surface antigen (HBsAg) carrier state. Therapy of delta hepatitis is currently unsatisfactory. We have evaluated lamivudine (3-thiacytidine), an oral nucleoside analogue with marked effects against hepatitis B, as therapy in 5 patients with chronic hepatitis D, Five men, ages 38 to 65 years, were treated. All had HBsAg, antibody to HDV, and HDV RNA in serum, as well as persistent elevations in alanine aminotransferase (ALT) levels and liver histology showing severe chronic hepatitis with fibrosis or cirrhosis. Lamivudine was given in a dose of 100 mg orally daily for 12 months. Patients were monitored carefully and tested for HBsAg, HBV-DNA and HDV-RNA levels serially during the year of treatment and for 6 months thereafter. Liver biopsies were performed before therapy and repeated after 1 year. Serum levels of HBV DNA fell rapidly in all 5 patients, becoming undetectable even by polymerase chain reaction (PCR) in 4. However, all 5 patients remained HBsAg- and HDV-RNA-positive, and serum ALT levels and liver histology did not improve. All patients tolerated therapy well. When lamivudine was stopped, HBV-DNA levels returned to pretreatment values without a change in disease activity. Lamivudine is a potent inhibitor of HBV-DNA replication, but does not improve disease activity or lower HDV-RNA levels in patients with chronic delta hepatitis. C1 NIDDK, Liver Dis Sect, Div Digest Dis & Nutr, Digest Dis Branch,NIH, Bethesda, MD 20892 USA. NIDDK, Dept Nursing, Warren E Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Natl Inst Genet, Los Angeles, CA USA. Abbott Labs, Abbott Pk, IL 60064 USA. RP Hoofnagle, JH (reprint author), NIDDK, Liver Dis Sect, Div Digest Dis & Nutr, Digest Dis Branch,NIH, Bldg 31,Room 9A23, Bethesda, MD 20892 USA. OI Kleiner, David/0000-0003-3442-4453 NR 30 TC 90 Z9 92 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD AUG PY 1999 VL 30 IS 2 BP 546 EP 549 DI 10.1002/hep.510300217 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 221ER UT WOS:000081711500027 PM 10421666 ER PT J AU Nickel, RG Willadsen, SA Freidhoff, LR Huang, SK Caraballo, L Naidu, RP Levett, P Blumenthal, M Banks-Schlegel, S Bleecker, E Beaty, T Ober, C Barnes, KC AF Nickel, RG Willadsen, SA Freidhoff, LR Huang, SK Caraballo, L Naidu, RP Levett, P Blumenthal, M Banks-Schlegel, S Bleecker, E Beaty, T Ober, C Barnes, KC TI Determination of Duffy genotypes in three populations of African descent using PCR and sequence-specific oligonucleotides SO HUMAN IMMUNOLOGY LA English DT Article DE Duffy; DARC; SSO ID POLYMERASE-CHAIN-REACTION; ISCHEMIC-HEART-DISEASE; ABO BLOOD-GROUP; NEGATIVE INDIVIDUALS; CHEMOKINE RECEPTOR; GENE; POLYMORPHISM; ASSOCIATION; EXPRESSION; ALLELES AB The expression of the Duffy Antigen/Receptor for Chemokines (DARC) on red blood cells (RBC) has been commonly determined using hemagglutination tests. Because the vast majority of African individuals are Duffy-negative, screening for DARC expression on RBC is a valuable tool to assess Caucasian admixture in populations of African descent. Furthermore, blood group antigens have been frequently tested as potential risk factors for complex diseases. We established a dot-blotting protocol using sequence-specific oligonucleotides (SSOs) for the DARC-IGT ("Duffy-positive") and -46C ("Duffy-negative") alleles, With this method, but not with serological methods, Duffy-positive individuals can be further characterized as homozygous or heterozygous for the dominant Duffy-positive allele, allowing more precise estimation of allele frequencies and admixture in heterogeneous populations, In unrelated African American (n = 235), Afro-Caribbean (n = 90) and Colombian (tr = 93) subjects, the frequency of the -46T allele was 21.7%, 12.2% and 74.7%, respectively, The percentage of Duffy-positive individuals (homozygous or heterozygous for the -46T allele) in each population was in accordance with published frequencies, As expected, the -46C allele was not detected in 20 Caucasian subjects, This sensitive and specific method allows for the rapid and inexpensive screening of large samples for Duffy genotypes using small quantities of genomic DNA. (C) American Society for Histocompatibility and Immunogenetics, 1999 Published by Elsevier Science Inc. C1 Johns Hopkins Univ, Dept Med, Div Clin Immunol, Baltimore, MD 21218 USA. Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. Univ Cartagena, Cartagena, Colombia. Univ Minnesota, Minneapolis, MN 55455 USA. NHLBI, Bethesda, MD 20892 USA. Univ Maryland, Ctr Genet Asthma & Complex Dis, Baltimore, MD 21201 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD 21218 USA. RP Barnes, KC (reprint author), Johns Hopkins Asthma & Allergy Ctr, Unit Off 3, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 USA. RI Huang, Shau-Ku/F-5509-2010 FU NHLBI NIH HHS [HL/A1-49612, HL/AI-49596]; PHS HHS [A1-40274] NR 20 TC 19 Z9 19 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0198-8859 J9 HUM IMMUNOL JI Hum. Immunol. PD AUG PY 1999 VL 60 IS 8 BP 738 EP 742 DI 10.1016/S0198-8859(99)00039-7 PG 5 WC Immunology SC Immunology GA 220NZ UT WOS:000081673200014 PM 10439320 ER PT J AU Guillonneau, X Piriev, NI Danciger, M Kozak, CA Cideciyan, AV Jacobson, SG Farber, DB AF Guillonneau, X Piriev, NI Danciger, M Kozak, CA Cideciyan, AV Jacobson, SG Farber, DB TI A nonsense mutation in a novel gene is associated with retinitis pigmentosa in a family linked to the RP1 locus SO HUMAN MOLECULAR GENETICS LA English DT Article ID RETINAL DEGENERATION; BETA-SUBUNIT; MESSENGER-RNA; RD MOUSE; CGMP-PHOSPHODIESTERASE; ROD PHOSPHODIESTERASE; RHODOPSIN MUTATIONS; RECESSIVE MUTATIONS; IDENTIFICATION; TULP1 AB Retinitis pigmentosa (RP) represents a group of inherited human retinal diseases which involve degeneration of photoreceptor cells resulting in visual loss and often leading to blindness. In order to identify candidate genes for the causes of these diseases, we have been studying a pool of photoreceptor-specific cDNAs isolated by subtractive hybridization of mRNAs from normal and photoreceptorless rd mouse retinas. One of these cDNAs was of interest because it mapped to proximal mouse chromosome 1 in a region homologous to human 8q11-q13, the locus of autosomal dominant RP1, Therefore, using the mouse cDNA as probe, we cloned the human cDNA (hG28) and its corresponding gene and mapped it near to D8S509, which lies in the RP1 locus. This gene consists of four exons with an open reading frame of 6468 nt encoding a protein of 2156 amino acids with a predicted mass of 240 kDa, Given its chromosomal localization, we screened this gene for mutations in a large family affected with autosomal dominant RP previously linked to the RP1 locus. We found an R677X mutation that co-segregated with disease in the family and is absent from unaffected members and 100 unrelated controls. This mutation is predicted to lead to rapid degradation of hG28 mRNA or to the synthesis of a truncated protein lacking similar to 70% of its original length. Our results suggest that R677X is responsible for disease in this family and that the gene corresponding to hG28 is the RP1 gene. C1 Univ Calif Los Angeles, Sch Med, Jules Stein Eye Inst, Los Angeles, CA 90095 USA. Loyola Marymount Univ, Dept Biol, Los Angeles, CA 90045 USA. NIAID, Bethesda, MD 20892 USA. Univ Penn, Scheie Eye Inst, Philadelphia, PA 19104 USA. Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. RP Farber, DB (reprint author), Univ Calif Los Angeles, Sch Med, Jules Stein Eye Inst, Los Angeles, CA 90095 USA. RI Cideciyan, Artur/A-1075-2007; Guillonneau, xavier/E-3995-2017 OI Cideciyan, Artur/0000-0002-2018-0905; Guillonneau, xavier/0000-0001-7379-3935 FU NEI NIH HHS [EY02651, EY05627, EY08285] NR 35 TC 52 Z9 57 U1 0 U2 0 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 PY 1999 VL 8 IS 8 BP 1541 EP 1546 DI 10.1093/hmg/8.8.1541 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 223RF UT WOS:000081853500022 PM 10401003 ER PT J AU Parham, DM Hijazi, Y Steinberg, SM Meyer, WH Horowitz, M Tzen, CY Wexler, LH Tsokos, M AF Parham, DM Hijazi, Y Steinberg, SM Meyer, WH Horowitz, M Tzen, CY Wexler, LH Tsokos, M TI Neuroectodermal differentiation in Ewing's sarcoma family of tumors does not predict tumor behavior SO HUMAN PATHOLOGY LA English DT Article; Proceedings Paper CT 84th Annual Meeting of the United-States-Canadian-Academy-of-Pathology CY 1995 CL WASHINGTON, D.C. SP US Canadian Acad Pathol DE Ewing's sarcoma; primitive neuroectodermal tumor; diagnosis; clinical outcome; immunohistochemistry; electron microscopy ID NEURON-SPECIFIC ENOLASE; IMMUNOHISTOCHEMICAL ANALYSIS; PERIPHERAL NEUROEPITHELIOMA; INTERGROUP RHABDOMYOSARCOMA; BONE; EXPERIENCE; CHILDREN; IFOSFAMIDE; ETOPOSIDE; CHILDHOOD AB The observation that neuroectodermal differentiation imparts a worse prognosis to the Ewing family of tumors has been suggested by some studies and refuted by others. To assess whether the diagnosis of Ewing's sarcoma versus peripheral primitive neuroectodermal tumor (PNET) affects prognosis, we analyzed tumors from 63 analogously treated pediatric and young adult patients from the National Cancer Institute and St Jude Children's Research Hospital and retrospectively compared the results with clinical outcomes. The tumors were assessed using standard light microscopy and immunohistochemical stains for neuron-specific enolase, CD57, S100 protein, neurofilament protein, and synaptophysin with or without antigen retrieval. Ultrastructural evaluation was also performed in 39 tumors. Classification was performed using Kiel criteria as well as a modified classification. Kaplan-Meier analyses, with Mantel-Haenzel evaluation of the significance of the differences, were performed separately for localized or metastatic tumors. Using the Kiel classification on a subset of 60 cases, 39 tumors qualified as PNET and 21 as Ewing's sarcoma. Using the modified classification on a subset of 61 cases, 14 were classified as PNET, 21 as atypical Ewing's sarcoma, and 26 as Ewing's sarcoma. The addition of electron microscopy to the diagnostic armamentarium significantly increased the likelihood of identifying PNET. No significant differences in event-free or overall survival were seen using either the modified or Kiel classification, regardless of the ancillary diagnostic techniques employed. In this exploratory analysis, neuroectodermal differentiation did not play a role in clinical outcome. Confirmation of this finding will require a larger, separate study of similarly treated patients, and it may not apply to older patients. (C) 1999 by W.B. Saunders Company. C1 NCI, Pathol Lab, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA. St Jude Childrens Res Hosp, Dept Hematol Oncol, Memphis, TN 38105 USA. Univ Tennessee, Dept Pathol, Memphis, TN USA. Univ Tennessee, Dept Pediat, Memphis, TN USA. RP Tsokos, M (reprint author), NCI, Pathol Lab, Biostat & Data Management Sect, NIH, Bldg 10,Room 2A10, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA23099, P30 CA21765] NR 33 TC 49 Z9 53 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD AUG PY 1999 VL 30 IS 8 BP 911 EP 918 DI 10.1016/S0046-8177(99)90244-7 PG 8 WC Pathology SC Pathology GA 226KR UT WOS:000082019600006 PM 10452503 ER PT J AU Castle, PE Dean, J AF Castle, PE Dean, J TI Manipulating the genome to study reproduction - Mice with 'humanized' zonae pellucidae SO HUMAN REPRODUCTION LA English DT Article ID AUTOIMMUNE OVARIAN DISEASE; SPERM RECEPTOR; FEMALE MICE; ANTIBODIES; REQUIREMENT; INFERTILITY; PROTEIN; GENES C1 NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Castle, PE (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bldg 6,Room B 1-26, Bethesda, MD 20892 USA. NR 20 TC 4 Z9 4 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD AUG PY 1999 VL 14 IS 8 BP 1927 EP 1929 DI 10.1093/humrep/14.8.1927 PG 3 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 225KU UT WOS:000081959700003 PM 10438400 ER PT J AU Azorsa, D AF Azorsa, D TI AX15.2, human steroid receptor coactivator AIB1 SO HYBRIDOMA LA English DT Article C1 NHGRI, CGB, NIH, Bethesda, MD 20892 USA. RP Azorsa, D (reprint author), NHGRI, CGB, NIH, Bldg 49-Rm 4A15,49 Convent Dr MSC 4470, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0272-457X J9 HYBRIDOMA JI Hybridoma PD AUG PY 1999 VL 18 IS 4 BP 390 EP 390 PG 1 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Immunology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Immunology GA 253ZG UT WOS:000083586600016 ER PT J AU Masilamani, SME Kim, GH AF Masilamani, SME Kim, GH TI Aldosterone regulates ENaC sodium channel subunit abundance and distribution in renal collecting duct SO HYPERTENSION LA English DT Meeting Abstract C1 NHLBI, Bethesda, MD 20892 USA. Univ Maryland, Baltimore, MD 21201 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD AUG PY 1999 VL 34 IS 2 MA 59 BP 338 EP 338 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 227YW UT WOS:000082108500087 ER PT J AU Kailasam, MT O'Connor, DT Wilson, AF Parmer, RJ AF Kailasam, MT O'Connor, DT Wilson, AF Parmer, RJ TI Evidence for heritability of renal microalbumin excretion in essential hypertension SO HYPERTENSION LA English DT Meeting Abstract C1 Univ Calif San Diego, San Diego, CA 92103 USA. Natl Human Genome Res Inst, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD AUG PY 1999 VL 34 IS 2 MA P81 BP 355 EP 355 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 227YW UT WOS:000082108500189 ER PT J AU Tenney, CR Smith, MF Greer, KL Jaszczak, RJ AF Tenney, CR Smith, MF Greer, KL Jaszczak, RJ TI Uranium pinhole collimators for I-131SPECT imaging SO IEEE TRANSACTIONS ON NUCLEAR SCIENCE LA English DT Article; Proceedings Paper CT 1998 Medical Imaging Conference CY NOV 12-14, 1998 CL TORONTO, CANADA ID EMISSION COMPUTED-TOMOGRAPHY; ULTRA-HIGH-RESOLUTION; GAMMA-CAMERA; MALIGNANT GLIOMAS; SPECT; RADIOIMMUNOTHERAPY; PENETRATION; APERTURE; TUMORS AB Pinhole apertures made of depleted uranium were evaluated for high-resolution SPE:CT brain tumor imaging of therapeutic doses (30-100 mCi) of intratumorally administered I-131 radiolabeled monoclonal antibodies. High resolution is required for imaging residual tumor tissue, although for therapeutic doses, high collimator sensitivity is less important. Resolution of uranium and tungsten pinhole apertures was compared in planar and SPECT images of I-131 sources. Planar sensitivity was studied on- and off-axis. On-axis planar resolution for uranium pinholes is higher than that of tungsten pinholes for all cases examined; full-width-half-max (FWHM) is narrower for a 3 mm uranium pinhole than for a I mm tungsten pinhole, indicating significantly lower penetration at pinhole edges for uranium than for tungsten. Collimator sensitivity is higher for tungsten than for uranium, which also indicates higher edge penetration for tungsten. On-axis SPECT(14.4 cm radius) scans also show better resolution for a 2 mm uranium pinhole (7.8 mm FWHM) than for a 2 mm tungsten pinhole (9.5 mm FWHM). Background radiation from a uranium collimator (102 cts/sec) is acceptably low compared to expected clinical count rates. C1 Duke Univ, Med Ctr, Durham, NC 27710 USA. NIH, Bethesda, MD 20892 USA. RP Tenney, CR (reprint author), Duke Univ, Med Ctr, Durham, NC 27710 USA. NR 21 TC 13 Z9 13 U1 0 U2 1 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017-2394 USA SN 0018-9499 J9 IEEE T NUCL SCI JI IEEE Trans. Nucl. Sci. PD AUG PY 1999 VL 46 IS 4 BP 1165 EP 1171 DI 10.1109/23.790851 PN 2 PG 7 WC Engineering, Electrical & Electronic; Nuclear Science & Technology SC Engineering; Nuclear Science & Technology GA 235WN UT WOS:000082566000030 ER PT J AU Dracheva, SV Remmers, EF Gulko, PS Kawahito, Y Longman, RE Reese, VR Cannon, GW Griffiths, MM Wilder, RL AF Dracheva, SV Remmers, EF Gulko, PS Kawahito, Y Longman, RE Reese, VR Cannon, GW Griffiths, MM Wilder, RL TI Identification of a new quantitative trait locus on Chromosome 7 controlling disease severity of collagen-induced arthritis in rats SO IMMUNOGENETICS LA English DT Article DE rheumatoid arthritis; quantitative trait locus; inbred rats; linkage mapping; comparative maps ID GENETIC-LINKAGE MAP; GROWTH-FACTOR-I; RHEUMATOID-ARTHRITIS; IMMUNE-RESPONSE; AUTOIMMUNE-DISEASES; LABORATORY RAT; SUSCEPTIBILITY; IMMUNOGENETICS; CARTILAGE; LUMICAN AB Autoimmune diseases, such as rheumatoid arthritis, Crohn's disease, and multiple sclerosis, are regulated by multiple genes. Major histocompatibility complex (MHC) genes have the strongest effects, but non-MHC genes also contribute to disease susceptibility/severity. In this paper, we describe a new non-MHC quantitative trait locus, Cia8, on rat Chromosome (Chr) 7 that controls collagen-induced arthritis severity in F2 progeny of DA and F344 inbred rats, and present an updated localization of Cia4 on the same chromosome. We also describe the location of mouse and human genes, orthologous to the genes in the genomic intervals containing Cia4 and Cia8, and provide evidence that the segment of rat Chr 7 containing Cia4 and Cia8 is homologous to segments of mouse Chr 10 and 15 and human Chr 8, 12, and 19. C1 NIAMSD, Inflammatory Joint Dis Sect, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. Univ Utah, Dept Med Rheumatol, Salt Lake City, UT 84132 USA. Vet Affairs Med Ctr, Res Serv, Salt Lake City, UT 84148 USA. Columbia Univ, Coll Phys & Surg, Div Autoimmune & Mol Dis, New York, NY 10032 USA. RP Wilder, RL (reprint author), NIAMSD, Inflammatory Joint Dis Sect, Arthrit & Rheumatism Branch, NIH, Bldg 10,Room 9N240,10 Ctr Dr,MSC 1820, Bethesda, MD 20892 USA. NR 31 TC 30 Z9 30 U1 0 U2 1 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0093-7711 J9 IMMUNOGENETICS JI Immunogenetics PD AUG PY 1999 VL 49 IS 9 BP 787 EP 791 DI 10.1007/s002510050552 PG 5 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 219ZK UT WOS:000081638500005 PM 10398805 ER PT J AU Schlom, J Hodge, JW AF Schlom, J Hodge, JW TI The diversity of T-cell co-stimulation in the induction of antitumor immunity SO IMMUNOLOGICAL REVIEWS LA English DT Review ID RECOMBINANT VACCINIA VIRUS; MEDIATED TUMOR-IMMUNITY; CARCINOEMBRYONIC ANTIGEN; SERONEGATIVE ADULTS; CYTOLYTIC ACTIVITY; CTLA-4 BLOCKADE; LYMPHOCYTE-T; DOUBLE-BLIND; PHASE-I; RESPONSES AB T-cell activation has now been shown to require at least two signals. The first signal is antigen-specific, is delivered through the T-cell receptor (TCR) via the peptide/major histocompatibility complex (MHC), and causes the T cell to enter the cell cycle. The second, or co-stimulatory, signal is required for cytokine production and proliferation, and is mediated through ligand interaction on the surface of the T cell. This chapter deals with: 1) comparative studies on the use of a dual-gene construct of a recombinant vaccinia (rV) vector containing a tumor-associated antigen (TAA) gene and a co-stimulatory molecule gene vs the use of admixtures of rV-TAA and rV containing the co-stimulatory molecule to induce antitumor immunity; 2) the use of an admixture of vaccinia viruses containing a TAA gene and the B7-1 co-stimulatory molecule gene to induce a therapeutic response in a lung metastasis tumor model; 3) the antitumor efficacy of whole-tumor-cell vaccines in which the B7-1 co-stimulatory molecule is expressed in a tumor-cell vaccine via a vaccinia vs a retroviral vector; 4) the use of recombinant poxviruses containing the genes for the co-stimulatory molecules ICAM-1 or LFA-3 to induce antitumor immunity; and 5) the use of poxvirus vectors containing a triad of co-stimulatory molecules (B7-1, ICAM-1 and LFA-3) that synergize to enhance both CD4(+) and CD8(+) T-cell responses to a new threshold. C1 NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, NIH, 10 Ctr Dr,Room 8B07, Bethesda, MD 20892 USA. RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 NR 64 TC 23 Z9 26 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD AUG PY 1999 VL 170 BP 73 EP 84 DI 10.1111/j.1600-065X.1999.tb01330.x PG 12 WC Immunology SC Immunology GA 249GZ UT WOS:000083326100007 PM 10566143 ER PT J AU Wang, RF Rosenberg, SA AF Wang, RF Rosenberg, SA TI Human tumor antigens for cancer vaccine development SO IMMUNOLOGICAL REVIEWS LA English DT Review ID CYTOLYTIC T-LYMPHOCYTES; HUMAN-MELANOMA ANTIGEN; TYROSINASE-RELATED PROTEIN-2; PULSED DENDRITIC CELLS; BETA-CATENIN GENE; INFILTRATING LYMPHOCYTES; METASTATIC MELANOMA; HLA-A2 MELANOMAS; BREAST-CANCER; DIFFERENTIATION ANTIGEN AB The adoptive transfer of tumor-infiltrating lymphocytes (TIL) along with interleukin (IL)-2 into autologous patients with cancer resulted in the objective regression of tumor, indicating that T cells play an important role in tumor regression. In the last few years, efforts have been made towards understanding the molecular basis of T-cell-mediated antitumor immunity and elucidating the molecular nature of tumor antigens recognized by T cells. Tumor antigens identified thus far could be classified into several catagories: tissue-specific differentiation antigens, tumor-specific shared antigens and tumor-specific unique antigens. CD4(+) T cells play,a central role in orchestrating the host immune response against cancer, infectious diseases and autoimmune deseases, and we thus have attempted to identify major histocompatibility complex (MHC) class II-restricted tumor antigens as well. The identification of tumor rejection antigens provides new opportunities for the development of therapeutic strategies against cancer. This review will summarize the current status of MHC class I- and class II-restricted human tumor antigens, and their potential application to cancer treatment. C1 NCI, Surg Branch, NIH, Bethesda, MD 20814 USA. RP Wang, RF (reprint author), NCI, Surg Branch, NIH, Bldg 10,Rm 2B42, Bethesda, MD 20814 USA. NR 150 TC 228 Z9 235 U1 2 U2 11 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD AUG PY 1999 VL 170 BP 85 EP 100 DI 10.1111/j.1600-065X.1999.tb01331.x PG 16 WC Immunology SC Immunology GA 249GZ UT WOS:000083326100008 PM 10566144 ER PT J AU Biragyn, A Kwak, LW AF Biragyn, A Kwak, LW TI B-cell malignancies as a model for cancer vaccines: from prototype protein to next generation genetic chemokine fusions SO IMMUNOLOGICAL REVIEWS LA English DT Review ID COLONY-STIMULATING FACTOR; SURFACE-IMMUNOGLOBULIN IDIOTYPE; MATURE DENDRITIC CELLS; DNA VACCINES; IMMUNE-RESPONSES; T-CELLS; ANTITUMOR IMMUNITY; LYMPHOMA-CELLS; LISTERIA-MONOCYTOGENES; PROTECTIVE IMMUNITY AB B-cell malignancy-derived Ig may be considered a model tumor antigen for vaccine development. However, as a non-immunogenic self antigen, it must also be first rendered immunogenic by chemical or genetic fusion to carriers which enable the induction of protective antitumor immunity in murine tumor models. Our group has demonstrated that active immunizations of human patients with idiotypic vaccines elicited antigen-specific CD8(+) T-cell responses and antitumor effects. Several alternative preclinical strategies to develop vaccines have been previously reported, including fusion of tumor idiotype-derived single chain Fv with cytokines and immunogenic peptides. On the other hand, we have recently explored a different approach in which the model antigen is tendered immunogenic in mice by genetically fusing it to a chemokine moiety. Administration of these vaccines as fusion proteins or naked DNA vaccines may allow efficient targeting of antigen-presenting cells in vivo. Potent antitumor immunity was dependent on the generation of specific anti-idiotypic antibodies and both CD4(+) and CD8(+) effector T cells. We propose that chemokine fusion may represent a novel, general strategy for formulating existing or newly identified tumor and HIV antigens into vaccines for cancer and AIDS, respectively, which elicit potent CD8(+) T-cell immunity. C1 NCI, Dept Expt Transplantat & Immunol, Med Branch, Div Clin Sci,SAIC, Frederick, MD 21702 USA. RP Biragyn, A (reprint author), NCI, Dept Expt Transplantat & Immunol, Med Branch, Div Clin Sci,SAIC, Frederick, MD 21702 USA. NR 96 TC 21 Z9 23 U1 0 U2 1 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD AUG PY 1999 VL 170 BP 115 EP 126 DI 10.1111/j.1600-065X.1999.tb01333.x PG 12 WC Immunology SC Immunology GA 249GZ UT WOS:000083326100010 PM 10566146 ER PT J AU Letvin, NL Schmitz, JE Jordan, HL Seth, A Hirsch, VM Reimann, KA Kuroda, MJ AF Letvin, NL Schmitz, JE Jordan, HL Seth, A Hirsch, VM Reimann, KA Kuroda, MJ TI Cytotoxic T lymphocytes specific for the simian immunodeficiency virus SO IMMUNOLOGICAL REVIEWS LA English DT Review ID INFECTED RHESUS-MONKEYS; ATTENUATED MVA STRAIN; VACCINIA VIRUS; MONOCLONAL-ANTIBODY; SYNTHETIC PEPTIDE; HOST-RANGE; SIV; MACAQUES; QUANTITATION; IMMUNIZATION AB A non-human primate model for acquired immunodeficiency syndrome (AIDS), the simian immunodeficiency virus (SIV)-infected rhesus monkey, was used to explore the role of the AIDS virus-specific cytotoxic T-lymphocyte (CTL) response in disease pathogenesis. This CTL response was measured using the major histocompatibility complex (MHC) class I/peptide tetramer technology Large numbers of tetramer-binding CD8(+) T lymphocytes were demonstrable not only in the peripheral blood, but in lymph nodes and even in semen of chronically SIV-infected monkeys. The central role of these effector T lymphocytes in containing SIV spread during primary infection was demonstrated by showing that early SIV clearance during primary infection correlated with the emergence of the tetramer binding CD8(+) T lymphocytes and that in vivo depletion of CD8(+) lymphocytes eliminated the ability of the infected monkeys to contain SN replication. These observations suggest that an effective AIDS vaccine should elicit a potent virus-specific CTL response. In fact, a live, recombinant SIV vaccine constructed using the attenuated pox virus vector modified vaccinia Ankara (MVA) elicited a high-frequency CTL response, comparable in magnitude to that elicited by SIV infection itself This suggests that vaccine modalities such as MVA may prove useful in creating an effective human immunodeficiency virus (HIV) vaccine. These studies also indicate the power of both the SIV/macaque model and MHC class I/peptide tetramers for assessing AIDS vaccine strategies. C1 Harvard Univ, Sch Med, Dept Med,Div Viral Pathogenesis, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Letvin, NL (reprint author), Harvard Univ, Sch Med, Dept Med,Div Viral Pathogenesis, Beth Israel Deaconess Med Ctr, RE-113,POB 15732, Boston, MA 02215 USA. NR 33 TC 51 Z9 52 U1 1 U2 1 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD AUG PY 1999 VL 170 BP 127 EP 134 DI 10.1111/j.1600-065X.1999.tb01334.x PG 8 WC Immunology SC Immunology GA 249GZ UT WOS:000083326100011 PM 10566147 ER PT J AU Berzofsky, JA Ahlers, JD Derby, MA Pendleton, CD Arichi, T Belyakov, IM AF Berzofsky, JA Ahlers, JD Derby, MA Pendleton, CD Arichi, T Belyakov, IM TI Approaches to improve engineered vaccines for human immunodeficiency virus and other viruses that cause chronic infections SO IMMUNOLOGICAL REVIEWS LA English DT Review ID CYTOTOXIC T-LYMPHOCYTES; HEPATITIS-C VIRUS; MAJOR HISTOCOMPATIBILITY COMPLEX; HIV-SEROPOSITIVE INDIVIDUALS; LYMPH-NODE IMMUNIZATION; ATTENUATED MVA STRAIN; TUMOR-NECROSIS-FACTOR; IN-VIVO INDUCTION; ENVELOPE PROTEIN; PROTECTIVE IMMUNITY AB We used several approaches to develop enhanced vaccines for chronic viral infections such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV). 1) Selected epitopes were used to avoid potentially harmful immune responses. 2) Linkage between helper and cytotoxic T-lymphocyte (CTL) epitopes was found to be important. 3) We developed an "epitope enhancement" approach modifying the sequences of epitopes to make more potent vaccines, including examples for HIV and HCV epitopes presented by murine class II and human class I major histocompatibility complex (MHC) molecules. 4) CTL avidity was found to be important for clearing viral infections in vivo, and the mechanism was examined. High-avidity CTLs, however, were found to undergo apoptosis when confronted with high-density antigen, through a mechanism involving tumor necrosis factor (TNF), TNF-RII, and a permissive state induced through the T-cell receptor. 5) We employed cytokines in the adjuvant to steer immune responses toward desired phenotypes, and showed synergy between cytokines. 6) Intrarectal immunization with peptide vaccine induced mucosal and systemic CTL. Local mucosal CTL were found to be critical for resistance to mucosal viral transmission and this resistance was enhanced with mucosally delivered interleukin-12. 7) We used an asymmetry in induction of mucosal and systemic immune responses to circumvent pre-existing vaccinia immunity for use of recombinant vaccinia vaccines. C1 NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Berzofsky, JA (reprint author), NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, NIH, Bldg 10,Room 6B-12,MSC 1578, Bethesda, MD 20892 USA. NR 172 TC 78 Z9 81 U1 0 U2 1 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD AUG PY 1999 VL 170 BP 151 EP 172 DI 10.1111/j.1600-065X.1999.tb01336.x PG 22 WC Immunology SC Immunology GA 249GZ UT WOS:000083326100013 PM 10566149 ER PT J AU Mountford, AP Coulson, PS Cheever, AW Sher, A Wilson, RA Wynn, TA AF Mountford, AP Coulson, PS Cheever, AW Sher, A Wilson, RA Wynn, TA TI Interleukin-12 can directly induce T-helper 1 responses in interferon-gamma (IFN-gamma) receptor-deficient mice, but requires IFN-gamma signalling to downregulate T-helper 2 responses SO IMMUNOLOGY LA English DT Article ID MURINE SCHISTOSOMIASIS-MANSONI; CELL STIMULATORY FACTOR; GRANULOMA-FORMATION; IMMUNOREGULATORY FUNCTIONS; PROINFLAMMATORY CYTOKINE; IMMUNE-RESPONSES; LEISHMANIA-MAJOR; TH1 DEVELOPMENT; IN-VIVO; IL-12 AB An in vivo model of pulmonary granuloma formation around embolized schistosome eggs was investigated as an environment in which to analyse a role for interleukin-12 (IL-12) in the differentiation of T-helper 1 (Thl) and Th2 subsets. Specifically, mice deficient for the interferon-gamma receptor( IFN-gamma R-/-) were used to determine the role for IL-12 in the absence of IFN-gamma-mediated signalling. We show that recombinant IL-12 administered to IFN-gamma R-/- mice caused the up-regulation of mRNA for IFN-gamma in lung tissue, and the secretion of abundant IFN-gamma by in vitro-cultured lymph node cells in response to egg antigens. This indicates that IL-12 can act independently of IFN-gamma to induce the development of Th I cells. Administration of rIL-12 to wildtype mice markedly reduced the secretion of Th2-associated cytokines, IL-4 and IL-5. However, these cytokines were not dramatically reduced in TFN-gamma R-/- mice treated with IL-12. We conclude that inhibition of these cytokines by IL-12 is primarily dependent upon effective IFN-gamma signalling, although abrogation of T-cell derived IL-10 appeared to be dependent upon IL-IZ. We also show that increases in mRNA for the beta 2 subunit of the IL-12 receptor and the p40 subunit of IL-12 after rIL-12 treatment were lower in IFN-gamma R-/- mice, compared to wild-type mice, indicating that their expression was primarily dependent upon IFN-gamma with only a minor role for IL-12. C1 Univ York, Dept Biol, York, N Yorkshire YO10 5YW, England. NIAID, Parasit Dis Lab, Immunobiol Sect, NIH, Bethesda, MD 20892 USA. RP Mountford, AP (reprint author), Univ York, Dept Biol, POB 373, York, N Yorkshire YO10 5YW, England. RI Wynn, Thomas/C-2797-2011 FU Wellcome Trust NR 31 TC 32 Z9 35 U1 0 U2 2 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD AUG PY 1999 VL 97 IS 4 BP 588 EP 594 PG 7 WC Immunology SC Immunology GA 226WX UT WOS:000082046900006 PM 10457211 ER PT J AU Rubartelli, A Poggi, A Sitia, R Zocchi, MR AF Rubartelli, A Poggi, A Sitia, R Zocchi, MR TI HIV-I Tat: immunosuppression via TGF-beta 1 induction - Reply to Reinhold et al. SO IMMUNOLOGY TODAY LA English DT Letter ID SECRETION; CALCIUM; CELLS; INHIBITORS; BETA; CNS C1 Natl Canc Inst, Genoa, Italy. San Raffaele Sci Inst, I-20132 Milan, Italy. RP Rubartelli, A (reprint author), Natl Canc Inst, Genoa, Italy. RI Poggi, Alessandro/K-6664-2016 OI Poggi, Alessandro/0000-0002-1860-430X NR 9 TC 0 Z9 1 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0167-5699 J9 IMMUNOL TODAY JI Immunol. Today PD AUG PY 1999 VL 20 IS 8 BP 384 EP 385 DI 10.1016/S0167-5699(99)01490-5 PG 2 WC Immunology SC Immunology GA 223TJ UT WOS:000081856700011 ER PT J AU Khalil, SB Cassels, FJ Shaheen, HI Pannell, LK El-Ghorab, N Kamal, K Mansour, M Savarino, SJ Peruski, LF AF Khalil, SB Cassels, FJ Shaheen, HI Pannell, LK El-Ghorab, N Kamal, K Mansour, M Savarino, SJ Peruski, LF TI Characterization of an enterotoxigenic Escherichia coli strain from Africa expressing a putative colonization factor SO INFECTION AND IMMUNITY LA English DT Article ID GM1-ENZYME-LINKED IMMUNOSORBENT-ASSAY; MONOCLONAL-ANTIBODIES; FACTOR ANTIGENS; IDENTIFICATION; DIARRHEA; PROTEINS; SEQUENCE; CHILDREN; VACCINES; TOXIN AB An enterotoxigenic Escherichia coli (ETEC) strain of serotype O114:H- that expressed both heat-labile and heat-stable enterotoxins and tested negative for colonization factors (CF) was isolated from a child with diarrhea in Egypt. This strain, WS0115A, induced hemagglutination of bovine erythrocytes and adhered to the enterocyte-like cell line Caco-2, suggesting that it may elaborate novel fimbriae. Surface-expressed antigen purified by differential ammonium sulfate precipitation and column chromatography yielded a single protein band with M-r 14,800 when resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (16% polyacrylamide). A monoclonal antibody against this putative fimbrial antigen was generated and reacted with strain WS0115A and also with CS1-, CS17-, and CS19-positive strains in a dot blot assay. Reactivity was temperature dependent, with cells displaying reactivity when grown at 37 degrees C but not when grown at 22 degrees C. Immunoblot analysis of a fimbrial preparation from strain WS0115A showed that the monoclonal antibody reacted with a single protein band. Electron microscopy and immunoelectron microscopy revealed fimbria-like structures on the surface of strain WS0115A. These structures were rigid and measured 6.8 to 7.4 nm in diameter. Electrospray mass-spectrometric analysis showed that the mass of the purified fimbria was 14,965 Da. The N-terminal sequence of the fimbria established that it was a member of the CFA/I family, with sequence identity to the amino terminus of CS19, a new CF recently identified in India. Cumulatively, our results suggest that this fimbria is CS19. Screening of a collection of ETEC strains isolated from children with diarrhea in Egypt found that 4.2% of strains originally reported as CF negative were positive for this CF, suggesting that it is biologically relevant in the pathogenesis of ETEC. C1 USN, Med Res Unit 3, Res Sci Dept, Cairo, Egypt. Walter Reed Army Med Ctr, Walter Reed Army Inst Res, Div Communicable Dis & Immunol, Dept Enter Infect, Washington, DC 20307 USA. NIDDKD, Struct Mass Spectrometry Grp, NIH, Bethesda, MD 20892 USA. RP Peruski, LF (reprint author), USN, Med Res Unit 3, PSC 452,Box 5000, FPO, AE 09835 USA. RI Savarino, Stephen/A-8030-2011 FU NICHD NIH HHS [Y1-HD-0026-01] NR 46 TC 8 Z9 8 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD AUG PY 1999 VL 67 IS 8 BP 4019 EP 4026 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 219ZA UT WOS:000081637400043 PM 10417169 ER PT J AU Hu, L Kopecko, DJ AF Hu, L Kopecko, DJ TI Campylobacter jejuni 81-176 associates with microtubules and dynein during invasion of human intestinal cells SO INFECTION AND IMMUNITY LA English DT Article ID HUMAN EPITHELIAL-CELLS; CULTURED ANIMAL-CELLS; CHLAMYDIA-TRACHOMATIS; HELA-CELLS; YERSINIA-ENTEROCOLITICA; INTRACELLULAR SURVIVAL; NEISSERIA-GONORRHOEAE; ACTIN POLYMERIZATION; SHIGELLA-FLEXNERI; ESCHERICHIA-COLI AB Campylobacter jejuni uptake into cultured INT407 cells was analyzed kinetically over a wide range of starting multiplicities of infection (MOI; from 0.02 to 20,000 bacteria/epithelial cell). The efficiency of internalization was the highest at MOI of 0.02 and decreased steadily at higher MOIs, presumably due to reported C. jejuni autoagglutination at higher densities. Total internalized Campylobacter CFU increased gradually from an MOI of 0.02 to a peak at an MOI of 200 (reaching an average of two bacteria internalized per epithelial cell) and decreased at higher MOIs. The invasion process was apparently saturated within 2 h at an MOI of 200, indicating stringent host cell limitations on this entry process. Furthermore, whereas control Salmonella typhi invaded all monolayer cells within 1 h, only two-thirds of monolayer cells were infected after 2 h with C. jejuni at MOIs of 200 to 2,000. The percentage of Campylobacter-infected host cells gradually increased to 85% after 7 h of infection, suggesting that C. jejuni entry may be host cell cycle dependent. Direct evidence of the involvement of microtubules in C. jejuni internalization, suggested previously by biochemical inhibitor studies, was obtained by time course immunofluorescence microscopic analyses. Bacteria initially bound to the tips of host cell membrane extensions containing microtubules, then aligned in parallel with microtubules during entry, colocalized specifically with microtubules and dynein but not with microfilaments, and moved over 4 h, presumably via min rotubules to the perinuclear region of host cells. Orthovanadate, which inhibits dynein activity, specifically reduced C. jejuni 81-176 entry, suggesting that this molecular motor is involved in entry and endosome trafficking during this novel bacterial internalization process. Collectively, these data suggest that C. jejuni enters host cells in a targeted and tightly controlled process leading to uptake into an endosomal vacuole which apparently moves intracellularly along microtubules via the molecular motor, dynein, to the perinuclear region. C1 US FDA, Lab Enter & Sexually Transmitted Dis, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Kopecko, DJ (reprint author), US FDA, Lab Enter & Sexually Transmitted Dis, Ctr Biol Evaluat & Res, Bldg 29-420,NIH Campus, Bethesda, MD 20892 USA. NR 65 TC 110 Z9 115 U1 1 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD AUG PY 1999 VL 67 IS 8 BP 4171 EP 4182 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 219ZA UT WOS:000081637400063 PM 10417189 ER PT J AU King, LB Tolosa, E Lenczowski, JM Lu, F Lind, EF Hunziker, R Petrie, HT Ashwell, JD AF King, LB Tolosa, E Lenczowski, JM Lu, F Lind, EF Hunziker, R Petrie, HT Ashwell, JD TI A dominant-negative mutant of c-Jun inhibits cell cycle progression during the transition of CD4(-)CD8(-) to CD4(+) CD8(+) thymocytes SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE cellular differentiation; thymus; transcription factor; transgenic/knockout ID PRE-T-CELL; DEFICIENT MICE; INTERLEUKIN-2 RECEPTOR; INDUCED TRANSFORMATION; TRANSCRIPTION FACTORS; GENE-TRANSCRIPTION; THYMIC SELECTION; ANTIGEN RECEPTOR; PROTO-ONCOGENE; NUCLEAR FACTOR AB While Jun/Fos-containing transcription factors are known to be necessary for many TCR-mediated events in mature T cells, relatively little is known about their roles in thymocyte development. We have generated transgenic mice that express a trans-dominant-negative mutant of c-Jun (TAM-67) specifically in thymocytes. Expression of TAM-67 inhibited the up-regulation of AP-1-responsive genes such as c-jun and IL-2 in stimulated thymocytes from transgenic mice. In addition, altered thymocyte development in TAM-67-expressing mice was revealed by a decrease in thymic cellularity (similar to 50%) which could be accounted for primarily by a reduction in the number of CD4(+)CD8(+) thymocytes, a large percentage of which retained CD25, The decrease in the number of CD4(+)CD8(+) thymocytes did not appear to be due to an enhanced rate of apoptosis but rather to a decrease in the number of CD4(-)CD8(-)CD25(-) cells in the S + G(2)/M stages of the cell cycle. These results indicate that Jun/Fos-containing transcription factors promote the proliferative burst that accompanies the transition from the CD4(-)CD8(-) to the CD4(+)CD8(+) stage of thymocyte development. C1 Natl Inst Hlth, Lab Immune Cell Biol, Natl Canc Inst, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Natl Inst Hlth, Immunol Lab, NIAID, Bethesda, MD 20892 USA. RP King, LB (reprint author), Univ Penn, Sch Med, Room 535 CRB,415 Curie Blvd, Philadelphia, PA 19104 USA. FU NCI NIH HHS [CA09162]; NIAID NIH HHS [AI 33940] NR 64 TC 12 Z9 12 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD AUG PY 1999 VL 11 IS 8 BP 1203 EP 1215 DI 10.1093/intimm/11.8.1203 PG 13 WC Immunology SC Immunology GA 224CW UT WOS:000081880100003 PM 10421778 ER PT J AU Sun, B Sun, SH Chan, CC Wiggert, B Caspi, RR AF Sun, B Sun, SH Chan, CC Wiggert, B Caspi, RR TI Autoimmunity to a pathogenic retinal antigen begins as a balanced cytokine response that polarizes towards type 1 in a disease-susceptible and towards type 2 in a disease-resistant genotype SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE autoimmunity cytokines; rodent; T(h)1/T(h)2; uveitis ID T-CELLS; GENETIC SUSCEPTIBILITY; UVEORETINITIS; PHENOTYPE; UVEITIS; MODEL; MICE AB Susceptible, but not resistant, strains of rodents immunized for induction of experimental autoimmune uveitis (EAU) with the uveitogenic protein interphotoreceptor retinoid-binding protein (IRBP) exhibit a type 1 response at the time of disease expression. Here we investigate the evolution of this response using the prototypic EAU-susceptible and EAU-resistant mouse strains, B10.A and BALB/c, Disease severity and IRBP-specific responses (proliferation, cytokines and antibody isotypes) were evaluated 7, 14 and 21 days after uveitogenic immunization. B10.A mice initially exhibited an IgG1-dominated antibody response, and their lymph node cells produced IL-4 and IL-5 in addition to IFN-gamma, On day 14 and 21, however, the IgG2a isotype became predominant, and the primed lymph node cells produced mainly IFN-gamma and IL-12, B10.A mice developed EAU before day 14, BALB/c mice initially produced IL-12 and IFN-gamma in addition to IL-5, IL-4 and IL-10, At later time points IL-12 and IFN-gamma production diminished, and IL-4, IL-5 and IL-10 increased. An IgG1-dominated antibody response was maintained throughout. BALB/c mice failed to develop EAU even at day 21, Thus, both susceptible and resistant genotypes initially mount a balanced, type 0-like cytokine response to a uveitogenic challenge, that subsequently polarizes towards type 1 in the susceptible strain and towards type 2 in the resistant strain. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Caspi, RR (reprint author), NEI, Immunol Lab, NIH, 10 Ctr Dr,MSC 1857,10-10N222, Bethesda, MD 20892 USA. NR 19 TC 30 Z9 37 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD AUG PY 1999 VL 11 IS 8 BP 1307 EP 1312 DI 10.1093/intimm/11.8.1307 PG 6 WC Immunology SC Immunology GA 224CW UT WOS:000081880100013 PM 10421788 ER PT J AU Albert, MR AF Albert, MR TI Fever therapy for general paresis SO INTERNATIONAL JOURNAL OF DERMATOLOGY LA English DT Article ID MALARIOTHERAPY; NEUROSYPHILIS C1 Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. RP Albert, MR (reprint author), NIH, Dermatol Branch, Bldg 10,Room 12N260,10 Ctr Dr, Bethesda, MD 20892 USA. NR 53 TC 5 Z9 6 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0011-9059 J9 INT J DERMATOL JI Int. J. Dermatol. PD AUG PY 1999 VL 38 IS 8 BP 633 EP 637 DI 10.1046/j.1365-4362.1999.00659.x PG 5 WC Dermatology SC Dermatology GA 235LH UT WOS:000082542800017 PM 10487458 ER PT J AU Ioannidis, JPA Taha, TE Kumwenda, N Broadhead, R Mtimavalye, L Miotti, P Yellin, F Contopoulos-Ioannidis, DG Biggar, RJ AF Ioannidis, JPA Taha, TE Kumwenda, N Broadhead, R Mtimavalye, L Miotti, P Yellin, F Contopoulos-Ioannidis, DG Biggar, RJ TI Predictors and impact of losses to follow-up in an HIV-1 perinatal transmission cohort in Malawi SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE missing data; HIV-1; perinatal transmission; Africa; vaginal cleansing; simple trials ID HUMAN-IMMUNODEFICIENCY-VIRUS; MOTHER-TO-CHILD; RANDOMIZED TRIAL; MORTALITY; INFECTION; INFANT; RISK AB Background Large simple trials which aim to study therapeutic interventions and epidemiological associations of human immunodeficiency virus (HIV) infection, including perinatal transmission, in Africa may have substantial rates of loss to follow-up. A better understanding of the characteristics and the impact of women and children lost to follow-up is needed. Methods We studied predictors and the impact of losses to follow-up of infants born in a large cohort of delivering women in urban Malawi. The cohort was established as part of a trial of vaginal cleansing with chlorhexidine during delivery to prevent mother-to-infant transmission of HIV. Results The HIV infection status could not be determined for 797 (36.9%) of 2156 infants born to HIV-infected mothers; 144 (6.7%) with missing status because of various sample problems and 653 (30.3%) because they never returned to the clinic. Notably, the observed rates of perinatal transmission were significantly lower in infants who returned later for determination of their infection status (odds ratio = 0.94 per month, P = 0.03), even though these infants must have had an additional risk of infection from breastfeeding. In multivariate models, infants of lower birthweight (P = 0.003) and, marginally, singletons (P = 0.09) were less likely to return for follow-up. The parents of infants lost to follow-up tended to be less educated (P < 0.001) and more likely to be in farming occupations, although one educated group, teachers and students, were also significantly less likely to return. Of these variables, infant birthweight, twins versus singletons, and maternal education were also associated with significant variation in the observed risk of perinatal transmission among infants of known HIV status. Conclusions Several predictors of loss to follow-up were identified in this large HIV perinatal cohort. Losses to follow-up can impact the observed transmission rate and the risk associations in different studies. C1 NIAID, HIV Res Branch, Div AIDS, NIH, Bethesda, MD 20892 USA. Johns Hopkins Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Johns Hopkins Univ Malawi Project, Blantyre, Malawi. Univ Malawi, Sch Med, Dept Paediat, Blantyre, Malawi. Univ Malawi, Sch Med, Dept Obstet, Blantyre, Malawi. NIAID, HIV Net, NIH, Bethesda, MD 20892 USA. Comp Sci Corp, Rockville, MD USA. George Washington Univ, Sch Med, Dept Pediat, Washington, DC 20052 USA. NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Ioannidis, JPA (reprint author), 23A Kalavryton St, Ano Voula 16673, Greece. RI Ioannidis, John/G-9836-2011 NR 25 TC 28 Z9 29 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD AUG PY 1999 VL 28 IS 4 BP 769 EP 775 DI 10.1093/ije/28.4.769 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 232AR UT WOS:000082344000026 PM 10480709 ER PT J AU Toma, S Ugolini, D Palumbo, R AF Toma, S Ugolini, D Palumbo, R TI Tamoxifen in the treatment of metastatic malignant melanoma: Still a controversy? (Review) SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE tamoxifen; malignant melanoma; biological response modifiers ID SOUTHWEST-ONCOLOGY-GROUP; PHASE-II TRIAL; ANTIESTROGEN-BINDING SITES; PROTEIN-KINASE-C; ESTROGEN-RECEPTOR; COMBINATION CHEMOTHERAPY; 13-CIS-RETINOIC ACID; INTERFERON-ALPHA; PLUS TAMOXIFEN; BREAST-CANCER AB This review attempts to summarize the available preclinical and clinical evidence supporting the inclusion of tamoxifen (TAM) in the treatment of malignant melanoma, in the attempt to identify what role, if any, the antiestrogen could have in the present and future therapeutic approach to this disease. Emphasis has been given to the biological basis of the potential TAM mechanisms of action, as well as to the rational basis underlying the study design of the reported clinical experiences. Results to date show that TAM has no useful activity as a single agent in melanoma patients, most published response rates reaching less than 10%. A still controversial question is the inclusion of the antiestrogen in different active chemotherapy regimens, since clinical investigations on the role of TAM in combination therapy of advanced melanoma have produced inconclusive results. While several early trials suggested that TAM may improve the response rates when combined with different cytotoxic agents, the majority of subsequent reports, including recent randomized studies, did not show a significant benefit stemming from TAM addition to various single-agent or multi-agent combinations. Only one controlled trial showed a significant improvement in both response rate and survival for patients receiving dacarbazine plus TAM, an effect primarily noted in women, and confirmatory studies have not been reported. From a biological standpoint, why the activity of this poorly effective single-agent is potentiated when given in combination with some cytotoxic agents is not clearly understood, although preclinical and clinical experiences support a possible synergistic effect of TAM combined with cisplatin, particularly when the former is added at high doses. Of major interest is a body of experimental studies producing confirmatory data that induction of apoptosis, probably through the inhibition of protein kinase C, as well angiogenesis inhibition, at least in part mediated by TGF-beta stimulation, are alternative ways through which TAM suppresses tumor cell growth, independently of the expression of estrogen receptors. These findings also provide a model and rationale for combining TAM with agents which are able to modify cell biology in melanoma. The investigation on TAM-containing biological combinations appears to be a promising avenue to be explored in the near future. To this end, clinical research should incorporate biological studies to allow the selection of subgroups of patients who are most likely to benefit from TAM-based treatment. C1 Univ Genoa, Dept Clin & Exptl Oncol, Documentat Ctr, Genoa, Italy. Univ Genoa, Natl Canc Inst, Genoa, Italy. RP Toma, S (reprint author), Univ Genoa, Natl Inst Canc Res, Dept Med Oncol, Largo Rosanna Benzi 10, I-16132 Genoa, Italy. NR 87 TC 11 Z9 11 U1 0 U2 2 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD AUG PY 1999 VL 15 IS 2 BP 321 EP 337 PG 17 WC Oncology SC Oncology GA 216XH UT WOS:000081469400017 PM 10402244 ER PT J AU Zahn, TP Mirsky, AF AF Zahn, TP Mirsky, AF TI Autonomic activity during task performance in adults with closed head injury SO INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY LA English DT Article DE brain injury; autonomic nervous system; skin conductance; heart rate; attention; task demands ID TRAUMATIC BRAIN INJURY; DISRUPTIVE BEHAVIOR DISORDERS; REACTION-TIME; SCHIZOPHRENIA; DYSFUNCTION; BOYS AB Skin conductance (SC) and heart rate (HR) were recorded in two experiments in persons who had suffered a closed head injury (CHI) at least 2 years previously and in control subjects. Experiment 1 consisted of a rest period, a series of innocuous tones, and a short simple reaction time (RT) task. Experiment 2 consisted of initial and final rest periods and a longer RT task with constant and variable preparatory intervals. The results from both protocols showed no group differences in HR, SC levels, or SC fluctuations during rest periods, but the SC variables increased less to the task instructions in the CHI group. There were no differences in SC response frequency or magnitude to innocuous tones, but the CHI subjects had fewer SC responses to the RT stimuli in both experiments. SC responses to both innocuous tones and RT stimuli had longer latencies in the CHI group. The results show that selective deficits in tonic and phasic autonomic responding to meaningful, significant, or demanding situations and stimuli are long-term sequelae to CHI. These attenuated activation increases may be related to inadequate mobilization of processing resources and to behavioral deficits shown by these patients. Published by Elsevier Science B.V. C1 NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Zahn, TP (reprint author), NIMH, Lab Brain & Cognit, Bldg 10,Rm 4C104,MSC 1366, Bethesda, MD 20892 USA. NR 25 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8760 J9 INT J PSYCHOPHYSIOL JI Int. J. Psychophysiol. PD AUG PY 1999 VL 33 IS 2 BP 113 EP 126 DI 10.1016/S0167-8760(99)00030-6 PG 14 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 232LT UT WOS:000082372800002 PM 10489076 ER PT J AU Senderowicz, AM AF Senderowicz, AM TI Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE cell cycle; flavopiridol; cyclin-dependent kinases; cyclin D1; flavonoids; chemotherapy; protein kinases; signal transduction; clinical trials ID SQUAMOUS-CELL CARCINOMAS; CDK-ACTIVATING KINASE; BREAST-CANCER CELLS; RNA-POLYMERASE-II; RETINOBLASTOMA PROTEIN; DRUG FLAVOPIRIDOL; APOPTOSIS; ARREST; GROWTH; LEUKEMIA AB The discovery and cloning of the cyclin-dependent kinases (cdks), main regulators of cell cycle progression, allowed several investigators to design novel modulators of cdk activity. Flavopiridol (HMR 1275, L86-8275), a flavonoid derived from an indigenous plant from India, demonstrated potent and specific in vitro inhibition of all cdks tested (cdks 1, 2, 4 and 7) with clear block in cell cycle progression at the G1/S and G2/M boundaries. Moreover, preclinical studies demonstrated the capacity of flavopiridol to induce programmed cell death, promote differentiation, inhibit angiogenic processes and modulate transcriptional events. The relationship between the latter effects and cdk inhibition is still unclear. Initial testing in early clinical human trials with infusional flavopiridol showed activity in some patients with non-Hodgkin's lymphoma, renal, prostate, colon and gastric carcinomas. Main side effects were secretory diarrhea and a pro-inflammatory syndrome associated with hypotension. Biologically active plasma concentrations of flavopiridol (similar to 300-500 nM) are easily achievable in patients receiving infusional flavopiridol. Phase 2 trials with infusional flavopiridol in several tumor types, other schedules and combination with standard chemotherapies are being assessed. In conclusion, flavopiridol is the first cdk inhibitor to be tested in clinical trials. Although important questions remain to be answered, this positive experience will stimulate the development of novel cdk modulators for cancer therapy. C1 NCI, Div Canc Treatment & Diag, Dev Therapeut Program, DTP Clin Trials Unit, Bethesda, MD 20892 USA. RP Senderowicz, AM (reprint author), NCI, Div Canc Treatment & Diag, Dev Therapeut Program, DTP Clin Trials Unit, 10 Ctr Dr,Bldg 10,Room 6N113, Bethesda, MD 20892 USA. NR 55 TC 163 Z9 174 U1 3 U2 17 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0167-6997 J9 INVEST NEW DRUG JI Invest. New Drugs PD AUG PY 1999 VL 17 IS 3 BP 313 EP 320 DI 10.1023/A:1006353008903 PG 8 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 269LH UT WOS:000084478300008 PM 10665481 ER PT J AU Ohta, K Wiggert, B Taylor, AW Streilein, JW AF Ohta, K Wiggert, B Taylor, AW Streilein, JW TI Effects of experimental ocular inflammation on ocular immune privilege SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID ENDOTOXIN-INDUCED UVEITIS; EXPERIMENTAL AUTOIMMUNE UVEORETINITIS; ORTHOTOPIC CORNEAL ALLOGRAFTS; RETINOID-BINDING PROTEIN; GENE-RELATED PEPTIDE; ANTERIOR-CHAMBER; AQUEOUS-HUMOR; HISTOCOMPATIBILITY ANTIGENS; ACTIVE SUPPRESSION; SOLUBLE-ANTIGEN AB PURPOSE. TO determine whether the inflammation of endotoxin-induced uveitis (EIU) andexperi mental autoimmune uveoretinitis (EAU) alters key in vivo and in vitro parameters of ocular immune privilege. METHODS. For EIU induction, C3H/HeN mice received 200 mu g lipopolysaccharide (LPS). Por EAU induction, B10.A mice were immunized with 50 mu g interphotoreceptor retinoid-binding protein (IRBP) mixed with complete Freund's adjuvant. aqueous humor (AqH) was collected at periodic intervals and assayed for leukocyte content and the ability to suppress or enhance T-cell proliferation. Eyes with EAU were assessed for the capacity to support anterior chamber (AC)-associated immune deviation (ACAID) induction after injection of ovalbumin (OVA). RESULTS. Inflammation within the anterior segment in EIU peaked at 12 to 24 hours and was detected from 10 days onward in EAU. In AqH of EIU, protein content rose within 4 hours, followed by infiltrating leukocytes. EIU AqH promptly lost its capacity to suppress T-cell proliferation and became mitogenic for T cells. In AqH of EAU, protein and leukocyte content rose at 11 days and continued to remain elevated thereafter. Whereas 11-day EAU AqH failed to suppress T-cell proliferation, AqH at later time points reacquired immunosuppressive properties. Injection of OVA into the AC of eyes of mice with EAU failed to induce ACAID. CONCLUSIONS. The intraocular inflammation of EIU and EAU disrupted important parameters of immune privilege, ranging from breakdown of the blood- ocular barrier, to loss of an immunosuppressive microenvironment, to abrogation of ACAID. Because AqH from inflamed EAU reacquired the ability to suppress T-cell proliferation, the authors conclude that the capacity to regulate immune expression and inflammation can be a property even of inflamed eyes. C1 Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. NIH, Lab Retinal & Mol Biol, Bethesda, MD 20892 USA. RP Streilein, JW (reprint author), Harvard Univ, Sch Med, Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. FU NEI NIH HHS [EY05678] NR 30 TC 38 Z9 42 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 1999 VL 40 IS 9 BP 2010 EP 2018 PG 9 WC Ophthalmology SC Ophthalmology GA 221XY UT WOS:000081754000017 PM 10440255 ER PT J AU Del Rio-Tsonis, K Tomarev, SI Tsonis, PA AF Del Rio-Tsonis, K Tomarev, SI Tsonis, PA TI Regulation of Prox 1 during lens regeneration SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID VERTEBRATE EYE DEVELOPMENT; HOMEOBOX-CONTAINING GENE; EYELESS GENE; EXPRESSION; DROSOPHILA; PAX-6; INDUCTION; PROSPERO; ANIRIDIA; RETINA AB PURPOSE. To determine the expression pattern of Prox 1 during the process of lens regeneration in the urodele Notophthalmus viridescens. METHODS. Polymerase chain reaction was performed to amplify a partial newt Prox 1 sequence. In situ hybridization and immunodetection methods were used to detect the Prox 1 mRNA and the Prox 1 protein, respectively. RESULTS. Prox 1 mRNA was present in the retina and in the lens (in the epithelium and bow region) of the intact eye. Prox 1 protein was found to be predominantly present in the lens and dorsal iris of the intact eye, although some trace levels of Prox 1 protein were detected in the ventral iris as well. After lentectomy, expression of the mRNA was also pronounced in the dorsal dedifferentiating iris and the regenerating lens. The ventral iris also expressed Prox 1 but seemingly at lower levels. Although Prox 1 protein showed upregulation in the dorsal iris during the process of lens regeneration, trace levels were also detected in the ventral iris. In the retina, Prox 1 protein was distributed in horizontal cells of the inner nuclear layer, whereas the mRNA was expressed in all layers of the retina. CONCLUSIONS. Prox 1 was unevenly distributed in the intact cells of the newt iris, with significantly higher levels of Prox 1 protein present in the dorsal versus the ventral margin. This protein was differentially regulated during the process of lens regeneration, with obvious upregulation in the dorsal iris. Prox 1 is the first transcriptional factor to be shown to be regulated in the dorsal versus ventral iris during the process of lens regeneration. C1 Univ Dayton, Mol Biol Lab, Dept Biol, Dayton, OH 45469 USA. NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Del Rio-Tsonis, K (reprint author), Univ Dayton, Mol Biol Lab, Dept Biol, Dayton, OH 45469 USA. FU NEI NIH HHS [EY10540] NR 34 TC 30 Z9 30 U1 1 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 1999 VL 40 IS 9 BP 2039 EP 2045 PG 7 WC Ophthalmology SC Ophthalmology GA 221XY UT WOS:000081754000021 PM 10440259 ER PT J AU Wiesler, DG Wen, H Wolff, SD Balaban, RS AF Wiesler, DG Wen, H Wolff, SD Balaban, RS TI Improved field of view-reducing gradient insert: Artifacts and application to cardiac imaging SO JMRI-JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE reduced field of view; perfusion; cardiac MRI; coverage; resolution; artifacts; homogeneity spoiling ID MRI AB An improved homogeneity-spoiling local gradient insert has been constructed and built into the patient bed to reduce its impact on bore size and setup time, It allows the field of view to be reduced without introducing aliasing artifacts, Image quality and artifacts were evaluated for pulse sequences relevant to cardiac imaging, The utility of the insert is demonstrated by a contrast-enhanced perfusion study, in which the reduced field of view allowed a 25% increase in resolution and one more slice to be imaged per heartbeat. (C) 1999 Wiley-Liss, Inc. C1 NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. RP Wen, H (reprint author), NHLBI, Cardiac Energet Lab, NIH, Bldg 10,Room B1D-416,MSC-1061,10 Ctr Dr, Bethesda, MD 20892 USA. RI Balaban, Robert/A-7459-2009; Wen, Han/G-3081-2010 OI Balaban, Robert/0000-0003-4086-0948; Wen, Han/0000-0001-6844-2997 NR 20 TC 2 Z9 2 U1 0 U2 1 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1053-1807 J9 JMRI-J MAGN RESON IM JI JMRI-J. Magn. Reson. Imaging PD AUG PY 1999 VL 10 IS 2 BP 209 EP 215 DI 10.1002/(SICI)1522-2586(199908)10:2<209::AID-JMRI16>3.0.CO;2-I PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 270ZL UT WOS:000084567000016 PM 10441027 ER PT J AU Hertle, RW Dell'Osso, LF AF Hertle, RW Dell'Osso, LF TI Vertical latent nystagmus component and vertical saccadic asymmetries in subjects with dissociated vertical deviation SO JOURNAL OF AAPOS LA English DT Letter C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. Case Western Reserve Univ, Dept Neurol, Cleveland, OH 44106 USA. Case Western Reserve Univ, Dept Neurol & Biochem Engn, Cleveland, OH 44106 USA. RP Hertle, RW (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Room 2A50, Bethesda, MD 20892 USA. NR 1 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 1091-8531 J9 J AAPOS JI J. AAPOS PD AUG PY 1999 VL 3 IS 4 BP 257 EP 257 DI 10.1016/S1091-8531(99)70014-5 PG 1 WC Ophthalmology; Pediatrics SC Ophthalmology; Pediatrics GA 226VG UT WOS:000082042700014 PM 10477232 ER PT J AU Lahey, BB Goodman, SH Waldman, ID Bird, H Canino, G Jensen, P Regier, D Leaf, PJ Gordon, R Applegate, B AF Lahey, BB Goodman, SH Waldman, ID Bird, H Canino, G Jensen, P Regier, D Leaf, PJ Gordon, R Applegate, B TI Relation of age of onset to the type and severity of child and adolescent conduct problems SO JOURNAL OF ABNORMAL CHILD PSYCHOLOGY LA English DT Article DE conduct problems; age of onset; conduct disorder; attention-deficit hyperactivity disorder; oppositional defiant disorder ID DISRUPTIVE BEHAVIOR DISORDERS; DSM-III DISORDERS; CRITERION VALIDITY; DELINQUENCY RISK; OF-ONSET; TAXONOMY AB In a cross-sectional household sample of 9-through 17-year-old youths from 4 U.S. communities, youths with earlier ages of onset of conduct problems engaged in more conduct problems than youths with later ages of onset when current age and gender were controlled. Specifically, youths with earlier ages of onset were more likely to engage in several types of physical aggression, frequent lying, theft, and vandalism and were less likely to engage in only truancy. There also was an inverse relation between age of onset and level of functional impairment, mental health service use, and meeting diagnostic criteria for conduct disorder, attention-deficit hyperactivity disorder, and oppositional defiant disorder. Within the limits of cross-sectional data, these results support the hypothesis that key aspects of the heterogeneity of conduct problems among youths are related to the age of onset of conduct problems. C1 Univ Chicago, Dept Psychiat MC 3077, Chicago, IL 60637 USA. Univ Chicago, Natl Opin Res Ctr, Chicago, IL 60637 USA. Emory Univ, Atlanta, GA 30322 USA. Columbia Univ, New York, NY USA. Univ Puerto Rico, San Juan, PR 00936 USA. NIMH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD USA. Univ Miami, Coral Gables, FL 33124 USA. RP Lahey, BB (reprint author), Univ Chicago, Dept Psychiat MC 3077, 5841 S Maryland Ave, Chicago, IL 60637 USA. OI Jensen, Peter/0000-0003-2387-0650 NR 30 TC 41 Z9 42 U1 3 U2 6 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0091-0627 J9 J ABNORM CHILD PSYCH JI J. Abnorm. Child Psychol. PD AUG PY 1999 VL 27 IS 4 BP 247 EP 260 DI 10.1023/A:1022661224769 PG 14 WC Psychology, Clinical; Psychology, Developmental SC Psychology GA 231NZ UT WOS:000082317800001 PM 10503644 ER PT J AU Richters, JE Hinshaw, SP AF Richters, JE Hinshaw, SP TI The abduction of disorder in psychiatry SO JOURNAL OF ABNORMAL PSYCHOLOGY LA English DT Article ID MENTAL DISORDER; HARMFUL DYSFUNCTION; DEVELOPMENTAL PSYCHOPATHOLOGY; CONDUCT DISORDER; CRITIQUE AB The evolutionary cornerstone of J. C. Wakefield's (1999) harmful dysfunction thesis is a faulty assumption of comparability between mental and biological processes that overlooks the unique plasticity and openness of the brain's functioning design. This omission leads Wakefield to an idealized concept of natural mental functions, illusory interpretations of mental disorders as harmful dysfunctions, and exaggerated claims for the validity of his explanatory and stipulative proposals. The authors argue that there are numerous ways in which evolutionarily intact mental and psychological processes, combined with striking discontinuities within and between evolutionary and contemporary social/cultural environments, may cause nondysfunction variants of many widely accepted major mental disorders. These examples undermine many of Wakefield's arguments for adopting a harmful dysfunction concept ol mental disorder. C1 NIMH, Dev Psychopathol & Prevent Res Branch, Rockville, MD 20852 USA. Univ Calif Berkeley, Berkeley, CA 94720 USA. RP Richters, JE (reprint author), NIMH, Dev Psychopathol & Prevent Res Branch, 6001 Execut Blvd, Rockville, MD 20852 USA. EM jrichter@nih.gov OI Richters, John/0000-0002-6780-1828 NR 31 TC 17 Z9 17 U1 0 U2 0 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0021-843X J9 J ABNORM PSYCHOL JI J. Abnorm. Psychol. PD AUG PY 1999 VL 108 IS 3 BP 438 EP 445 PG 8 WC Psychology, Clinical; Psychology, Multidisciplinary SC Psychology GA 228CV UT WOS:000082120000008 PM 10466267 ER PT J AU Daar, ES Lynn, H Donfield, S Gomperts, E Hilgartner, MW Hoots, K Chernoff, D Winkler, C O'Brien, SJ AF Daar, ES Lynn, H Donfield, S Gomperts, E Hilgartner, MW Hoots, K Chernoff, D Winkler, C O'Brien, SJ CA Hemophilia Growth Dev Study TI Effects of plasma HIV RNA, CD4(+) T lymphocytes, and the chemokine receptors CCR5 and CCR2b on HIV disease progression in hemophiliacs SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE genetic resistance; host factors; markers; viral load; chemokine receptors ID IMMUNODEFICIENCY-VIRUS TYPE-1; VIRAL LOAD; INFECTION; AIDS; COHORT; GENE; TRANSMISSION; PHENOTYPE; VARIANTS; POLYMORPHISM AB We have investigated the effects of plasma HIV RNA, CD4(+) T lymphocytes and chemokine receptors CCR5 and CCR2b on HIV disease progression in hemophiliacs. We prospectively observed during follow-up 207 HIV-infected hemophiliacs in the Hemophilia Growth and Development Study. Plasma HIV RNA was measured on cryopreserved plasma from enrollment using the Chiron Corporation bDNA (version 2.0) assay. Genoytpe variants CCR2b-64I and CCR5-Delta 32 were detected using standard molecular techniques. Those with the mutant allele for CCR2b, and to a lesser extent CCR5, had lower plasma HIV RNA, and higher CD4(+) T lymphocytes than did those without these genetic variants. After controlling for the effects of plasma HIV RNA and CD4(+) T lymphocytes, those with the CCR2b mutant allele compared with those wild-type, had a trend toward a lower risk of progression to AIDS, adjusted relative hazard of 1.94 (95% confidence interval [CI], 0.9-4.18; p = .092), and AIDS-related death, relative hazard 1.97 (95% CI, 0.98-4.00; p = .059). We conclude that plasma HIV RNA, CD4(+) T lymphocytes, and CCR genotypes are correlated, and the protective affect of CCR2b against HIV disease progression is not completely explained by plasma HIV RNA or CD4(+) T-lymphocyte number. C1 Cedar Sinai Burns & Allen Res Inst, Div Infect Dis, Dept Med, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. Rho Inc, Chapel Hill, NC USA. Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. New York Hosp, Cornell Med Ctr, Div Pediat Hematol & Oncol, New York, NY 10021 USA. Univ Texas, Sch Med, Dept Pediat, Houston, TX USA. Univ Texas, Sch Med, Dept Internal Med, Houston, TX USA. Chiron Corp, Emeryville, CA 94608 USA. Sci Applicat Int Corp, Frederick, MD USA. NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, SAIC Frederick, Frederick, MD USA. NCI, Lab Genom Divers, Frederick, MD 21701 USA. RP Daar, ES (reprint author), Cedars Sinai Med Ctr, Div Infect Dis, B217,8700 Beverly Blvd, Los Angeles, CA 90048 USA. FU NCRR NIH HHS [MO1-RR06020]; NICHD NIH HHS [N01-HD-4-3200]; PHS HHS [MCJ-060570] NR 44 TC 15 Z9 16 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-9450 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. PD AUG 1 PY 1999 VL 21 IS 4 BP 317 EP 325 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 219NU UT WOS:000081614000010 PM 10428111 ER PT J AU Feigal, E AF Feigal, E TI Second National AIDS Malignancy Conference SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Editorial Material C1 NCI, NIH, Bethesda, MD 20892 USA. RP Feigal, E (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-9450 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. PD AUG 1 PY 1999 VL 21 SU 1 BP S2 EP S4 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 220KH UT WOS:000081663800001 ER PT J AU Jacobson, LP Yamashita, TE Detels, R Margolick, JB Chmiel, JS Kingsley, LA Melnick, S Munoz, A AF Jacobson, LP Yamashita, TE Detels, R Margolick, JB Chmiel, JS Kingsley, LA Melnick, S Munoz, A CA Multicenter AIDS Cohort Study TI Impact of potent antiretroviral therapy on the incidence of Kaposi's sarcoma and non-Hodgkin's lymphomas among HIV-1-infected individuals SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article; Proceedings Paper CT 2nd National Aids Malignancy Conference CY APR 06-08, 1998 CL NATL INST HLTH, BETHESDA, MARYLAND SP NIH, NCI HO NATL INST HLTH DE Kaposi's sarcoma; non-Hodgkin's lymphoma; potent antiretroviral therapy; incidence; effectiveness ID MULTICENTER AIDS COHORT; PERIPHERAL-BLOOD; HIV-INFECTION; HERPESVIRUS; VIRUS; ANTIBODIES; HHV-8; CELLS; DNA AB Effective HIV-1 therapies may directly or indirectly impact the development of AIDS-associated malignancies. Using data from the Multicenter AIDS Cohort Study, a longitudinal cohort study of the natural history of HIV-1 infection among homosexual men, the incidence rates of Kaposi's sarcoma (KS) and non-Hodgkin's lymphoma (NHL) over calendar time were determined for the 1813 HIV-1-seropositive men enrolled in 1984 through 1985. Poisson regression models were used to identify statistically significant temporal trends. Nested case control studies were used to assess whether recent cases of these malignancies represented treatment breakthroughs. The incidence of KS as a presenting AIDS illness significantly (p = .003) declined from 25.6 cases per 1000 person-years (95% confidence interval [CI], 21.8-29.9) in the early 1990s to an average incidence of 7.5 per 1000 person-years (95% CI, 3.4-16.7) in 1996 through 1997. In contrast, the incidence of NHL has continued to increase significantly (p < .001) at a rate of 21% per year since 1985, although a possible recent decrease is suggested. None of the recent KS cases and only 1 of 8 NHL cases had used the potent antiretroviral therapies, compared with >70 percent of the HIV-1-seropositive men who were free of malignancies and observed over the same time period. These results may be due to an indirect protection against developing KS by the boosting of the immune system by antiretroviral therapies. However, it is important to clarify the direct therapeutic effect on the pathogenic disease mechanism of human herpesvirus type 8 (HHV-8), the agent postulated to be important in the causal pathway of KS. The absence of a similar effect on NHL may be due to a lack of effect on its pathogenesis or because potent antiretroviral therapies need to be administered early in the disease process and the cases that have occurred represent outcomes following a long latency period. With additional follow-up, an impact on NHL may yet be observed. C1 Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. Northwestern Univ, Sch Med, Chicago, IL USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. NCI, NIH, Bethesda, MD 20892 USA. RP Jacobson, LP (reprint author), Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. FU NCRR NIH HHS [5-M01-RR-00722]; NIAID NIH HHS [UO1-AI-35042, UO1-AI-35043] NR 30 TC 121 Z9 122 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-9450 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. PD AUG 1 PY 1999 VL 21 SU 1 BP S34 EP S41 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 220KH UT WOS:000081663800008 PM 10430217 ER PT J AU Rabkin, CS Testa, MA Huang, J Von Roenn, JH AF Rabkin, CS Testa, MA Huang, J Von Roenn, JH TI Kaposi's sarcoma and non-Hodgkin's lymphoma incidence trends in AIDS clinical trial group study participants SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article; Proceedings Paper CT 2nd National Aids Malignancy Conference CY APR 06-08, 1998 CL NATL INST HLTH, BETHESDA, MARYLAND SP NIH, NCI HO NATL INST HLTH DE AIDS; antiretroviral therapy; protease inhibitors; Kaposi's sarcoma; non-Hodgkin's lymphoma ID THERAPY; INFECTION; DRUGS; RISK AB Combination therapy with protease inhibitors and nucleoside analogues dramatically suppresses plasma HIV-1 RNA and delays progression to AIDS, but the impact on HIV-associated malignancy remains to be established. We therefore examined incidence trends of Kaposi's sarcoma and non-Hodgkin's lymphoma in patients with advanced HIV infection in nine AIDS Clinical Trial Group studies of antiviral therapies for HIV and cytomegalovirus infections. Among a total of 6587 patients enrolled between November 1987 and February 1997, there were 280 cases of Kaposi's sarcoma and 68 cases of non-Hodgkin's lymphoma. Incidence rates per 100 person-years of both malignancies declined in concert with decreases in mortality, but the decreases in Kaposi's sarcoma were more profound and consistent than the decreases in non-Hodgkin's lymphoma. These data suggest that current therapies have ameliorated the incidence of Kaposi's sarcoma, but may not have had an equal effect on non-Hodgkin's lymphoma. C1 NCI, Viral Epidemiol Branch, Rockville, MD 20852 USA. Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. Northwestern Univ, Dept Med, Div Hematol Oncol, Chicago, IL 60611 USA. RP Rabkin, CS (reprint author), NCI, Viral Epidemiol Branch, 6120 Execut Blvd,MSC 7248, Rockville, MD 20852 USA. NR 8 TC 48 Z9 50 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-9450 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. PD AUG 1 PY 1999 VL 21 SU 1 BP S31 EP S33 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 220KH UT WOS:000081663800007 PM 10430216 ER PT J AU Yarchoan, R AF Yarchoan, R TI Therapy for Kaposi's sarcoma: Recent advances and experimental approaches SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article; Proceedings Paper CT 2nd National Aids Malignancy Conference CY APR 06-08, 1998 CL NATL INST HLTH, BETHESDA, MARYLAND SP NIH, NCI HO NATL INST HLTH DE Kaposi's sarcoma; therapy; angiogenesis; human herpesvirus type 8; liposomal anthracyclines; paclitaxel ID ACQUIRED IMMUNODEFICIENCY SYNDROME; INTERFERON-INDUCIBLE PROTEIN-10; TRANS-RETINOIC ACID; PEGYLATED-LIPOSOMAL DOXORUBICIN; HUMAN CHORIONIC-GONADOTROPIN; IMMUNE-DEFICIENCY SYNDROME; FIBROBLAST GROWTH-FACTOR; BLOOD MONONUCLEAR-CELLS; ANGIOGENESIS IN-VIVO; DNA-SEQUENCES AB The past several years have seen demonstrable progress in the therapy of Kaposi's sarcoma (KS). Liposomal anthracyclines and paclitaxel have been found to be highly effective chemotherapeutic agents for this disease. Recent advances in our understanding of the pathogenesis of KS have led to the consideration of various new experimental agents. Two antiangiogenesis agents, TNP-470 and thalidomide, have been determined to induce some responses in KS, and others are now in early clinical trials or in preclinical development. Oral 9-cis retinoic acid has been shown to have anti-KS activity, and preliminary studies suggest that a urinary protein found in preparations of human chorionic gonadotropin also has activity. Effective anti-HIV treatment has been shown to affect the growth of KS, and the discovery of a new herpesvirus as a causative agent for KS has offered new potential targets for attack. C1 NCI, HIV & AIDS Malignancy Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Yarchoan, R (reprint author), NCI, HIV & AIDS Malignancy Branch, Div Clin Sci, NIH, Bldg 10,Room 12N226,MSC 1906,10 Ctr Dr, Bethesda, MD 20892 USA. NR 82 TC 23 Z9 23 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-9450 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. PD AUG 1 PY 1999 VL 21 SU 1 BP S66 EP S73 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 220KH UT WOS:000081663800012 PM 10430221 ER PT J AU Cassano, GB Dell'Osso, L Frank, E Miniati, M Fagiolini, A Shear, K Pini, S Maser, J AF Cassano, GB Dell'Osso, L Frank, E Miniati, M Fagiolini, A Shear, K Pini, S Maser, J TI The bipolar spectrum: a clinical reality in search of diagnostic criteria and an assessment methodology SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE bipolar spectrum; bipolar II disorder; hypomania; subthreshold bipolarity ID DEFICIT HYPERACTIVITY DISORDER; II DISORDER; UNIPOLAR DEPRESSION; MIXED STATES; MANIA; COMORBIDITY; PREVALENCE; TEMPERAMENT; HYPOMANIA; SYMPTOMS AB Failure to recognize subthreshold expressions of mania contributes to the frequent under-diagnosis of bipolar disorder. There are several reasons for the lower rate of recognition of subthreshold manic symptoms, when compared to the analogous pure depressive ones. These include the lack of subjective suffering, enhanced productivity, ego-syntonicity, and diurnal and seasonal rhythmicity associated with many of the manic and hypomanic symptoms, and the psychiatrists' tendency to subsume persistent or even alternating symptoms among personality disorders. Furthermore, the central diagnostic importance placed on alterations in mood distracts clinicians from paying attention to other more subtle but clinically meaningful symptoms, such as changes in energy, neurovegetative symptoms and distorted cognitions. Although officially accepted in both ICD-10 and DSM-IV, we believe bipolar II disorder is underdiagnosed because of inattention to symptoms of hypomania, Moreover, by requiring the presence of both full-blown hypomanic and major depressive episodes, current nosology fails to include symptoms or signs which are mild and do not meet threshold criteria. There is already agreement in the field that such symptoms are important for depression. We now propose that attention should also be devoted to mild symptomatic manifestations of a manic diathesis, even if such manifestations may sometimes enhance quality of life. The term 'spectrum' is used to refer to the broad range of such manifestations of a disorder from core symptoms to temperamental traits. Spectrum manifestations may be present during, between, or even in the absence of, an episode of full-blown disorder. We have developed a structured clinical interview to assess the mood spectrum (SCI-MOODS) to evaluate the whole range of depressive and manic symptoms. This instrument is currently undergoing psychometric testing procedures. Similar to the SCID interview, the SCI-MOODS interview provides a separate rating for each of the major DSM-IV(TM) symptoms, but the latter also identifies and rates subthreshold and atypical manifestations. This paper presents the concept of a subthreshold bipolar disorder and discusses the potential epidemiological, diagnostic and therapeutic relevance of such a spectrum conditions. We also describe the SCI-MOODS interview used reliably to identify the occurrence of a bipolar spectrum condition. Obviously a great deal of systematic research needs to be conducted to ascertain the reliability and validity of subthreshold bipolarity as summarized in this paper and embodied in our instrument. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Univ Pisa, Dept Psychiat Neurobiol Pharmacol & Biotechnol, I-56100 Pisa, Italy. Univ Pittsburgh, Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. Univ Modena, Inst Psychiat, I-41100 Modena, Italy. NIMH, Rockville, MD 20857 USA. RP Cassano, GB (reprint author), Univ Pisa, Dept Psychiat Neurobiol Pharmacol & Biotechnol, Via Roma 67, I-56100 Pisa, Italy. RI Miniati, Mario/N-1226-2016; OI Miniati, Mario/0000-0001-7536-9927; FAGIOLINI, ANDREA/0000-0001-5827-0853 NR 62 TC 150 Z9 158 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD AUG PY 1999 VL 54 IS 3 BP 319 EP 328 DI 10.1016/S0165-0327(98)00158-X PG 10 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 225LB UT WOS:000081962100013 PM 10467978 ER PT J AU Cohen, SG AF Cohen, SG TI Max Samter, MD - In lasting tribute SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Biographical-Item C1 NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Cohen, SG (reprint author), NIH, Dept Hlth & Human Serv, Bldg 10, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD AUG PY 1999 VL 104 IS 2 BP 274 EP 275 DI 10.1016/S0091-6749(99)70364-7 PN 1 PG 2 WC Allergy; Immunology SC Allergy; Immunology GA 232HH UT WOS:000082364800013 ER PT J AU Liddington, R Pannifer, A Hanna, P Collier, RJ AF Liddington, R Pannifer, A Hanna, P Collier, RJ TI Crystallographic studies of the anthrax lethal toxin SO JOURNAL OF APPLIED MICROBIOLOGY LA English DT Article; Proceedings Paper CT 3rd International Conference on Anthrax CY SEP 07-10, 1998 CL UNIV PLYMOUTH, PLYMOUTH, ENGLAND SP Soc Appl Microbiol, DERA, Chem & Biol Defence Sector, Ctr Appl Microbiol & Res, Federat European Microbiol Soc, Soc Gen Microbiol, US DOE, US Army Med Res & Mat Command HO UNIV PLYMOUTH ID PROTECTIVE ANTIGEN C1 Univ Leicester, Dept Biochem, Leicester LE1 7RH, Leics, England. Duke Univ, Med Ctr, Durham, NC 27706 USA. NIH, Microbial Ecol Lab, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. RP Liddington, R (reprint author), Univ Leicester, Dept Biochem, Leicester LE1 7RH, Leics, England. NR 2 TC 8 Z9 10 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 1364-5072 J9 J APPL MICROBIOL JI J. Appl. Microbiol. PD AUG PY 1999 VL 87 IS 2 BP 282 EP 282 DI 10.1046/j.1365-2672.1999.00888.x PG 1 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 237MJ UT WOS:000082659900023 ER PT J AU Leppla, SH Arora, N Varughese, M AF Leppla, SH Arora, N Varughese, M TI Anthrax toxin fusion proteins for intracellular delivery of macromolecules SO JOURNAL OF APPLIED MICROBIOLOGY LA English DT Article; Proceedings Paper CT 3rd International Conference on Anthrax CY SEP 07-10, 1998 CL UNIV PLYMOUTH, PLYMOUTH, ENGLAND SP Soc Appl Microbiol, DERA, Chem & Biol Defence Sector, Ctr Appl Microbiol & Res, Federat European Microbiol Soc, Soc Gen Microbiol, US DOE, US Army Med Res & Mat Command HO UNIV PLYMOUTH ID PROTECTIVE ANTIGEN; LETHAL FACTOR; MAMMALIAN-CELLS; DOMAIN C1 NIDR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Leppla, SH (reprint author), NIDR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. NR 7 TC 27 Z9 29 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 1364-5072 J9 J APPL MICROBIOL JI J. Appl. Microbiol. PD AUG PY 1999 VL 87 IS 2 BP 284 EP 284 DI 10.1046/j.1365-2672.1999.00890.x PG 1 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 237MJ UT WOS:000082659900025 ER PT J AU Duesbery, NS Vande Woude, GF AF Duesbery, NS Vande Woude, GF TI Anthrax lethal factor causes proteolytic inactivation of mitogen-activated protein kinase kinase SO JOURNAL OF APPLIED MICROBIOLOGY LA English DT Article; Proceedings Paper CT 3rd International Conference on Anthrax CY SEP 07-10, 1998 CL UNIV PLYMOUTH, PLYMOUTH, ENGLAND SP Soc Appl Microbiol, DERA, Chem & Biol Defence Sector, Ctr Appl Microbiol & Res, Federat European Microbiol Soc, Soc Gen Microbiol, US DOE, US Army Med Res & Mat Command HO UNIV PLYMOUTH ID MICROTUBULE-ASSOCIATED PROTEIN; MEIOTIC MATURATION; MAP-KINASE; TYROSINE PHOSPHORYLATION; XENOPUS OOCYTES; TRANSFORMATION; INHIBITORS; INDUCTION; CASCADE; P34CDC2 AB A search of the National Cancer Institute's Anti-Neoplastic Drug Screen for compounds with; an inhibitory profile similar to that of the mitogen-activated protein kinase kinase (MAPKK) inhibitor PD098059 yielded anthrax lethal toxin. Anthrax lethal factor was found to inhibit progesterone-induced meiotic maturation of frog oocytes by preventing the phosphorylation and activation of mitogen-activated protein kinase (MAPK). Similarly, lethal tor;in prevented the activation of MAPK in serum stimulated, ras-transformed NIH3T3 cells. In vitro analyses using recombinant proteins indicated that lethal factor proteolytically modified the NH2-terminus of both MAPKK1 and 2, rendering them inactive and hence incapable of activating MAPK. The consequences of this inactivation upon meiosis and transformed cells are also discussed. C1 NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. RP Vande Woude, GF (reprint author), NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, POB B, Frederick, MD 21702 USA. OI DUESBERY, NICK/0000-0002-4258-5655 NR 32 TC 29 Z9 30 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 1364-5072 J9 J APPL MICROBIOL JI J. Appl. Microbiol. PD AUG PY 1999 VL 87 IS 2 BP 289 EP 293 DI 10.1046/j.1365-2672.1999.00892.x PG 5 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 237MJ UT WOS:000082659900028 PM 10475971 ER PT J AU De Voss, JJ Rutter, K Schroeder, BG Barry, CE AF De Voss, JJ Rutter, K Schroeder, BG Barry, CE TI Iron acquisition and metabolism by mycobacteria SO JOURNAL OF BACTERIOLOGY LA English DT Review ID SIDEROPHORE PRODUCTION; EXTRACELLULAR SIDEROPHORE; PSEUDOMONAS-AERUGINOSA; BINDING COMPOUNDS; OXIDATIVE-STRESS; TUBERCULOSIS; SMEGMATIS; IDENTIFICATION; AVIUM; GENES C1 NIAID, Host Def Lab, TB Res Sect, Rockville, MD 20852 USA. Univ Queensland, Dept Chem, Brisbane, Qld 4072, Australia. RP Barry, CE (reprint author), NIAID, Host Def Lab, TB Res Sect, Twinbrook II,Rm 239,12441 Parklawn Dr,MSC 8180, Rockville, MD 20852 USA. RI Barry, III, Clifton/H-3839-2012; OI Rutter, Kerry/0000-0002-1668-6276 FU Intramural NIH HHS [Z01 AI000783-11] NR 86 TC 159 Z9 164 U1 0 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD AUG PY 1999 VL 181 IS 15 BP 4443 EP 4451 PG 9 WC Microbiology SC Microbiology GA 221CH UT WOS:000081706100001 PM 10419938 ER PT J AU Newitt, JA Ulbrandt, ND Bernstein, HD AF Newitt, JA Ulbrandt, ND Bernstein, HD TI The structure of multiple polypeptide domains determines the signal recognition particle targeting requirement of Escherichia coli inner membrane proteins SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ENDOPLASMIC-RETICULUM MEMBRANE; MALTOSE-BINDING PROTEIN; CELL-FREE SYSTEM; 4.5S RNA; SACCHAROMYCES-CEREVISIAE; NASCENT POLYPEPTIDES; ALKALINE-PHOSPHATASE; SECRETORY PROTEIN; TRIGGER FACTOR; ALPHA-FACTOR AB The signal recognition particle (SRP) targeting pathway is required for the efficient insertion of many polytopic inner membrane proteins (IMPs) into the Escherichia coli inner membrane, but in the absence of SRP protein export proceeds normally. To define the properties of IMPs that impose SRP dependence, we analyzed the targeting requirements of bitopic IMPs that are structurally intermediate between exported proteins and polytopic IMPs. We found that disruption of the SRP pathway inhibited the insertion of only a subset of bitopic IMPs. Studies on a model bitopic AcrB-alkaline phosphatase fusion protein (AcrB 265-AP) showed that the SRP requirement for efficient insertion correlated with the presence of a large periplasmic domain (P1). As previously reported, perturbation of the SRP pathway also affected the insertion of a polytopic AcrB-AP fusion. Even exhaustive SRP depletion, however, failed to block the insertion of any AcrB derivative by more than 50%. Taken together, these data suggest that many proteins that are normally targeted by SRP can utilize alternative targeting pathways and that the structure of both hydrophilic and membrane-spanning domains determines the degree to which the biogenesis of a protein is SRP dependent. C1 NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Bernstein, HD (reprint author), NIDDKD, Genet & Biochem Branch, NIH, Bldg 10,Rm 9D-20, Bethesda, MD 20892 USA. EM harris_bernstein@nih.gov NR 53 TC 24 Z9 24 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD AUG PY 1999 VL 181 IS 15 BP 4561 EP 4567 PG 7 WC Microbiology SC Microbiology GA 221CH UT WOS:000081706100017 PM 10419954 ER PT J AU Zheng, M Doan, B Schneider, TD Storz, G AF Zheng, M Doan, B Schneider, TD Storz, G TI OxyR and SoxRS regulation of fur SO JOURNAL OF BACTERIOLOGY LA English DT Article ID UPTAKE REGULATION PROTEIN; ESCHERICHIA-COLI K-12; IRON TRANSPORT; SUPEROXIDE-DISMUTASE; HYDROGEN-PEROXIDE; DNA-BINDING; SEQUENCE; REGULON; FLAVODOXIN; DAMAGE AB The cytotoxic effects of reactive oxygen species are largely mediated by iron. Hydrogen peroxide reacts with iron to form the extremely reactive and damaging hydroxyl radical via the Fenton reaction. Superoxide anion accelerates this reaction because the dismutation of superoxide leads to increased levels of hydrogen peroxide and because superoxide elevates the intracellular concentration of iron by attacking iron-sulfur proteins. We found that regulators of the Escherichia coli responses to oxidative stress, OxyR and SoxRS, activate the expression of Fur, the global repressor of ferric ion uptake. A transcript encoding Fur was induced by hydrogen peroxide in a wild-type strain but not in a Delta oxyR strain, and DNase I footprinting assays showed that OxyR binds to the fur promoter. In cells treated with the superoxide-generating compound paraquat, we observed the induction of a longer transcript encompassing both fur and its immediate upstream gene fldA, which encodes a flavodoxin. This polycistronic mRNA is induced by paraquat in a wild-type strain but not in a Delta soxRS strain, and SoxS was shown to bind to the fldA promoter. These results demonstrate that iron metabolism is coordinately regulated with the oxidative stress defenses. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. NCI, Lab Expt & Computat Biol, Frederick, MD 21702 USA. RP Storz, G (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bldg 18T,Room 101,18 Lib Dr,MSC 5430, Bethesda, MD 20892 USA. OI Schneider, Thomas/0000-0002-9841-1531; Storz, Gisela/0000-0001-6698-1241 NR 35 TC 265 Z9 273 U1 1 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD AUG PY 1999 VL 181 IS 15 BP 4639 EP 4643 PG 5 WC Microbiology SC Microbiology GA 221CH UT WOS:000081706100027 PM 10419964 ER PT J AU Powell, B Peters, HK Nakamura, Y Court, D AF Powell, B Peters, HK Nakamura, Y Court, D TI Cloning and analysis of the rnc-era-recO operon from Pseudomonas aeruginosa SO JOURNAL OF BACTERIOLOGY LA English DT Article ID GTP-BINDING PROTEIN; ESCHERICHIA-COLI; GENE AB The me operon from Pseudomonas aeruginosa has been cloned and characterized. The three genes comprising this operon, me, era, and recO, are arranged similarly to those in some other gram-negative bacteria. Multicopy plasmids carrying the me operon of P. aeruginosa functionally complement mutations of the me, era, and recO genes in Escherichia coli. In particular, the P, aeruginosa era homolog rescues the conditional lethality of era mutants in E, coli, and the presumptive protein has 60% identity with the Era of E. coli. We discuss these data and evidence suggesting that a GTPase previously purified from P. aeruginosa and designated Pra is not an Era homolog. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. Univ Tokyo, Inst Med Sci, Dept Tumor Biol, Tokyo 108, Japan. RP Court, D (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Gene Regulat & Chromosome Biol Lab, POB B, Frederick, MD 21702 USA. NR 18 TC 7 Z9 10 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD AUG PY 1999 VL 181 IS 16 BP 5111 EP 5113 PG 3 WC Microbiology SC Microbiology GA 226GN UT WOS:000082012100053 PM 10438789 ER PT J AU Bohr, VA Anson, RM AF Bohr, VA Anson, RM TI Mitochondrial DNA repair pathways SO JOURNAL OF BIOENERGETICS AND BIOMEMBRANES LA English DT Article DE mitochondrial DNA; DNA; aging ID BASE-EXCISION-REPAIR; HAMSTER OVARY CELLS; XENOPUS-LAEVIS OOCYTES; COLI ENDONUCLEASE-III; OXIDATIVE DAMAGE; POLYMERASE-BETA; MAMMALIAN-CELLS; HUMAN HOMOLOG; SACCHAROMYCES-CEREVISIAE; XERODERMA-PIGMENTOSUM AB It has long been held that there is no DNA repair in mitochondria. Early observations suggested that the reason for the observed accumulation of DNA damage in mitochondrial DNA is that DNA lesions are not removed. This is in contrast to the very efficient repair that is seen in the nuclear DNA. Mitochondrial DNA does not code for any DNA repair proteins, but it has been observed that a number of repair factors can be found in mitochondrial extracts. Most of these participate in the base excision DNA repair pathway which is responsible for the removal of simple lesions in DNA. Recent work has shown that there is efficient base excision repair in mammalian mitochondria and there are also indications of the presence of more complex repair processes. Thus, an active Field of mitochondrial DNA repair is emerging. An understanding of the DNA repair processes in mammalian mitochondria is an important current challenge and it is likely to lead to clarification of the etiology of the common mutations and deletions that are found in mitochondria, and which are thought to cause various human disorders and to play a role in the aging phenotype. C1 NIA, Genet Mol Lab, NIH, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Genet Mol Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 61 TC 47 Z9 48 U1 0 U2 1 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0145-479X J9 J BIOENERG BIOMEMBR JI J. Bioenerg. Biomembr. PD AUG PY 1999 VL 31 IS 4 BP 391 EP 398 DI 10.1023/A:1005484004167 PG 8 WC Biophysics; Cell Biology SC Biophysics; Cell Biology GA 276XV UT WOS:000084904400009 PM 10665528 ER PT J AU Munoz, A Laib, F Petering, DH Shaw, CF AF Munoz, A Laib, F Petering, DH Shaw, CF TI Characterization of the cadmium complex of peptide 49-61: a putative nucleation center for cadmium-induced folding in rabbit liver metallothionein IIA SO JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY LA English DT Article DE metallothionein; peptide-metal complexes; Cd-111 NMR; protein folding; molecular mechanics ID MAGNETIC-RESONANCE SPECTROSCOPY; METAL-BINDING PROPERTIES; 3-DIMENSIONAL STRUCTURE; THIOLATE CLUSTERS; NMR-SPECTROSCOPY; ALPHA-FRAGMENT; BETA-DOMAINS; FORCE-FIELD; AMINO-ACIDS; RAT-LIVER AB The synthetic peptide fragment containing residues 49-61 of rabbit liver metallothionein II (MTII) (Ac-IIe-Cys-Lys- Gly-Ala-Ser-Asp- Lys-Cys-Ser-Cys-Cys-Ala-COOH), which includes the only sequential four cysteines bound to the same metal ion in Cd7MT, forms a stable, monomeric Cd-peptide complex with 1:1 stoichiometry (Cd:peptide) via Cd-thiolate interactions. This represents the first synthesis of a single metal-binding site of MT independent of the domains. The Cd-111 NMR chemical shift at 716 ppm indicates that the Cd-111(2+) in the metal site is terminally coordinated to four side-chain thiolates of the cysteine residues. The pH of half dissociation for this Cd-peptide derivative, similar to 3.3, demonstrates an affinity similar to that for Cd7MT. Molecular mechanics calculations show that the thermodynamically most stable folding for this isolated Cd2+ center has the same counterclockwise chirality (A or S) observed in the native hole-protein. These properties are consistent with its proposed role as a nucleation center for cadmium-induced protein folding. However, the kinetic reactivity of the CdS4 structure toward 5,5' -dithiobis(5-nitrobenzoate) (DTNB) and EDTA is greatly increased compared to the complete cluster (a-domain or hole-protein). The rate law for the reaction with DTNB is rate = (k(uf)+k(1,f) + k(2,f) [DTNB])[peptide], where k(uf)=0.15 s(-1), k(1,f) = 2.59 x 10(-3) s(-1), and k(2,f) = 0.88 M-l s(-l). The ultrafast step (uf), observable only by stopped-flow measurement, is unprecedented for mammalian (M7MT) and crustacean (M6MT) hole-proteins or the isolated domains. The accommodation of other metal ions by the peptide indicates a rich coordination chemistry, including stoichiometries of M-peptide for Hg2+, Cd2+, and Zn2+ M-peptide for Hg2+ and Au+, and (Et3PAu)(2-)peptide. C1 Univ Wisconsin, Dept Chem, Milwaukee, WI 53201 USA. Univ Wisconsin, NIEHS, Marine & Freshwater Biomed Core Ctr, Milwaukee, WI 53201 USA. RP Shaw, CF (reprint author), Eastern Kentucky Univ, Dept Chem, Richmond, KY 40475 USA. FU NIDDK NIH HHS [DK51308]; NIEHS NIH HHS [ES 04184, ES 04026] NR 80 TC 16 Z9 18 U1 1 U2 4 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0949-8257 J9 J BIOL INORG CHEM JI J. Biol. Inorg. Chem. PD AUG PY 1999 VL 4 IS 4 BP 495 EP 507 DI 10.1007/s007750050335 PG 13 WC Biochemistry & Molecular Biology; Chemistry, Inorganic & Nuclear SC Biochemistry & Molecular Biology; Chemistry GA 233NQ UT WOS:000082433300012 PM 10555583 ER PT J AU Ishima, R Torchia, DA AF Ishima, R Torchia, DA TI Estimating the time scale of chemical exchange of proteins from measurements of transverse relaxation rates in solution SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE chemical exchange; protein; relaxation ID N-15 AB Chemical (conformational) exchange on the ms-mu s time scale is reliably identified by the observation of transverse relaxation rates, R-ex, that depend upon the strength of the effective field (omega(1eff) = gamma B-1eff) used in spin lock or CPMG experiments. In order to determine if the exchange correlation time, tau(ex), is the fast or slow limit, measurements of (i) signal line shape and (ii) temperature dependence of R-ex have been commonly used in studies of stable, small molecules. However, these approaches are often not applicable to proteins, because sample stability and solubility, respectively, limit the temperature range and signal sensitivity of experiments. Herein we use a complex, but general, two-site exchange equation to show when the simple fast exchange equations for R-ex are good approximations, in the case of proteins. We then present a simple empirical equation that approximately predicts R-ex in all exchange regimes, and explains these results in a clear, straightforward manner. Finally we show how one can reliably determine whether tau(ex) is in the fast or slow exchange limit. C1 Natl Inst Dent & Craniofacial Res, Struct Mol Biol Unit, NIH, Bethesda, MD 20892 USA. RP Torchia, DA (reprint author), Natl Inst Dent & Craniofacial Res, Struct Mol Biol Unit, NIH, Bethesda, MD 20892 USA. NR 15 TC 78 Z9 78 U1 0 U2 18 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD AUG PY 1999 VL 14 IS 4 BP 369 EP 372 DI 10.1023/A:1008324025406 PG 4 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 234VK UT WOS:000082504900007 PM 10526408 ER PT J AU Sidorova, NY Rau, DC AF Sidorova, NY Rau, DC TI Removing water from an EcoRI-noncognate DNA complex with osmotic stress SO JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS LA English DT Article ID CRYSTAL-STRUCTURE; GEL-ELECTROPHORESIS; PROTEIN STABILITY; LAC REPRESSOR; BINDING; THERMODYNAMICS; SPECIFICITY; ENDONUCLEASE; OPERATOR; SITE AB We recently showed that a nonspecific complex of the restriction nuclease EcoRI with poly (dI-dC) sequesters significantly more water at the protein-DNA interface than the complex with the specific recognition sequence. The nonspecific complex seems to retain almost a full hydration layer at the interface. We now find that at low osmotic pressures a complex of the restriction nuclease EcoRI with a DNA sequence that differs by only one base pair from the recognition site (a 'star' sequence) sequesters about 70 waters more than the specific one, a value virtually indistinguishable from nonspecific DNA. Unlike complexes with oligo (dI-dC) or with a sequence that differs by two base pairs from the recognition sequence, however, much of the water in the 'star' sequence complex is removed at high osmotic pressures. The energy of removing this water can be calculated simply from the osmotic pressure work done on the complex. The ability to measure not only the changes in water sequestered by DNA-protein complexes for different sequences, but also the work necessary to remove this water is a potentially powerful new tool for coupling inferred structural changes and thermodynamics. C1 NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. RP Sidorova, NY (reprint author), NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. NR 43 TC 11 Z9 11 U1 0 U2 1 PU ADENINE PRESS INC PI GUILDERLAND PA PO BOX 355/340, GUILDERLAND, NY 12084 USA SN 0739-1102 J9 J BIOMOL STRUCT DYN JI J. Biomol. Struct. Dyn. PD AUG PY 1999 VL 17 IS 1 BP 19 EP 31 PG 13 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 234YD UT WOS:000082511200002 PM 10496418 ER PT J AU Uzawa, K Grzesik, WJ Nishiura, T Kuznetsov, SA Robey, PG Brenner, DA Yamauchi, M AF Uzawa, K Grzesik, WJ Nishiura, T Kuznetsov, SA Robey, PG Brenner, DA Yamauchi, M TI Differential expression of human lysyl hydroxylase genes, lysine hydroxylation, and cross-linking of type I collagen during osteoblastic differentiation in vitro SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article; Proceedings Paper CT 76th General and Exhibition of the Internatonal-Association-for-Dental-Research Meeting CY JUN, 1998 CL NICE, FRANCE SP Int Assoc Dental Res ID MOLECULAR PACKING; MESSENGER-RNA; BONE; MATRIX; TISSUE; CELLS; OSTEOGENESIS; OSTEOPOROSIS; CLONING; FIBRILS AB The pattern of lysyl hydroxylation in the nontriple helical domains of collagen is critical in determining the cross-linking pathways that are tissue specific. We hypothesized that the tissue specificity of type I collagen cross-linking is, in part, due to the differential expression of lysyl hydroxylase genes (Procollagen-lysine,2-oxyglutarate,5-dioxygenase 1, 2, and 3 [PLOD1, PLOD2, and PLOD3]), In this study, we have examined the expression patterns of these three genes during the course of in vitro differentiation of human osteoprogenitor cells (bone marrow stromal cells [BMSCs]) and normal skin fibroblasts (NSFs), In addition, using the medium and cell layer/matrix fractions in these cultures, lysine hydroxylation of type I collagen or chains and collagen cross-linking chemistries have been characterized, High levels of PLOD1 and PLOD3 genes were expressed in both BMSCs and NSFs, and the expression levels did not change in the course of differentiation. In contrast to the PLOD1 and PLOD3 genes, both cell types showed low PLOD2 gene expression in undifferentiated and early differentiated conditions. However, fully differentiated BMSCs, but not NSFs, exhibited a significantly elevated level (6-fold increase) of PLOD2 mRNA, This: increase coincided with the onset of matrix mineralization and with the increase in lysyl hydroxylation in the nontriple helical domains of at chains of type I collagen molecule. Furthermore, the collagen cross-links that are derived from the nontriple helical hydroxylysine-aldehyde were found only in fully differentiated BMSC cultures. The data suggests that PLOD2 expression is associated with lysine hydroxylation in the nontriple helical domains of collagen and, thus, could be partially responsible for the tissue-specific collagen cross-linking pattern. C1 Univ N Carolina, Dent Res Ctr, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Med, Div Digest Dis, Chapel Hill, NC USA. NIDR, Craniofacial & Skeletal Dis Branch, Bethesda, MD 20892 USA. RP Yamauchi, M (reprint author), Univ N Carolina, Dent Res Ctr, CB 7455,Room 212, Chapel Hill, NC 27599 USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU NIDCR NIH HHS [DE10489]; NIGMS NIH HHS [GM41804] NR 33 TC 83 Z9 85 U1 0 U2 7 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD AUG PY 1999 VL 14 IS 8 BP 1272 EP 1280 DI 10.1359/jbmr.1999.14.8.1272 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 220RV UT WOS:000081682000003 PM 10457259 ER PT J AU Plaut, K Maple, R Ginsburg, E Vonderhaar, B AF Plaut, K Maple, R Ginsburg, E Vonderhaar, B TI Progesterone stimulates DNA synthesis and lobulo-alveolar development in mammary glands in ovariectomized mice SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID BREAST-CANCER-CELLS; ESTROGEN; RECEPTORS; DIFFERENTIATION; ANTIPROGESTIN; ONTOGENY; CULTURE; GROWTH AB The objective of this study was to determine whether sustained progesterone (P) use in the absence of estrogen could influence mammary development in mice. Three-week-old intact or ovariectomized mice were primed with subcutaneous (s.c.) cholesterol (C), estrogen (E), P, or estrogen and progesterone (E/P) together. Nine days after priming, mammary glands were removed and incubated as a whole organ in media supplemented with various combinations of lactogenic hormones. After 5 days in whole organ culture, glands were removed and end buds, alveolar buds and lobulo-alveoli were quantified. Glands from mice primed with C or E developed significantly less lobulo-alveoli than glands from mice primed with P or E/P. While the development was greater in animals treated with E/P compared to those treated with P, it was clear that P in the absence of E could still induce lobulo-alveolar development. We have shown in this paper that P, in the absence of E, can stimulate cell proliferation during priming; Subsequently, the P primed glands can differentiate in response to lactogenic hormones. (C) 1999 Wiley-Liss, Inc. C1 Univ Vermont, Dept Anim Sci, Burlington, VT 05405 USA. NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. RP Plaut, K (reprint author), Univ Vermont, Dept Anim Sci, 113 Terrill Hall, Burlington, VT 05405 USA. NR 26 TC 16 Z9 16 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD AUG PY 1999 VL 180 IS 2 BP 298 EP 304 DI 10.1002/(SICI)1097-4652(199908)180:2<298::AID-JCP17>3.0.CO;2-V PG 7 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 210YF UT WOS:000081132600017 PM 10395299 ER PT J AU Beason-Held, LL Desmond, RE Herscovitch, P Carson, RE AF Beason-Held, LL Desmond, RE Herscovitch, P Carson, RE TI Bolus injection versus slow infusion of [(15)O]water for positron emission tomography activation studies SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE positron emission tomography; [(15)O]water; cerebral blood flow; activation ID CEREBRAL BLOOD-FLOW; INTRAVENOUS (H2O)-O-15; SINGLE SUBJECTS; PET; IMAGES; EVENTS AB In positron emission tomography studies using bolus injection of [(15)O]water, activation responses reflect underlying CBF changes during a short time (15 to 20 seconds) after arrival of the bolus in the brain. This CBF sensitivity window may be too short for complex activation paradigms, however, particularly those of longer duration. To perform such paradigms, we used a slow infusion method of tracer administration to lengthen the CBF sensitivity window. The present study was designed to determine if this slow infusion technique yields similar results to a bolus injection with a short activation task involving memory for faces. When analyzed using statistical parametric mapping, scanning durations of either 90 or 120 seconds and a 90-second slow infusion schedule produced very similar results to a standard 60-second scan collected after bolus injection, indicating that statistically similar brain activation maps can be produced with the two infusion techniques. This slow infusion approach allows for increased flexibility in designing future studies in which a short CBF sensitivity window is a limiting factor. C1 NIH, Dept PET, Bethesda, MD 20892 USA. NIA, Bethesda, MD 20892 USA. RP Carson, RE (reprint author), NIH, Dept PET, Bldg 10,Room 1C-401,10 Ctr Dr,MSC 1180, Bethesda, MD 20892 USA. RI Carson, Richard/H-3250-2011 OI Carson, Richard/0000-0002-9338-7966 NR 24 TC 7 Z9 7 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD AUG PY 1999 VL 19 IS 8 BP 843 EP 852 PG 10 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 277TD UT WOS:000084948900003 PM 10458591 ER PT J AU Vgontzas, AN Papanicolaou, DA Bixler, EO Lotsikas, A Zachman, K Kales, A Prolo, P Wong, ML Licinio, J Gold, PW Hermida, RC Mastorakos, G Chrousos, GP AF Vgontzas, AN Papanicolaou, DA Bixler, EO Lotsikas, A Zachman, K Kales, A Prolo, P Wong, ML Licinio, J Gold, PW Hermida, RC Mastorakos, G Chrousos, GP TI Circadian interleukin-6 secretion and quantity and depth of sleep SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID TIME-SERIES; IL-6 AB Patients with pathologically increased daytime sleepiness and fatigue have elevated levels of circulating interleukin-6 (IL-6). The latter is an inflammatory cytokine, which causes sickness manifestations, including somnolence and fatigue, and activation of the hy pothalamic-pituitary-adrenal axis. In this study, we examined: 1) the relation between serial measurements of plasma IL-6 and quantity and depth of sleep, evaluated by polysomnography; and 2) the effects of sleep deprivation on the nyctohemeral pattern of IL-6 secretion. Eight healthy young male volunteers were sampled for 24 h twice, at the baseline state, after a normal night's sleep and after total overnight sleep deprivation. At the baseline state, IL-6 was secreted in a biphasic circadian pattern with two nadirs at 0800 and 2100 and two zeniths at 1900 and 0500 (P < 0.01). The baseline amount of sleep correlated negatively with the overall daytime secretion of the cytokine (P < 0.05). Also, depth of sleep at baseline correlated negatively with the postdeprivation increase of daytime secretion of IL-6 (P < 0.05). Sleep deprivation changed the temporal pattern of circadian IL-6 secretion but not the overall amount. Indeed, during the postdeprivation period, the mean daytime (0800-2200 h) levels of IL-6 were significantly higher (P < 0.05), whereas the nighttime (2200-0600 h) levels were lower than the predeprivation values. Thus, sleep-deprived subjects had daytime oversecretion and nighttime undersecretion of IL-6; the former might be responsible for their daylong somnolence and fatigue, the latter for the better quality (depth) of their sleep. These data suggest that a good night's sleep is associated with decreased daytime secretion of IL-6 and a good sense of wellbeing and that good sleep is associated with decreased exposure of tissues to the proinflammatory and potentially detrimental actions of IL-6. Sleep deprivation increases daytime IL-6 and causes somnolence and fatigue during the next day, whereas postdeprivation decreases nighttime IL-6 and is associated with deeper sleep. C1 Penn State Univ, Sleep Res & Treatment Ctr, Dept Psychiat, Coll Med, Hershey, PA 17033 USA. NICHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIMH, Clin Neuroendocrinol Branch, Bethesda, MD 20892 USA. ETSI Telecommun, Chronobiol Lab, Pontevedra 36200, Spain. Univ Athens, Endocrine Unit, Evgenid Hosp, Athens 11528, Greece. RP Vgontzas, AN (reprint author), Penn State Univ, Sleep Res & Treatment Ctr, Dept Psychiat, Coll Med, 500 Univ Dr, Hershey, PA 17033 USA. EM axv3@psu.edu RI Wong, Ma-Li/D-7903-2011; OI Licinio, Julio/0000-0001-6905-5884 NR 18 TC 256 Z9 265 U1 1 U2 5 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 1999 VL 84 IS 8 BP 2603 EP 2607 DI 10.1210/jc.84.8.2603 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 223KL UT WOS:000081840200003 PM 10443646 ER PT J AU Patel, JN Eisenhofer, G Coppack, SW Miles, JM AF Patel, JN Eisenhofer, G Coppack, SW Miles, JM TI Norepinephrine spillover in forearm and subcutaneous adipose tissue before and after eating SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PLASMA NORADRENALINE MEASUREMENTS; IN-VIVO; MIXED MEAL; LIPOLYSIS; HUMANS; MUSCLE; METABOLISM; OBESITY; FAT; FALLIBILITY AB The sympathetic nervous system regulates lipolysis. There are regional differences in the sensitivity of lipolysis to adrenergic regulation. Little is known about regional sympathetic activity in response to eating in humans. We studied the effect of feeding on systemic and local sympathetic nervous system activity and lipolysis in lean healthy subjects (three women and five men; age, 27.0 +/- 2.0; body mass index, 23.4 +/- 1.2 kg/m(-2)) using isotope dilution methodology and arterio-venous sampling. Feeding increased arterial norepinephrine (NE) concentration (mean premeal, 0.96 +/- 0.12 nmol/L.L; mean postmeal, 1.28 +/- 0.14 nmol/L.L; P < 0.02) and total body NE spillover (mean premeal, 2.11 +/- 0.30 nmol/min.L; mean postmeal, 2.76 +/- 0.31 nmol/min.L; P < 0.02), whereas the arterial epinephrine concentration decreased (mean premeal, 289 +/- 61 pmol/L; mean post-meal, 170 +/- 5 pmol/L; P < 0.02). Palmitate concentration and total body systemic rate of appearance of palmitate declined postprandially (mean premeal, 117 +/- 15 mu mol/min; mean postmeal, 38 +/- 4 mu mol/min; P < 0.01). NE spillover increased by the same proportion in both forearm and adipose tissue [in forearm, mean premeal and postmeal, 1.02 +/- 0.11 and 2.41 +/- 0.44. nmol/100 mL.min, respectively (P < 0.02); in adipose tissue, mean premeal and postmeal, 0.41 +/- 0.12 and 0.73 +/- 0.17 nmol/100 g.min, respectively (P < 0.02)]. The results show that a meal caused differential changes in systemic sympatho-adrenal activity and an increase in sympathetic activity in adipose tissue postprandially, However, this increase in postprandial sympathetic activity was not enough to overcome the inhibition of lipolysis by insulin. C1 NINDS, Clin Neurosci Branch, NIH, Bethesda, MD 20892 USA. Royal London Hosp, Coll Med, London E1 18B, England. St Lukes Hosp, Kansas City, MO 64110 USA. RP Patel, JN (reprint author), NINDS, Clin Neurosci Branch, NIH, 10 Ctr Dr,MSC-1424,Bldg 20,Room 6N252, Bethesda, MD 20892 USA. EM jnpatel@box-j.nih.gov FU NCRR NIH HHS [RR-00585]; NIDDK NIH HHS [DK-38092]; Wellcome Trust NR 31 TC 24 Z9 24 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 1999 VL 84 IS 8 BP 2815 EP 2819 DI 10.1210/jc.84.8.2815 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 223KL UT WOS:000081840200042 PM 10443685 ER PT J AU Franchimont, D Martens, H Hagelstein, MT Louis, E Dewe, W Chrousos, GP Belaiche, J Geenen, V AF Franchimont, D Martens, H Hagelstein, MT Louis, E Dewe, W Chrousos, GP Belaiche, J Geenen, V TI Tumor necrosis factor alpha decreases, and interleukin-10 increases, the sensitivity of human monocytes to dexamethasone: Potential regulation of the glucocorticoid receptor SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID NF-KAPPA-B; CYTOKINE PRODUCTION; CLINICAL IMPLICATIONS; MOLECULAR-MECHANISMS; BINDING AFFINITY; GENE-EXPRESSION; CROHNS-DISEASE; WHOLE-BLOOD; IFN-GAMMA; TNF-ALPHA AB Resistance to glucocorticoid therapy has been observed in patients with autoimmune/inflammatory diseases and may be related to the inflammatory process itself. The aim of this study was to examine the ability of tumor necrosis factor alpha (TNF alpha, a proinflammatory cytokine) and interleukin (IL)-10 (an anti-inflammatory cytokine) to differentially regulate the sensitivity of human monocytes/macrophages to glucocorticoids. To accomplish this, we first analyzed the pattern of TNF alpha and IL-10 inhibition by dexamethasone in LPS-stimulated whole-blood cell cultures. Second, we studied the modulation of the sensitivity of these cells to dexamethasone by preincubation with TNF alpha or IL-10 and measurement of LPS-stimulated IL-6 secretion. In addition, we evaluated the effect of dexamethasone on phorbol-myristate-acetate-stimulated IL-1 receptor antagonist secretion by the human monocytic cell line U937. Finally, we investigated whether the modulation of corticosensitivity in TNF alpha- and IL-10-pretreated U937 cells was related to a change of the glucocorticoid receptor concentration and affinity. Dexamethasone had different effects on LPS-induced TNF alpha and IL-10 secretion; whereas it suppressed TNF alpha in a dose-dependent fashion, its effect on IL-10 secretion was biphasic, producing stimulation at lower, and inhibition at higher doses. The concentration of LPS employed influenced the effect of dexamethasone on IL-10 secretion (P < 0.001). Pretreatment with TNF alpha diminished, and with IL-10 improved, the ability of dexamethasone to suppress IL-6 secretion in whole-blood cell cultures (P < 0.01 for both) and to enhance IL-1 receptor antagonist secretion by U937 cells (P < 0.05 for both). TNF alpha decreased (P < 0.001), while IL-10 increased (P < 0.001), the concentration of dexamethasone binding sites in these cells, with no discernible effect on their binding affinity. We conclude that glucocorticoids differentially modulate TNF alpha and IL-10 secretion by human monocytes in a LPS dose-dependent fashion and that the sensitivity of these cells to glucocorticoids is altered by TNF alpha or IL-10 pretreatment; TNF alpha blocks their effects, whereas IL-10 acts synergistically with glucocorticoids. This is accompanied by opposite glucocorticoid receptor changes, respectively opposing and favoring glucocorticoid actions. This study suggests that the pattern of pro-/antiinflammatory cytokine secretion may alter the response of patients to glucocorticoid therapy. C1 NICHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Univ Liege, Lab Radioimmunol & Neuroendocrine Immunol, B-4000 Liege, Belgium. Univ Liege, CHU, Dept Gastroenterol, Inst Pathol, B-4000 Liege, Belgium. RP Franchimont, D (reprint author), NICHD, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N262,10 Ctr Dr, Bethesda, MD 20892 USA. NR 36 TC 143 Z9 151 U1 0 U2 6 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 1999 VL 84 IS 8 BP 2834 EP 2839 DI 10.1210/jc.84.8.2834 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 223KL UT WOS:000081840200045 PM 10443688 ER PT J AU Pluta, RM Nieman, L Doppman, JL Watson, JC Tresser, N Katz, DA Oldfield, EH AF Pluta, RM Nieman, L Doppman, JL Watson, JC Tresser, N Katz, DA Oldfield, EH TI Extrapituitary parasellar microadenoma in Cushing's disease SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ECTOPIC PITUITARY-ADENOMA; CORTICOTROPIN-RELEASING HORMONE; DEXAMETHASONE-SUPPRESSION TEST; TRANS-SPHENOIDAL SURGERY; DIFFERENTIAL-DIAGNOSIS; STIMULATION TEST; PHARYNGEAL PITUITARY; NELSONS SYNDROME; SINUS; TUMOR AB Negative sellar exploration (despite the results of endocrine evaluation indicating Cushing's disease), the high incidence of failure of total hypophysectomy, and remission of Cushing's syndrome after unsuccessful hypophysectomy and sellar irradiation suggest that the etiology of refractory Cushing's disease, in some patients, lies near the sella but not in the pituitary gland. We present 5 patients, out of 626 who received surgery for Cushing's disease, in whom an ACTH-secreting extrapituitary parasellar adenoma was identified: 2 after unsuccessful total hypophysectomy for the treatment of refractory Cushing's disease, 2 after unsuccessful hemihypophysectomy (the first, 2 yr before treatment at the NIH for Nelson's syndrome; and the second, with recurrent Cushing's disease 5 yr after negative transsphenoidal exploration), and 1 with a preoperative diagnosis of an intraclival microadenoma, which was cured by resection of the tumor. In all cases, an extrapituitary parasellar microadenoma was confirmed unequivocally as the cause of the disease, by negative pathology of the resected pituitary gland (patients 1, 2, 3, and 5), and/or the remission of the disease after selective resection of the extrasellar adenoma (patients 3, 4, and 5). Three of 5 patients had a partial empty sella. These patients support the thesis that ACTH-secreting tumors can arise exclusively from remnants of Rathke's pouch, rather than from the adenohypophysis (anterior lobe or pars tuberalis of the pituitary gland) and can he a cause of Cushing's disease. In the sixth presented case, an extrapituitary tumor was suspected at surgery after negative pituitary exploration, but serial sections of the hemihypophysectomy specimen revealed a microscopic focus of tumor at the margin of the resected gland. This case demonstrates the importance of negative pituitary histology to establish the presence of an extrapituitary parasellar tumor as an exclusive source of ACTH, and it supports the value of clinical outcome to establish the diagnosis with selective adenomectomy of an extrapituitary parasellar tumor. In patients with negative pituitary magnetic resonance imaging, especially in the presence of a partial empty sella, the diagnostic and surgical approach in Cushing's disease should consider the identification and resection of extrapituitary parasellar adenoma, which can avoid total hypophysectomy, as was possible in 3 of our 5 patients. C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Off Clin Director, Ctr Clin, NIH, Bethesda, MD 20892 USA. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Dept Radiol, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Oldfield, EH (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,Room 5D37,10 Ctr Dr, Bethesda, MD 20892 USA. NR 62 TC 40 Z9 41 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 1999 VL 84 IS 8 BP 2912 EP 2923 DI 10.1210/jc.84.8.2912 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 223KL UT WOS:000081840200056 PM 10443699 ER PT J AU Mitsiades, N Poulaki, V Mastorakos, G Tseleni-Balafouta, S Kotoula, V Koutras, DA Tsokos, M AF Mitsiades, N Poulaki, V Mastorakos, G Tseleni-Balafouta, S Kotoula, V Koutras, DA Tsokos, M TI Fas ligand expression in thyroid carcinomas: A potential mechanism of immune evasion SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID OCCULT PAPILLARY CARCINOMA; HASHIMOTOS-THYROIDITIS; SEQUENTIAL AUTOPSIES; MOLECULAR-CLONING; INDUCED APOPTOSIS; CANCER; GLAND; TUMORS; CELLS; PATHOGENESIS AB Fas ligand (FasL) induces apoptosis by cross-linking the Fas receptor and is expressed by cells of the immune system. Recently, Fast was found in malignant tumors, suggesting that it helps them escape immune surveillance by eliminating infiltrating lymphocytes. We investigated the presence of Fast immunohistochemically in 48 thyroid carcinomas and by Western blotting and RT-PCR in 5 thyroid carcinoma cell lines. We found that in contrast to normal thyroid tissue, Fast was highly expressed in all papillary, follicular, and Huerthle carcinomas. Medullary carcinomas lacked or had minimal Fast expression. In papillary carcinomas, high levels of expression correlated independently with aggressive histology and unfavorable clinical presentation. Fast was also present in all thyroid cell lines. Thyroid carcinoma cells killed Fas-sensitive targets in a FasL-dependent manner in a coculture experiment. Cross-linking of Fas induced apoptosis in thyroid carcinoma cells only in the presence of cycloheximide. We conclude that Fast is specifically expressed in thyroid carcinomas of follicular epithelial origin, may help them evade the immune system, and may have prognostic implications in papillary carcinoma, as it is associated with a more aggressive phenotype. Thyroid carcinoma cells avoid Fas-mediated suicide possibly by expressing an inhibitor of the Fas apoptotic pathway. C1 NIH, Pathol Lab, Bethesda, MD 20892 USA. Evgenid Hosp, Endocrine Unit, Athens, Greece. Univ Athens, Athens, Greece. RP Mitsiades, N (reprint author), Massachusetts Gen Hosp, Mol Pathol Unit, 7th Floor,149 13th St, Charlestown, MA 02129 USA. NR 49 TC 50 Z9 54 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 1999 VL 84 IS 8 BP 2924 EP 2932 DI 10.1210/jc.84.8.2924 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 223KL UT WOS:000081840200057 PM 10443700 ER PT J AU Weil, S Vendola, K Zhou, J Bondy, CA AF Weil, S Vendola, K Zhou, J Bondy, CA TI Androgen and follicle-stimulating hormone interactions in primate ovarian follicle development SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID POLYCYSTIC OVARIES; OVULATION INDUCTION; MENSTRUAL-CYCLE; RECEPTOR; GROWTH; STEROIDOGENESIS; LOCALIZATION; EXPRESSION; WOMEN; FLUID AB We have previously shown that androgens stimulate early stages of follicular development and that granulosal androgen receptor (AR) gene expression is positively correlated with follicular growth. The present study was aimed at elucidating potential interactions between FSH and androgens in follicular development. Study groups included eight normal cycling rhesus monkeys (five follicular and three luteal-phase), eight testosterone (T)-treated, and four FSH-treated animals. Examination of sequential ovary sections revealed selective colocalization of AR and FSH receptor (FSHR) messenger RNAs (mRNAs) in healthy, growing follicles. Moreover, individual follicles demonstrate a highly significant (P < 0.001) positive correlation between FSHR and AR mRNA levels in all study groups. Androgen treatment significantly increased granulosa cell FSHR mRNA abundance (by approximately 50-100%, depending on follicle size). FSH treatment increased granulosa AR mRNA levels only in primary follicles. The finding that T augments follicular FSHR expression suggests that androgens promote follicular growth and estrogen biosynthesis indirectly, by amplifying FSH effect, and may partially explain the enhanced responsiveness to gonadotropin stimulation noted in women with polycystic ovary syndrome. 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. EM bondyc@exchange.nih NR 23 TC 277 Z9 290 U1 0 U2 9 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 1999 VL 84 IS 8 BP 2951 EP 2956 DI 10.1210/jc.84.8.2951 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 223KL UT WOS:000081840200060 PM 10443703 ER PT J AU Cronin, KA Freedman, LS Lieberman, R Weiss, HL Beenken, SW Kelloff, GJ AF Cronin, KA Freedman, LS Lieberman, R Weiss, HL Beenken, SW Kelloff, GJ TI Bayesian monitoring of Phase II trials in cancer chemoprevention SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE clinical trial design; sequential analysis; group sequential designs; Bayesian inference; cancer chemoprevention; Phase II trials ID MULTIPLE TESTING PROCEDURE; GROUP SEQUENTIAL-METHODS; CLINICAL-TRIALS; DESIGN; GUIDELINES AB Early randomized Phase II cancer chemoprevention trials which assess short-term biological activity are critical to the decision process to advance to late Phase II/Phase III trials. We have adapted published Bayesian interim analysis methods (Spiegelhalter et al., J. R. Statist. Soc A, 1994; 157: 357-416) which give greater flexibility and simplicity of inference to the monitoring of randomized controlled Phase II trials using intermediate endpoints. The Bayesian stopping rule is designed to stop the trial more quickly when the evidence suggests ineffectiveness rather than when it suggests biological activity, thus allowing resources to be concentrated on those agents that show the most promise in this early stage of testing. We investigate frequentist performance characteristics of the proposed method through simulation of randomized placebo controlled trials with a growth factor intermediate end-point using mean and variance values derived from the literature. Simulation results show expected error rates and trial size similar to other commonly used group sequential methods for this setting. These results suggest that the Bayesian approach to interim analysis is well suited for monitoring small randomized controlled Phase II chemoprevention trials fur early detection of either inactive or promising agents. J CLIN EPIDEMIOL 52;8:705-711, 1999. (C) 1999 Elsevier Science Inc. C1 NCI, Biometry Branch, Div Canc Prevent, Bethesda, MD 20892 USA. NCI, Chemoprevent Branch, Div Canc Prevent, Bethesda, MD 20892 USA. Univ Alabama, Ctr Comprehens Canc, Birmingham, AL 35294 USA. RP Cronin, KA (reprint author), NCI, Biometry Branch, Div Canc Prevent, EPN 313,6130 Execut Blvd, Bethesda, MD 20892 USA. NR 24 TC 9 Z9 9 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD AUG PY 1999 VL 52 IS 8 BP 705 EP 711 PG 7 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 227DD UT WOS:000082062300001 PM 10465313 ER PT J AU Lu, LJ Kaliyaperumal, A Boumpas, DT Datta, SK AF Lu, LJ Kaliyaperumal, A Boumpas, DT Datta, SK TI Major peptide autoepitopes for nucleosome-specific T cells of human lupus SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID ANTI-DNA AUTOANTIBODIES; MYELIN BASIC-PROTEIN; DOUBLE-STRANDED DNA; DRUG-INDUCED LUPUS; X-SWR MODEL; MURINE LUPUS; AUTOIMMUNE-DISEASE; INTERFERON-GAMMA; NZB/W F1-MICE; HELPER CELLS AB We tested 154 peptides spanning the entire length of core histones of nucleosomes for the ability to stimulate an anti-DNA autoantibody-inducing T helper (TH) clone, as well as CD4(+) T-cell Lines and T cells, in fresh PBMCs from 23 patients with lupus erythematosus. In contrast to normal T cells, lupus T cells responded strongly to certain histone peptides, irrespective of the patient's disease status. Nucleosomal peptides in histone regions H2B(10-33), H4(16-39) (and overlapping H4(14-28)), H4(71-94), and H3(91-105) (and overlapping H3(100-114)) were recurrently recognized by CD4 T cells from the patients with lupus. Remarkably, these same peptides overlap with major epitopes far the TH cells that induce anti-DNA autoantibodies and nephritis in lupus-prone mice. We localized 2 other recurrent epitopes for human lupus T cells in H2A(34-48) and H4(49-63). All the T-cell autoepitopes have multiple HLA-DR binding motifs, and the epitopes are located in histone regions recognized by lupus autoantibodies, suggesting a basis for their immunodominance. Native nucleosomes and their peptides H4(16-39), H4(71-94), and H3(91-105) induced a stronger IFN-gamma response, whereas others, particularly, H2A(34-48), favored an IL10- and/or IL-4-positive T-cell response. The major autoepitopes may reveal the mechanism of autoimmune T-cell expansion and lead to antigen-specific therapy of human lupus. C1 Northwestern Univ, Sch Med, Arthrit Div, Dept Med, Chicago, IL 60611 USA. Northwestern Univ, Sch Med, Arthrit Div, Dept Immunol Microbiol, Chicago, IL 60611 USA. NIH, Arthrit & Rheumatism Branch, Bethesda, MD 20892 USA. RP Datta, SK (reprint author), Northwestern Univ, Sch Med, Arthrit Div, Dept Med, Ward 3-315,303 E Chicago Ave, Chicago, IL 60611 USA. FU NIAID NIH HHS [AI41985, R01 AI041985]; NIAMS NIH HHS [R01 AR039157, AR46309, R01-AR39157] NR 50 TC 123 Z9 128 U1 0 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD AUG PY 1999 VL 104 IS 3 BP 345 EP 355 DI 10.1172/JCI6801 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 251WC UT WOS:000083468500015 PM 10430616 ER PT J AU Porzio, O Federici, M Hribal, ML Lauro, D Accili, D Lauro, R Borboni, P Sesti, G AF Porzio, O Federici, M Hribal, ML Lauro, D Accili, D Lauro, R Borboni, P Sesti, G TI The Gly(972)-> Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic beta cells SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID DEPENDENT DIABETES-MELLITUS; RECEPTOR SUBSTRATE-1; PHOSPHATIDYLINOSITOL 3-KINASE; GLUCOSE-TRANSPORT; GENE; RESISTANCE; MUTATIONS; PHOSPHORYLATION; WORTMANNIN; OBESITY AB Recent studies have identified several polymorphisms in the human insulin receptor substrate-1 (IRS-1) gene. The most prevalent IRS-1 variant, a Gly-->Arg change at the codon 972, has been reported to be increased in prevalence among patients with type 2 diabetes. Carriers of the Arg(972) substitution are characterized by lower fasting insulin and C-peptide levels compared with non-carriers, suggesting that the Arg(972) IRS-1 variant may contribute to impairment of insulin secretion. In this study, we stably overexpressed both wild-type IRS-1 (RIN-WT) and Arg(972) IRS-1 variant (RIN-Arg(972)) in RIN beta cells to investigate directly whether the polymorphism in codon 972 of IRS-1 impairs insulin secretion. The Arg(972) IRS-1 variant did not affect expression or function of endogenous IRS-2. RIN-WT showed a marked increase in both glucose- and insulin-stimulated tyrosine phosphorylation of IRS-1 compared with control RIN cells. The Arg(972) IRS-1 variant did not alter the extent of either glucose-or insulin-stimulated tyrosine phosphorylation of recombinant IRS-1. However, RIN-Arg(972) showed a significant decrease in binding of the p85 subunit of phosphatidylinositol-3-kinase (PI 3-kinase) with IRS-1, compared with RIN-WT. Compared with control RIN cells, insulin content was reduced to the same extent in RIN-WT or RIN-Arg(972) at both the protein and mRNA levels. Both glucose- and sulfonylurea-induced insulin secretion was increased in RIN-WT compared with control RIN cells. By contrast, RIN cells expressing Arg(972) IRS-1 exhibited a marked decrease in both glucose- and sulfonylurea-stimulated insulin secretion compared with RIN-WT. These data suggest that the insulin signaling pathway involving the IRS-1/PI 3-kinase may play an important role in the insulin secretory process in pancreatic beta cells. More importantly, the results suggest that the common Arg(972) IRS-1 polymorphism may impair glucose-stimulated insulin secretion, thus contributing to the relative insulin deficiency observed in carriers of this variant. C1 Univ Roma Tor Vergata, Dept Internal Med, Mol Med Lab, I-00173 Rome, Italy. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Sesti, G (reprint author), Univ Roma Tor Vergata, Dept Internal Med, Mol Med Lab, Via Orazio Raimondo, I-00173 Rome, Italy. RI Sesti, Giorgio/B-1509-2012; Federici, Massimo/G-9940-2012; OI Federici, Massimo/0000-0003-4989-5194; Lauro, Davide/0000-0002-8597-4415 FU Telethon [E.0695] NR 36 TC 110 Z9 115 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD AUG PY 1999 VL 104 IS 3 BP 357 EP 364 DI 10.1172/JCI5870 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 251WC UT WOS:000083468500016 PM 10430617 ER PT J AU Chanock, SJ Foster, CB AF Chanock, SJ Foster, CB TI SNPing away at innate immunity SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID MANNAN-BINDING PROTEIN; CYSTIC-FIBROSIS; GENE; IDENTIFICATION; POLYMORPHISM; INFECTION; LUNG C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Chanock, SJ (reprint author), NCI, Immunocompromised Hosp Sect, Pediat Oncol Branch, Ctr Adv Technol, 8718 Grovemont Circle, Gaithersburg, MD 20877 USA. NR 20 TC 15 Z9 15 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD AUG PY 1999 VL 104 IS 4 BP 369 EP 370 DI 10.1172/JCI7986 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 251WE UT WOS:000083468700002 PM 10449427 ER PT J AU Weir, S Cuccherini, B Whiney, AM Ray, ML MacGregor, JP Steigerwalt, A Daneshvar, MI Weyant, R Wray, B Steele, J Strober, W Gill, VJ AF Weir, S Cuccherini, B Whiney, AM Ray, ML MacGregor, JP Steigerwalt, A Daneshvar, MI Weyant, R Wray, B Steele, J Strober, W Gill, VJ TI Recurrent bacteremia caused by a "Flexispira"-like organism in a patient with X-linked (Bruton's) agammaglobulinemia SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID RIBOSOMAL-RNA SEQUENCE; SP-NOV; HELICOBACTER; AIDS; GASTROENTERITIS; CULTURES; STRAINS; RAPPINI; HUMANS; BLOOD AB Helicobacter spp., except for Helicobaeter cinaedi, have only rarely been reported in cases of septicemia. A patient with X-linked (Bruton's) agammaglobulinemia was found to have persistent sepsis with a Helicobacter-like organism despite multiple courses of antibiotics, His periods of sepsis were associated with leg swelling thought to be consistent with cellulitis. The organism was fastidious and required a microaerophilic environment containing H-2 for growth. Optimal growth was observed at 35 to 37 degrees C on sheep blood, CDC anaerobe, and Bordet-Gengou agars. Serial subcultures every it to 5 days were required to maintain viability. The organism was strongly urease positive and showed highest relatedness to Helicobacter-like organisms with the vernacular name "Flexispira rappini" by 16S rRNA gene sequence analysis. Genomic DNA hybridization studies, however, found 24 to 37% relatedness to "F. rappini'' and even less to other Helicobacter spp. Although the organism phenotypically resembles "Flexispira" and Helicobacter, it is thought to represent a new taxon, The patient's infection was eventually cleared with a prolonged (5-month) course of intravenous imipenem and gentamicin. C1 NIH, WG Magnuson Clin Ctr, Dept Clin Pathol, Microbiol Serv, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Natl Ctr Infect Dis, Div Bacterial & Mycot Dis, Meningitis & Special Pathogens Branch, Atlanta, GA USA. Georgia Dept Human Resources, Bacteriol Lab, Atlanta, GA USA. Med Coll Georgia, Dept Pediat, Sect Allergy Immunol, Augusta, GA 30912 USA. Med Coll Georgia, Dept Internal Med, Sect Allergy Immunol, Augusta, GA 30912 USA. Med Coll Georgia, Dept Pathol, Clin Microbiol Lab, Augusta, GA 30912 USA. RP Gill, VJ (reprint author), NIH, WG Magnuson Clin Ctr, Dept Clin Pathol, Microbiol Serv, Bldg 10,Rm 2C-385, Bethesda, MD 20892 USA. NR 29 TC 35 Z9 36 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD AUG PY 1999 VL 37 IS 8 BP 2439 EP 2445 PG 7 WC Microbiology SC Microbiology GA 216VR UT WOS:000081465600009 PM 10405381 ER PT J AU Munderloh, UG Jauron, SD Fingerle, V Leitritz, L Hayes, SF Hautman, JM Nelson, CM Huberty, BW Kurtti, TJ Ahlstrand, GG Greig, B Mellencamp, MA Goodman, JL AF Munderloh, UG Jauron, SD Fingerle, V Leitritz, L Hayes, SF Hautman, JM Nelson, CM Huberty, BW Kurtti, TJ Ahlstrand, GG Greig, B Mellencamp, MA Goodman, JL TI Invasion and intracellular development of the human granulocytic ehrlichiosis agent in tick cell culture SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID ANAPLASMA-MARGINALE RICKETTSIALES; RIBOSOMAL-RNA GENE; WHITE-TAILED DEER; BORRELIA-BURGDORFERI; IXODES-SCAPULARIS; CAUSATIVE AGENT; NORTHERN CALIFORNIA; UNITED-STATES; INFECTION; IXODIDAE AB Human granulocytotropic ehrlichias are tick-borne bacterial pathogens that cause an acute, life-threatening illness, human granulocytic ehrlichiosis (HGE). Ehrlichias within neutrophil granulocytes that invade tick bite sites are likely ingested by the vector, to be transmitted to another mammalian host during the tick's next blood meal. Thus, the cycle of replication and development in the vector is prerequisite to mammalian infection, and yet these events have not been described. We report tick cell culture isolation of two strains of the HGE agent directly from an infected horse and a dog and have also established a human isolate from HL60 culture in tick cells, proving that the blood stages of the HGE agent are infectious for tick cells, as are those replicating in the human cell line HL60. This required changes to the culture system, including a new tick cell line. In tick cell layers, the HGE agent induced foci of infection that caused necrotic plaques and eventual destruction of the culture. Using the human isolate and electron microscopy, we monitored adhesion, internalization, and replication in vector tick cells. Both electron-lucent and -dense forms adhered to and entered cells by a mechanism reminiscent of phagocytosis. Ehrlichial cell division was initiated soon after, resulting in endosomes filled with numerous ehrlichias. During early development, pale ehrlichias with a tight cell wall dominated, but by day 2, individual bacteria condensed into dark forms with a rippled membrane. These may become compacted into clumps where individual organisms are barely discernible. Whether these are part of an ehrlichia life cycle or are degenerating is unknown. C1 Univ Minnesota, Dept Entomol, St Paul, MN 55108 USA. Univ Minnesota, Dept Plant Pathol, St Paul, MN 55108 USA. Univ Minnesota, Dept Clin & Populat Sci, St Paul, MN 55108 USA. Univ Minnesota, Vet Diagnost Labs, St Paul, MN 55108 USA. Natl Inst Hlth, Rocky Mt Lab, Hamilton, MT USA. Univ Munich, Dept Med, Div Infect Dis, Munich, Germany. Univ Munich, Max Von Pettenkofer Inst, Munich, Germany. RP Munderloh, UG (reprint author), Univ Minnesota, Dept Entomol, 219 Hodson Hall,1980 Folwell Ave, St Paul, MN 55108 USA. FU NIAID NIH HHS [1RO1AI40952, R29 AI042792]; PHS HHS [1R29AK42792] NR 41 TC 115 Z9 118 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD AUG PY 1999 VL 37 IS 8 BP 2518 EP 2524 PG 7 WC Microbiology SC Microbiology GA 216VR UT WOS:000081465600022 PM 10405394 ER PT J AU Weir, SC Gibert, CL Gordin, FM Fischer, SH Gill, VJ AF Weir, SC Gibert, CL Gordin, FM Fischer, SH Gill, VJ TI An uncommon Helicobacter isolate from blood: Evidence of a group of Helicobacter spp. pathogenic in AIDS patients SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID RIBOSOMAL-RNA SEQUENCE; FLEXISPIRA-RAPPINI; SP-NOV; BACTEREMIA; ARTHRITIS; CULTURES AB An unusual Helicobacter sp, was isolated from the blood of a human immunodeficiency virus (HIV)-infected patient. This organism had spiral morphology, with single amphitrichous flagella, and was negative for hippurate hydrolysis, production of urease, and reduction of nitrate, 16S rRNA gene sequence analysis verified that the isolate was a species of Helicobacter, most closely related to an undescribed Helicobacter-like isolate from Vancouver, British Columbia, Canada, and to Helicobacter westmeadii, a recently described species from Australia. Both organisms had also been isolated from the blood of HIV-infected patients. These blood isolates, along with Helicobacter cinaedi, form a cluster of closely related Helicobacter spp, that may represent an emerging group of pathogens in immunocompromised patients. C1 NIH, Dept Clin Pathol, Microbiol Serv, Bethesda, MD 20892 USA. Vet Affairs Med Ctr, Dept Infect Dis, Washington, DC 20422 USA. RP Gill, VJ (reprint author), NIH, Dept Clin Pathol, Microbiol Serv, Bldg 10,Room 2C-385,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 11 TC 17 Z9 17 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD AUG PY 1999 VL 37 IS 8 BP 2729 EP 2733 PG 5 WC Microbiology SC Microbiology GA 216VR UT WOS:000081465600062 PM 10405434 ER PT J AU Cheson, BD Vena, DA Barrett, J Freidlin, B AF Cheson, BD Vena, DA Barrett, J Freidlin, B TI Second malignancies as a consequence of nucleoside analog therapy for chronic lymphoid leukemias SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HAIRY-CELL LEUKEMIA; CHRONIC-LYMPHOCYTIC-LEUKEMIA; TERM FOLLOW-UP; NATIONAL-CANCER-INSTITUTE; ACUTE MYELOID-LEUKEMIA; C PROTOCOL MECHANISM; 2ND MALIGNANCIES; FLUDARABINE; INTERFERON; 2-CHLORODEOXYADENOSINE AB Purpose: The nucleoside analogs fludarabine, 2'-deoxycoformycin (DCF), and 2-chlorodeoxyadenosine (CdA), commonly used in the treatment of patients with indolent lymphoid malignancies such as chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HCL), are associated with myelosuppression and profound and prolonged immunosuppression. These complications raise the possibility of an increase in secondary malignancies in patients whose disease already places them at greater risk. The purpose of the present study was to assess the frequency of second tumors in patients with CLL who are treated with fludarabine and in patients with HCL who are treated with DCF and CdA. Patients and Methods: We reviewed the long-term follow-up data for 2,014 patients treated on National Cancer Institute Group C protocols with fludarabine for relapsed and refractory CLL and with DCF and CdA for HCL using a Second Cancer Report. The numbers of observed and expected secondary tumors were compared. Results: Median follow-vp periods for the DCF (n = 409), fludarabine (n = 724), and CdA (n = 979) studies were 6.9, 7.4, and 5.1 years, respectively. The 111 malignancies were most commonly lymphoma (25 patients), prostate (19), lung (15), colorectal (nine), bladder (six), and breast (six), but also CNS, stomach, ovary, head and neck, melanoma, sarcoma, testicular, and myeloid leukemias. Compared with age-adjusted 1994 Surveillance and Epidemiology End-Results rates for the general population, the observed/expected frequencies for DCF, fludarabine, and CdA were 1.43 (95% confidence interval [CI], 0.93 to 2.10), 1.65 (95% CI, 1.04 to 2.47), and 1.50 (95% CI, 1.14 to 1.93), respectively, indicating a significant (at P = .05) increase in risk for patients treated on the latter two protocols compared with a normal population. However, these values are consistent with the increase already associated with these diseases. Conclusion: Despite their immunosuppression, nucleoside analogs can be safely administered to patients with CLL or HCL without a significantly increased risk of secondary malignancies. (C) 1999 by American Society of Clinical Oncology. C1 NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. EMMES Corp, Potomac, MD USA. RP Cheson, BD (reprint author), NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Execut Plaza N,Rm 741, Bethesda, MD 20892 USA. NR 51 TC 147 Z9 149 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG PY 1999 VL 17 IS 8 BP 2454 EP 2460 PG 7 WC Oncology SC Oncology GA 223HJ UT WOS:000081835300020 PM 10561309 ER PT J AU Bishop, PC Wilson, WH Pearson, D Janik, J Jaffe, ES Elwood, PC AF Bishop, PC Wilson, WH Pearson, D Janik, J Jaffe, ES Elwood, PC TI CNS involvement in primary mediastinal large B-cell lymphoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; NON-HODGKINS-LYMPHOMA; DIFFUSE LARGE-CELL; RISK-FACTORS; COMBINATION CHEMOTHERAPY; IMMUNOBLASTIC LYMPHOMA; MALIGNANT-LYMPHOMAS; POOR-PROGNOSIS; SCLEROSIS; PROPHYLAXIS AB Purpose: The risk of CNS involvement by non-Hodgkin's Lymphoma (NHL) has been associated with bane marrow and/or testicular involvement; however, it was recently reported that the number of extranodal sites is a more reliable predictor of CNS disease. Because primary mediastinal thymic large B-cell lymphoma (PMLCL) has a high propensity for involving extranodal sites, we investigated the frequency and pattern of CNS involvement in PMLCL. Patients and Methods: The medical records of 219 patients with aggressive NHL, consecutively entered onto protocols at the National Cancer Institute between 1987 and 1998, were retrospectively reviewed. Results: Twenty-three patients (11%) had clinical and pathologic features of PMLCL, These patients were young (median age, 29 years), female (61%), and presented with massive mediastinal adenopathy (70%). Extranodal disease occurred at presentation in 70% and relapse in 93% of patients and involved contiguous intrathoracic structures and/or distant sites, including the lungs, kidneys, liver, adrenals, ovaries, pancreas, and bone. Six patients (26%) developed CNS involvement, two (9%) at presentation and four (27%) at relapse. All had extranodal disease, but only one had bone marrow involvement. Parenchymal and leptomeningeal CNS disease occurred in four and three patients, respectively. Conclusion: CNS involvement in PMLCL is associated with extranodal involvement other than bane marrow and may reflect the unique biology of this disease. The propensity to involve the CNS parenchyma raises the concern that intrathecal prophylaxis may not be effective and suggests that CNS imaging should be considered in patients with extranodal disease. (C) 1999 by American Society of Clinical Oncology. C1 NCI, Div Clin Sci, Med Branch, Bethesda, MD 20892 USA. RP Elwood, PC (reprint author), NCI, Div Clin Sci, Med Branch, 9000 Rockville Pike,Bldg 10-12N226, Bethesda, MD 20892 USA. NR 40 TC 53 Z9 54 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG PY 1999 VL 17 IS 8 BP 2479 EP 2485 PG 7 WC Oncology SC Oncology GA 223HJ UT WOS:000081835300023 PM 10561312 ER PT J AU Goldstein, TR Frye, MA Denicoff, KD Smith-Jackson, E Leverich, GS Bryan, AL Ali, SO Post, RM AF Goldstein, TR Frye, MA Denicoff, KD Smith-Jackson, E Leverich, GS Bryan, AL Ali, SO Post, RM TI Antidepressant discontinuation-related mania: Critical prospective observation and theoretical implications in bipolar disorder SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 151st Annual Meeting of the American-Psychiatric-Association CY MAY 30-JUN 05, 1998 CL TORONTO, CANADA SP Amer Psychiat Assoc ID WITHDRAWAL; HYPOMANIA; ILLNESS; DEPRESSION; DRUGS AB Background: Development of manic symptoms on antidepressant discontinuation has primarily been reported in unipolar patients. This case series presents preliminary evidence for a similar phenomenon in bipolar patients. Method: Prospectively obtained life chart ratings of 73 bipolar patients at the National Institute of Mental Health were reviewed for manic episodes that emerged during antidepressant taper or discontinuation. Medical records were utilized as a corroborative resource. Six cases of antidepressant discontinuation-related mania were identified and critically evaluated. Results: All patients were taking conventional mood stabilizers. The patients were on antidepressant treatment a mean of 6.5 months prior to taper, which lasted an average of 20 days (range, 1-43 days). First manic symptoms emerged, on average, 2 weeks into the taper (range, 1-23 days). These 6 cases of antidepressant discontinuation-related mania involved 3 selective serotonin reuptake inhibitors (SSRIs), 2 tricyclic antidepressants (TCAs), and 1 serotonin-norepinephrine reuptake inhibitor. Mean length of the ensuing manic episode was 27.8 days (range, 12-49 days). Potential confounds such as antidepressant induction, phenomenological misdiagnosis of agitated depression, physiologic drug withdrawal syndrome, and course of illness were carefully evaluated and determined to be noncontributory. Conclusion: These 6 cases suggest a paradoxical effect whereby antidepressant discontinuation actually induces mania in spite of adequate concomitant mood-stabilizing treatment. These preliminary observations, if replicated in larger and controlled prospective studies, suggest the need for further consideration of the potential biochemical mechanisms involved so that new preventive treatment approaches can be assessed. C1 NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. Univ Colorado, Dept Clin Psychol, Boulder, CO 80309 USA. Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA USA. RP Post, RM (reprint author), NIMH, Biol Psychiat Branch, Bldg 10,Room 3N212, Bethesda, MD 20892 USA. OI Ali, Syed/0000-0003-3131-3299 NR 39 TC 46 Z9 48 U1 0 U2 1 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD AUG PY 1999 VL 60 IS 8 BP 563 EP 567 PG 5 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 230WR UT WOS:000082275100020 PM 10485646 ER PT J AU Stewart, P Stenzel, M AF Stewart, P Stenzel, M TI Data needs for occupational epidemiologic studies SO JOURNAL OF ENVIRONMENTAL MONITORING LA English DT Editorial Material ID RETROSPECTIVE COHORT MORTALITY; AIRCRAFT MAINTENANCE FACILITY; HISTORICAL EXPOSURES; WORKERS AB Data needs in an epidemiologic study can appear to be substantial in light of the other responsibilities of an industrial hygienist. Many of the data needed for this type of investigation, however, are already collected for other exposure assessment purposes. To increase understanding of this concept, the data needs for the major purposes for conducting an exposure assessment are identified. The purposes include determining compliance; implementing industrial hygiene programs, such as personal protective and respiratory equipment, hazard communication training, and medical surveillance; investigating health complaints and worker concerns;investigating tasks or engineering control effectiveness; investigating toxic tort or worker compensation claims; and conducting epidemiologic studies. A comprehensive exposure assessment system is then described that incorporates the data needs for all these purposes, including epidemiologic studies. The data needs of epidemiologic studies and how the data are used are then described and illustrated with examples taken from published epidemiologic studies. C1 NCI, Bethesda, MD 20892 USA. OxyChem, Dallas, TX 75244 USA. RP Stewart, P (reprint author), NCI, EPS 810, Bethesda, MD 20892 USA. NR 21 TC 1 Z9 1 U1 0 U2 2 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1464-0325 J9 J ENVIRON MONITOR JI J. Environ. Monit. PD AUG PY 1999 VL 1 IS 4 BP 75N EP 82N DI 10.1039/a903405f PG 8 WC Chemistry, Analytical; Environmental Sciences SC Chemistry; Environmental Sciences & Ecology GA 255XW UT WOS:000083696300005 PM 11529156 ER PT J AU Terai, S Okita, K AF Terai, S Okita, K TI Does cytoplasmic cyclin D1 regulate the cell cycle directly? SO JOURNAL OF GASTROENTEROLOGY LA English DT Editorial Material ID HUMAN HEPATOCELLULAR-CARCINOMA; RETINOBLASTOMA PROTEIN; OVEREXPRESSION; EXPRESSION; ACTIVATION; TRANSITION; KINASES C1 NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Okita, K (reprint author), NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. NR 20 TC 1 Z9 2 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0944-1174 J9 J GASTROENTEROL JI J. Gastroenterol. PD AUG PY 1999 VL 34 IS 4 BP 547 EP 548 DI 10.1007/s005350050314 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 223KP UT WOS:000081840500023 PM 10452695 ER PT J AU Michielutte, R Alciati, MH El Arculli, R AF Michielutte, R Alciati, MH El Arculli, R TI Cancer control research and literacy SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Review DE cancer control; literacy; health ID PATIENT EDUCATION MATERIALS; INFORMED CONSENT FORMS; HEALTH INFORMATION; READING-ABILITY; SOCIOECONOMIC-STATUS; UNITED-STATES; READABILITY; COMPREHENSION; PREVENTION; CARE AB Low literacy may be an important predictor of increased cancer risk and poor participation in cancer control programs. Results of the National Adult Literacy Survey indicate that about 90 million individuals, slightly less than half of the U.S. adult population, demonstrate low or limited literacy skills. In contrast, the average health education brochure, pamphlet, or instruction sheet requires a 10th-grade or higher level of reading ability to be understood. Guidelines exist for the development of move readable printed materials; studies have also found that nonprint approaches such as video education are viable alternatives to printed materials. Research on patient populations indicates that educational approaches targeted to low-literacy groups can be effective in reaching individuals with cancer control information. This review identifies the most important areas of needed research and makes recommendations for the development of a research agenda on cancer control and literacy. C1 Wake Forest Univ, Sch Med, Dept Family & Community Med, Winston Salem, NC 27157 USA. Management Solut Hlth, Reston, VA 20190 USA. NCI, Div Canc Prevent & Control, Rockville, MD 20852 USA. RP Michielutte, R (reprint author), Wake Forest Univ, Sch Med, Dept Family & Community Med, Med Ctr Blvd, Winston Salem, NC 27157 USA. OI Alciati, Marianne/0000-0001-6294-1090 NR 111 TC 20 Z9 20 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1049-2089 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD AUG PY 1999 VL 10 IS 3 BP 281 EP 297 PG 17 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 217NA UT WOS:000081504800002 PM 10436728 ER PT J AU Anderson, DE Parsons, DJ Scuteri, A AF Anderson, DE Parsons, DJ Scuteri, A TI End tidal CO2 is an independent determinant of systolic blood pressure in women SO JOURNAL OF HYPERTENSION LA English DT Article DE age; blood pressure; end tidal CO2; sex; hypertension; pCO(2) ID ESSENTIAL-HYPERTENSION; SALT SENSITIVITY; SODIUM-INTAKE; SLEEP-APNEA; HYPOXIA; HYPOVENTILATION; ASSOCIATION; VENTILATION; INHIBITION; HORMONES AB Objective Recent studies have shown that high resting end tidal CO2 (PECO2) is a marker for blood pressure sensitivity to high sodium intake by normotensive humans. The present study investigated the association of resting PECO2 with resting blood pressure in participants in the Baltimore Longitudinal Study on Aging (BLSA). Design PECO2 of 314 healthy participants (153 men and 161 women, aged 21 -79 years) was measured by a respiratory gas monitor during 25 min of seated rest, and blood pressure every 5 min by an automated oscillometric system. The independent associations of PECO2 and other variables with systolic (SBP) and diastolic (DBP) blood pressure were analysed via multiple regression. Sex differences in age-associated changes in PECO2 and in the role of pulmonary capacity in the PECO2 - blood pressure relationships were also studied. Results Resting PECO2 was an independent predictor of SEP in women (beta = 0.215; P < 0.0015; overall r(2) = 0.27; P < 0.0001), and accounted for more than 10% of the variance in SEP in women over age 50 years. No such associations of PECO2 with SEP of men, or with DBP of men or women, were observed, PECO2 was lower in younger women (36.0 +/- 0.9 mmHg) than in younger men (40.4 +/- 2.0), but higher in older women (37.1 +/- 0.5) than in older men (35.5 +/- 0.4). Conclusions PECO2 is an independent determinant of resting SEP in women, especially those aged 50 years or more. The origin of individual differences in resting PECO2 and its possible role in the development of chronic hypertension remain to be clarified. J Hypertens 1999, 17:1073-1080 (C) Lippincott Williams & Wilkins. C1 NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. RP Anderson, DE (reprint author), NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 37 TC 14 Z9 14 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD AUG PY 1999 VL 17 IS 8 BP 1073 EP 1080 DI 10.1097/00004872-199917080-00005 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 225MD UT WOS:000081964600005 PM 10466461 ER PT J AU Liese, AD Mayer-Davis, EJ Chambless, LE Folsom, AR Sharrett, AR Brancati, FL Heiss, G AF Liese, AD Mayer-Davis, EJ Chambless, LE Folsom, AR Sharrett, AR Brancati, FL Heiss, G CA Atherosclerosis Risk Communities Study Investig TI Elevated fasting insulin predicts incident hypertension: the ARIC study SO JOURNAL OF HYPERTENSION LA English DT Article DE hypertension; insulin; insulin resistance; obesity ID MIAMI COMMUNITY-HEALTH; HIGH BLOOD-PRESSURE; SYNDROME SYNDROME-X; MIDDLE-AGED MEN; ATHEROSCLEROSIS RISK; RESISTANCE-SYNDROME; METABOLIC SYNDROME; CARDIOVASCULAR-DISEASE; YOUNG-ADULTS; SHORT-TERM AB Objective The prospective association of insulin and hypertension has been under debate in the context of the development of the insulin resistance or multiple metabolic syndrome. We examined the predictive associations of fasting serum insulin with incident hypertension occurring alone or as part of the multiple metabolic syndrome. Design Analyses were restricted to 5221 middle-aged participants of the Atherosclerosis Risk in Communities Study cohort who were free of component disorders of the multiple metabolic syndrome (hypertension; diabetes; high triglycerides and/or low HDL cholesterol (dyslipidaemias)) at baseline. Outcome A total of 1018 individuals developed hypertension, 801 in the absence of components of the metabolic syndrome and 217 in combination with diabetes or dyslipidaemias, between 1987 and 1993, Results Elevated fasting insulin (top quartile versus lowest quartile) was associated with overall incident hypertension in European Americans [hazard rate ratio (HRR) 2.0, 95% confidence interval (CI) 1.7-2.43 but the results were inconclusive in African Americans (HRR 1.3, 95% CI 0.9-1.8) after adjustment for age, gender and study centre. Among European Americans, body mass index and abdominal girth only partly explained the observed association. Elevated fasting insulin was more strongly predictive of hypertension occurring as a component of the multiple metabolic syndrome (HRR 2.4, 95% CI 1.5-3.9) than of hypertension occurring alone (HRR 1.3, 95% CI 1.0-1.7) adjusting statistically for age, gender, study centre, body mass index and abdominal girth. Conclusions The results are consistent with the concept of an aetiological heterogeneity for hypertension and may explain previously reported inconsistent findings on the association of insulin with incident hypertension. I Hypertens 1999, 17:1169-1177 (C) Lippincott Williams & Wilkins. C1 Univ Munster, Inst Epidemiol & Social Med, D-48129 Munster, Germany. Univ S Carolina, Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. Univ N Carolina, Sch Publ Hlth, Dept Biostat, Chapel Hill, NC USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. NHLBI, NIH, DECA, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. RP Liese, AD (reprint author), Univ Munster, Inst Epidemiol & Social Med, Domagkstr 3, D-48129 Munster, Germany. FU NHLBI NIH HHS [N01-HC-55015, N01-HC-55016, N01-HC-55018] NR 48 TC 39 Z9 43 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD AUG PY 1999 VL 17 IS 8 BP 1169 EP 1177 DI 10.1097/00004872-199917080-00017 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 225MD UT WOS:000081964600017 PM 10466473 ER PT J AU Lopatin, DA Ailamazian, EK Dmitrieva, RI Shpen, VM Fedorova, OV Doris, PA Bagrov, AY AF Lopatin, DA Ailamazian, EK Dmitrieva, RI Shpen, VM Fedorova, OV Doris, PA Bagrov, AY TI Circulating bufodienolide and cardenolide sodium pump inhibitors in preeclampsia SO JOURNAL OF HYPERTENSION LA English DT Article DE pregnancy; preeclampsia; hypertension; Na+/K+ ATPase; high-performance liquid chromatography; bufadienodide; ouabain; umbilical artery ID DIGITALIS-LIKE-FACTOR; IMMUNOREACTIVE SUBSTANCE; MARINOBUFAGENIN-LIKE; INDUCED HYPERTENSION; VOLUME EXPANSION; HUMAN-PLASMA; RAT AORTA; PREGNANCY; OUABAIN; ANTIBODIES AB Objective To determine plasma levels of the endogenous bufodienolide Na+/K+ ATPase inhibitor, marinobufagenin-like factor (MBG), in normotensive pregnancy and in preeclampsia, to compare changes of MBG with that of ouabain-like compound (OLC), and to characterize the purified MBG immunoreactive factor from preeclamptic plasma. Design and methods Consecutive sample study. The levels of MEG and OLC compounds were measured in extracted plasma by solid phase fluoroimmunoassays. MBG and ouabain immunoreactive materials were partially purified from preeclamptic plasma via reverse-phase highperformance liquid chromatography (HPLC) and studied for their ability to cross react with MBG and ouabain antibodies, and to inhibit the Na+/K+ ATPase from human mesenteric arteries. Vasoconstrictor effect of authentic MEG was studied in isolated rings of human umbilical arteries. Results In 11 nonpregnant control individuals, plasma concentrations of MEG and OLC were 0.190 +/- 0.04 nmol/l and 0.297 +/- 0.037 nmol/l, respectively. In the third trimester of noncomplicated pregnancy (n = 6), plasma MBG increased (0.625 +/- 0.067 nmol/l, P < 0.05), and OLC did not (0.32 +/- 0.07 nmol/l), In 15 patients with preeclampsia, plasma levels of both MBG and OLC increased dramatically (2.63 +/- 0.10 nmol/l and 0.697 +/- 0.16 nmol/l, respectively, P < 0.01 versus both control groups). When fractionated by reverse phase HPLC, OLC was eluted by 18% acetonitrile, and MBG by 48% acetonitrile, Serially diluted samples of MEG and OLC immunoreactive materials from HPLC fractions reacted with MEG and ouabain antibody in solid phase immunoassay in a concentration dependent fashion. Authentic MBG caused contractile responses of isolated rings of human mesenteric arteries in a concentration-dependent manner. Similarly to the authentic MEG, HPLC purified MBG immunoreactive material from preeclamptic plasma inhibited Na+/K+ ATPase purified from human mesenteric artery. Conclusions Our observations demonstrate the coexistence of two endogenous cardiotonic steroids in preeclamptic plasma, a more polar OLC and a less polar MEG-like compound. Substantial increases in plasma OLC and MEG immunoreactivity in preeclampsia, along with the vasoconstrictor properties of authentic MBG and Na+,K+ ATPase inhibitory activity of human MBG immunoreactive factor, suggest, that in preeclampsia, plasma concentrations of MBG are enough to substantially inhibit the sodium pump in cardiovascular tissues, and are in accordance with the views attributing endogenous digitalis-like factors a pathogenic role in the preeclamptic hypertension. I Hypertens 1999, 17:1179-1187 (C) Lippincott Williams & Wilkins. C1 NIA, Cardiovasc Sci Lab, Intramural Res Program, Baltimore, MD 21224 USA. DO Ott Inst Obstet & Gynaecol, St Petersburg, Russia. Univ Texas, Inst Mol Med, Houston, TX USA. Verta Peptides Inc, St Petersburg, Russia. IM Sechenov Evolutionary Physiol & Biochem Inst, St Petersburg 194223, Russia. RP Bagrov, AY (reprint author), NIA, Cardiovasc Sci Lab, Intramural Res Program, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Dmitrieva, Renata/0000-0002-3073-7914 FU NIDDK NIH HHS [R01-DK45538] NR 43 TC 119 Z9 121 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD AUG PY 1999 VL 17 IS 8 BP 1179 EP 1187 DI 10.1097/00004872-199917080-00018 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 225MD UT WOS:000081964600018 PM 10466474 ER PT J AU Di Rosa, F Ramaswamy, S Ridge, JP Matzinger, P AF Di Rosa, F Ramaswamy, S Ridge, JP Matzinger, P TI On the lifespan of virgin T lymphocytes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CELL REPERTOIRE; PERIPHERAL SELECTION; MEMORY; NAIVE; ANTIGEN; MICE; PHENOTYPE; RECOGNITION; RESPONSES; SURVIVAL AB To study the lifespan of virgin T lymphocytes, we removed the thymus from adult female mice and then, at various times afterward, tested their ability to mount an immune response to a newly encountered Ag, the male Ag H-Y, We found that unprimed thymectomized mice were able to generate a primary response to H-Y for some time after thymectomy but lost this ability at similar to 6 mo. In contrast, mice that were primed to H-Y just after thymectomy continued to display immunological memory to H-Y for >1 year. These experiments show that primary immune responses disappear in the absence of a thymus. C1 NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Di Rosa, F (reprint author), Ist Regina Elena, Ctr Ric Sperimentale, Lab Fisiopatol, Via Messi Oro 156, I-00158 Rome, Italy. RI Di Rosa, Francesca/J-8116-2014 NR 38 TC 48 Z9 48 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 1 PY 1999 VL 163 IS 3 BP 1253 EP 1257 PG 5 WC Immunology SC Immunology GA 219ZX UT WOS:000081640000021 PM 10415021 ER PT J AU Vacchio, MS Lee, JYM Ashwell, JD AF Vacchio, MS Lee, JYM Ashwell, JD TI Thymus-derived glucocorticoids set the thresholds for thymocyte selection by inhibiting TCR-mediated thymocyte activation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD8+ T-CELLS; NF-KAPPA-B; POSITIVE SELECTION; RECEPTOR EXPRESSION; NEGATIVE SELECTION; ANTIGEN; ALPHA; REPERTOIRE; MICE; IMMUNOSUPPRESSION AB Selection processes in the thymus eliminate nonfunctional or harmful T cells and allow the survival of those cells with the potential to recognize Ag in association with self-MHC-encoded molecules (Ag/MHC). We have previously demonstrated that thymus-derived glucocorticoids antagonize TCR-mediated deletion, suggesting a role for endogenous thymic glucocorticoids in promoting survival of thymocytes following TCR engagement. Consistent with this hypothesis, we now show that inhibition of thymus glucocorticoid biosynthesis causes an increase in thymocyte apoptosis and a decrease in recovery that are directly proportional to the number of MHC-encoded molecules present and, therefore, the number of ligands available for TCR recognition. Expression of CD5 on CD4(+)CB8(+) thymocytes, an indicator of TCR-mediated activation, increased in a TCR- and MHC-dependent manner when corticosteroid production or responsiveness was decreased. These results indicate that thymus-derived glucocorticoids determine where the window of thymocyte selection occurs in the TCR avidity spectrum by dampening the biological consequences of TCR occupancy and reveal that glucocorticoids mask the high percentage of self-Ag/MHC-reactive thymocytes that exist in the preselection repertoire. C1 NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Ashwell, JD (reprint author), NCI, Lab Immune Cell Biol, NIH, Room 1B-40,Bldg 10, Bethesda, MD 20892 USA. NR 39 TC 78 Z9 78 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 1 PY 1999 VL 163 IS 3 BP 1327 EP 1333 PG 7 WC Immunology SC Immunology GA 219ZX UT WOS:000081640000031 PM 10415031 ER PT J AU Doherty, TM Chougnet, C Schito, M Patterson, BK Fox, C Shearer, GM Englund, G Sher, A AF Doherty, TM Chougnet, C Schito, M Patterson, BK Fox, C Shearer, GM Englund, G Sher, A TI Infection of HIV-1 transgenic mice with Mycobacterium avium induces the expression of infectious virus selectively from a mac-1-positive host cell population SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; TOXOPLASMA-GONDII; IMMUNE ACTIVATION; MEDIATED-IMMUNITY; KAPPA-B; MACROPHAGES; TUBERCULOSIS; DISEASE; AIDS; REPLICATION AB Infection of HIV-l-transgenic mice with Mycobacterium avium, a common opportunistic pathogen in AIDS patients, was shown to result in increased tissue expression of viral specific transcripts. Moreover, by coculturing splenocytes from the transgenic animals with human T cells it was possible to demonstrate that the elevation in HIV-1 mRNA triggered by M, avium infection reflects increased production of infectious virions. Viral immune activation was also shown to correlate with a marked elevation of p24 in supernatants of ex vivo cultured tissues and, more importantly, in systemic increases in the HIV-1 protein in plasma. Interestingly, these tissue and systemic p24 responses were found to be differentially regulated. Thus, while in vitro p24 production by cultured splenocytes increased concurrently with bacterial loads during the first 6 wk of infection, levels of the Ag in plasma actually decreased. In situ localization experiments together with FAGS analysis of HIV-l-expressing splenocytes indicated that virus production is restricted largely to cells of the monocyte/macrophage lineage. Indeed, in vitro p24 expression by cells from noninfected transgenic mice was up-regulated by polyclonal stimulation of macrophages but not T cells. Together these results underscore the importance of the macrophage reservoir in persistent virus expression and establish a convenient and relevant animal model for studying the factors responsible for immune activation of HIV-1 induced by mycobacterial as well as other common coinfections encountered by AIDS patients. C1 NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Northwestern Univ, Sch Med, Dept Obstet Gynecol & Med, Div Infect Dis, Chicago, IL 60611 USA. Mol Histol Inc, Gaithersburg, MD 20879 USA. RP Sher, A (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bldg 4,Room 126,4 Ctr Dr, Bethesda, MD 20892 USA. NR 39 TC 26 Z9 26 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 1 PY 1999 VL 163 IS 3 BP 1506 EP 1515 PG 10 WC Immunology SC Immunology GA 219ZX UT WOS:000081640000053 PM 10415053 ER PT J AU Chougnet, C Cohen, SS Kawamura, T Landay, AL Kessler, HA Thomas, E Blauvelt, A Shearer, GM AF Chougnet, C Cohen, SS Kawamura, T Landay, AL Kessler, HA Thomas, E Blauvelt, A Shearer, GM TI Normal immune function of monocyte-derived dendritic cells from HIV-Infected individuals: Implications for immunotherapy SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; C-C CHEMOKINE; T-CELLS; IL-12 PRODUCTION; MONONUCLEAR-CELLS; INTERLEUKIN-12 PRODUCTION; VIRAL REPLICATION; HUMAN MACROPHAGES; LANGERHANS CELLS; PERIPHERAL-BLOOD AB Dendritic cells (DC) are the most potent cells involved in the generation of primary and secondary immune responses. To assess the feasibility of using autologous DC as immunotherapy for HIV disease, we analyzed a variety of immune parameters using DC isolated from HIV-infected (HIV+) individuals, as well as DC obtained from HIV-uninfected (HIV-) individuals infected in vitro with HIV, After stimulation with recombinant CD40 ligand (CD40LT), cytokine and beta-chemokine production were similar by DC from HIV- donors infected in vitro with the CCR5-using HIV Ba-L strain (n = 8) compared with uninfected DC from the same donors. Production of beta-chemokines, but not of cytokines, was increased by a CXCR4-using IIIB strain-infected DC (n = 7), Stimulation of HIV-infected DC with CD40LT decreased infection in Ba-L-infected DC, but had no effect on IIIB-infected DC. Consistent with this finding, CD40LT down-regulated CCR5 and up-regulated CXCR4 expression on DC. Monocyte-derived DC were also propagated from 15 HIV+ and 13 HIV- donors. They exhibited similar expression of costimulatory molecules and produced similar amounts of IL-12, IL-10, and beta-chemokines, following stimulation. By contrast, stimulated PBMC from HIV+ patients exhibited decreased IL-12 and increased IL-10 production. In summary, phenotype, cytokine secretion, and beta-chemokine production by DC from HIV+ individuals were normal. These cells may prove useful in boosting cellular immune responses in HIV+ individuals. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. Rush Presbyterian St Lukes Med Ctr, Dept Med Microbiol & Immunol, Chicago, IL 60617 USA. Immunex Corp, Seattle, WA 98101 USA. RP Shearer, GM (reprint author), NCI, Expt Immunol Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 4B36, Bethesda, MD 20892 USA. NR 56 TC 65 Z9 66 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 1999 VL 163 IS 3 BP 1666 EP 1673 PG 8 WC Immunology SC Immunology GA 219ZX UT WOS:000081640000073 PM 10415073 ER PT J AU Rosenberg, SA Yang, JC Schwartzentruber, DJ Hwu, P Marincola, FM Topalian, SL Restifo, NP Sznol, M Schwarz, SL Spiess, PJ Wunderlich, JR Seipp, CA Einhorn, JH Rogers-Freezer, L White, DE AF Rosenberg, SA Yang, JC Schwartzentruber, DJ Hwu, P Marincola, FM Topalian, SL Restifo, NP Sznol, M Schwarz, SL Spiess, PJ Wunderlich, JR Seipp, CA Einhorn, JH Rogers-Freezer, L White, DE TI Impact of cytokine administration on the generation of antitumor reactivity in patients with metastatic melanoma receiving a peptide vaccine SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-INFILTRATING LYMPHOCYTES; ESTABLISHED PULMONARY METASTASES; ANTIGEN GP100; T-LYMPHOCYTES; INTERLEUKIN-2; IDENTIFICATION; IMMUNIZATION; REGRESSION; APOPTOSIS AB Patients with metastatic melanoma were immunized with an immunodominant peptide derived from the gp100 melanoma-melanocyte differentiation Ag that was modified to increase binding to HLA-A(+)0201, A total of 10 of 11 patients who received the g209-2M peptide alone developed precursors reactive with the native g209 peptide, compared with only 5 of 16 patients who received g209-2M peptide plus IL-2 (p(2) = 0.005), Peptide reactivity closely correlated with the recognition of HLA-A(+)0201 melanoma cells (p < 0.001), The decrease in immune reactivity when peptide was administered with IL-2 appeared specific for the immunizing peptide, since reactivity to an influenza peptide resulting from prior exposure was not affected. Preexisting antitumor precursors did not decrease when peptide plus IL-2 was administered. The administration of GM-CSF or IL-12 also resulted in a decrease in circulating precursors compared with the administration of peptide alone, though not as great a decrease as that seen with IL-2, Immunization with peptide plus IL-2 did, however, appear to have clinical impact since 6 of the 16 patients (38%) that received peptide plus IL-2 had objective cancer regressions. It thus appeared possible that immunization with peptide plus IL-2 resulted in sequestering or apoptotic destruction of newly activated immune cells at the tumor site. These represent the first detailed studies of the impact of immunization,vith tumor peptides in conjunction with a variety of cytokines in patients with metastatic cancer. C1 NCI, Div Clin Sci, Surg Branch, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Div Clin Sci, Surg Branch, 9000 Rockville Pike,Bldg 10,Room 2B42, Bethesda, MD 20892 USA. RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 BC010763-01, Z99 CA999999] NR 20 TC 143 Z9 148 U1 0 U2 4 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 1 PY 1999 VL 163 IS 3 BP 1690 EP 1695 PG 6 WC Immunology SC Immunology GA 219ZX UT WOS:000081640000076 PM 10415076 ER PT J AU Evans, TG Keefer, MC Weinhold, KJ Wolff, M Montefiori, D Gorse, GJ Graham, BS McElrath, MJ Clements-Mann, ML Mulligan, MJ Fast, P Walker, MC Excler, JL Duliege, AM Tartaglia, J AF Evans, TG Keefer, MC Weinhold, KJ Wolff, M Montefiori, D Gorse, GJ Graham, BS McElrath, MJ Clements-Mann, ML Mulligan, MJ Fast, P Walker, MC Excler, JL Duliege, AM Tartaglia, J CA NIAID AIDS Vaccine Evaluation Grp TI A canarypox vaccine expressing multiple human immunodeficiency virus type 1 genes given alone or with Rgp120 elicits broad and durable CD8(+) cytotoxic T lymphocyte responses in seronegative volunteers SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 5th Conference on Retroviruses and Opportunistic Infections CY FEB 01-05, 1998 CL CHICAGO, ILLINOIS ID NEUTRALIZING ANTIBODY-RESPONSES; CANDIDATE AIDS VACCINES; ALTERED PEPTIDE LIGANDS; UNINFECTED RECIPIENTS; RABIES GLYCOPROTEIN; RECOMBINANT GP160; PRIMARY INFECTION; HIV-1 VACCINES; CELL RESPONSES; CD8+ CELLS AB Induction of CD8(+) cytotoxic T cells is considered one of the important correlates for the protective efficacy of candidate human immunodeficiency virus type 1 (HIV-1) vaccines. To induce CD8(+) cytotoxic T lymphocytes (CTLs) along with neutralizing antibody and CD4(+) T cell help, a live canarypox virus construct expressing gp120, transmembrane gp41, the gag and protease genes, and sequences containing CTL epitopes in nef and pol was given simultaneously with, or followed by, rgp120 SF2. CD8(+) CTLs were detected in 61% of volunteers at some time during the trial. Three to 6 months after the last immunization, the gene-specific responses were gag, 26/81; env, 17/77; nef; 12/77; and pol, 3/16, Simultaneous immunization with the canarypox vector and the subunit, beginning with the initial immunization, resulted in earlier antibody responses. In summary, a strategy of immunization with a canarypox vector expressing multiple genes of HIV-1 given with gp120 results in durable CD8(+) CTL responses to a broad range of epitopes. C1 Univ Rochester, Sch Med & Dent, Rochester, NY 14642 USA. Virogenet Corp, Troy, NY 12180 USA. Duke Univ, Med Ctr, Durham, NC 27710 USA. EMMES Corp, Potomac, MD 20854 USA. Johns Hopkins Univ, Sch Publ Hlth, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. NIAID, Div Aids, Bethesda, MD 20892 USA. St Louis Univ, Sch Med, St Louis, MO 63103 USA. Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. Univ Washington, Sch Med, Seattle, WA 98195 USA. Univ Alabama, Birmingham, AL 35294 USA. Pasteur Merieux Connaught, Marnes La Coquette, France. Chiron Vaccines, Emeryville, CA 94608 USA. RP Evans, TG (reprint author), Univ Rochester, Sch Med & Dent, Box 689,601 Elmwood Ave, Rochester, NY 14642 USA. FU NIAID NIH HHS [N01 AI-45208, N01 AI-45209, N01 AI-45210] NR 49 TC 150 Z9 154 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG PY 1999 VL 180 IS 2 BP 290 EP 298 DI 10.1086/314895 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 222CZ UT WOS:000081767000007 PM 10395842 ER PT J AU Keet, IPM Tang, J Klein, MR LeBlanc, S Enger, C Rivers, C Apple, RJ Mann, D Goedert, JJ Miedema, F Kaslow, RA AF Keet, IPM Tang, J Klein, MR LeBlanc, S Enger, C Rivers, C Apple, RJ Mann, D Goedert, JJ Miedema, F Kaslow, RA TI Consistent associations of HLA class I and II and transporter gene products with progression of human immunodeficiency virus type 1 infection in homosexual men SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT Meeting of the British-Society-for-Histocompatibility-and-Immunogenetics CY MAR, 1998 CL LONDON, ENGLAND SP British Soc Histocompatibil & Immunogenet ID MAJOR HISTOCOMPATIBILITY COMPLEX; T-LYMPHOCYTE EPITOPES; HIV-RELATED DISEASE; HELPER LYMPHOCYTES; CLINICAL COURSE; AIDS; ANTIGEN; ALLELES; RESTRICTION; HAPLOTYPES AB Polymorphic products of genes in the HLA region contributing to variability in the course of human immunodeficiency virus type 1 (HIV-1) infection were identified by screening 375 Caucasian seroconverters who were aggregated from 3 cohorts. AIDS-free time was related to numerous (15) class I alleles, alone or in conjunction with transporter protein variants, to homozygosity at the A or B locus, and to alleles of two class II haplotypes. A prognostic scoring algorithm derived from the 3 cohorts captured multiple HLA contributions to protection or to risk (relative hazard = 0.57-60 per unit increase in score, all P << .001). The impact of HLA was strong and appeared independent of the effects of chemokine receptor/ligand polymorphisms and antiretroviral treatment. The algorithm also predicted divergent rates of CD4(+) cell decline in 2 other groups, totaling 227 seropositive persons (P = .06 - < .001), Confirmation of these relationships should encourage investigation of HIV-1 antigen processing and presentation mediated by polymorphisms in the HLA region. C1 Univ Alabama, Sch Publ Hlth, Dept Epidemiol Med & Microbiol, Program Epidemiol Infect & Immun, Birmingham, AL 35294 USA. Municipal Hlth Serv, Amsterdam, Netherlands. Red Cross Blood Transfus Serv, Cent Lab, Amsterdam, Netherlands. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Baltimore, MD USA. Roche Mol Syst, Alameda, CA USA. Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. NCI, EPN, Viral Epidemiol Branch, NIH, Bethesda, MD 20892 USA. RP Kaslow, RA (reprint author), Univ Alabama, Sch Publ Hlth, Dept Epidemiol Med & Microbiol, Program Epidemiol Infect & Immun, Ryals Bldg 220A,1665 Univ Blvd, Birmingham, AL 35294 USA. RI apple, raymond/I-4506-2012 OI apple, raymond/0000-0002-8007-0345 FU NCI NIH HHS [N01-CO-56000]; NIAID NIH HHS [UO1-AI-35042, AI 41951] NR 49 TC 77 Z9 81 U1 2 U2 4 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG PY 1999 VL 180 IS 2 BP 299 EP 309 DI 10.1086/314862 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 222CZ UT WOS:000081767000008 PM 10395843 ER PT J AU Watts, DH Rabe, L Krohn, MA Aura, J Hillier, SL AF Watts, DH Rabe, L Krohn, MA Aura, J Hillier, SL TI The effects of three nonoxynol-9 preparations on vaginal flora and epithelium SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT Annual Meeting of the Infectious-Diseases-Society-for-Obstetrics-and-Gynecology CY AUG 06-09, 1997 CL LOS CROABAS, PUERTO RICO SP Infect Dis Soc Obstet & Gynecol ID URINARY-TRACT INFECTION; BACTERIAL VAGINOSIS; ESCHERICHIA-COLI; CHLAMYDIA-TRACHOMATIS; CLINICAL-TRIAL; HIV-INFECTION; DIAPHRAGM USE; WOMEN; ASSOCIATION; ACQUISITION AB To evaluate the effects of nonoxynol-9 (N-9) on the vaginal flora and epithelium, 48 women (16 in each group) were evaluated by use of quantitative vaginal. cultures and colposcopy, at baseline and at 0.5, 4, 24, 48, and 72 h after insertion of one of three N-9 preparations (4% gel [Conceptrol], 3.5% gel [Advantage-24], or a 28% vaginal contraceptive film). The proportion positive for H2O2+ or H2O2- lactobacilli did not change significantly with any of the preparations, but lactobacilli concentrations decreased transiently. Both the proportion of women with Gardnerella vaginalis and the concentration of G. vaginalis decreased transiently. The proportion of women with Escherichia coli increased with the 4% gel, and the concentration increased with all preparations. The number with anaerobic gram-negative rods increased, although the concentrations decreased. Symptoms and colposcopic abnormalities were rare. Changes in levels of vaginal bacteria were transient after single applications of N-9, but adverse effects may be enhanced with frequent, chronic use. C1 Univ Pittsburgh, Magee Womens Res Inst, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. Univ Washington, Dept Obstet & Gynecol, Seattle, WA 98195 USA. RP Watts, DH (reprint author), NICHD, CRMC, Maternal AIDS Branch, NIH, 6100 Execut Blvd,Room 4B11, Bethesda, MD 20892 USA. FU NIAID NIH HHS [AI-37830] NR 33 TC 36 Z9 39 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG PY 1999 VL 180 IS 2 BP 426 EP 437 DI 10.1086/314881 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 222CZ UT WOS:000081767000024 PM 10395859 ER PT J AU Hafner, R Inderlied, CB Peterson, DM Wright, DJ Standiford, HC Drusano, G Muth, K AF Hafner, R Inderlied, CB Peterson, DM Wright, DJ Standiford, HC Drusano, G Muth, K CA Div AIDS Treatment Res Initiative Protocol 007 TI Correlation of quantitative bone marrow and blood cultures in AIDS patients with disseminated Mycobacterium avium complex infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; IMMUNE-DEFICIENCY-SYNDROME; INTRACELLULARE BACTEREMIA; COMBINATION THERAPY; CLARITHROMYCIN; ETHAMBUTOL; CLOFAZIMINE; SURVIVAL; DISEASE; HIV AB The relationship between Mycobacterium avium complex (MAC) infection of blood and bone marrow was studied in human immunodeficiency virus-infected patients before and during treatment, Quantitative cultures were obtained at baseline from 17 persons with newly detected MAC bacteremia, Serial blood cultures were obtained, and a second bone marrow sample was obtained at 4 or 8 weeks. At baseline, the median MAC load in bone marrow core samples was 3 log(10) higher than in blood. Bone marrow MAC loads ranged widely (866-847,315 cfu/g), and no significant correlation was found between MAC load in blood and that in bone marrow core samples. MAC loads in bilateral bone marrow biopsy samples from 7 subjects were highly correlated, MAC loads declined in blood and bone marrow at similar rates during therapy, but blood was sterilized before bone marrow. Length of survival was inversely associated with initial bone marrow core MAC load but not with blood MAC load. Initiation of treatment when tissue MAC load is low may increase the Likelihood of favorable clinical outcome. C1 NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. WESTAT Corp, Rockville, MD 20850 USA. Dept Vet Affairs Med Ctr, Baltimore, MD USA. Univ So Calif, Sch Med, Dept Pathol & Lab Med, Los Angeles, CA USA. Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Albany Med Coll, Albany, NY 12208 USA. RP Hafner, R (reprint author), NIAID, Div Aids, NIH, 6700-B Rockledge Dr,MSC 7624, Bethesda, MD 20892 USA. FU NIAID NIH HHS [AI-15123] NR 46 TC 14 Z9 15 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG PY 1999 VL 180 IS 2 BP 438 EP 447 DI 10.1086/314865 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 222CZ UT WOS:000081767000025 PM 10395860 ER PT J AU Lira, R Sundar, S Makharia, A Kenney, R Gam, A Saraiva, E Sacks, D AF Lira, R Sundar, S Makharia, A Kenney, R Gam, A Saraiva, E Sacks, D TI Evidence that the high incidence of treatment failures in Indian kala-azar is due to the emergence of antimony-resistant strains of Leishmania donovani SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 46th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene CY OCT, 1998 CL SAN JUAN, PUERTO RICO SP Amer Soc Trop Med & Hygiene ID SODIUM STIBOGLUCONATE; VISCERAL LEISHMANIASIS; PENTAVALENT ANTIMONY; DRUG-RESISTANCE; IN-VITRO; AMASTIGOTES; BIHAR AB The possibility that the high frequency of treatment failures in Indian kala-azar might be due to infection with antimony-resistant strains of Leishmania donovani has not been experimentally addressed. L. donovani isolates were obtained from splenic aspiration smears of 24 patients in Bihar, India, who either did not respond (15) or did respond (9) to 1 or more full courses of treatment with sodium antimony gluconate (SAG), A strong correlation (P < .001) between clinical response and SAG sensitivity in vitro was observed only when strains were assayed as intracellular amastigotes: responsive isolates ED50 = 2.4 +/- 2.6, ED90 = 6.4 +/- 7.8 mu g SAG/mL; unresponsive isolates ED50 = 7.4 +/- 3.7 mu g SAG/mL, ED90 = 29.1 +/- 11.1 SAG/mL. No correlation with clinical response was found by use of extracellular promastigotes (ED50 = 48 +/- 22 vs. 52 +/- 29 mu g/mL). The emergence of antimony-resistant L. donovani strains appears to be a cause of treatment failures in India. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. US FDA, CBER, Lab Parasit Biol & Biochem, OVRR,DAPP, Rockville, MD 20857 USA. Benares Hindu Univ, Inst Med Sci, Varanasi, Uttar Pradesh, India. RP Sacks, D (reprint author), NIAID, Parasit Dis Lab, NIH, Bldg 4,Rm 126,4 Ctr Dr,MSC 0425, Bethesda, MD 20892 USA. NR 16 TC 240 Z9 249 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG PY 1999 VL 180 IS 2 BP 564 EP 567 DI 10.1086/314896 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 222CZ UT WOS:000081767000049 PM 10395884 ER PT J AU Ship, JA Fox, PC Michalek, JE Cummins, MJ Richards, AB AF Ship, JA Fox, PC Michalek, JE Cummins, MJ Richards, AB CA IFN Protocol Study Grp TI Treatment of primary Sjogren's syndrome with low-dose natural human interferon-alpha administered by the oral mucosal route: A phase II clinical trial SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Article ID IFN-ALPHA; SALIVARY; CLASSIFICATION; POPULATION; XEROSTOMIA; TOXICITY; CRITERIA; SICCA AB The purpose of this investigation was to examine the safety and efficacy of four dosages of natural human interferon-alpha (nHuIFN-alpha) delivered over a 12-week period orally in lozenges (150 IU and 450 IU, once [QD] or three times [TID] daily) compared to placebo in subjects with primary Sjogren's syndrome. This randomized, double-blinded clinical trial demonstrated that nHuIFN-alpha at a dose of 150 IU administered TLD by oral lozenge significantly improved stimulated whole saliva output compared to placebo after 12 weeks of treatment. The 150 IU TID dose also was suggestive of benefit for 5 of 7 subjective measures of oral and ocular comfort. IFN lozenges demonstrated a good safety profile, with no serious adverse events found in any treatment group. There were no significant differences between the placebo and the four doses of IFN for adverse events by total number, organ system, severity, dropouts, and number judged to be related to treatment. In conclusion, these results demonstrated that the use of 150 IU IFN lozenges TID for 12 weeks in subjects with primary Sjogren's syndrome improved salivary output and decreased complaints of xerostomia without causing significant adverse medical events. C1 Univ Michigan, Sch Dent, Dept Oral Med Pathol Oncol, Ann Arbor, MI 48109 USA. NIDCR, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. Univ Texas, Dept Math & Stat, San Antonio, TX 78284 USA. Amarillo Biosci Inc, Amarillo, TX 79101 USA. Hayashibara USA, Amarillo, TX 79109 USA. RP Ship, JA (reprint author), Univ Michigan, Sch Dent, Dept Oral Med Pathol Oncol, 1011 N Univ,Room 2012, Ann Arbor, MI 48109 USA. NR 44 TC 77 Z9 78 U1 1 U2 3 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1079-9907 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD AUG PY 1999 VL 19 IS 8 BP 943 EP 951 DI 10.1089/107999099313497 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 229CB UT WOS:000082175000020 PM 10476942 ER PT J AU Baldwin, DC Alpert, HR Emanuel, EJ Emanuel, LL AF Baldwin, DC Alpert, HR Emanuel, EJ Emanuel, LL TI Quantitative validation of a conceptual model of the good death SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract C1 Amer Med Assoc, Inst Eth, Chicago, IL USA. Vital Sci, Newtonville, MA USA. NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD AUG PY 1999 VL 47 IS 7 SU S BP 231A EP 231A PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 231AW UT WOS:000082284700081 ER PT J AU Tycko, R AF Tycko, R TI Selection rules for multiple quantum NMR excitation in solids: Derivation from time-reversal symmetry and comparison with simulations and C-13 NMR experiments SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE multiple quantum NMR; time-reversal; NMR theory; solid state NMR; peptides ID NUCLEAR-MAGNETIC-RESONANCE; ROTATING SOLIDS; DYNAMICS; FILMS; SILICON; POWDERS; PROBE AB New derivations of selection rules for excitation and detection of multiple quantum coherences in coupled spin-1/2 systems are presented. The selection rules apply to experiments in which the effective coupling Hamiltonian used for multiple quantum excitation is both time-reversal invariant and time-reversible by a phase shift of the radiofrequency pulse sequence that generates the effective couplings. The selection rules are shown to be consequences of time-reversal invariance and time-reversibility and otherwise independent of the specific form of the effective coupling Hamiltonian. Numerical simulations of multiple quantum NMR signal amplitudes and experimental multiple quantum excitation spectra are presented for the case of a multiply C-13-labeled helical polypeptide. The simulations and experiments confirm the selection rules and demonstrate their impact on multiple quantum C-13 NMR spectra in this biochemically relevant case. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. NR 26 TC 22 Z9 22 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD AUG PY 1999 VL 139 IS 2 BP 302 EP 307 DI 10.1006/jmre.1999.1776 PG 6 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 225XQ UT WOS:000081991600012 PM 10423367 ER PT J AU Nathanson, N Mathieson, BJ AF Nathanson, N Mathieson, BJ TI Towards an AIDS vaccine: The role of nonhuman primates SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Article; Proceedings Paper CT 16th Annual Symposium on Nonhuman Primate Models for AIDS CY OCT 07-10, 1998 CL ATLAND, GEORGIA SP Natl Ctr Res Resources, Natl Inst Allergy & Infect Dis, Yerkes Reg Primate Res Ctr, Pharmingen, BioTech Imaging Inc, Cosh Healthcare Ltd, Gilead Sci, Merck Res Lab, Surburban Surgical Co Inc DE HIV; SIV; SHIV; attenuated virus; muscosal immunity; superinfection; immunity; protection ID SIMIAN IMMUNODEFICIENCY VIRUS; HIV-1 INFECTION; RHESUS MACAQUES; NATURAL PROTECTION; SOOTY MANGABEYS; SIV VACCINE; LIVE; CHALLENGE; DISEASE; RESPONSES AB Over the last 10 years, about 20 human immunodeficiency virus (HIV) vaccine candidates have been tried in humans, with disappointing results as gauged by limited immune responses or protection against infection. These difficulties suggest that a new strategy is needed to test systematically new vaccine candidates. That opportunity is now afforded by nonhuman primate models with SIV, which have been shown to provide an excellent mirror of HIV infection in humans. The recent introduction of SHIVs, chimeric viruses that carry the HIV envelope and are able to infect and cause AIDS in monkeys, also has added an important additional research tool. These models call be used to address a series of questions, including the following: (1) Can protection be provided by partial immunity or is sterilizing immunity required? (2) What are the immune parameters that best predict protection against a potentially pathogenic challenge? (3) What role does mucosal immunity play and can it be induced by practical modes of immunization? (4) Can an attenuated virus be selected that is both protective and safe? An orderly strategy for the evaluation of vaccine candidates could be adopted that would involve several phases: (a) the selection of a limited set of challenge models, ranging from very severe to mild and requiring consideration of primate species, age, route of infection, and challenge viruses; (b) the assessment of candidate vaccines using comparable virus challenges; and (c) accelerated testing in humans of any candidate vaccines that have met a 'proof of efficacy' in primates. C1 NIH, Off AIDS Res, Bethesda, MD 20892 USA. RP Nathanson, N (reprint author), NIH, Off AIDS Res, Bethesda, MD 20892 USA. NR 63 TC 6 Z9 6 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD AUG-OCT PY 1999 VL 28 IS 4-5 BP 146 EP 153 PG 8 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 254YW UT WOS:000083642800002 PM 10593479 ER PT J AU Mossman, SP Pierce, CC Robertson, MN Watson, AJ Montefiori, DC Rabin, M Kuller, L Thompson, J Lynch, JB Morton, WR Benveniste, RE Munn, R Hu, SL Greenberg, P Haigwood, NL AF Mossman, SP Pierce, CC Robertson, MN Watson, AJ Montefiori, DC Rabin, M Kuller, L Thompson, J Lynch, JB Morton, WR Benveniste, RE Munn, R Hu, SL Greenberg, P Haigwood, NL TI Immunization against SIVmne in macaques using multigenic DNA vaccines SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Article; Proceedings Paper CT 16th Annual Symposium on Nonhuman Primate Models for AIDS CY OCT 07-10, 1998 CL ATLAND, GEORGIA SP Natl Ctr Res Resources, Natl Inst Allergy & Infect Dis, Yerkes Reg Primate Res Ctr, Pharmingen, BioTech Imaging Inc, Cosh Healthcare Ltd, Gilead Sci, Merck Res Lab, Surburban Surgical Co Inc DE cytokines; primate models; subunits ID SIMIAN IMMUNODEFICIENCY VIRUS; ATTENUATED SIV; PROTECTION; INFECTION; GENE; VACCINATION; ANTIBODY; DELETION; PATTERNS; VIREMIA AB All structural and regulatory genes of SIVmne were cloned into mammalian expression vectors to optimize expression in vitro and immunogenicity in mice. Macaca fascicularis were immunized four times with plasmid DNA (n = 4), or two DNA priming inoculations followed by two boosts of recombinant gp160 plus Gag-Pol particles (n = 4). Following intrarectal challenge with SIVmne, all macaques be came infected. Three monkeys immunized with DNA alone maintained low plasma virus loads by 1 year post-challenge; the fourth exhibited high virus loads and significant CD4(+) cell decline. Two of the DNA plus boost and three control macaques had high virus loads and associated CD4(+) cell decline. Both vaccine protocols elicited antibodies and comparable helper T-cell proliferative responses to gp160. Cytokine mRNA levels in activated peripheral blood mononuclear cells (PBMC) takes at time of challenge suggested a dominant T helper (Th) 1 state in three DNA-immunized and one protein-boosted macaque, which correlated with low virus loads and high CD4(+) cell counts post-challenge. C1 Seattle Biomed Res Inst, Seattle, WA 98109 USA. Univ Washington, Dept Med, Seattle, WA USA. Duke Univ, Med Ctr, Durham, NC USA. Univ Washington, Washington Reg Primate Res Ctr, Seattle, WA 98195 USA. NCI, Viral Carcinogenesis Lab, Frederick, MD USA. Univ Calif Davis, Sch Med, Davis, CA 95616 USA. RP Haigwood, NL (reprint author), Seattle Biomed Res Inst, 4 Nickerson St, Seattle, WA 98109 USA. RI Hu, Shiu-Lok/A-3196-2008 OI Hu, Shiu-Lok/0000-0003-4336-7964 NR 23 TC 17 Z9 19 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD AUG-OCT PY 1999 VL 28 IS 4-5 BP 206 EP 213 PG 8 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 254YW UT WOS:000083642800010 PM 10593487 ER PT J AU Grant, DJ Shi, H Teng, CT AF Grant, DJ Shi, H Teng, CT TI Tissue and site-specific methylation correlates with expression of the mouse lactoferrin gene SO JOURNAL OF MOLECULAR ENDOCRINOLOGY LA English DT Article ID TRANSCRIPTION FACTOR; REPRODUCTIVE-TRACT; ESTROGEN-RECEPTOR; MESSENGER-RNA; PROMOTER; PROTEIN; DEMETHYLATION; ACTIVATION; ELEMENTS; BINDING AB We have previously examined the regulatory region of the mouse lactoferrin gene and have identified sequences essential for basal and hormonally induced expression. In this study, we explore the relationship between the methylation state of the mouse lactoferrin gene promoter and its expression in selected mouse tissues. In a transient expression system, transcriptional activity was blocked after in vitro methylation of the regulatory region of the mouse lactoferrin gene. In addition, the in vivo methylation state of three promoter region sites was assessed using Southern blot analysis of DNA digested with methylation-insensitive and -sensitive restriction enzymes. The results showed that site -455, upstream of the mouse lactoferrin estrogen response module, was highly unmethylated in DNA from both hormone-treated and -untreated mouse lung, liver, and spleen tissues. Also, in both treated and untreated samples, the -54 site is uniquely highly unmethylated in liver DNA, while the -22 site is unmethylated in spleen DNA. Northern blot analysis showed lactoferrin expression in tissues that were unmethylated at a minimum of two sites. These results show that the alteration of the methylation status of the three sites are tissue-specific and are associated with constitutive expression of lactoferrin. C1 NIEHS, Gene Regulat Grp, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Teng, CT (reprint author), NIEHS, Gene Regulat Grp, Reprod & Dev Toxicol Lab, NIH, POB 12233 MD E201, Res Triangle Pk, NC 27709 USA. NR 21 TC 11 Z9 11 U1 0 U2 0 PU SOC ENDOCRINOLOGY PI BRISTOL PA 17/18 THE COURTYARD, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4NQ, ENGLAND SN 0952-5041 J9 J MOL ENDOCRINOL JI J. Mol. Endocrinol. PD AUG PY 1999 VL 23 IS 1 BP 45 EP 55 DI 10.1677/jme.0.0230045 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 223EY UT WOS:000081829000005 PM 10425446 ER PT J AU Mattson, MP Duan, WZ Chan, SL Camandola, S AF Mattson, MP Duan, WZ Chan, SL Camandola, S TI Par-4 - An emerging pivotal player in neuronal apoptosis and neurodegenerative disorders SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Review DE Alzheimer's; bcl-2; caspase; hippocampus; ischemia; NF-kappa B; oxidative stress; Parkinson's ID AMYOTROPHIC-LATERAL-SCLEROSIS; AMYLOID BETA-PEPTIDE; PROTEIN-KINASE-C; SUPEROXIDE-DISMUTASE; PARKINSONS-DISEASE; LIPID-PEROXIDATION; CELL-DEATH; OXIDATIVE STRESS; PC12 CELLS; MITOCHONDRIAL DYSFUNCTION AB Prostate apoptosis response-4 (Par-4) is a 38-kDa protein initially identified as the product of a gene upregulated in prostate tumor cells undergoing apoptosis. Par-4 contains both a death domain and a leucine zipper domain, and has been shown to interact with several proteins known to modulate apoptosis, including protein kinase C zeta, Bcl-2, and caspase-8. A rapid increase in Par-4 levels occurs in neurons undergoing apoptosis in a variety of paradigms, including trophic factor withdrawal, and exposure to oxidative and metabolic insults. Par-4, which can be induced at the translational level, acts at an early stage of the apoptotic cascade prior to caspase activation and mitochondrial dysfunction. The-mechanism whereby Par-4 promotes apoptosis may involve inhibition of the antiapoptotic transcription factor NF-kappa B and suppression of Bcl-2 expression and/or function. Studies of postmortem tissues from patients and animal models of neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases, amyotrophic lateral sclerosis (ALS), and HIV encephalitis,have documented increased levels of Par-4 in vulnerable neurons. Manipulations that block Par-4 expression or function prevent neuronal cell death in models of each disorder, suggesting a critical role for Par-4 in the neurodegenerative process Interestingly, Par-4 levels rapidly increase in synaptic terminals following various insults, and such local increases in Par-4 levels appear to play important roles in synaptic dysfunction and degeneration. A better understanding of the molecular and cellular biology of Par-4 will help clarify mechanisms of neuronal apoptosis, and may lead to the development of novel preventative and therapeutic strategies for neurodegenerative disorders. C1 Univ Kentucky, Sanders Brown Res Ctr Aging, Lexington, KY 40536 USA. Univ Kentucky, Dept Anat & Neurobiol, Lexington, KY 40536 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, 5600 Nathan Sheck Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 70 TC 31 Z9 35 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD AUG-OCT PY 1999 VL 13 IS 1-2 BP 17 EP 30 DI 10.1385/JMN:13:1-2:17 PG 14 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 283CC UT WOS:000085257700002 PM 10691289 ER PT J AU Pedersen, WA Culmsee, C Ziegler, D Herman, JP Mattson, MP AF Pedersen, WA Culmsee, C Ziegler, D Herman, JP Mattson, MP TI Aberrant stress response associated with severe hypoglycemia in a transgenic mouse model of Alzheimer's disease SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE amyloid; corticosterone; glucocorticoids; hypothalamus; pituitary; transgenic ID PITUITARY-ADRENAL AXIS; MEMORY DEFICITS; GLUCOCORTICOIDS; RESTRICTION; PROTEIN; NEURONS; PLAQUES; HORMONE AB Patients with Alzheimer's disease (AD) exhibit alterations in glucose metabolism and dysregulation of the stress-responsive hypothalamic-pituitary-adrenal (HPA) neuroendocrine system. The mechanisms responsible for these alterations and their possible contributions to the neurodegenerative process in AD are unknown. We now report that transgenic mice expressing a mutant form of human amyloid precursor protein (APP) that causes inherited early-onset AD exhibit increased sensitivity to physiological stressors, which is associated with aberrancies in HPA function and regulation of blood glucose levels. Specifically, APP mutant mice exhibit severe hypoglycemia and death following food restriction, and sustained elevations of plasma glucocorticoid levels and hypoglycemia following restraint stress. The alterations in HPA function and glucose regulation were evident in relatively young mice prior to overt deposition of amyloid beta-peptide (A beta). However, diffuse accumulations of A beta were present in the hypothalamus of older mice, suggesting a role for soluble forms of A beta in dysregulation of HPA function. Our data demonstrate disturbances in neuroendocrine function in APP mutant mice similar to those seen in AD patients. These impairments in stress response, glucocorticoid signaling, and regulation of blood glucose should be considered in interpretations of data from past and future studies of APP mutant mice. C1 Univ Kentucky, Sanders Brown Res Ctr Aging, Lexington, KY 40536 USA. Univ Kentucky, Dept Anat & Neurobiol, Lexington, KY 40536 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012; Herman, James/D-4960-2015 OI Herman, James/0000-0003-3571-2406 NR 24 TC 48 Z9 50 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD AUG-OCT PY 1999 VL 13 IS 1-2 BP 159 EP 165 DI 10.1385/JMN:13:1-2:159 PG 7 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 283CC UT WOS:000085257700015 PM 10691302 ER PT J AU Bokesch, HR Groweiss, A McKee, TC Boyd, MR AF Bokesch, HR Groweiss, A McKee, TC Boyd, MR TI Laxifloranone, a new phloroglucinol derivative from Marila laxiflora SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID NATURAL-PRODUCTS; ANTI-HIV AB A new polyisoprenylated phloroglucinol derivative has been isolated from the twigs of Marila laxiflora and characterized on the basis of 1D and 2D NMR spectra. Laxifloranone (1) shows moderate inhibition of the cytopathic effects of in vitro HIV infection. C1 NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program,Div Canc Treatment & Diag, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Boyd, MR (reprint author), NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program,Div Canc Treatment & Diag, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. EM mckee@dtpax2.ncifcrf.gov; boyd@dtpax2.ncifcrf.gov FU NCI NIH HHS [N01-CO-56000] NR 13 TC 19 Z9 20 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 AUG PY 1999 VL 62 IS 8 BP 1197 EP 1199 DI 10.1021/np990136e PG 3 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 232QM UT WOS:000082381500034 PM 10479340 ER PT J AU Mezzich, JE Kirmayer, LJ Kleinman, A Fabrega, H Parron, DL Good, BJ Lin, KM Manson, SM AF Mezzich, JE Kirmayer, LJ Kleinman, A Fabrega, H Parron, DL Good, BJ Lin, KM Manson, SM TI The place of culture in DSM-IV SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Review ID PSYCHIATRIC-DIAGNOSIS; III-R; PUERTO-RICO; ILLNESS; PREVALENCE AB This paper critically reviews the process and outcome of an effort to enhance the cultural validity of DSM-IV and outlines recommendations to improve future diagnostic systems. An ordered presentation of the antecedents and the main phases of this developmental effort is followed by a content analysis of what was proposed and what was actually incorporated, and a conceptual analysis of underlying biases and their implications. The cultural effort for DSM-IV, spearheaded by a scholarly independent NIMH workgroup, resulted in significant innovations including an introductory cultural statement, cultural considerations for the use of diagnostic categories and criteria, a glossary of culture-bound syndromes and idioms of distress, and an outline for a cultural formulation. However, proposals that challenged universalistic nosological assumptions and argued for the contextualization of illness, diagnosis, and care were minimally incorporated and marginally placed. Although a step forward has been taken to introduce cultural elements in DSM-IV much remains to be done. Further culturally informed research is needed to ensure that future diagnostic systems incorporate a genuinely comprehensive framework, responsive to the complexity of health problems in increasingly multicultural societies. C1 CUNY Mt Sinai Sch Med, Int Ctr Mental Hlth, New York, NY 10029 USA. McGill Univ, Div Social & Transcultural Psychiat, Montreal, PQ, Canada. Harvard Univ, Dept Social Med, Cambridge, MA 02138 USA. Harvard Univ, Dept Anthropol & Psychiat, Cambridge, MA 02138 USA. Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. Univ Pittsburgh, Dept Anthropol, Pittsburgh, PA USA. NIMH, Rockville, MD 20857 USA. Univ Calif Los Angeles, Res Ctr Psychobiol Ethn, Los Angeles, CA USA. Univ Colorado, Natl Ctr Amer Indian & Alaska Native Mental Hlth, Denver, CO 80202 USA. RP Mezzich, JE (reprint author), CUNY Mt Sinai Sch Med, Int Ctr Mental Hlth, 5th Ave & 100th St,Box 1093, New York, NY 10029 USA. OI Kirmayer, Laurence/0000-0002-6228-1739 NR 50 TC 95 Z9 97 U1 2 U2 20 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3018 J9 J NERV MENT DIS JI J. Nerv. Ment. Dis. PD AUG PY 1999 VL 187 IS 8 BP 457 EP 464 DI 10.1097/00005053-199908000-00001 PG 8 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 225XC UT WOS:000081990400001 PM 10463062 ER PT J AU King, VL Brooner, RK Kidorf, MS Stoller, KB Mirsky, AF AF King, VL Brooner, RK Kidorf, MS Stoller, KB Mirsky, AF TI Attention deficit hyperactivity disorder and treatment outcome in opioid abusers entering treatment SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Article ID PSYCHIATRIC STATUS; FOLLOW-UP; COCAINE ABUSERS; OPIATE ADDICTS; RESIDUAL TYPE; ADULTS; COMORBIDITY; CHILDREN; POPULATION; PREVALENCE AB Symptoms of DSM-IV attention-deficit hyperactivity disorder (ADHD) were determined in patients entering methadone maintenance treatment. The relationship of ADHD to psychiatric and substance abuse comorbidity, attention testing, and treatment outcome was analyzed; 19% of patients had a history of ADHD, and 88% of these had current symptoms. Continuous Performance Testing indicated poorer attention in patients with ADHD. The only substance use disorder more common in the ADHD group was clonidine. There was significantly more current axis I, dysthymic disorder, anxiety disorder (including social phobia), and antisocial personality disorder in the ADHD patients. There was no difference between groups at the 1-year follow-up for illicit drug use, treatment retention, or treatment performance. The ADHD diagnosis did not convey significant prognostic implications for methadone maintenance treatment. A strong psychiatric assessment and treatment focus in the treatment program may help to explain the good treatment outcome. C1 Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD USA. NIMH, Psychol & Psychopathol Lab, Bethesda, MD 20892 USA. RP King, VL (reprint author), Johns Hopkins Bayview Med Ctr, Addict Treatment Serv Hopkins Bayview, 5510 Nathan Shock Dr,Suite 1500, Baltimore, MD 21224 USA. FU NIDA NIH HHS [P50 DA-05273]; NIMH NIH HHS [R03 MH 55013] NR 41 TC 60 Z9 62 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3018 J9 J NERV MENT DIS JI J. Nerv. Ment. Dis. PD AUG PY 1999 VL 187 IS 8 BP 487 EP 495 DI 10.1097/00005053-199908000-00005 PG 9 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 225XC UT WOS:000081990400005 PM 10463066 ER PT J AU Gomes, I Xiong, W Miki, T Rosner, MR AF Gomes, I Xiong, W Miki, T Rosner, MR TI A proline- and glutamine-rich protein promotes apoptosis in neuronal cells SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE apoptosis; programmed cell death; neuronal development; proline- and glutamine-rich protein ID NERVOUS-SYSTEM; CDNA CLONING; ADULT CNS; DEATH; EXPRESSION; LINE; GENE; DIFFERENTIATION; DROSOPHILA; BINDING AB During development, excess neurons are eliminated by programmed cell death. Similarly, conditionally immortalized (SV40-T-ts) rat hippocampal and septal cells undergo cell death following differentiation with several factors such as fibroblast growth factor, constitutively activated Raf-1, or phorbol esters. The mechanism by which cell death occurs has not been identified. Using RNA differential display, we have identified and characterized a novel immediate early gene (denoted PQR for proline- and glutamine-rich) induced during differentiation of both rat hippocampal and septal cell lines. The 44-kDa PQR protein, rich in PQ, PH, and QQ repeats, is homologous to a murine protein (TDAG51) required for Fas-mediated apoptosis in T cells. To determine whether PQR acts as a mediator of apoptosis in neuronal cells, the hippocampal H19-7 cells were microinjected with either a plasmid expressing PQR cDNA or an antibody against PQR. Microinjection of differentiating H19-7 cells with a neutralizing antibody against PQR increased the number of surviving cells by 50%. Transient expression of PQR in both differentiating and nondifferentiating H19-7 cells decreased the number of surviving cells by 35-50%; this reduction was reversed by microinjection of PQR antibody. Finally, levels of Fas transcripts are not increased in the neuronal cells, indicating that the mechanism of action differs from that in T cells. These results demonstrate that PQR can be induced by growth factors and differentiating agents and can itself induce apoptosis in hippocampal H19-7 cells. Furthermore, these data suggest that PQR can function more generally as a mediator of apoptosis and provide a possible mechanism for induction of programmed cell death during neuronal development. C1 Univ Chicago, Ben May Inst Canc Res, Chicago, IL 60637 USA. Univ Illinois, Dept Med, Sect Hematol & Oncol, Chicago, IL USA. Univ Chicago, Dept Pharmacol & Physiol Sci, Chicago, IL 60637 USA. Stanford Univ, Sch Med, Dept Mol Pharmacol, Palo Alto, CA 94304 USA. NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. RP Rosner, MR (reprint author), Univ Chicago, Ben May Inst Canc Res, MC6027,5841 S Maryland Ave, Chicago, IL 60637 USA. FU NINDS NIH HHS [1R01 NS33858] NR 47 TC 42 Z9 44 U1 0 U2 0 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 AUG PY 1999 VL 73 IS 2 BP 612 EP 622 DI 10.1046/j.1471-4159.1999.0730612.x PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 218CG UT WOS:000081535200020 PM 10428057 ER PT J AU Chen, L He, M Sibille, E Thompson, A Sarnyai, Z Baker, H Shippenberg, T Toth, M AF Chen, L He, M Sibille, E Thompson, A Sarnyai, Z Baker, H Shippenberg, T Toth, M TI Adaptive changes in postsynaptic dopamine receptors despite unaltered dopamine dynamics in mice lacking monoamine oxidase B SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE monoamine oxidase B; dopamine receptor; tyrosine hydroxylase; knockout mice; in vivo microdialysis ID CENTRAL-NERVOUS-SYSTEM; TYROSINE-HYDROXYLASE; STRIATAL DOPAMINE; IN-VIVO; QUANTITATIVE MICRODIALYSIS; TRANSGENIC MICE; RAT STRIATUM; INHIBITION; TRANSPORTER; METABOLISM AB Monoamine oxidase (MAO) B is considered a key enzyme in dopamine metabolism. The present studies, conducted in MAO B knockout mice, show that lack of MAO B does not alter extracellular levels of dopamine in striatum. Similarly, the synthesis, storage, uptake, and release of dopamine are also unaltered. However, autoradiography revealed a significant up-regulation of the D2-like dopamine receptors in the striatum of MAO B knockout mice. Mutant mice also exhibit a functional supersensitivity of D1-dopamine receptors in the nucleus accumbens. Thus, the agonist SKF 38,393-induced c-Fos immunoreactivity was significantly increased in knockout mice as compared with wild-type controls. In view of the apparently normal basal dopamine dynamics observed in MAO B knockout mice, we hypothesize that a dopamine-independent mechanism underlies adaptations in dopamine receptor function that occur as a consequence of MAO B depletion. Finally, these findings suggest that chronic administration of MAO inhibitors, as occurs in the treatment of Parkinson's disease and depression, may be associated with an increased responsiveness of CNS neurons to dopamine receptor ligands. C1 Cornell Univ, Weill Med Coll, Dept Pharmacol, New York, NY 10021 USA. Rockefeller Univ, Neuroendocrinol Lab, New York, NY 10021 USA. Rockefeller Univ, Lab Biol Addict Dis, New York, NY 10021 USA. Cornell Univ, Weill Med Coll, Burke Med Res Inst, White Plains, NY USA. NIDA, Integrat Neurosci Unit, Behav Neurosci Branch, Intramural Res Program, Baltimore, MD USA. RP Toth, M (reprint author), Cornell Univ, Weill Med Coll, Dept Pharmacol, Bldg LC,Room 519,1300 York Ave, New York, NY 10021 USA. RI Sarnyai, Zoltan/A-3283-2009 NR 47 TC 22 Z9 22 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 1999 VL 73 IS 2 BP 647 EP 655 DI 10.1046/j.1471-4159.1999.0730647.x PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 218CG UT WOS:000081535200024 PM 10428061 ER PT J AU Koennecke, LA Zito, MA Proescholdt, MG van Rooijen, N Heyes, MP AF Koennecke, LA Zito, MA Proescholdt, MG van Rooijen, N Heyes, MP TI Depletion of systemic macrophages by liposome-encapsulated clodronate attenuates increases in brain quinolinic acid during CNS-localized and systemic immune activation SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE quinolinic acid; macrophage; endotoxin; liposome-encapsulated clodronate; inflammation ID KYNURENINE PATHWAY METABOLISM; TRANSIENT CEREBRAL-ISCHEMIA; CONVERT L-TRYPTOPHAN; INDOLEAMINE 2,3-DIOXYGENASE; GERBIL HIPPOCAMPUS; NEUROACTIVE KYNURENINES; MICROGLIAL CELLS; SPATIAL CHANGES; MICE; RAT AB Quinolinic acid is a neurotoxic tryptophan metabolite produced locally during immune activation. The present study tested the hypothesis that macrophages are an important source. In normal gerbils, the macrophage toxin liposome-encapsulated clodronate depleted blood monocytes and decreased quinolinic acid levels in liver (85%), duodenum (33%), and spleen (51%) but not serum or brain. In a model of CNS inflammation (an intrastriatal injection of 5 mu g of lipopolysaccharide), striatal quinolinic acid levels were markedly elevated on day 4 after lipopolysaccharide in conjunction with infiltration with macrophages (lectin slain). Liposome-encapsulated clodronate given 1 day before intrastriatal lipopolysaccharide markedly reduced parenchymal macrophage invasion in response to lipopolysaccharide infusion and attenuated the increases in brain quinolinic acid (by 60%). A systemic injection of lipopolysaccharide (450 mu g/kg) increased blood (by 38-fold), lung (34-fold), liver (23-fold), spleen (8-fold), and striatum (25-fold) quinolinic acid concentrations after 1 day. Liposome-encapsulated clodronate given 4 days before systemic lipopolysaccharide significantly attenuated the increases in quinolinic acid levels in blood (by 80%), liver (87%), spleen (80%), and striatum (68%) but had no effect on the increases in quinolinic acid levels in lung. These results are consistent with the hypothesis that macrophages are an important local source of quinolinic acid in brain and systemic tissues during immune activation. C1 NIMH, Lab Neurotoxicol, Bethesda, MD 20892 USA. Free Univ Amsterdam, Fac Med, Dept Histol, NL-1081 HV Amsterdam, Netherlands. RP Heyes, MP (reprint author), NIMH, Lab Neurotoxicol, Bldg 10,Rm 3D42,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 45 TC 10 Z9 10 U1 0 U2 0 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 AUG PY 1999 VL 73 IS 2 BP 770 EP 779 DI 10.1046/j.1471-4159.1999.0730770.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 218CG UT WOS:000081535200038 PM 10428075 ER PT J AU Quaia, C Lefevre, P Optican, LM AF Quaia, C Lefevre, P Optican, LM TI Model of the control of saccades by superior colliculus and cerebellum SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Review ID STEM OMNIPAUSE NEURONS; FRONTAL EYE-FIELD; RETICULARIS TEGMENTI PONTIS; FASTIGIAL OCULOMOTOR REGION; INHIBITORY BURST NEURONS; ALERT SQUIRREL-MONKEY; NEURAL-NETWORK MODEL; HEAD-FREE CAT; MACAQUE MONKEY; PURKINJE-CELLS AB Experimental evidence indicates that the superior colliculus (SC) is important but neither necessary nor sufficient to produce accurate saccadic eye movements. Furthermore both clinical and experimental evidence points to the cerebellum as an indispensable component of the saccadic system. Accordingly, we have devised a new model of the saccadic system in which the characteristics of saccades are determined by the cooperation of two pathways, one through the SC and the other through the cerebellum. Both pathways are influenced by feedback information: the feedback determines the decay of activity for collicular neurons and the timing of the activation for cerebellar neurons. We have modeled three types of cells (burst, buildup, and fixation neurons) found in the intermediate layers of the superior colliculus. We propose that, from the point of view of motor execution, the burst neurons and the buildup neurons are not functionally distinct with both providing a directional drive to the brain stem circuitry. The fixation neurons determine the onset of the saccade by disfacilitating the omnipause neurons in the brain stem. Excluding noise-related variations, the ratio of the horizontal to the vertical components of the collicular drive is fixed throughout the saccade (i.e., its direction is fixed); the duration of the drive is such that it always would produce hypermetric movements. The cerebellum plays three roles: first, it provides an additional directional drive, which improves the acceleration of the eyes. second, it keeps track of the progress of the saccade toward the target; and third, it ends the saccade by choking off the collicular drive. The drive provided by the cerebellum can be adjusted in direction to exert a directional control over the saccadic trajectory. We propose here a control mechanism that incorporates a spatial displacement integrator in the cerebellum; under such conditions, we show that a partial directional control arises automatically. Our scheme preserves the advantages of several previous models of the saccadic system (e.g., the lack of a spatial-to-temporal transformation between the SC and the brain stem: the use of efference copy feedback to control the saccade), without incurring many of their drawbacks, and it accounts for a large amount of experimental data. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. Univ Trieste, Dipartimento Elettr Elettrotecn & Informat, I-34100 Trieste, Italy. Univ Catholique Louvain, Neurophysiol Lab, B-1348 Louvain, Belgium. Univ Catholique Louvain, Ctr Syst Engn & Appl Mech, B-1348 Louvain, Belgium. RP Optican, LM (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Rm 2A50, Bethesda, MD 20892 USA. NR 150 TC 178 Z9 183 U1 2 U2 16 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD AUG PY 1999 VL 82 IS 2 BP 999 EP 1018 PG 20 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 226TM UT WOS:000082038000043 PM 10444693 ER PT J AU Pivovarova, NB Hongpaisan, J Andrews, SB Friel, DD AF Pivovarova, NB Hongpaisan, J Andrews, SB Friel, DD TI Depolarization-induced mitochondrial Ca accumulation in sympathetic neurons: Spatial and temporal characteristics SO JOURNAL OF NEUROSCIENCE LA English DT Article DE mitochondria; calcium; calcium signaling; calcium regulation; neurons; depolarization; electron probe x-ray microanalysis ID ELECTRON-PROBE ANALYSIS; X-RAY-MICROANALYSIS; CALCIUM TRANSIENTS; SMOOTH-MUSCLE; CELLS; BULLFROG; LOADS; PARTICIPATION; CRYOSECTIONS; LOCALIZATION AB Several lines of evidence suggest that neuronal mitochondria accumulate calcium when the cytosolic free Ca2+ concentration ([Ca2+](i)) is elevated to levels approaching similar to 500 nM, but the spatial, temporal, and quantitative characteristics of net mitochondrial Ca uptake during stimulus-evoked [Ca2+](i) elevations are not well understood. Here, we report direct measurements of depolarization-induced changes in intramitochondrial total Ca concentration ([Ca](mito)) obtained by x-ray microanalysis of rapidly frozen neurons from frog sympathetic ganglia. Unstimulated control cells exhibited undetectably low [Ca](mito), but high K+ depolarization (50 mM, 45 sec), which elevates [Ca2+](i) to similar to 600 nM, increased [Ca](mito) to 13.0 +/- 1.5 mmol/kg dry weight; this increase was abolished by carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP). The elevation of [Ca](mito) was a function of both depolarization strength and duration. After repolarization, [Ca](mito) recovered to prestimulation levels with a time course that paralleled the decline in [Ca2+](i). Depolarization-induced increases in [Ca](mito) were spatially heterogeneous. At the level of single mitochondria, [Ca](mito) elevations depended on proximity to the plasma membrane, consistent with predictions of a diffusion model that considers radial [Ca2+](i) gradients that exist early during depolarization. Within individual mitochondria, Ca was concentrated in small, discrete sites, possibly reflecting a high-capacity intramitochondrial Ca storage mechanism. These findings demonstrate that in situ Ca accumulation by mitochondria, now directly identified as the structural correlate of the "FCCP-sensitive store," is robust, reversible, graded with stimulus strength and duration, and dependent on spatial location. C1 Case Western Reserve Univ, Dept Neurosci, Cleveland, OH 44106 USA. NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Friel, DD (reprint author), Case Western Reserve Univ, Dept Neurosci, 10900 Euclid Ave, Cleveland, OH 44106 USA. NR 58 TC 123 Z9 125 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 1 PY 1999 VL 19 IS 15 BP 6372 EP 6384 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 220DC UT WOS:000081648400016 PM 10414966 ER PT J AU Fuhrer, C Gautam, M Sugiyama, JE Hall, ZW AF Fuhrer, C Gautam, M Sugiyama, JE Hall, ZW TI Roles of rapsyn and agrin in interaction of postsynaptic proteins with acetylcholine receptors SO JOURNAL OF NEUROSCIENCE LA English DT Article DE synaptogenesis; acetylcholine receptor; agrin; rapsyn; neuromuscular junction; tyrosine phosphorylation; protein interactions ID TYROSINE KINASE MUSK; UTROPHIN-DEFICIENT MICE; SKELETAL-MUSCLE; NEUROMUSCULAR-JUNCTIONS; MAMMALIAN MUSCLE; EXTRACELLULAR-MATRIX; CLUSTERING ACTIVITY; CULTURED-CELLS; 43-KDA PROTEIN; BETA-SUBUNIT AB At the neuromuscular junction, aggregates of acetylcholine receptors (AChRs) are anchored in the muscle membrane by association with rapsyn and other postsynaptic proteins. We have investigated the interactions between the AChR and these proteins in cultured C2 myotubes before and after treatment with agrin, a nerve-derived protein that induces AChRs to cluster. When AChRs were isolated from detergent extracts of untreated C2 myotubes, they were associated with rapsyn and, to a lesser degree, with utrophin, beta-dystroglycan, MuSK, and src-related kinases, but not with syntrophin. Treatment with agrin increased the association of AChRs with MuSK, a receptor tyrosine kinase that forms part of the agrin receptor complex, without affecting other interactions. Analysis of rapsyn-deficient myotubes, which do not form protein clusters in response to agrin, revealed that rapsyn is required for association of the AChR with utrophin and beta-dystroglycan, and for the agrin-induced increase in association with MuSK, but not for constitutive interactions with MuSK and src-related kinases. In rapsyn -/- myotubes, agrin caused normal tyrosine phosphorylation of AChR-associated and total MuSK, whereas phosphorylation of the AChR beta subunit, both constitutive and agrin-induced, was strongly reduced. These results show first that aneural myotubes contain preassembled AChR protein complexes that may function in the assembly of the postsynaptic apparatus, and second that rapsyn, in addition to its role in AChR phosphorylation, mediates selected protein interactions with the AChR and serves as a link between the AChR and the dystrophin/utrophin glycoprotein complex. C1 NIMH, Sect Synapt Mechanisms, Lab Cellular & Mol Recognit, NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Mol Biol & Pharmacol, St Louis, MO 63110 USA. RP Fuhrer, C (reprint author), Univ Zurich Irchel, Brain Res Inst, Winterthurerstr 190, CH-8057 Zurich, Switzerland. NR 61 TC 83 Z9 84 U1 0 U2 2 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 1 PY 1999 VL 19 IS 15 BP 6405 EP 6416 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 220DC UT WOS:000081648400019 PM 10414969 ER PT J AU Farrer, RG Quarles, RH AF Farrer, RG Quarles, RH TI GT3 and its O-acetylated derivative are the principal A2B5-reactive gangliosides in cultured O2A lineage cells and are down-regulated along with O-acetyl GD3 during differentiation to oligodendrocytes SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE A2B5; ganglioside; glia; O-acetylated gangliosides; oligodendrocyte-type 2 astrocyte (O2A) progenitor ID EXOGENOUS GM3 GANGLIOSIDE; MONOCLONAL-ANTIBODY A2B5; CENTRAL-NERVOUS-SYSTEM; SIALIC ACIDS; RAT-BRAIN; DEVELOPMENTAL REGULATION; MOUSE CEREBELLUM; CEREBRAL-CORTEX; T-LYMPHOCYTES; FETAL-RAT AB Among the developmentally regulated antigens expressed on the surface of bipotential glial precursors isolated from neonatal rat brain are the gangliosides recognized by the monoclonal antibody A2B5, Immunostaining of thin layer chromatograms showed that oligodendrocyte-type 2 astrocyte (O2A) progenitors in culture express two ganglioside antigens that react strongly with the A2B5 antibody. Both ganglioside antigens are down-regulated as the cells differentiate to oligodendrocytes, corresponding to the disappearance of cell surface immunostaining by A2B5 in mature oligodendrocytes. By contrast, both gangliosides continue to be expressed when the cells differentiate to type-2 astrocytes. These two A2B5-reactive gangliosides in O2A lineage cells were identified as GT3 and O-acetyl GT3 by using the monoclonal antibody 18B8 that recognizes GT3 and an influenza C virus esterase that specifically removes O-acetyl moieties from sialic acids. Thin-layer chromatographic immunostaining with the JONES monoclonal antibody demonstrated that the progenitor cells in culture also express O-acetyl GD3, which is similarly down-regulated in oligodendrocytes, but retained in type-2 astrocytes. The 18B8 and JONES antibodies also immunostained the surface of O2A progenitors. Therefore, expression of GT3 and O-acetylation of GT3 and GD3 occur during the proliferative and migratory stages of glial cell development. Published 1999 Wiley-Liss, Inc. C1 NINDS, Myelin & Brain Dev Sect, Mol & Cellular Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Quarles, RH (reprint author), Bldg 49,Rm 2A28,49 Convent Dr,MSC 4440, Bethesda, MD 20892 USA. EM rquarles@box-r.nih.gov NR 53 TC 26 Z9 27 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0360-4012 EI 1097-4547 J9 J NEUROSCI RES JI J. Neurosci. Res. PD AUG 1 PY 1999 VL 57 IS 3 BP 371 EP 380 DI 10.1002/(SICI)1097-4547(19990801)57:3<371::AID-JNR9>3.3.CO;2-F PG 10 WC Neurosciences SC Neurosciences & Neurology GA 216UU UT WOS:000081463500009 PM 10412028 ER PT J AU Lonser, RR Corthesy, ME Morrison, PF Gogate, N Oldfield, EH AF Lonser, RR Corthesy, ME Morrison, PF Gogate, N Oldfield, EH TI Convection-enhanced selective excitotoxic ablation of the neurons of the globus pallidus internus for treatment of parkinsonism in nonhuman primates SO JOURNAL OF NEUROSURGERY LA English DT Article DE bulk flow; convection; drug delivery; Parkinson's disease; quinolinic acid; Macaca mulatta ID QUINOLINIC ACID CONCENTRATIONS; POSTERIOR GPI PALLIDOTOMY; BASAL GANGLIA; VENTRICULOCISTERNAL PERFUSION; POSTEROVENTRAL PALLIDOTOMY; LEVODOPA THERAPY; RAT-BRAIN; DISEASE; INFUSION; BLOOD AB Object. Selective treatment of central nervous system (CNS) structures holds therapeutic promise for many neurological disorders, including Parkinson's disease (PD). The ability to inhibit or augment specific neuronal populations within the CNS reliably by using present therapeutic techniques is limited. To overcome this problem, the authors modeled and developed a method in which convection was used to deliver compounds to deep brain nuclei in a reproducible, homogeneous, and targeted manner. To determine the feasibility and clinical efficacy of convective drug delivery for treatment of a neurological disorder, the investigators selectively ablated globus pallidus internus (GPi) neurons with quinolinic acid (QA), an excitotoxin, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced model of primate parkinsonism. Methods. After the parameters of convective distribution to the GPi were confirmed by infusion of biotinylated albumin into the GPI of a primate (Macaca mulatta), seven adult monkeys of this species were rendered either fully parkinsonian by intravenous injections of MPTP (five animals) or hemiparkinsonian by a right-sided intracarotid injection of this agent (two monkeys). Using convection-enhanced delivery to the GPi, animals were infused with either QA (three fully parkinsonian, two hemiparkinsonian) or saline (two fully parkinsonian). The three fully parkinsonian animals that underwent GPi lesioning with QA had substantial improvement of PD symptoms, manifested by a marked increase in activity (34 +/- 2.5%; mean +/- standard deviation) and dramatic improvement of parkinsonian clinical scores. In contrast, the control animals did not improve (activity monitor change = -1.5 +/- 0.5%). The two hemiparkinsonian animals that underwent QA lesioning of the GPi had dramatic recovery of extremity use. Histological examination revealed selective neural ablation of GPi neurons (mean loss 87%) with sparing of surrounding gray and white matter structures. No animal developed worsening signs of PD or neurological deficits after infusion. Conclusions. Convection-enhanced delivery of QA permits selective, region-specific (GPi), and safe lesioning of neuronal subpopulations, resulting in dramatic improvement in parkinsonian symptomatology. The properties of convection-enhanced delivery indicate that this method could be used for chemical neurosurgery for medically refractory PD and that it may be ideal for cell-specific therapeutic ablation or trophic treatment of other targeted structures associated with CNS disorders. C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NIH, Bioengn & Phys Sci Program, Bethesda, MD 20892 USA. RP Oldfield, EH (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,Room 5D37,MSC-1414, Bethesda, MD 20892 USA. RI Gogtay, Nitin/A-3035-2008; Kipke, Daryl/A-2167-2009 NR 43 TC 48 Z9 48 U1 1 U2 3 PU AMER ASSOC NEUROLOGICAL SURGEONS PI CHARLOTTESVILLE PA UNIV VIRGINIA, 1224 WEST MAIN ST, STE 450, CHARLOTTESVILLE, VA 22903 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD AUG PY 1999 VL 91 IS 2 BP 294 EP 302 DI 10.3171/jns.1999.91.2.0294 PG 9 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 220RT UT WOS:000081681800016 PM 10433318 ER PT J AU Petito, CK Kerza-Kwiatecki, AP Gendelman, HE McCarthy, M Nath, A Podack, ER Shapshak, P Wiley, CA AF Petito, CK Kerza-Kwiatecki, AP Gendelman, HE McCarthy, M Nath, A Podack, ER Shapshak, P Wiley, CA TI Review: Neuronal injury in HIV infection SO JOURNAL OF NEUROVIROLOGY LA English DT Editorial Material DE brain injury; microglia; monocytechemokine receptor; apoptosis; AIDS; HIV C1 Dept Pathol, Miami, FL USA. NINDS, NIH, Bethesda, MD 20892 USA. Univ Nebraska, Med Ctr, Ctr Neurovirol & Neurodegenerat Disorders, Omaha, NE USA. VA Med Ctr, Dept Neurol, Miami, FL USA. Univ Kentucky, Dept Neurol, Lexington, KY 40536 USA. Univ Miami, Dept Immunol & Microbiol, Miami, FL 33152 USA. Univ Miami, Dept Psychiat, Miami, FL 33152 USA. Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15260 USA. RP Petito, CK (reprint author), Dept Pathol, 1550 NW 10th Ave,PAP Bldg,Room 417, Miami, FL USA. NR 0 TC 28 Z9 31 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD AUG PY 1999 VL 5 IS 4 BP 327 EP 330 DI 10.3109/13550289909029474 PG 4 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 224MN UT WOS:000081903000002 PM 10463855 ER PT J AU Kobayashi, H Sun, BF Yoo, TM Le, N Kim, MK Paik, CH Pastan, I Waldmann, TA Carrasquillo, JA AF Kobayashi, H Sun, BF Yoo, TM Le, N Kim, MK Paik, CH Pastan, I Waldmann, TA Carrasquillo, JA TI Methods to avoid adverse effect of circulating antigen on biodistribution of I-125-labeled antiTac dsFv: Preinjection of intact antibody versus clearance of antigen with avidin-biotin system SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE Fv fragment; radioimmunodetection; monoclonal antibody; interleukin-2; avidin ID DISULFIDE-STABILIZED FV; SOLUBLE INTERLEUKIN-2 RECEPTOR; SINGLE-CHAIN FV; MONOCLONAL-ANTIBODY; CARCINOEMBRYONIC ANTIGEN; TAC ANTIBODY; RENAL UPTAKE; NUDE-MICE; TUMOR; RADIOIMMUNOTHERAPY AB The presence of circulating antigen may adversely affect the biodistribution of a radiolabeled antibody. The alpha subunit of the interleukin-2 receptor (IL-2R alpha) is a cell-surface receptor that is overexpressed in various hematologic malignancies and in benign disorders. This receptor is cleaved from the cell surface and can be found in high concentrations in serum. Radiolabeled antiTac antibodies are being evaluated to target this receptor. Previous studies have shown that circulating soluble IL-2Ra (sIL-2R alpha) adversely affected the biodistribution of radiolabeled antiTac disulfide-stabilized (ds)Fv. In this study, we compared blocking and clearing sIL-2R alpha to see which better minimized its interference with the biodistribution of radiolabeled antiTac dsFv Methods: Two models of sIL-2R alpha were used: one consisted of mice given intravenous sIL-2R alpha and the other consisted of mice bearing SP2/Tac tumor xenografts (IL-2Ra: positive), which shed sIL-2R alpha. We biotinylated humanized antiTac monoclonal antibody (bt-HuTac) and radiolabeled it with I-125. We then compared its biodistribution with that of humanized antiTac monoclonal antibody IgG (HuTac). We examined the biodistribution of an injected dose of I-125-labeled antiTac dsFv after a preinjection of HuTac to block the sIL-2R alpha epitope and after a preinjection of bt-HuTac, followed by an avidin chase. Result: The I-125-labeled bt-HuTac cleared from the serum at a rate similar to that of HuTac. The avidin chase effectively cleared >92% of circulating I-125-labeled bt-HuTac within 20 min and was also effective in clearing sIL-2R alpha. In comparison, HuTac prolonged the retention of I-125-labeled sIL-2R alpha in the circulation, and the avidin chase decreased I-125-labeled sIL-2R alpha to <18% of control. Although the two-step antigen-clearing system effectively cleared the antigen from the circulation and improved the biodistribution of I-125-labeled dsFv, the HuTac preinjection method had a similar but longer lasting beneficial effect on I-125-labeled dsFv biodistribution. Conclusion: Preinjection of either HuTac or bt-HuTac with avidin chase improved the biodistribution of subsequently administered I-125-labeled antiTac dsFv by preventing the dsFv from binding to the sIL-2R alpha, but the HuTac blocking method is simpler and longer lasting. C1 NCI, Dept Nucl Med, Warren G Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NCI, Mol Biol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NCI, Metab Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RI Carrasquillo, Jorge/E-7120-2010; OI Carrasquillo, Jorge/0000-0002-8513-5734 NR 40 TC 4 Z9 4 U1 0 U2 2 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD AUG PY 1999 VL 40 IS 8 BP 1381 EP 1391 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 224MF UT WOS:000081902300023 PM 10450692 ER PT J AU Donovan, EF Tyson, JE Ehrenkranz, RA Verter, J Wright, LL Korones, SB Bauer, CR Shankaran, S Stoll, BJ Fanaroff, AA Oh, W Lemons, JA Stevenson, DK Papile, LA AF Donovan, EF Tyson, JE Ehrenkranz, RA Verter, J Wright, LL Korones, SB Bauer, CR Shankaran, S Stoll, BJ Fanaroff, AA Oh, W Lemons, JA Stevenson, DK Papile, LA CA Natl Inst Child Hlth Human Dev Neonatal Res Net TI Inaccuracy of Ballard scores before 28 weeks' gestation SO JOURNAL OF PEDIATRICS LA English DT Article ID 24-26 WEEKS GESTATION; INFANTS BORN; BIRTH-WEIGHT; AGE; MATURITY; MATURATION; ULTRASOUND; VIABILITY; PREGNANCY AB Objective: Ballard scores are commonly used to estimate gestational age (GA). The purpose of this study was to determine the accuracy of the New Ballard Score (NBS) for infants <28 weeks GA by accurate menstrual history and to evaluate NBS as an outcome predictor. Methods: Infants weighing 401 to 1500 g in 12 National Institute of Child Health and Human Development Neonatal Research Network centers had NBS performed before age 48 hours. Accuracy of NBS estimates of GA was assessed for infants with GA determined by accurate menstrual history. In a larger cohort of infants, NBS was included in regression models of the association of NBS and death, poor outcome, and duration of hospital stay. Results: At each week from 22 to 28 weeks GA by accurate menstrual history, NBS estimates exceeded GA by dates by 1.3 to 3.3 weeks, and estimates varied widely (range of widths of 95% CIs for the observations, 6.8 to 11.9 weeks). NBS did not contribute significantly to regression models of death, poor outcome, or duration of hospital stay. Conclusions: Inaccuracies in GA determined by the NBS should be considered when treating extremely premature infants, particularly in decisions to forego or administer intensive care. Refinement of GA scoring systems is needed to optimize clinical benefit. C1 Univ Cincinnati, Med Ctr, Dept Pediat, Cincinnati, OH 45267 USA. Univ Texas, SW Med Ctr, Dept Pediat, Dallas, TX USA. Yale Univ, Dept Pediat, New Haven, CT 06520 USA. George Washington Univ, Ctr Biostat, Rockville, MD USA. NICHHD, Dept Pediat, Bethesda, MD 20892 USA. Univ Miami, Dept Pediat, Miami, FL 33152 USA. Wayne State Univ, Dept Pediat, Detroit, MI USA. Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. Case Western Reserve Univ, Dept Pediat, Cleveland, OH 44106 USA. Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI USA. Indiana Univ, Dept Pediat, Indianapolis, IN 46204 USA. Stanford Univ, Dept Pediat, Stanford, CA 94305 USA. Univ New Mexico, Dept Pediat, Albuquerque, NM 87131 USA. RP Donovan, EF (reprint author), Univ Cincinnati, Med Ctr, Dept Pediat, POB 670541, Cincinnati, OH 45267 USA. FU NICHD NIH HHS [U10 HD21385, U10 HD27853, U10 HD27871] NR 24 TC 41 Z9 43 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 AUG PY 1999 VL 135 IS 2 BP 147 EP 152 DI 10.1016/S0022-3476(99)70015-6 PN 1 PG 6 WC Pediatrics SC Pediatrics GA 224FC UT WOS:000081885900006 PM 10431107 ER PT J AU Zhong, Z Arteel, GE Connor, HD Schemmer, P Chou, SC Raleigh, JA Mason, RP Lemasters, JJ Thurman, RG AF Zhong, Z Arteel, GE Connor, HD Schemmer, P Chou, SC Raleigh, JA Mason, RP Lemasters, JJ Thurman, RG TI Binge drinking disturbs hepatic microcirculation after transplantation: Prevention with free radical scavengers SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID ORTHOTOPIC LIVER-TRANSPLANTATION; RAT-LIVER; PRIMARY NONFUNCTION; REPERFUSION INJURY; KUPFFER CELLS; ALCOHOL; SURVIVAL; MACROPHAGES; ELIMINATION; MECHANISMS AB Disturbances in hepatic microcirculation increase graft injury and failure; therefore, this study evaluates the effects of ethanol on microcirculation after liver transplantation. Donor rats were given one dose of ethanol (5 g/kg) by gavage 20 h before explantation, and grafts were stored in University of Wisconsin solution for 24 h before implantation. Acute ethanol treatment decreased 7-day survival of grafts from about 90 to 30%, increased transaminase release nearly 4-fold, and decreased bile production by 60%. Moreover, portal pressure increased significantly and liver surface oxygen tension decreased about 50%, indicating that ethanol disturbs hepatic microcirculation. Pimonidazole, a 2-nitroimidazole hypoxia marker, was given i.v. to recipients 30 min after implantation, and grafts were harvested 1 h later. Ethanol increased hepatic pimonidazole binding about 3-fold, indicating that ethanol led to hypoxia in fatty grafts. Ethanol also significantly increased free radicals in bile. Catechin (30 mg/kg i.v. upon reperfusion), a free radical scavenger, and Carolina Rinse solution, which contains several agents that inhibit free radical formation, minimized disturbances in microcirculation and prevented pimonidazole adduct formation significantly. These treatments also blunted increases in transaminase release and improved survival of fatty grafts. Destruction of Kupffer cells with GdCl3 (20 mg/kg i.v. 24 h before explantation) or inhibition of formation of leukotrienes with MK-886 (50 mu M in University of Wisconsin or rinse solution) also minimized hypoxia and improved survival after transplantation. Taken together, these results demonstrate that ethanol disturbs hepatic microcirculation, leading to graft hypoxia after transplantation, most likely by activating Kupffer cells and increasing free radical production. C1 Univ N Carolina, Dept Pharmacol, Hepatobiol & Toxicol Lab, Chapel Hill, NC 27599 USA. Univ N Carolina, Curriculum Toxicol, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Radiat Oncol, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Cell Biol & Anat, Chapel Hill, NC 27599 USA. NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC USA. RP Thurman, RG (reprint author), Univ N Carolina, Dept Pharmacol, Hepatobiol & Toxicol Lab, CB 7365,Mary Ellen Jones Bldg, Chapel Hill, NC 27599 USA. FU NCI NIH HHS [CA 50995]; NIAAA NIH HHS [AA 69156]; NIDDK NIH HHS [DK 37034] NR 39 TC 14 Z9 14 U1 0 U2 0 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 AUG PY 1999 VL 290 IS 2 BP 611 EP 620 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 219AB UT WOS:000081583900018 PM 10411569 ER PT J AU Ibeanu, GC Blaisdell, J Ferguson, RJ Ghanayem, BI Brosen, K Benhamou, S Bouchardy, C Wilkinson, GR Dayer, P Goldstein, JA AF Ibeanu, GC Blaisdell, J Ferguson, RJ Ghanayem, BI Brosen, K Benhamou, S Bouchardy, C Wilkinson, GR Dayer, P Goldstein, JA TI A novel transversion in the intron 5 donor splice junction of CYP2C19 and a sequence polymorphism in exon 3 contribute to the poor metabolizer phenotype for the anticonvulsant drug S-mephenytoin SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID GENETIC-DEFECT; OXIDATION POLYMORPHISM; CHINESE SUBJECTS; HYDROXYLATION; IDENTIFICATION; POPULATION; MUTATION; ALLELES; DEBRISOQUIN AB Cytochrome P-450 (CYP) 2C19 is responsible for the metabolism of a number of therapeutic agents such as S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Genetic polymorphisms in this enzyme are responsible for the poor metabolizers (PM) of mephenytoin, which represent similar to 13-23% of Asians and 3-5% of Caucasians. Several polymorphisms contribute to this phenotype. We have isolated two new allelic variants that contribute to the PM phenotype in Caucasians. CYP2C19*7 contained a single T --> A nucleotide transversion in the invariant GT at the 5' donor splice site of intron 5. The second PM allele, CYP2C19*8, consisted of a T358C nucleotide transition in exon 3 that results in a Trp120Arg substitution. In a bacterial expression system, CYP2C198 protein exhibited a dramatic (similar to 99% and 70%) reduction in the metabolism of S-mephenytoin and tolbutamide, respectively, when compared with the wild-type CYP2C191B protein. Restriction fragment length polymerase chain reaction tests were developed to identify the new allelic variants. C1 NIEHS, NIH, Durham, NC 27708 USA. Univ Florida, Gainesville, FL USA. Odense Univ, Dept Clin Pharmacol, Odense, Denmark. INSERM, U351, Villejuif, France. Geneva Canc Registry, Geneva, Switzerland. Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37212 USA. Univ Hosp Geneva, Geneva, Switzerland. RP Goldstein, JA (reprint author), NIEHS, NIH, MD-C3-01,POB 12233, Durham, NC 27708 USA. RI Goldstein, Joyce/A-6681-2012; Brosen, Kim/F-6023-2011; Benhamou, Simone/K-6554-2015 OI Brosen, Kim/0000-0001-8444-7835; FU NIGMS NIH HHS [GM3B04] NR 40 TC 76 Z9 84 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD AUG PY 1999 VL 290 IS 2 BP 635 EP 640 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 219AB UT WOS:000081583900021 PM 10411572 ER PT J AU Nakao, Y Gotoh, J Kuang, TY Cohen, DM Pettigrew, KD Sokoloff, L AF Nakao, Y Gotoh, J Kuang, TY Cohen, DM Pettigrew, KD Sokoloff, L TI Cerebral blood flow responses to somatosensory stimulation are unaffected by scopolamine in unanesthetized rat SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID POSITRON EMISSION TOMOGRAPHY; CHOLINE-ACETYLTRANSFERASE; FUNCTIONAL ACTIVATION; GLUCOSE-UTILIZATION; VESSELS; MONKEYS; NEURONS; CORTEX; MICROVESSELS; INNERVATION AB Studies with positron-emission tomography have indicated that muscarinic acetylcholine receptors may be involved in the mechanism of enhancement of cerebral blood flow (CBF) by neuronal functional activation. We examined the effects of muscarinic receptor blockade by scopolamine on the local CBF responses to vibrissal stimulation in the whisker-to-barrel cortex sensory pathway in unanesthetized rats. Local CBF was measured by the quantitative autoradiographic [C-14]iodoantipyrine method. Scopolamine (0.4 or 0.8 mg/kg) was injected i.v. 30 min before measurement of local CBF; control rats received equivalent volumes of physiological saline. Vibrissae on the left side of the face were stroked continuously throughout the 1-min period of measurement of CBF. Local CBF was determined bilaterally in four structures of the pathway, i.e., spinal and principal sensory trigeminal nuclei, ventral posteromedial thalamic nucleus, and barrel field of the sensory cortex, as well as in four representative structures unrelated to the pathway. The higher dose of scopolamine raised baseline CBF in the two trigeminal nuclei, but neither dose diminished the percentage of increases in local CBF because of vibrissal stimulation in any of the stations of the pathway. These results do not support involvement of muscarinic receptors in the mechanism of enhancement of local CBF by functional neuronal activation, at least not in the whisker-barrel cortex sensory pathway in the unanesthetized rat. C1 NIMH, Cerebral Metab Lab, Bethesda, MD 20892 USA. RP Sokoloff, L (reprint author), NIMH, Cerebral Metab Lab, Bldg 36,Room 1A-05,36 Convent Dr,MSC 4030, Bethesda, MD 20892 USA. NR 40 TC 9 Z9 9 U1 0 U2 0 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 AUG PY 1999 VL 290 IS 2 BP 929 EP 934 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 219AB UT WOS:000081583900060 PM 10411611 ER PT J AU Sun, XP Schlichter, LC Stanley, EF AF Sun, XP Schlichter, LC Stanley, EF TI Single-channel properties of BK-type calcium-activated potassium channels at a cholinergic presynaptic nerve terminal SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID CA2+-ACTIVATED K+ CHANNELS; CRAYFISH NEUROMUSCULAR-JUNCTION; TRANSMITTER RELEASE; LARGE-CONDUCTANCE; RAT-BRAIN; BETA-SUBUNIT; HAIR-CELLS; NONINACTIVATING CA2+; VOLTAGE; CHARYBDOTOXIN AB 1. A high-conductance calcium-activated potassium channel (BK K-Ca) was characterized at a cholinergic presynaptic nerve terminal using the calyx synapse isolated from the chick ciliary ganglion. 2. The channel had a conductance of 210 pS in a 150 mM:150 mM K+ gradient, was highly selective for K+ over Na+, and was sensitive to block by external charybdotoxin or tetraethylammonium (TEA) and by internal Ba2+. At +60 mV it was activated by cytoplasmic calcium [Ca2+](i) with a K-d of similar to 0.5 mu M and a Hill coefficient of similar to 2.0. At 10 mu M [Ca2+](i) the channel was 50% activated (V-1/2) at -8.0 mV with a voltage dependence (Boltzmann slope-factor) of 32.7 mV. The V-1/2 values hyperpolarized with an increase in [Ca2+](i) while the slope factors decreased. There were no overt differences in conductance or [Ca2+](i) sensitivity between BK channels from the transmitter release face and the non-release face. 3. Open and closed times were fitted by two and three exponentials, respectively. The slow time constants were strongly affected by both [Ca2+](i) and membrane potential changes. 4. In cell-attached patch recordings BK channel opening was enhanced by a prepulse permissive for calcium influx through the patch, suggesting that the: channel can be activated by calcium ion influx through neighbouring calcium channels. 5. The properties of the presynaptic BK channel are well suited for rapid activation during the presynaptic depolarization and Ca2+ influx that are associated with transmitter release. This channel may play an important role in terminating release by rapid repolarization of the action potential. C1 NINDS, Synapt Mechanisms Sect, DIR, NIH, Bethesda, MD 20892 USA. RP Stanley, EF (reprint author), NINDS, Synapt Mechanisms Sect, DIR, NIH, Bldg 36,Room 5A25, Bethesda, MD 20892 USA. NR 51 TC 34 Z9 35 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD AUG 1 PY 1999 VL 518 IS 3 BP 639 EP 651 DI 10.1111/j.1469-7793.1999.0639p.x PG 13 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 228EW UT WOS:000082125000004 PM 10420003 ER PT J AU Ziemann, U Ishii, K Borgheresi, A Yaseen, Z Battaglia, F Hallett, M Cincotta, M Wassermann, EM AF Ziemann, U Ishii, K Borgheresi, A Yaseen, Z Battaglia, F Hallett, M Cincotta, M Wassermann, EM TI Dissociation of the pathways mediating ipsilateral and contralateral motor-evoked potentials in human hand and arm muscles SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; CONGENITAL MIRROR MOVEMENTS; HEMIPLEGIC CEREBRAL-PALSY; VOLUNTARY MOVEMENT; KALLMANNS-SYNDROME; CORTEX; RESPONSES; REORGANIZATION; MONKEY; BRAIN AB 1. Growing evidence points toward involvement of the human motor cortex in the control of the ipsilateral hand. We used focal transcranial magnetic stimulation (TMS) to examine the pathways of these ipsilateral motor effects. 2. Ipsilateral motor-evoked potentials (MEPs) were obtained in hand and arm muscles of all 10 healthy adult subjects tested. They occurred in the finger and wrist extensors and the biceps, but no response or inhibitory responses were observed in the opponens pollicis, finger and wrist flexors and the triceps. 3. The production of ipsilateral MEPs required contraction of the target muscle. The threshold TMS intensity for ipsilateral MEPs was on average 1.8 times higher, and the onset was 5.7 ms later (in the wrist extensor muscles) compared with size-matched contralateral MEPs. 4. The corticofugal pathways of ipsilateral and contralateral MEPs could be dissociated through differences in cortical map location and preferred stimulating current direction. 5. Both ipsi- and contralateral MEPs in the wrist extensors increased with lateral head rotation toward, and decreased with head rotation away from, the side of the TMS, suggesting a privileged input of the asymmetrical tonic neck reflex to the pathway of the ipsilateral MEP. 6. Large ipsilateral MEPs were obtained in a patient with complete agenesis of the corpus callosum. 7. The dissociation of the pathways for ipsilateral and contralateral MEPs indicates that corticofugal motor fibres other than the fast-conducting crossed corticomotoneuronal system can be activated by TMS. Our data suggest an ipsilateral oligosynaptic pathway, such as a corticoreticulospinal or a corticopropriospinal projection as the route for the ipsilateral MEP. Other pathways, such as branching of corticomotoneuronal axons, a transcallosal projection or a slow-conducting monosynaptic ipsilateral pathway are very unlikely or can be excluded. C1 NINDS, NIH, Human Motor Control Sect, Bethesda, MD 20892 USA. Univ Gottingen, Dept Clin Neurophysiol, D-3400 Gottingen, Germany. Osped Santa Maria Nuova, Unita Operat Neurol, Florence, Italy. RP Ziemann, U (reprint author), NINDS, NIH, Human Motor Control Sect, Bldg 10,Room 5N242,10 Ctr Dr, Bethesda, MD 20892 USA. NR 51 TC 178 Z9 179 U1 1 U2 4 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD AUG 1 PY 1999 VL 518 IS 3 BP 895 EP 906 DI 10.1111/j.1469-7793.1999.0895p.x PG 12 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 228EW UT WOS:000082125000024 PM 10420023 ER PT J AU Exner, DV Reiffel, JA Epstein, AE Ledingham, R Reiter, MJ Yao, Q Duff, HJ Follmann, D Schron, E Greene, HL Carlson, MD Brodsky, MA Akiyama, T Baessler, C Anderson, JL AF Exner, DV Reiffel, JA Epstein, AE Ledingham, R Reiter, MJ Yao, Q Duff, HJ Follmann, D Schron, E Greene, HL Carlson, MD Brodsky, MA Akiyama, T Baessler, C Anderson, JL CA AVID Investigators TI Beta-blocker use and survival in patients with ventricular fibrillation or symptomatic ventricular tachycardia: The Antiarrhythmics Versus Implantable Defibrillators (AVID) trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; SUDDEN CARDIAC DEATH; RANDOMIZED TRIAL; CLINICAL-TRIALS; HEART-FAILURE; MORTALITY; AMIODARONE; EFFICACY; TACHYARRHYTHMIAS; METOPROLOL AB OBJECTIVES To evaluate whether use of beta-adrenergic blocking agents, alone or in combination with specific antiarrhythmic therapy, is associated with improved survival in persons with ventricular fibrillation (VF) or symptomatic ventricular tachycardia (VT). BACKGROUND The ability of beta-blockers to alter the mortality of patients with VF or VT receiving contemporary medical management is not well defined. METHODS Survival of 1,016 randomized and 2,101 eligible, nonrandomized patients with VF or symptomatic VT followed in the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial through December 31, 1996 was assessed using Cox proportional hazards analysis. RESULTS The 817 (28%) patients discharged from hospital receiving beta-blockers had less ventricular dysfunction, fewer symptoms of heart failure and a different pattern of medication use compared with patients not receiving beta-blockers. Before adjustment for important prognostic variables, beta-blockade was not significantly associated with survival in randomized or in eligible, nonrandomized patients treated with specific antiarrhythmic therapy. After adjustment, beta-blockade remained unrelated to survival in randomized or in eligible, nonrandomized patients treated with amiodarone alone (n = 1142; adjusted relative risk [RR] = 0.96; 95% confidence interval [CI] 0.64-1.45; p = 0.85) or a defibrillator alone (n = 1347; adjusted RR = 0.88; 95% CI 0.55 to 1.40; p = 0.58). In contrast, beta-blockade was independently associated with improved survival in eligible, nonrandomized patients who were not treated with specific antiarrhythmic therapy (n = 412; adjusted RR = 0.47; 95% CI 0.25 to 0.88; p = 0.018). CONCLUSIONS Beta-blocker use was independently associated with improved survival in patients with VF or symptomatic VT who were not treated with specific antiarrhythmic therapy, but a protective effect was not prominent in patients already receiving amiodarone or a defibrillator. (C) 1999 by the American College of Cardiology. C1 NHLBI, Bethesda, MD 20892 USA. Univ Washington, Seattle, WA 98195 USA. RP Exner, DV (reprint author), NHLBI, 6701 Rockledge Dr,Room 8146, Bethesda, MD 20892 USA. OI Duff, Henry/0000-0001-9292-5411 FU NHLBI NIH HHS [N01 HC-25117] NR 33 TC 53 Z9 54 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 AUG PY 1999 VL 34 IS 2 BP 325 EP 333 DI 10.1016/S0735-1097(99)00234-X PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 244EQ UT WOS:000083039200003 PM 10440140 ER PT J AU Prasad, A Andrews, NP Padder, FA Husain, M Quyyumi, AA AF Prasad, A Andrews, NP Padder, FA Husain, M Quyyumi, AA TI Glutathione reverses endothelial dysfunction and improves nitric oxide bioavailability SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID HUMAN CORONARY CIRCULATION; N-ACETYLCYSTEINE; RELAXING FACTOR; SERUM-ALBUMIN; IN-VIVO; NITROGLYCERIN; INHIBITION; ATHEROSCLEROSIS; DISEASE; PLASMA AB OBJECTIVES We investigated whether glutathione (GSH), a reduced thiol that modulates redox state and forms adducts of nitric oxide (NO), improves endothelium-dependent vasomotion and NO activity in atherosclerosis. BACKGROUND Endothelial dysfunction and reduced NO activity are associated with atherosclerosis and its clinical manifestations such as unstable angina. METHODS In the femoral circulation of 17 patients with atherosclerosis or its risk factors, endothelium-dependent vasodilation with acetylcholine (ACH), and endothelium-independent vasodilation with nitroglycerin and sodium nitroprusside were studied before and after GSH. In 10 patients, femoral vein plasma cyclic guanylate monophosphate (cGMP) levels were measured during an infusion of ACH before and after GSH. Femoral artery flow velocity was measured using a Doppler flow wire and the resistance index (FVRI) calculated as mean arterial pressure divided by flow velocity. RESULTS Glutathione strongly potentiated AGH-mediated vasodilation; at the two doses, FVRI decreased by 47% and 56% before, and by 61% and 67% after GSH (p = 0.003). Glutathione also elevated cGMP levels in the femoral vein during ACH infusion from 17.6 +/- 3 to 23.3 rt 3 pmol/ml (p = 0.006). Augmentation of ACH responses was only observed in patients with depressed endothelial function. Glutathione did not influence endothelium-independent vasodilation with either NO donor. CONCLUSIONS Thiol supplementation with GSH selectively improves human endothelial dysfunction by enhancing NO activity. (C) 1999 by the American College of Cardiology. C1 NHLBI, NIH, Cardiol Branch, Bethesda, MD 20892 USA. RP Quyyumi, AA (reprint author), NHLBI, NIH, Cardiol Branch, Bldg 10,Rm 7B15,10 Ctr Dr,MSC 1650, Bethesda, MD 20892 USA. NR 43 TC 70 Z9 72 U1 1 U2 1 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 AUG PY 1999 VL 34 IS 2 BP 507 EP 514 DI 10.1016/S0735-1097(99)00216-8 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 244EQ UT WOS:000083039200029 PM 10440166 ER PT J AU Shiota, T Jones, M Aida, S Chikada, M Tsujino, H El-Kadi, T Sahn, DJ AF Shiota, T Jones, M Aida, S Chikada, M Tsujino, H El-Kadi, T Sahn, DJ TI Validation of the accuracy of both right and left ventricular outflow volume determinations and semiautomated calculation of shunt volumes through atrial septal defects by digital color Doppler flow mapping in a chronic animal model SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID SYSTEMIC BLOOD-FLOW; VELOCITY DISTRIBUTIONS; AORTIC REGURGITATION; CARDIAC-OUTPUT; SAMPLING SITE; ECHO-DOPPLER; PULMONARY; ECHOCARDIOGRAPHY; QUANTIFICATION; OVERLOAD AB OBJECTIVES The aim of the present study was to quantitate shunt flow volumes through atrial septal defects (ASDs) in a chronic animal model with surgically created ASDs using a new semiautomated color Doppler flow calculation method (ACM). BACKGROUND Because pulsed Doppler is cumbersome and often inappropriate for color flow computation, new methods such as ACM are of interest. METHODS In this study, 13 to 25 weeks after ASDs were surgically created in eight sheep, a total of 24 hemodynamic states were studied at a separate open chest experimental session. Electromagnetic (EM) flow probes and meters were used to provide reference flow volumes as the pulmonary and aortic flow volumes (Q(p) and Q(s)) and shunt flow volumes (Q(p) minus Q(s)). Epicardial echocardiographic studies were performed to image the left and right ventricular outflow tract (LVOT and RVOT) forward flow signals. The ACM method digitally integrated spatial and temporal color flow velocity data to provide stroke volumes. RESULTS Left ventricular outflow tract and RVOT flow volumes obtained by the ACM method agreed well with those obtained by the EM method (r = 0.96, mean difference = 0.78 +/- 1.7 mi for LVOT and r = 0.97, mean difference = -0.35 +/- 3.6 mi for RVOT). As a result, shunt flow volumes and Q(p)/Q(s) by the ACM method agreed well with those obtained by the EM method (r = 0.96, mean difference = -1.1 +/- 3.6 ml/beat for shunt volumes and r = 0.95, mean difference = -0.11 +/- 0.22 for Q(p)/Q(s)). CONCLUSIONS This animal study, using strictly quantified shunt flow volumes, demonstrated that the ACM method can provide Q(p)/Q(s), and shunt measurements semiautomatically and noninvasively. (C) 1999 by the American College of Cardiology. C1 NHLBI, Lab Anim Med & Surg, Bethesda, MD 20892 USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Toshiba Corp, Tokyo, Japan. Oregon Hlth Sci Univ, Portland, OR 97201 USA. RP Jones, M (reprint author), NHLBI, Lab Anim Med & Surg, 9000 Rockville Pike,Bldg 14E,Room 1074A, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [HL 43287] NR 30 TC 12 Z9 13 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG PY 1999 VL 34 IS 2 BP 587 EP 593 DI 10.1016/S0735-1097(99)00210-7 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 244EQ UT WOS:000083039200040 PM 10440177 ER PT J AU Slavkin, HC AF Slavkin, HC TI Atherosclerosis, Russell Ross and the passion of science SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article ID GROWTH-FACTOR; ACTINOBACILLUS-ACTINOMYCETEMCOMITANS; PNEUMONIA; INFECTION; CELLS C1 Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. RP Slavkin, HC (reprint author), Natl Inst Dent & Craniofacial Res, 31 Ctr Dr,MBC 2290,Bldg 31,Room 2039, Bethesda, MD 20892 USA. NR 18 TC 1 Z9 2 U1 0 U2 0 PU AMER DENTAL ASSN PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD AUG PY 1999 VL 130 IS 8 BP 1219 EP 1222 PG 4 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 225EA UT WOS:000081944400025 PM 10491935 ER PT J AU Appel, LJ Vollmer, WM Obarzanek, E Aicher, KM Conlin, PR Kennedy, BM Charleston, JB Reams, PM AF Appel, LJ Vollmer, WM Obarzanek, E Aicher, KM Conlin, PR Kennedy, BM Charleston, JB Reams, PM CA DASH Collaborative Res Grp TI Recruitment and baseline characteristics of participants in the Dietary Approaches to Stop Hypertension trial SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID CLINICAL-TRIAL AB Dietary Approaches to Stop Hypertension (DASH) was a randomized, multicenter feeding study designed to assess the effects of modifying dietary patterns on blood pressure. Among the most challenging aspects of conducting the DASH trial nas the recruitment of participants at the 4 clinical centers. As part of the recruitment drive, 347,500 brochures were mailed, 250,500 coupons were distributed in coupon packs, 114 advertisements were published in newspapers or bulletins, 140 radio and 74 television advertisements were broadcast, and 68 screening events and presentations were conducted. These efforts yielded a total of 459 enrolled participants, ahead of schedule. The most common source of participants was mass mailing of individual brochures (n=194, 42.3%), followed by word-of-mouth (n=82, 17.8%), and then other types of mass mailing (n=44, 9.6%). Recruitment of minority participants followed a similar pattern. Among the 3,192 persons attending the first in-person screening visit, the major reason for nonenrollment was low blood pressure (56%) rather than a diet-related factor. The study population was demographically heterogeneous (49% women, 60% African American, 48% married, and 77% employed full-time). On average, the diet of participants before the DASH feeding study was more similar to the trial control diet than to the combination diet, which reduced blood pressure more effectively. In summary, recruitment of a heterogeneous study population that includes a substantial number of minority participants is a feasible undertaking. However, the effort is considerable and requires a major commitment of resources. C1 Johns Hopkins Univ, Baltimore, MD USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. NHLBI, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Durham, NC USA. Harvard Univ, Sch Med, Boston, MA USA. Pennington Biomed Res Ctr, Baton Rouge, LA USA. RP Appel, LJ (reprint author), Welch Ctr Prevent Epidemiol & Clin Res, 2024 E Monument St,Suite 2-600, Baltimore, MD 21205 USA. FU NHLBI NIH HHS [HL50968, HL50972, HL50977] NR 16 TC 14 Z9 15 U1 0 U2 1 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD AUG PY 1999 VL 99 IS 8 SU S BP S69 EP S75 DI 10.1016/S0002-8223(99)00419-8 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 225BX UT WOS:000081937100011 PM 10450297 ER PT J AU Harsha, DW Lin, PH Obarzanek, E Karanja, NM Moore, TJ Caballero, B AF Harsha, DW Lin, PH Obarzanek, E Karanja, NM Moore, TJ Caballero, B CA Dash Collaborative Res Grp TI Dietary Approaches to Stop Hypertension: A summary of study results SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article AB The Dietary Approaches to Stop Hypertension multicenter trial examined the impact of dietary patterns on blood pressure in 459 adults with blood pressure <160 mm Hg systolic and 80 to 95 mm Hg diastolic. After a 3-week run-in period on a control diet low in fruits, vegetables, and dairy products, and with a fat content typical for Americans, participants were randomized for 8 weeks to either the control diet, a diet rich in fruits and vegetables, or a combination diet that emphasized fruits, vegetables, and low-fat dairy products. Body weight and sodium intake were held constant, and physical activity did not change during the intervention. Baseline mean+/-standard deviation systolic and diastolic blood pressures were 131.3+/-10.8 mm Hg and 84.7+/-4.7 mm Hg, respectively. Relative to the control diet, the combination diet reduced blood pressure by 5.5 mm Hg and diastolic blood pressure by 3.0 mm Hg (P<.001). For those on the fruits and vegetables diet, blood pressure reductions relative to control were 2.8 mm Hg systolic (P<.001) and 1.1 mm Hg diastolic (P<.07). in 133 participants with hypertension, the combination diet produced a net blood pressure reduction of 11.4 and 5.5 mm Hg systolic and diastolic, respectively (P<.001). In participants without hypertension (n=326), the corresponding blood pressure reductions were 3.5 mm Hg systolic (P<.001) and 2.1 mm Hg diastolic (P<.003). In other subgroup analyses, minorities showed relatively larger reductions in blood pressure than nonminorities (P<.001). We conclude that the dietary pattern reflected in the combination diet can substantially reduce blood pressure, and, accordingly, provides an additional lifestyle approach to preventing and treating hypertension. C1 Pennington Biomed Res Ctr, Body Composite Dept, Baton Rouge, LA 70808 USA. Duke Univ, Med Ctr, Sarah W Stedman Nutr Ctr, Durham, NC USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. NHLBI, Bethesda, MD 20892 USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. Merck & Co Inc, Westwood, MA USA. Harvard Univ, Sch Med, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Johns Hopkins Univ, Ctr Human Nutr, Baltimore, MD USA. RP Harsha, DW (reprint author), Pennington Biomed Res Ctr, Body Composite Dept, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. FU NHLBI NIH HHS [HL50977, HL50968, HL50972] NR 15 TC 56 Z9 56 U1 2 U2 11 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD AUG PY 1999 VL 99 IS 8 SU S BP S35 EP S39 DI 10.1016/S0002-8223(99)00414-9 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 225BX UT WOS:000081937100006 PM 10450292 ER PT J AU Karanja, NM McCullough, ML Kumanyika, SK Pedula, KL Windhauser, MM Obarzanek, E Lin, PH Champagne, CM Swain, JF AF Karanja, NM McCullough, ML Kumanyika, SK Pedula, KL Windhauser, MM Obarzanek, E Lin, PH Champagne, CM Swain, JF CA DASH Collaborative Res Grp TI Pre-enrollment diets or Dietary Approaches to Stop Hypertension trial participants SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID BLOOD-PRESSURE; NUTRITIONAL FACTORS; UNITED-STATES; WOMEN; QUESTIONNAIRE; MAGNESIUM; CALCIUM; SUPPLEMENTATION; METAANALYSIS; POTASSIUM AB A large body of evidence suggests that several nutrients are related to blood pressure. Less is known about the eating patterns of special populations, such as those at risk for hypertension, or how demographic factors affect the diets of these populations. This article characterizes the usual diets of participants before they enrolled in the Dietary Approaches to Stop Hypertension (DASH) trial. During screening for DASH, 380 participants completed the National Cancer Institute food frequency questionnaire. Nutrient and food group intake, the Keys score (a measure of a diet's atherogenicity), and the Diet Quality Index were estimated from the food frequency questionnaire. The effects of age, sex, race, baseline weight, and education on these dietary factors were assessed among DASH participants and compared with similar data from the Third National Health and Nutrition Examination Survey and other published reports. Among DASH participants, African-Americans reported lower intakes of dairy products (P<.001), calcium (P<.001), and magnesium (P<.05) than did whites. Older women reported greater intakes of calcium, magnesium, and potassium (all P<.05) and less fat (P<.05) than did younger women. Older men consumed fewer servings of fruits (P<.03), less vitamin C (P<.05), and had a higher Keys score (P<.05) than did younger men. Heavier (body mass index greater than or equal to 25) participants reported lower intakes of protein and potassium, but higher fat and energy intakes (all P<.05). Taken together, these data show that younger, overweight African-American women have the least healthful diets, because they consume more atherogenic foods and fewer of the nutrients related to decreased blood pressure. Overall Diet Quality Index scores did not differ between African-American and white participants. Despite differences in dietary assessment methods between the population samples of DASH and the Third National Health and Nutrition Examination Survey, within each population sample patterns of micronutrient intake were similar between African-American and whites participants. C1 Kaiser Permanente Ctr Hlth Res, Portland, OR 97227 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Nutr, Boston, MA 02115 USA. Brigham & Womens Hosp, Gen Clin Res Ctr, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Endocrinol & Hypertens, Boston, MA 02115 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Univ Illinois, Dept Human Nutr & Dietet, Chicago, IL USA. Pennington Biomed Res Ctr, Baton Rouge, LA USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC USA. RP Karanja, NM (reprint author), Kaiser Permanente Ctr Hlth Res, 3800 N Interstate Ave, Portland, OR 97227 USA. FU NHLBI NIH HHS [HL50968, HL50972, HL50977] NR 41 TC 8 Z9 8 U1 0 U2 1 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD AUG PY 1999 VL 99 IS 8 SU S BP S28 EP S34 DI 10.1016/S0002-8223(99)00413-7 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 225BX UT WOS:000081937100005 PM 10450291 ER PT J AU Karanja, NM Obarzanek, E Lin, PH McCullough, ML Phillips, KM Swain, JF Champagne, CM Hoben, KP AF Karanja, NM Obarzanek, E Lin, PH McCullough, ML Phillips, KM Swain, JF Champagne, CM Hoben, KP CA DASH Collaborative Res Grp TI Descriptive characteristics of the dietary patterns used in the Dietary Approaches to Stop Hypertension trial SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID CANCER PREVENTION; BLOOD-PRESSURE; VEGETABLES; FRUIT AB The Dietary Approaches to Stop Hypertension trial was a randomized, multicenter, controlled feeding study to compare the effect on blood pressure of 3 dietary patterns: control, fruits and vegetables, and combination diets. The patterns differed in selected nutrients hypothesized to alter blood pressure. This article examines the food-group structure and nutrient composition of the study diets and reports participant nutrient consumption during intervention. Participants consumed the control dietary pattern during a 3-week run-in period. They were then randomized either to continue on the control diet or to change to the fruits and vegetables or the combination diet for 8 weeks. Sodium intake and body weight were constant during the entire feeding period. Analysis of variance models compared the nutrient content of the 3 diets. Targeting a few nutrients thought to influence blood pressure resulted in diets that were profoundly different in their food-group and nutrient composition. The control and fruits and vegetables diets contained more oils, table fats, salad dressings, and red meats and were higher in saturated fat, total fat, and cholesterol than was the combination diet. The fruits and vegetables and combination diets contained relatively more servings of fruits, juices, vegetables, and nuts/seeds, and were higher in magnesium, potassium, and fiber than was the control diet. Both the fruits and vegetables and combination diets were low in sweets and sugar-containing drinks. The combination diet contained a greater variety of fruits, and its high calcium content was obtained by increasing low-fat dairy products. In addition, the distinct food grouping pattern across the 3 diets resulted in substantial differences in the levels of vitamins A, C, E, folate, B-6, and zinc. C1 Kaiser Permanente Ctr Hlth Res, Portland, OR 97227 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC USA. Duke Univ, Med Ctr, Sarah W Stedman Nutr Ctr, Durham, NC USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Brigham & Womens Hosp, Gen Clin Res Ctr, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Endocrinol & Hypertens, Boston, MA 02115 USA. Virginia Polytech Inst & State Univ, Blacksburg, VA 24061 USA. Pennington Biomed Res Ctr, Baton Rouge, LA USA. Chandler Chico Agcy, New York, NY USA. Sarah W Stedman Nutr Ctr, Durham, NC USA. RP Karanja, NM (reprint author), Kaiser Permanente Ctr Hlth Res, 3800 N Interstate Ave, Portland, OR 97227 USA. FU NHLBI NIH HHS [HL50968, HL50972, HL50977] NR 31 TC 118 Z9 119 U1 3 U2 11 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD AUG PY 1999 VL 99 IS 8 SU S BP S19 EP S27 DI 10.1016/S0002-8223(99)00412-5 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 225BX UT WOS:000081937100004 PM 10450290 ER PT J AU Lin, PH Windhauser, MM Plaisted, CS Hoben, KP McCullough, ML Obarzanek, E AF Lin, PH Windhauser, MM Plaisted, CS Hoben, KP McCullough, ML Obarzanek, E CA DASH Collaborative Res Grp TI The Linear Index Model for establishing nutrient goals in the Dietary Approaches to Stop Hypertension trial SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID POTASSIUM-CHLORIDE; BLOOD-PRESSURE; PLASMA-RENIN; CALCIUM; SODIUM; BLACKS; NATRIURESIS AB Establishing target levels of nutrients in feeding studies presents a challenge to dietitians. Although researchers studying energy-containing nutrients, such as protein and fat, commonly establish target levels according to body weight or as a percentage of energy, it is less clear how to establish levels of micronutrients. Typically, a constant target level is used regardless of energy requirements. Alternatively, nutrients could be provided at a fixed level per 1,000 kcal. Such an approach, however, could result in absolute levels of nutrient intakes that are difficult to achieve through foods alone, particularly for persons with high energy requirements. This report describes the Linear Index Model, a new approach for establishing target levels of selected micronutrients in the Dietary Approaches to Stop Hypertension trial. This model indexes micronutrient levels to energy levels to achieve a linear range of targeted intake in proportion to the energy intake. The Linear Index Model has several benefits: it takes advantage of indexing nutrients according to energy requirements, thus providing levels of nutrient intakes that can be readily achieved by foods; it is based on population consumption data, thus providing a realistic range of intakes for the experimental conditions; and it ensures distinct contrasts in experimental conditions. The Linear Index Model is a feasible and practical approach for establishing target levels of nutrients in feeding studies. C1 Duke Univ, Med Ctr, Sarah W Stedman Nutr Ctr, Dept Med, Durham, NC 27710 USA. Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. Univ N Carolina, Chapel Hill, NC USA. Chandler Chico Agcy, New York, NY USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Lin, PH (reprint author), Duke Univ, Med Ctr, Sarah W Stedman Nutr Ctr, Dept Med, POB 3487, Durham, NC 27710 USA. FU NHLBI NIH HHS [HL50972, HL50968, HL50977] NR 21 TC 12 Z9 13 U1 0 U2 0 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD AUG PY 1999 VL 99 IS 8 SU S BP S40 EP S44 DI 10.1016/S0002-8223(99)00415-0 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 225BX UT WOS:000081937100007 PM 10450293 ER PT J AU McCullough, ML Karanja, NM Lin, PH Obarzanek, E Phillips, KM Laws, RL Vollmer, WM O'Connor, EA Champagne, CM Windhauser, MM AF McCullough, ML Karanja, NM Lin, PH Obarzanek, E Phillips, KM Laws, RL Vollmer, WM O'Connor, EA Champagne, CM Windhauser, MM CA DASH Collaborative Res Grp TI Comparison of 4 nutrient databases with chemical composition data from the Dietary Approaches to Stop Hypertension trial SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID STANDARD REFERENCE; ANALYSIS SYSTEMS; DATA-BASES; SOFTWARE; PROGRAMS; VALUES; VIEW AB Accuracy of computerized nutrient databases is an important consideration in selecting a nutrient analysis system. We project compared the nutrient content of daily menus calculated from 4 microcomputer programs to chemical analysis of menus analyzed for the Dietary Approaches to Stop Hypertension (DASH) trial. Thirty-six menus were entered at 2 independent DASH sites using the ESHA Food Processor, Minnesota Nutrition Data System, Moore's Extended Nutrient Database, and Nutritionist TV databases. Food prepared according to these menus was chemically analyzed at the Food Analysis Laboratory Control Center at Virginia Polytechnic Institute and State University, Department of Biochemistry, Blacksburg. Estimates for 13 nutrients were compared: energy, total fat, saturated fat, monounsaturated fat, polyunsaturated fat, carbohydrate, protein, cholesterol, calcium, potassium, magnesium, iron, and sodium. The overall intraclass correlation between the 2 sites' data entry was 0.998; thus, values were averaged for analyses. Databases varied significantly in their mean deviations from chemical analyses values for saturated, monounsaturated, and polyunsaturated fatty acids, potassium, magnesium, and iron (P<.05); however, these differences were small (<10%). Absolute deviations, which estimate the combined effect of bias and precision, were significantly different among databases for energy, saturated fatty acids, and polyunsaturated acids. Absolute differences from the laboratory values varied by <15%, except for iron. All 4 databases were comparable in accuracy and precision and performed well. Criteria for database selection depends not only on overall database accuracy, especially for nutrients of interest, but also on the ease of use of the program, relevant features of the associated software, and cost. C1 Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Duke Univ, Med Ctr, Sarah W Stedman Nutr Ctr, Durham, NC 27710 USA. NHLBI, Bethesda, MD 20892 USA. Virginia Polytech Inst & State Univ, Blacksburg, VA 24061 USA. Pennington Biomed Res Ctr, Baton Rouge, LA USA. RP McCullough, ML (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, Bldg 2,Room 437,665 Huntington Ave, Boston, MA 02115 USA. FU NHLBI NIH HHS [HL50977, HL50968, HL50972] NR 32 TC 36 Z9 37 U1 2 U2 3 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD AUG PY 1999 VL 99 IS 8 SU S BP S45 EP S53 DI 10.1016/S0002-8223(99)00416-2 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 225BX UT WOS:000081937100008 PM 10450294 ER PT J AU Obarzanek, E Moore, TJ AF Obarzanek, E Moore, TJ TI Using feeding studies to test the efficacy of dietary interventions: Lessons from the Dietary Approaches to Stop Hypertension trial SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Editorial Material C1 NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Merck & Co Inc, Westpoint, PA USA. Harvard Univ, Sch Med, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Obarzanek, E (reprint author), NHLBI, Div Epidemiol & Clin Applicat, Bldg 10, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [HL50968, HL50977, HL50972] NR 6 TC 6 Z9 6 U1 0 U2 1 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD AUG PY 1999 VL 99 IS 8 SU S BP S9 EP S11 DI 10.1016/S0002-8223(99)00409-5 PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 225BX UT WOS:000081937100001 PM 10450288 ER PT J AU Phillips, KM Stewart, KK Karanja, NM Windhauser, MM Champagne, CM Swain, JF Lin, PH Evans, MA AF Phillips, KM Stewart, KK Karanja, NM Windhauser, MM Champagne, CM Swain, JF Lin, PH Evans, MA CA DASH Collaborative Res Grp TI Validation of diet composition for the Dietary Approaches to Stop Hypertension trial SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article AB The Dietary Approaches to Stop Hypertension trial involved 4 clinical sites at which 459 participants (in 5 cohorts) were fed 3 dietary patterns over 11 weeks per cohort. The 3 patterns were a control diet, a fruits and vegetables diet, and a combination diet. Before the intervention, key nutrient levels in each diet were validated at 2 energy levels (2,100 and 3,100 kcal) by chemical analysis of the prepared menus. During intervention, diets were sampled across all cohorts, sites, and energy levels, and 7-day menu cycle composites were assayed. In general, sodium, potassium, calcium, and magnesium in the validated menus for each diet/energy level met lie nutrient targets, though moderate variability was evident among individual menus, particularly for potassium, calcium, and magnesium. However, as intended, there was clear separation and no overlap in mineral levels in individual menus of diets that were designed to differ. During intervention, macronutrient contents met nutrient goals. Sodium, potassium, calcium, and magnesium in the diets generally met target levels, though potassium in the fruits and vegetables diet was 11% to 23% below target. There were no consistent differences in nutrient levels between sites. The mean nutrient levels in the validated menus and diets sampled during intervention were in excellent agreement with each other, though sodium was somewhat higher (similar to 6%) in the diets from intervention vs validation. These results indicate the success of the quality control measures implemented and suggested consistent overall diet composition throughout the 28 months during which the study was conducted. C1 Virginia Polytech Inst & State Univ, Blacksburg, VA 24061 USA. Univ Texas, Dept Chem & Biochem, Austin, TX 78712 USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. Pennington Biomed Res Ctr, Baton Rouge, LA USA. Brigham & Womens Hosp, Dept Endocrinol & Hypertens, Boston, MA 02115 USA. Brigham & Womens Hosp, Gen Clin Res Ctr, Boston, MA 02115 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Duke Univ, Med Ctr, Sarah W Stedman Nutr Ctr, Durham, NC 27710 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Phillips, KM (reprint author), Virginia Polytech Inst & State Univ, 304 Engel Hall, Blacksburg, VA 24061 USA. OI Phillips, Katherine/0000-0002-4586-8538 FU NHLBI NIH HHS [HL50968, HL50972, HL50977] NR 17 TC 14 Z9 14 U1 0 U2 1 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD AUG PY 1999 VL 99 IS 8 SU S BP S60 EP S68 DI 10.1016/S0002-8223(99)00418-6 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 225BX UT WOS:000081937100010 PM 10450296 ER PT J AU Svetkey, LP Sacks, FM Obarzanek, E Vollmer, WM Appel, LJ Lin, PH Karanja, NM Harsha, DW Bray, GA Aickin, M Proschan, MA Windhauser, MM Swain, JF McCarron, PB Rhodes, DG Laws, RL AF Svetkey, LP Sacks, FM Obarzanek, E Vollmer, WM Appel, LJ Lin, PH Karanja, NM Harsha, DW Bray, GA Aickin, M Proschan, MA Windhauser, MM Swain, JF McCarron, PB Rhodes, DG Laws, RL CA DASH-Sodium Collaborative Res Grp TI The DASH diet, sodium intake and blood pressure trial (DASH-sodium): Rationale and design SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID SALT REDUCTION; IDIOPATHIC HYPERTENSION; OBSERVATIONAL DATA; RESTRICTION; CATECHOLAMINES; POPULATIONS; WHITES; BLACKS AB The DASH Diet, Sodium Intake and Blood Pressure Trial (DASH-Sodium) is a multicenter, randomized trial comparing the effects of 3 levels of sodium intake and 2 dietary patterns on blood pressure among adults with higher than optimal blood pressure or with stage 1 hypertension (120-159/80-95 mm Hg). The 2 dietary patterns are a control diet typical of what many Americans eat, and the DASH diet, which, by comparison, emphasizes fruits, vegetables, and low-fat dairy foods, includes whole grains, poultry, fish, and nuts, and is reduced in fats, red meat, sweets, and sugar-containing beverages. The 3 sodium levels are defined as higher (typical of current US consumption), intermediate (reflecting the upper limit of current US recommendations), and lower (reflecting potentially optimal levels). Participants are randomly assigned to 1 of the 2 dietary patterns using a parallel group design and are fed each of the 3 sodium levels using a randomized crossover design. The study provides participants with all of their food during a 2-week run-in feeding period and three 30-day intervention feeding periods. Participants attend the clinic for 1 meal per day, 5 days per week, and take home food for other meals. Weight is monitored and individual energy intake adjusted to maintain baseline weight. The primary outcome is systolic blood pressure measured at the end of each intervention feeding period. Systolic blood pressure is compared across the 3 sodium levels within each diet and across the 2 diets within each sodium level. If effects previously observed in clinical trials are additive, sodium reduction and the DASH diet together may lower blood pressure to an extent not as yet demonstrated for nonpharmacologic treatment. The DASH-Sodium results will have important implications for the prevention and treatment of high blood pressure. C1 Duke Hypertens Ctr, Durham, NC 27705 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Duke Univ, Med Ctr, Sarah W Stedman Ctr Nutr Studies, Durham, NC 27710 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. Johns Hopkins Univ, ProHlth Clin Ctr, Baltimore, MD USA. Pennington Biomed Res Ctr, Body Composit Dept, Baton Rouge, LA USA. Brigham & Womens Hosp, Gen Clin Res Ctr, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Endocrinol & Hypertens, Boston, MA 02115 USA. Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. RP Svetkey, LP (reprint author), Duke Hypertens Ctr, 3020 Pickett Rd, Durham, NC 27705 USA. FU NHLBI NIH HHS [U01HL57173, U01HL57156, U01HL57190] NR 38 TC 65 Z9 66 U1 2 U2 10 PU AMER DIETETIC ASSOC PI CHICAGO PA 120 S RIVERSIDE PLZ, STE 2000, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD AUG PY 1999 VL 99 IS 8 SU S BP S96 EP S104 DI 10.1016/S0002-8223(99)00423-X PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 225BX UT WOS:000081937100015 PM 10450301 ER PT J AU Swain, JF Windhauser, MM Hoben, KP Evans, MA McGee, BB Steele, PD AF Swain, JF Windhauser, MM Hoben, KP Evans, MA McGee, BB Steele, PD CA DASH Collaborative Res Grp TI Menu design and selection for multicenter controlled feeding studies: Process used in the Dietary Approaches to Stop Hypertension trial SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article AB Outpatient feeding studies are being used increasingly more often than inpatient studies because they are less expensive to conduct and less disruptive to participants' daily lives. Frequently, however, they are more difficult to implement. Studies involving multiple feeding centers add an additional layer of cooperation, coordination, and standardization to the already complex task of developing and delivering research diets. This was true for the 4-year Dietary Approaches to Stop Hypertension (DASH) trial, one of the first multicenter outpatient controlled feeding studies. This 4-center, randomized clinical trial was designed to compare the effects of 3 dietary patterns on blood pressure. After a year of development, 3 sets of 7-day cycle menus that met the study nutrient criteria and that were appropriate for varying food production routines and staffing patterns at the 4 clinical centers were adopted. The major development tasks were: defining methodologies to guide menu design and food production; selecting a nutrient database and calculating nutrient content of menus; evaluating and selecting the menus; and adjusting the menus for final use. The purpose of this article is to describe the steps and considerations in the design and selection of menus for the DASH trial, a process applicable to all well-controlled feeding studies. C1 Brigham & Womens Hosp, Gen Clin Res Ctr, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Endocrinol & Hypertens, Boston, MA 02115 USA. Pennington Biomed Res Ctr, Baton Rouge, LA USA. Chandler Chico Agcy, New York, NY USA. Duke Univ, Med Ctr, Duke Hypertens Ctr, Durham, NC USA. Duke Univ, Med Ctr, Sarah W Stedman Nutr Ctr, Durham, NC USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. So Univ, Div Family & Consumer Sci, Human Nutr & Food program, Baton Rouge, LA USA. USDA, Beltsville Human Nutr Res Ctr, Beltsville, MD 20705 USA. RP Swain, JF (reprint author), Brigham & Womens Hosp, Gen Clin Res Ctr, CRC-9A,75 Francis St, Boston, MA 02115 USA. FU NHLBI NIH HHS [HL50968, HL50972, HL50977] NR 14 TC 16 Z9 16 U1 0 U2 3 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD AUG PY 1999 VL 99 IS 8 SU S BP S54 EP S59 DI 10.1016/S0002-8223(99)00417-4 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 225BX UT WOS:000081937100009 PM 10450295 ER PT J AU Vogt, TM Appel, LJ Obarzanek, E Mooe, TJ Vollmer, WM Svetkey, LP Sacks, FM Bray, GA Cutler, JA Windhauser, MM Lin, PH Karanja, NM AF Vogt, TM Appel, LJ Obarzanek, E Mooe, TJ Vollmer, WM Svetkey, LP Sacks, FM Bray, GA Cutler, JA Windhauser, MM Lin, PH Karanja, NM CA DASH Collaborative Res Grp TI Dietary Approaches to Stop Hypertension: Rationale, design, and methods SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID ORAL MAGNESIUM SUPPLEMENTATION; RANDOMIZED CONTROLLED TRIAL; LOW-SODIUM DIET; BLOOD-PRESSURE; VEGETARIAN DIET; NUTRITIONAL FACTORS; CLINICAL-TRIALS; DOUBLE-BLIND; LOW-FAT; METAANALYSIS AB Epidemiologic studies across societies have shown consistent differences in blood pressure that appear to be related to diet. Vegetarian diets are consistently associated with reduced blood pressure in observational and interventional studies, but clinical trials of individual nutrient supplements have had an inconsistent pattern of results. Dietary Approaches to Stop Hypertension (DASH) was a multicenter, randomized feeding study, designed to compare the impact on blood pressure of 3 dietary patterns. DASH was designed as a test of eating patterns rather than of individual nutrients in an effort to identify practical, palatable dietary approaches that might have a meaningful impact on reducing morbidity and mortality related to blood pressure in the general population. The objectives of this article are to present the scientific rationale for this trial, review the methods used, and discuss important design considerations and implications. C1 Kaiser Permanente Ctr Hlth Res, Honolulu, HI 96813 USA. Johns Hopkins Univ, Baltimore, MD USA. NHLBI, Clin Applicat Programs, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. NHLBI, Prevent Program, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Merck & Co Inc, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. Duke Univ, Med Ctr, Nutr Ctr, Durham, NC USA. Duke Univ, Duke Hypertens Ctr, Durham, NC USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Pennington Biomed Res Ctr, Baton Rouge, LA USA. RP Vogt, TM (reprint author), Kaiser Permanente Ctr Hlth Res, 531 Ohohia St, Honolulu, HI 96813 USA. FU NHLBI NIH HHS [HL50968, HL50972, HL50977] NR 60 TC 46 Z9 47 U1 0 U2 8 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD AUG PY 1999 VL 99 IS 8 SU S BP S12 EP S18 DI 10.1016/S0002-8223(99)00411-3 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 225BX UT WOS:000081937100003 PM 10450289 ER PT J AU Windhauser, MM Ernst, DB Karanja, NM Crawford, SW Redican, SE Swain, JF Karimbakas, JM Champagne, CM Hoben, KP Evans, MA AF Windhauser, MM Ernst, DB Karanja, NM Crawford, SW Redican, SE Swain, JF Karimbakas, JM Champagne, CM Hoben, KP Evans, MA CA DASH Collaborative Res Grp TI Translating the Dietary Approaches to Stop Hypertension diet from research to practice: Dietary and behavior change techniques SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article AB The Dietary Approaches to Stop Hypertension (DASH) clinical trial demonstrated that a diet that emphasizes fruits, vegetables, and low-fat dairy products, includes whole grains, nuts, fish, and poultry, and is reduced in fats, red meats, sweets, and sugar-containing beverages can be highly effective in lowering blood pressure. The National High Blood Pressure Education Program now suggests the DASH diet for preventing and managing hypertension. For persons modifying their diets, the DASH diet offers varied choices. However, simultaneously modifying several dimensions of a diet can be challenging, even for knowledgeable and motivated persons. Persons who are uncertain about modifying their diet may become overwhelmed by the needed dietary changes. Dietitians and other health care practitioners can help patients adopt the DASH diet by exploring possible ambivalence, increasing motivation, and strengthening commitment to change, encouraging patients to select dietary modifications that will fit their lifestyle; and, finally, offering information about how to change their eating behavior. In this article, we offer dietary advice and counseling suggestions for tailoring interventions to match patients' readiness for adopting the DASH diet. C1 Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. Brigham & Womens Hosp, Dept Endocrinol & Hypertens, Boston, MA 02115 USA. Brigham & Womens Hosp, Gen Clin Res Ctr, Boston, MA 02115 USA. Prospect Associates, Silver Spring, MD USA. Chandler Chico Agcy, New York, NY USA. Duke Hypertens Ctr, Durham, NC USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Windhauser, MM (reprint author), Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. FU NHLBI NIH HHS [HL50968, HL50972, HL50977] NR 16 TC 11 Z9 13 U1 0 U2 3 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD AUG PY 1999 VL 99 IS 8 SU S BP S90 EP S95 DI 10.1016/S0002-8223(99)00422-8 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 225BX UT WOS:000081937100014 PM 10450300 ER PT J AU Windhauser, MM Evans, MA McCullough, ML Swain, JF Lin, PH Hoben, KP Plaisted, CS Karanja, NM Vollmer, WM AF Windhauser, MM Evans, MA McCullough, ML Swain, JF Lin, PH Hoben, KP Plaisted, CS Karanja, NM Vollmer, WM CA DASH Collaborative Res Grp TI Dietary adherence in the Dietary Approaches to Stop Hypertension trial SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID BALANCE AB Participants in controlled feeding studies must consume all study foods and abstain from all other foods. In outpatient studies in which adherence may be compromised by free-living conditions, promoting, documenting, and monitoring dietary adherence are necessary. In the Dietary Approaches to Stop Hypertension (DASH) trial, a thorough participant screening process, an orientation session, and a run-in feeding period before randomization aided in the selection of participants who would most likely adhere to the demands of the study protocol. Throughout the feeding period, various educational and motivational techniques were used to encourage DASH participants to adhere to the dietary protocol. Both objective and subjective methods documented excellent participant adherence. Daily monitoring of individual adherence was based on meal attendance, body weight measurements, and daily diaries. Urinary sodium, potassium, phosphorus, and urea nitrogen values and an anonymous poststudy survey were used to evaluate adherence at the end of the study. Most DASH participants adhered to the feeding regimen by consuming only study foods and no other foods. When adherence lapsed, participants generally cited the lack of menu variety as a reason. Successful participant adherence to the constraints of an outpatient controlled feeding study is possible with carefully selected participants and a variety of adherence-promoting strategies incorporated into the study protocol. C1 Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Brigham & Womens Hosp, Gen Clin Res Ctr, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Endocrinol & Hypertens, Boston, MA 02115 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Duke Univ, Med Ctr, Sarah W Stedman Nutr Ctr, Durham, NC 27710 USA. Chandler Chica Agcy, New York, NY USA. Duke Hypertens Ctr, Durham, NC USA. Univ N Carolina, Chapel Hill, NC USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. RP Windhauser, MM (reprint author), Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. FU NHLBI NIH HHS [HL50968, HL50972, HL50977] NR 20 TC 26 Z9 26 U1 0 U2 7 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD AUG PY 1999 VL 99 IS 8 SU S BP S76 EP S83 DI 10.1016/S0002-8223(99)00420-4 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 225BX UT WOS:000081937100012 PM 10450298 ER PT J AU Fleg, JL AF Fleg, JL TI Silent myocardial ischemia and low aerobic capacity: An unlucky combination SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Editorial Material ID ALL-CAUSE MORTALITY; CORONARY HEART-DISEASE; TIME PHYSICAL-ACTIVITY; ASYMPTOMATIC MEN; COLLEGE ALUMNI; FITNESS; INFARCTION; RISK; HEALTHY; WOMEN C1 NIA, Baltimore, MD 21224 USA. RP Fleg, JL (reprint author), NIA, Baltimore, MD 21224 USA. NR 25 TC 0 Z9 0 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 AUG PY 1999 VL 47 IS 8 BP 1026 EP 1028 PG 3 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 224DD UT WOS:000081880800016 PM 10443866 ER PT J AU Guralnik, JM AF Guralnik, JM TI The impact of vision and hearing impairments on health in old age SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Editorial Material ID BEAVER DAM EYE; RISK-FACTORS; CARDIOVASCULAR-DISEASE; VISUAL-ACUITY; HIP FRACTURE; EPIDEMIOLOGY; ADULTS; PREVALENCE C1 NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. RP Guralnik, JM (reprint author), NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. NR 21 TC 11 Z9 11 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 AUG PY 1999 VL 47 IS 8 BP 1029 EP 1031 PG 3 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 224DD UT WOS:000081880800017 PM 10443867 ER PT J AU Fernandez-Llama, P Andrews, P Turner, R Saggi, S Dimari, J Kwon, TH Nielsen, S Safirstein, R Knepper, MA AF Fernandez-Llama, P Andrews, P Turner, R Saggi, S Dimari, J Kwon, TH Nielsen, S Safirstein, R Knepper, MA TI Decreased abundance of collecting duct aquaporins in post-ischemic renal failure in rats SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID WATER CHANNEL EXPRESSION; INDUCED NEPHROTIC SYNDROME; INDUCED DOWN-REGULATION; CONCENTRATING DEFECT; KIDNEY MEDULLA; HEART-FAILURE; VASOPRESSIN; PROTEIN; FAMILY; URINE AB Increased urine flow is often a feature of mild to moderate acute renal failure. This study examines the possible role of dysregulation of collecting duct aquaporins as a factor in this increase. In rats. the left renal pedicle was clamped for 45 min followed by contralateral nephrectomy. Control rats were identical except that the renal pedicle was not clamped. Rats were sacrificed and the kidneys were homogenized at various time points after release of the clamp for semiquantitative immunoblotting of collecting duct aquaporins, as well as the thick ascending limb Na-K-2Cl cotransporter and the proximal tubule water channel, aquaporin-1. Urinary flow rate was significantly increased 18 h after the ischemic insult and remained increased through 72 h. Whole kidney aquaporin-2 protein abundance was 45% of controls at 18 h, 55% of controls, at 36 h, and returned to normal 72 h after ischemia. Whole kidney aquaporin-3 protein abundance was 37% of controls at 18 h, 13% of controls at 36 h, and 45% of controls at 72 h. The decline in aquaporin-2 and -3 was confirmed by immunocytochemistry. Abundance of the thick ascending limb Na-K-2Cl cotransporter protein was not significantly decreased. Aquaporin-1 protein abundance was not significantly decreased at 18 h after the ischemic insult, but was significantly reduced after 36 h. Thus, the post-ischemic state is associated with decreased levels of the collecting duct aquaporins, coinciding with an increase in water excretion. It is concluded that decreased aquaporin protein abundance in collecting duct cells is a contributing factor in the increased urine flow seen in moderate post-ischemic acute renal failure. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Dept Cell Biol, Washington, DC USA. Univ Texas, Med Branch, Dept Med, Galveston, TX 77550 USA. Univ Aarhus, Dept Cell Biol, Aarhus, Denmark. RP Knepper, MA (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bldg 10,Room 6N260,10 Ctr Dr,MSC 1603, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 HL999999, Z01 HL001285-21]; NHLBI NIH HHS [Z01-HL-01282-KE] NR 38 TC 51 Z9 53 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 AUG PY 1999 VL 10 IS 8 BP 1658 EP 1668 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 221HH UT WOS:000081721300004 PM 10446933 ER PT J AU Poliakova, L Kovesdi, I Wang, XT Capogrossi, MC Talan, M AF Poliakova, L Kovesdi, I Wang, XT Capogrossi, MC Talan, M TI Vascular permeability effect of adenovirus-mediated vascular endothelial growth factor gene transfer to the rabbit and rat skeletal muscle SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article ID PERIPHERAL ARTERY DISEASE; THERAPEUTIC ANGIOGENESIS; LIMB ISCHEMIA; THERAPIES; VEGF(165); MODEL AB Objective: Vascular endothelial growth factor has been used in preclinical studies and phase 1 and 2 clinical trials as a potent mediator of therapeutic angiogenesis; however, its ability to enhance the vascular permeability may be a source of potential complications. The objective of this work was to evaluate the effects of the intramuscular injection of an adenovirus vector coding for the 121-amino acid form of vascular endothelial growth factor (Ad.VEGF(121)) on vascular permeability and edema development in rabbits and rats. Methods: Different concentrations of Ad.VEGF(121) ranging from 10(5) to 10(10) plaque-forming units/mL (3 x 10(6)-3 x 10(11) particles/mL) were injected into hind limb or forelimb muscles of Wistar rats or rabbits. The size of the scrotum, the circumferences of limbs, and the concentration of vascular endothelial growth factor in the serum were measured daily after injection. Results: The injection of different concentrations of Ad.VEGF(121) into the hind limb muscles of rabbits led to a dose-dependent scrotal edema in rabbits at concentrations higher than 107 plaque-forming units/mL (P = .002). The edema developed slowly, reached its maximum level 6 days after the injection, and spontaneously resolved thereafter. At concentrations higher than 10(9) plaque-forming units/mL the scrotal edema was accompanied by skin necrosis (P = .0001). No scrotal edema was observed in rats. Conclusions: The massive species-specific scrotal edema accompanied by skin ulceration and necrosis was observed only in rabbits treated with Ad.VEGF(121) in concentrations exceeding therapeutic doses. The therapeutic doses of Ad.VEGF(121) resulted in only moderate transient scrotal edema in rabbits, suggesting that the potential for side effects of vascular endothelial growth factor therapy as a result of increased vascular permeability should not be very alarming for generally healthy patients and may not cause a significant clinical problem in the treatment of peripheral vascular diseases. C1 NIA, Intramural Res Program, Gerontol Res Ctr, Gene Therapy Unit,Lab Cardiovasc Sci,NIH, Baltimore, MD 21224 USA. GenVec Inc, Rockville, MD USA. Ist Dermopatico Immacolata, Lab Patol Vasc, Rome, Italy. RP Talan, M (reprint author), NIA, Intramural Res Program, Gerontol Res Ctr, Gene Therapy Unit,Lab Cardiovasc Sci,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Kovesdi, Imre/0000-0002-0322-3969 NR 28 TC 22 Z9 25 U1 0 U2 1 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD AUG PY 1999 VL 118 IS 2 BP 339 EP 347 DI 10.1016/S0022-5223(99)70225-4 PG 9 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 222NA UT WOS:000081790600017 PM 10425008 ER PT J AU Nguyen, DM Hill, AB Chughtai, T Robinson, R Mulder, DS AF Nguyen, DM Hill, AB Chughtai, T Robinson, R Mulder, DS TI Traumatic rupture of the descending thoracic aorta associated with severe pulmonary contusion: Requirement of full cardiopulmonary bypass for lifo support during surgical repair SO JOURNAL OF TRAUMA-INJURY INFECTION AND CRITICAL CARE LA English DT Article C1 McGill Univ, Montreal Gen Hosp, Dept Anesthesia, Dept Surg,Div Cardiothorac Surg, Montreal, PQ H3G 1A4, Canada. McGill Univ, Montreal Gen Hosp, Dept Anesthesia, Dept Surg,Div Vasc Surg, Montreal, PQ H3G 1A4, Canada. RP Nguyen, DM (reprint author), NCI, NIH, Room 2C708,Bldg 10,10 Ctr Dr,MSC1502, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-6061 J9 J TRAUMA JI J. Trauma-Injury Infect. Crit. Care PD AUG PY 1999 VL 47 IS 2 BP 406 EP 407 DI 10.1097/00005373-199908000-00038 PG 2 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA 226LK UT WOS:000082021300036 PM 10452484 ER PT J AU Linehan, WM AF Linehan, WM TI Kidney cancer: Novel model for cancer genetics and therapy SO JOURNAL OF UROLOGY LA English DT Editorial Material ID TUMOR-SUPPRESSOR GENE C1 NCI, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD AUG PY 1999 VL 162 IS 2 BP 291 EP 292 DI 10.1016/S0022-5347(05)68542-4 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 214UA UT WOS:000081344900001 PM 10411024 ER PT J AU Strup, SE Pozzatti, RO Florence, CD Emmert-Buck, MR Duray, PH Liotta, LA Bostwick, DG Linehan, WM Vocke, CD AF Strup, SE Pozzatti, RO Florence, CD Emmert-Buck, MR Duray, PH Liotta, LA Bostwick, DG Linehan, WM Vocke, CD TI Chromosome 16 allelic loss analysis of a large set of microdissected prostate carcinomas SO JOURNAL OF UROLOGY LA English DT Article DE prostate carcinoma; loss of heterozygosity; tumor suppressor gene; tissue microdissection; microsatellite polymorphism ID TUMOR-SUPPRESSOR GENE; FREQUENT LOSS; CANCER; HETEROZYGOSITY; LOCI; REGIONS; PROGRESSION; DELETION; 8P12-21; 7Q31.1 AB Purpose: To perform loss of heterozygosity (LOH) analysis on chromosome 16 in 102 highly purified DNA samples isolated from one or more adenocarcinomas, prostatic intraepithelial neoplasia (PIN), and matched benign prostatic epithelium from 95 radical prostatectomy patients. Materials and Methods: Specimens were procured by microdissection of frozen tissue samples, thus ensuring that highly select pure populations of cells were obtained for DNA extraction and LOH analysis. Multiple microsatellite markers were used to determine allelic loss on chromosome 16q. Results: Overall loss on 16q was seen in 31% of the cancers, and occurred more frequently in high stage cancers than low stage cancers. In contrast, allelic loss in PIN failed to exceed 6% at any of the loci that were examined. Conclusions: These results suggest that inactivation of a putative tumor suppressor gene on 16q may be involved in the progression of some prostate cancers. C1 NCI, Surg Branch, Bethesda, MD 20892 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. Mayo Clin, Dept Pathol, Rochester, MN USA. RP Strup, SE (reprint author), Thomas Jefferson Univ, Dept Urol, 1112 Coll Bldg,1025 Walnut St, Philadelphia, PA 19107 USA. NR 23 TC 11 Z9 12 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD AUG PY 1999 VL 162 IS 2 BP 590 EP 594 DI 10.1016/S0022-5347(05)68631-4 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 214UA UT WOS:000081344900092 PM 10411092 ER PT J AU Chabry, J Priola, SA Wehrly, K Nishio, J Hope, J Chesebro, B AF Chabry, J Priola, SA Wehrly, K Nishio, J Hope, J Chesebro, B TI Species-independent inhibition of abnormal prion protein (PrP) formation by a peptide containing a conserved PrP sequence SO JOURNAL OF VIROLOGY LA English DT Article ID CREUTZFELDT-JAKOB DISEASE; SCRAPIE AGENT; RESISTANT PRP; NEUROBLASTOMA-CELLS; DIFFERENT STRAINS; CONVERSION; MICE; SHEEP; HOST; ACCUMULATION AB Conversion of the normal protease-sensitive prion protein (PrP) to its abnormal protease-resistant isoform (PrP-res) is a major feature of the pathogenesis associated with transmissible spongiform encephalopathy (TSE) diseases. In previous experiments, PrP conversion was inhibited by a peptide composed of hamster PrP residues 109 to 141, suggesting that this region of the PrP molecule plays a crucial role in the conversion process. In this study, we used PrP-res derived from animals infected with two different mouse scrapie strains and one hamster scrapie strain to investigate the species specificity of these conversion reactions. Conversion of PrP was found to be completely species specific; however, despite having three amino acid differences, peptides corresponding to the hamster and mouse PrP sequences from residues 109 to 141 inhibited both the mouse and hamster PrP conversion systems equally. Furthermore, a peptide corresponding to hamster PrP residues 119 to 136, which was identical in both mouse and hamster PrP, was able to inhibit PrP-res formation in both the mouse and hamster cell-free systems as well as in scrapie-infected mouse neuroblastoma cell cultures. Because the PrP region from 119 to 136 is very conserved in most species, this peptide may have inhibitory effects on PrP conversion in a wide variety of TSE diseases. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. RP Chesebro, B (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. RI Hope, James/C-4966-2011; Chabry, Joelle/O-2101-2016 NR 37 TC 63 Z9 66 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 1999 VL 73 IS 8 BP 6245 EP 6250 PG 6 WC Virology SC Virology GA 215HZ UT WOS:000081377400005 PM 10400714 ER PT J AU Ostrowski, MA Chun, TW Justement, SJ Motola, I Spinelli, MA Adelsberger, J Ehler, LA Mizell, SB Hallahan, CW Fauci, AS AF Ostrowski, MA Chun, TW Justement, SJ Motola, I Spinelli, MA Adelsberger, J Ehler, LA Mizell, SB Hallahan, CW Fauci, AS TI Both memory and CD45RA(+)/CD62L(+) naive CD4(+) T cells are infected in human immunodeficiency virus type 1-infected individuals SO JOURNAL OF VIROLOGY LA English DT Article ID CHEMOKINE RECEPTORS; PREFERENTIAL REPLICATION; HIV-1 INFECTION; IN-VIVO; LYMPHOCYTES; ENTRY; CCR5; CORECEPTORS; TRANSITION; COFACTOR AB Cellular activation is critical for the propagation of human immunodeficiency virus type 1 (HIV-1) infection. It has been suggested that truly naive CD4(+) T cells are resistant to productive HIV-1 infection because of their constitutive resting state. Memory and naive CD4(+) T-cell subsets from 11 HIV-1-infected individuals were isolated ex vivo by a combination of magnetic bead depletion and fluorescence-activated cell sorting techniques with stringent criteria of combined expression of CD45RA and CD62L to identify naive CD4(+) T-cell subsets. In all patients HIV-1 provirus could be detected within naive CD45RA(+)/CD62L(+) CD4(+) T cells; in addition, replication-competent HIV-1 was isolated from these cells upon CD4(+) T-cell stimulation in tissue cultures. Memory CD4(+) T cells had a median of fourfold more replication-competent virus and a median of sixfold more provirus than naive CD4(+) T cells. Overall, there was a median of 16-fold more integrated provirus identified in memory CD4(+) T cells than in naive CD4(+) T cells within a given patient. Interestingly, there was a trend toward equalization of viral loads in memory and naive CD4(+) T-cell subsets in those patients who harbored CXCR4-using (syncytium-inducing) viruses. Within any given patient, there was no selective usage of a particular coreceptor by virus isolated from memory versus naive CD4(+) T cells. Our findings suggest that naive CD4(+) T cells may be a significant viral reservoir for HIV, particularly in those patients harboring CXCR4-using viruses. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Ostrowski, MA (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Room 6A11,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 37 TC 157 Z9 157 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 1999 VL 73 IS 8 BP 6430 EP 6435 PG 6 WC Virology SC Virology GA 215HZ UT WOS:000081377400027 PM 10400736 ER PT J AU Trovato, R Mulloy, JC Johnson, JM Takemoto, S de Oliveira, MP Franchini, G AF Trovato, R Mulloy, JC Johnson, JM Takemoto, S de Oliveira, MP Franchini, G TI A lysine-to-arginine change found in natural alleles of the human T-cell lymphotropic leukemia virus type 1 p12 protein greatly influences its stability SO JOURNAL OF VIROLOGY LA English DT Article ID GROWTH-FACTOR RECEPTOR; OPEN READING FRAMES; VACUOLAR H+-ATPASE; HTLV TYPE-I; BOVINE PAPILLOMAVIRUS; MESSENGER-RNA; PX REGION; PROTEASOME; TRANSFORMATION; UBIQUITIN AB The HTLV-1 singly spliced open reading frame I protein, p12(I), is highly unstable and appears to be necessary for persistent infection in rabbits. Here we demonstrate that p12(I) forms dimers through two putative leucine zipper domains and that its stability is augmented by specific proteasome inhibitors. p12(I) is ubiquitylated, and mutations of its unique carboxy-terminus lysine residue to an arginine greatly enhance its stability. Interestingly, analysis of 53 independent HTLV-1 strains revealed that the natural p12(I) alleles found in ex vivo samples of tropical spastic paraparesis-HTLV-1-associated myelopathy patients contain a Lys at position 88 in some cases, whereas arginine is consistently found at position 88 in HTLV-1 strains from all adult T-cell leukemia-lymphoma (ATLL) cases and healthy carriers studied. This apparent segregation of different alleles in tropical spastic paraparesis-HTLV-associated myelopathy and ATLL or healthy carriers may be relevant in vivo, since p12(I) binds the interleukin-2 receptor beta and gamma(c) chains, raising the possibility that the two natural alleles might affect differently the regulation of these molecules. C1 NCI, Basic Res Lab, NIH, Bethesda, MD 20892 USA. Inst Nacl Canc, Rio De Janeiro, Brazil. RP Franchini, G (reprint author), NCI, Basic Res Lab, NIH, 37 Convent Dr,Bldg 37,Rm 6A11,MSC 4255, Bethesda, MD 20892 USA. RI Pombo-de-Oliveira, Maria S./I-8884-2014 OI Pombo-de-Oliveira, Maria S./0000-0003-3986-8993 NR 31 TC 37 Z9 38 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 1999 VL 73 IS 8 BP 6460 EP 6467 PG 8 WC Virology SC Virology GA 215HZ UT WOS:000081377400031 PM 10400740 ER PT J AU Hasenkrug, KJ AF Hasenkrug, KJ TI Lymphocyte deficiencies increase susceptibility to friend virus-induced erythroleukemia in Fv-2 genetically resistant mice SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; ENVELOPE PROTEIN; T-CELLS; ERYTHROPOIETIN RECEPTORS; MONOCLONAL-ANTIBODIES; RETROVIRAL DISEASE; PUTATIVE ONCOGENE; ENV GENE; RECOVERY; ACTIVATION AB The study of genetic resistance to retroviral diseases provides insights into the mechanisms by which organisms overcome potentially lethal infections. Fv-2 resistance to Friend virus-induced erythroleukemia acts through noninmunological mechanisms to prevent early virus spread, but it does not completely block infection. The current experiments were done to determine whether Fv-2 alone could provide resistance or whether immunological mechanisms mere also required to bring infection under control. Fv-2-resistant mice that were CD4(+) T-cell deficient were able to restrict early virus replication and spread as well as normal Fv-2-resistant mice, but they could not maintain control and developed severe Friend virus-induced splenomegaly and erythroleukemia by 6 to 8 weeks postinfection, Mice deficient in CD8(+) T cells and, to a lesser extent, B cells were also susceptible to late Friend virus-induced disease. Thus, Fv-2 resistance does not independently prevent FV-induced erythroleukemia but works in concert with the immune system by limiting early infection long enough to allow virus-specific immunity time to develop and facilitate recovery. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. RP Hasenkrug, KJ (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 53 TC 42 Z9 42 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 1999 VL 73 IS 8 BP 6468 EP 6473 PG 6 WC Virology SC Virology GA 215HZ UT WOS:000081377400032 PM 10400741 ER PT J AU Sosnovtseva, SA Sosnovtsev, SV Green, KY AF Sosnovtseva, SA Sosnovtsev, SV Green, KY TI Mapping of the feline calicivirus proteinase responsible for autocatalytic processing of the nonstructural polyprotein and identification of a stable proteinase-polymerase precursor protein SO JOURNAL OF VIROLOGY LA English DT Article ID HEMORRHAGIC-DISEASE VIRUS; GENOME-LINKED PROTEIN; STRAND RNA VIRUSES; 3C-LIKE PROTEASE; POLIOVIRUS RNA; CLEAVAGE SITES; MESSENGER-RNA; RABBIT; TRANSLATION; POLYPEPTIDE AB Expression of the region of the feline calicivirus (FCV) ORF1 encoded by nucleotides 3233 to 4054 in an in vitro rabbit reticulocyte system resulted in synthesis of an active proteinase that specifically processes the viral nonstructural polyprotein, Site-directed mutagenesis of the cysteine (Cys(1193)) residue in the putative active site of the proteinase abolished autocatalytic cleavage as well as cleavage of the viral capsid precursor, suggesting that this "3C-like" proteinase plays an important role in proteolytic processing during viral replication. Expression of the region encoding the C-terminal portion of the FCV ORF1 (amino acids 942 to 1761) in bacteria allowed direct N-terminal sequence analysis of the virus-specific polypeptides produced in this system. The results of these analyses indicate that the proteinase cleaves at amino acid residues E-960-A(961), E-1071-S-1072, E-1345-T-1346, and E-1419-G(1420); however, the cleavage efficiency is varied. The E-1071-S-1072 cleavage site defined the N terminus of a 692-amino-acid protein that contains sequences with similarity to the picornavirus 3C proteinase and 3D polymerase domains. Immunoprecipitation of radiolabeled proteins from FCV-infected feline kidney cells with serum raised against the FCV ORF1 C-terminal region showed that this "3CD-like" proteinase-polymerase precursor protein is apparently stable and accumulates in cells during infection. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Green, KY (reprint author), 9000 Rockville Pike,Bldg 7,Room 137, Bethesda, MD 20892 USA. NR 43 TC 52 Z9 53 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 1999 VL 73 IS 8 BP 6626 EP 6633 PG 8 WC Virology SC Virology GA 215HZ UT WOS:000081377400051 PM 10400760 ER PT J AU Carteau, S Gorelick, RJ Bushman, FD AF Carteau, S Gorelick, RJ Bushman, FD TI Coupled integration of human immunodeficiency virus type 1 cDNA ends by purified integrase in vitro: Stimulation by the viral nucleocapsid protein SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; IN-VITRO; CONCERTED INTEGRATION; HIV-1 INTEGRASE; RETROVIRAL DNA; PREINTEGRATION COMPLEXES; REVERSE-TRANSCRIPTASE; GAG PROTEINS; ZINC-FINGER; INVITRO AB Integration of retroviral cDNA involves coupled joining of the two ends of the viral genome at precisely spaced positions in the host cell DNA. Correct coupled joining is essential for viral replication, as shown, for example, by the finding that viral mutants defective in coupled joining are defective in integration and replication. To date reactions with purified human immunodeficiency virus type 1 (HIV-1) integrase protein in vitro have supported mainly uncoupled joining of single cDNA ends. We have analyzed an activity stimulating coupled joining present in HIV-1 virions, which led to the finding that the HIV-1 nucleocapsid (NC) protein can stimulate coupled joining more than 1,000-fold under some conditions. The requirements for stimulating coupled joining were investigated in assays with mutant NC proteins, revealing that mutations in the zinc finger domains can influence stimulation of integration. These findings (i) provide a means for assembling more authentic integrase complexes for mechanistic studies, (ii) reveal a new activity of NC protein in vitro, (iii) indicate a possible role for NC in vivo, and (iv) provide a possible method for identifying a new class of inhibitors that disrupt coupled joining. C1 Salk Inst, Infect Dis Lab, La Jolla, CA 92037 USA. NCI, AIDS Vaccine Program, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Bushman, FD (reprint author), Salk Inst, Infect Dis Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. FU NIAID NIH HHS [AI34786, R01 AI034786]; NIGMS NIH HHS [GM56553]; PHS HHS [N01-30-56000] NR 59 TC 150 Z9 151 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 1999 VL 73 IS 8 BP 6670 EP 6679 PG 10 WC Virology SC Virology GA 215HZ UT WOS:000081377400055 PM 10400764 ER PT J AU McKenna, R Olson, NH Chipman, PR Baker, TS Booth, TF Christensen, J Aasted, B Fox, JM Bloom, ME Wolfinbarger, JB Agbandje-McKenna, M AF McKenna, R Olson, NH Chipman, PR Baker, TS Booth, TF Christensen, J Aasted, B Fox, JM Bloom, ME Wolfinbarger, JB Agbandje-McKenna, M TI Three-dimensional structure of Aleutian mink disease parvovirus: Implications for disease pathogenicity SO JOURNAL OF VIROLOGY LA English DT Article ID FELINE PANLEUKOPENIA VIRUS; CRYO-ELECTRON MICROSCOPY; AMINO-ACID SUBSTITUTIONS; CANINE HOST RANGE; MINUTE VIRUS; CAPSID STRUCTURE; CRYOELECTRON MICROSCOPY; FUNCTIONAL IMPLICATIONS; 3-DIMENSIONAL STRUCTURE; LYMPHOTROPIC STRAIN AB The three-dimensional structure of expressed VP2 capsids of Aleutian mink disease parvovirus strain G (ADV(G-VPZ)) has been determined to 22 Angstrom resolution by cryo-electron microscopy and image reconstruction techniques. A structure-based sequence alignment of the VP2 capsid protein of canine parvovirus (CPV) provided a means to construct an atomic model of the ADV(G-VP2) capsid. The ADV(G-VP2) reconstruction reveals a capsid structure with a mean external radius of 128 Angstrom and several surface features similar to those found in human parvovirus B19 (B19), CPV, feline panleukopenia virus (FPV), and minute virus of mice (MVM). Dimple-like depressions occur at the icosahedral twofold axes, canyon-like regions encircle the fivefold axes, and spike-like protrusions decorate the threefold axes. These spikes are not present in B19, and they are more prominent in ADV compared to the other parvoviruses owing to the presence of loop insertions which create mounds near the threefold axes. Cylindrical channels along the fivefold axes of CPV, FPV, and MVM, which are surrounded by five symmetry-related beta-ribbons, are closed in ADV(G-VP2) and B19. Immunoreactive peptides made from segments of the ADV(G-VP2) capsid protein map to residues in the mound structures. In vitro tissue tropism and in vivo pathogenic properties of ADV map to residues at the threefold axes and to the wall of the dimples. C1 Univ Warwick, Dept Biol Sci, Coventry CV4 7AL, W Midlands, England. NERC, Inst Virol & Environm Microbiol, Oxford OX1 3SR, England. Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. Royal Vet & Agr Univ, Lab Virol & Immunol, Dept Vet Microbiol, Copenhagen, Denmark. NIAID, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. RP Agbandje-McKenna, M (reprint author), Univ Florida, Dept Biochem & Mol Biol, Ctr Struct Biol, Inst Brain,Coll Med, POB 100245, Gainesville, FL 32610 USA. FU NIAID NIH HHS [P01 AI035212]; NIGMS NIH HHS [R37 GM033050, R01 GM033050, GM33050] NR 70 TC 55 Z9 63 U1 0 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 1999 VL 73 IS 8 BP 6882 EP 6891 PG 10 WC Virology SC Virology GA 215HZ UT WOS:000081377400077 PM 10400786 ER PT J AU Zheng, XQH Hughes, SH AF Zheng, XQH Hughes, SH TI An avian sarcoma leukosis virus-based gene trap vector for mammalian cells SO JOURNAL OF VIROLOGY LA English DT Article ID GREEN FLUORESCENT PROTEIN; EMBRYONIC STEM-CELLS; PHOSPHOLIPASE-C-ALPHA; RETROVIRAL VECTORS; TRANSGENIC ZEBRAFISH; EXPRESSION; MOUSE; MICE; REPORTER; DNA AB RCASBP-M2C is a retroviral vector derived from an avian sarcoma/leukosis virus which has been modified so that it uses the envelope gene from an amphotropic murine leukemia virus (E. V. Barsov and S. H. Hughes, J. Virol. 70:3922-3929, 1996). The vector replicates efficiently in avian cells and infects, but does not replicate in, mammalian cells. This makes the vector useful for gene delivery, mutagenesis, and other applications in mammalian systems. Here we describe the development of a derivative of RCASBP-M2C, pGT-GFP, that can be used in gene trap experiments in mammalian cells. The gene trap vector pGT-GFP contains a green fluorescent protein (GFP) reporter gene. Appropriate insertion of the vector into genes causes GFP expression; this facilitates the rapid enrichment and cloning of the trapped cells and provides an opportunity to select subpopulations of trapped cells based on the subcellular localization of GFP. With this vector, we have generated about 90 gene-trapped lines using D17 and NIH 3T3 cells. Five trapped NM 3T3 lines were selected based on the distribution of GFP in cells. The cellular genes disrupted by viral integration have been identified in four of these lines by using a 5' rapid amplification of cDNA ends protocol. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. RP Hughes, SH (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, POB B,Bldg 539, Frederick, MD 21702 USA. NR 40 TC 11 Z9 11 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 1999 VL 73 IS 8 BP 6946 EP 6952 PG 7 WC Virology SC Virology GA 215HZ UT WOS:000081377400084 PM 10400793 ER PT J AU Morse, HC McCarty, T Giese, NA Taddesse-Heath, L Grusby, MJ AF Morse, HC McCarty, T Giese, NA Taddesse-Heath, L Grusby, MJ TI STAT6-deficient mice exhibit normal induction of murine AIDS and expression of immunoglobulin E following infection with LP-BM5 murine leukemia viruses SO JOURNAL OF VIROLOGY LA English DT Article ID RETROVIRUS-INDUCED IMMUNODEFICIENCY; CD4+ T-CELLS; INTERLEUKIN-4 RECEPTOR; SYNDROME MAIDS; TH2 CELLS; MOUSE; IL-4; ACTIVATION; STAT6; PATHOGENESIS AB The unique Gag polyprotein of the replication-defective virus responsible for murine AIDS (MAIDS) induces B-cell activation, proliferation, and differentiation, including immunoglobulin class switch-recombination to immunoglobulin E (IgE). Secretion of IgE normally requires the serial induction of interleukin 4 (IL-4), engagement of the IL-4 receptor, activation of signal transducer and activator of transcription (STAT) 6, and induction of IE germline transcripts as a prelude to switching. Remarkably, expression of IgE is equivalent in normal and IL-l-deficient mice with MAIDS (Morawetz et al., a. Exp. Med. 184:1651-1661, 1996). To understand this anomaly, we studied mice with a null mutation of STAT6. Lymphoproliferation and immunodeficiency, the hallmarks of MAIDS, developed with comparable kinetics and degree in normal and mutant mice. In addition, serum IgE levels were indistinguishable in mice of either genotype. We conclude that B cells from mice with MAIDS activate unique IL-4- and STAT6-independent signaling pathways for B-cell activation and differentiation. C1 NIAID, LIP, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Morse, HC (reprint author), NIAID, LIP, NIH, 9000 Rockville Pike,Bldg 7,Room 304, Bethesda, MD 20892 USA. OI Morse, Herbert/0000-0002-9331-3705 FU NIAID NIH HHS [R01 AI040171, AI40171, N01-AI-45203] NR 20 TC 9 Z9 9 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 1999 VL 73 IS 8 BP 7093 EP 7095 PG 3 WC Virology SC Virology GA 215HZ UT WOS:000081377400107 PM 10400816 ER PT J AU Bhatia, K Magrath, I AF Bhatia, K Magrath, I TI EBNA-1 sequences in endemic and sporadic Burkitt's lymphoma SO JOURNAL OF VIROLOGY LA English DT Letter ID EPSTEIN-BARR-VIRUS C1 NIH, Lymphoma Biol Sect, Pediat Branch, Bethesda, MD 20892 USA. RP Bhatia, K (reprint author), NIH, Lymphoma Biol Sect, Pediat Branch, Bldg 10,Room 13N240, Bethesda, MD 20892 USA. NR 7 TC 4 Z9 4 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 1999 VL 73 IS 8 BP 7096 EP 7096 PG 1 WC Virology SC Virology GA 215HZ UT WOS:000081377400108 PM 10465649 ER PT J AU Miller, RA Burke, D Nadon, N AF Miller, RA Burke, D Nadon, N TI Announcement: Four-way cross mouse stocks: A new, genetically heterogeneous resource for aging research SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID LIFE-SPAN; MICE C1 Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA. Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI 48109 USA. Univ Michigan, Sch Med, Geriatr Ctr, Ann Arbor, MI 48109 USA. Univ Michigan, Inst Gerontol, Ann Arbor, MI 48109 USA. Ann Arbor VA Med Ctr, Ann Arbor, MI USA. NIA, Bethesda, MD 20892 USA. RP Miller, RA (reprint author), Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA. NR 9 TC 15 Z9 15 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD AUG PY 1999 VL 54 IS 8 BP B358 EP B360 DI 10.1093/gerona/54.8.B358 PG 3 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 331XD UT WOS:000088043200008 PM 10496542 ER PT J AU Guralnik, JM Ferrucci, L Penninx, BWJH Kasper, JD Leveille, SG Bandeen-Roche, K Fried, LP AF Guralnik, JM Ferrucci, L Penninx, BWJH Kasper, JD Leveille, SG Bandeen-Roche, K Fried, LP TI New and worsening conditions and change in physical and cognitive performance during weekly evaluations over 6 months: The women's health and aging study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID GERIATRIC DEPRESSION SCALE; OLDER ADULTS; DISABILITY; CARE; HYPOCHONDRIASIS; DEPENDENCE; MACARTHUR; SYMPTOMS; ILLNESS; ICEBERG AB Background. Despite the large burden of chronic disease in older persons, especially those with disability, little research has documented changes in symptomatology over short periods of time. Additionally, although it has been demonstrated that medical conditions strongly affect functional level, short-term worsening in condition status has not been investigated for its impact on functional change. Methods. In a substudy of the Women's Health and Aging Study, 102 women with mild to severe disability received weekly home visits over a 6-month period. Each week they were queried as to the onset of 14 acute, generally self-limited conditions and the worsening or new diagnosis of 12 chronic conditions (condition reporting). They also received a battery of physical and cognitive performance tests. Results. There was a high rate of condition reporting over 24 weekly interviews. Nearly all women reported acute and episodic conditions; the average number of weeks of reporting one or more conditions was 11.8 per woman. For chronic conditions, the average number of weeks of reporting worsening of one or more conditions was 5.2 per woman. Multiple reports of onset or worsening of specific conditions were common, especially for arthritis of the hands, hips, knees, or feet; urinary problems; dizziness or unsteadiness on feet: and back pain. The total number of condition reports and number of weeks of condition reporting were generally not associated with an individual's slope of change in performance tests. For specific conditions. there were generally small and nonsignificant changes in performance in those who reported onset or worsening after 3 or more weeks of not reporting this. Conclusions. Older disabled women frequently report the onset or worsening of acute and chronic conditions. In weekly observations, these conditions are not related to changes in physical and cognitive performance measures. Possible masons for this are that (a) condition reporting may not be valid, (b) changes or severity of conditions were of insufficient magnitude to affect functioning, or (c) performance measures are not sensitive to the kinds of changes in chronic and acute conditions that affect people From week to week. We concluded that performance measures are not useful in monitoring modest, short-term changes in health status, but may still be valuable for assessing more major changes in health and functioning over time. C1 NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. I Fraticini Natl Res Inst, Dept Geriatr, INRCA, Florence, Italy. Vrije Univ Amsterdam, EMGO Inst, Amsterdam, Netherlands. Johns Hopkins Med Inst, Dept Hlth Policy & Management, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Dept Biostat, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Dept Med & Epidemiol, Baltimore, MD 21205 USA. RP Guralnik, JM (reprint author), NIA, Epidemiol Demog & Biometry Program, Gateway Bldg,Suite 3C-309,7201 Wisconsin Ave, Bethesda, MD 20892 USA. FU NIA NIH HHS [N01-AG-1-2112] NR 42 TC 28 Z9 28 U1 0 U2 1 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD AUG PY 1999 VL 54 IS 8 BP M410 EP M422 DI 10.1093/gerona/54.8.M410 PG 13 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 331XD UT WOS:000088043200013 PM 10496547 ER PT J AU Marcell, TJ Taaffe, DR Hawkins, SA Tarpenning, KM Pyka, G Kohlmeier, L Wiswell, RA Marcus, R AF Marcell, TJ Taaffe, DR Hawkins, SA Tarpenning, KM Pyka, G Kohlmeier, L Wiswell, RA Marcus, R TI Oral arginine does not stimulate basal or augment exercise-induced GH secretion in either young or old adults SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID GROWTH-HORMONE SECRETION; RESISTANCE EXERCISE; MUSCLE HYPERTROPHY; MEN; AGE; RESPONSIVENESS; WOMEN AB Background. Growth hormone (GH) helps maintain body composition and metabolism in adults. However, basal and peak GH decline with age. Exercise produces a physiologic GH response that is subnormal in elderly people. Arginine (Arg) infusion can augment GH secretion, but the efficacy of oral Arg to improve GH response to exercise has not been explored. We investigated whether oral Arg increases GH secretion in young and old people at rest and during exercise. Methods. Twenty young (Y:22.1 +/-0.9 y; SEM) and 8 old (O: 68.5 +/- 2.1 y) male and female subjects underwent three different trials following determination of their one-repetition maximum strength (1-RM); exercise only (EO; 3 sets, 8-10 reps at 85% of 1-RM; on 12 separate resistive lifts), Arg only (5.0 g), or Arg + exercise. Blood samples were collected between successive lifts, and GH (ng . ml(-1)) was determined via RIA. Results, In Y vs O: Basal GH secreted (area under the curve) was 543.6 +/- 84.0 vs 211.5 +/- 63.0. During EO, values were 986.6 +/- 156.6 and 517.8 +/- 85.5. Both were significantly lower in the older individuals (p < .05). Oral Arg alone did not result in any increase in GH secretion at rest 1310.8 +/- 73.2 vs 262.9 +/- 141.2). When Arg was coadministered during exercise, GH release was not affected in either the young or old and appeared to be blunted in the young compared to the exercise only trial in the young. Conclusion. Based upon these findings, we concluded that oral Arg does not stimulate GH secretion and may impair GH release during resistive exercise. C1 VA Med Ctr, GRECC, Aging Study Unit, Palo Alto, CA USA. RP Marcell, TJ (reprint author), NIA, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr,Box 14, Baltimore, MD 21224 USA. NR 20 TC 13 Z9 14 U1 0 U2 1 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD AUG PY 1999 VL 54 IS 8 BP M395 EP M399 DI 10.1093/gerona/54.8.M395 PG 5 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 331XD UT WOS:000088043200010 PM 10496544 ER PT J AU Kim, CJ Chi, JG Thiele, CJ AF Kim, CJ Chi, JG Thiele, CJ TI Insulin-like growth factor-II expression is down-regulated in TrkA-transfected SK-N-AS neuroblastoma cells SO LABORATORY INVESTIGATION LA English DT Article ID TYROSINE PROTEIN-KINASE; NEUROTROPHIN RECEPTOR; SYMPATHETIC NEURONS; IGF2 EXPRESSION; NERVOUS-SYSTEM; IN-VIVO; DIFFERENTIATION; SURVIVAL; TUMORS; GENE AB Expression level of trkA tyrosine kinase receptor for nerve growth factor is a major prognostic determinant of neuroblastoma, suggesting that defective trkA-mediated signaling is responsible for the tumorigenesis of this childhood malignancy. We investigated the biologic effect of trkA, with special reference to its effect on insulin-like growth factor-it (IGF-II) expression, in SK-N-AS human neuroblastoma cells transfected with human trkA cDNA. Nerve growth factor treatment of trkA-transfected cells promoted growth and changed the morphologic phenotype into a substrate-adherent, flatter phenotype (S-type), and down-regulated the mRNA expression of IGF-II. The effects on both growth and the morphologic differentiation of SK-N-AS cells differed significantly from those of previous studies, and implied that trkA effects can be diverse, depending on the phenotype of the individual neuroblastoma cells. Immunohistochemical screening of trkA and IGF-II expression in adrenal neuroblastomas (n = 25) also favored the nonoverlapping pattern of trkA and IGF-II expression (p < 0.05). Because IGF-II is believed to play a significant role in the tumorigenesis of neuroblastoma, the inverse relationship between trkA and IGF-H strongly suggests that a low level of trkA can be a feature of the pathogenetic mechanism of IGF-II expressing adrenal neuroblastomas. C1 Seoul Natl Univ, Coll Med, Dept Pathol, Chongno Gu, Seoul 110799, South Korea. NCI, Cell & Mol Biol Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Kim, CJ (reprint author), Seoul Natl Univ, Coll Med, Dept Pathol, Chongno Gu, 28 Yongon Dong, Seoul 110799, South Korea. RI Library, JinyoungPark/F-3767-2011; Library, Park J/F-3768-2011; Chi, Je Geun/G-4989-2011; Seoul National University, Pathology/B-6702-2012; OI Library, JinyoungPark/0000-0003-0952-1374; Chi, Je-Geun/0000-0002-9950-2072 NR 30 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD AUG PY 1999 VL 79 IS 8 BP 1007 EP 1013 PG 7 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 227ZN UT WOS:000082110200010 PM 10462038 ER PT J AU Bulte, JWM Brooks, RA Moskowitz, BM Bryant, LH Frank, JA AF Bulte, JWM Brooks, RA Moskowitz, BM Bryant, LH Frank, JA TI Relaxometry and magnetometry of the MR contrast agent MION-46L SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE relaxometry; magnetometry; electron paramagnetic; resonance; iron oxide; superparamagnetism; paramagnetism ID SPIN RELAXATION AB MION-46L is an ultrasmall monocrystalline superparamagnetic (SPM) iron oxide that is of current interest as an MR contrast agent. It is believed to consist primarily of small maghemite or magnetite crystals that possess a SPM moment, but the exact magnetic properties and related mechanisms of T-1 and T-2 proton relaxation enhancement are not well understood. We have obtained a comprehensive data set consisting of magnetization curves, EPR spectra, and 1/T-1 and 1/T-2 nuclear magnetic relaxation dispersion (NMRD) profiles for this contrast agent. The magnetization curves show a primary curvature consistent with a SPM moment of 10,300 Bohr magnetons (BM) per particle. In addition, there is a secondary high-field curvature that is consistent with a smaller SPM moment of 1600 BM, which may be responsible for the observed high-field increase in 1/T-2, Finally, there appear to be a considerable number of paramagnetic ions present that are needed to account for the high-field increase in magnetization, and that can provide an alternative explanation for the magnitude of the low-field T-1 plateau. This "three-phase model" appears to be successful in explaining in a self-consistent and quantitative manner the combined results of the magnetometry, relaxometry, and EPR studies. Magn Reson Med 42:379-384, 1999. Published 1999 Wiley-Liss, Inc.dagger C1 NIH, Lab Diagnost Radiol Res, Ctr Clin, Bethesda, MD 20892 USA. NINDS, Neuroimaging Branch, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Dept Geol & Geophys, Minneapolis, MN USA. RP Bulte, JWM (reprint author), NIH, Lab Diagnost Radiol Res, Ctr Clin, B10,B1N256,10 Ct Dr,MSC-1074, Bethesda, MD 20892 USA. RI Bulte, Jeff/A-3240-2008 OI Bulte, Jeff/0000-0003-1202-1610 NR 15 TC 77 Z9 78 U1 1 U2 9 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 AUG PY 1999 VL 42 IS 2 BP 379 EP 384 DI 10.1002/(SICI)1522-2594(199908)42:2<379::AID-MRM20>3.0.CO;2-L PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 221ZQ UT WOS:000081758100020 PM 10440963 ER PT J AU Ye, FQ Yang, YH Duyn, J Mattay, VS Frank, TA Weinberger, DR McLaughlin, AC AF Ye, FQ Yang, YH Duyn, J Mattay, VS Frank, TA Weinberger, DR McLaughlin, AC TI Quantitation of regional cerebral blood flow increases during motor activation: A multislice, steady-state, arterial spin tagging study SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE cerebral blood flow; finger tapping; multislice; primary sensorimotor cortex; spin tagging ID HUMAN BRAIN; PERFUSION; MOVEMENTS; INVERSION; WATER AB Steady-state arterial spin tagging approaches were used to construct multislice images of relative cerebral blood flow changes during finger-tapping tasks. Statistically significant increases in cerebral blood flow were observed in primary sensorimotor cortex in all seven subjects. The mean volume of the activated region in the contralateral primary sensorimotor cortex was 0.9 cm(3), and the mean increase in cerebral blood flow in the activated area was 54% +/- 11%, Although the extended spatial coverage is advantageous for activation studies, the intrinsic sensitivity of the multislice approach is smaller than the intrinsic sensitivity of the single-slice, arterial spin tagging approach. Magn Reson Med 42:404-407, 1999. Published 1999 Wiley-Liss, Inc.dagger C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. NIH, Lab Diagnost Radiol Res, CC, Bethesda, MD 20892 USA. RP McLaughlin, AC (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Bldg 10,Room B1D-125,10 Ctr Dr,MSC-1060, Bethesda, MD 20892 USA. RI Duyn, Jozef/F-2483-2010 NR 17 TC 16 Z9 16 U1 0 U2 0 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 AUG PY 1999 VL 42 IS 2 BP 404 EP 407 DI 10.1002/(SICI)1522-2594(199908)42:2<404::AID-MRM23>3.0.CO;2-0 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 221ZQ UT WOS:000081758100023 PM 10440966 ER PT J AU de la Haba, G Khatami, M Cooper, GW Backlund, P Flaks, JG AF de la Haba, G Khatami, M Cooper, GW Backlund, P Flaks, JG TI Alanine or pyruvate is required for the development of myotubes from myoblasts and cortisol satisfies this requirement SO MOLECULAR AND CELLULAR BIOCHEMISTRY LA English DT Article DE alanine; pyruvate; serine; cortisol; myoblasts; development ID LACTATE TRANSPORT; DIFFERENTIATION; MYOGENESIS; INSULIN; INVITRO; CELLS AB Development of myotubes from chick embryo breast muscle myoblasts has been shown to occur in the combined presence of insulin, and both the low and high molecular weight components (LMW, HMW) of chick embryo extract. We report here that alanine, or pyruvate, will replace the LMW component with serine enhancing this effect. In addition, extracts of embryonic kidneys were the most active of five embryonic tissues tested in replacing the LMW component, which led to the finding that cortisol is active in promoting both the development of myotubes and the expression of creatine phosphokinase activity, a muscle-specific indicator of myogenesis. Since it was observed that myoblasts are highly glycolytic, it may be that pyruvate is limiting, suggesting that some aspect of oxidative metabolism is also limiting in these cells. C1 Univ Penn, Sch Med, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Ophthalmol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. NIMH, Lab Gen & Comparat Biochem, Bethesda, MD 20892 USA. NYU, N Shore Univ Hosp, Manhasset, NY USA. RP Khatami, M (reprint author), POB 98, Birchunville, PA 19421 USA. FU NCRR NIH HHS [SO7-RR-05415-24]; PHS HHS [03984] NR 25 TC 1 Z9 1 U1 0 U2 0 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 AUG PY 1999 VL 198 IS 1-2 BP 163 EP 170 DI 10.1023/A:1006989629438 PG 8 WC Cell Biology SC Cell Biology GA 235EP UT WOS:000082527300021 PM 10497892 ER PT J AU Bustin, M AF Bustin, M TI Regulation of DNA-dependent activities by the functional motifs of the high-mobility-group chromosomal proteins SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Review ID MEDIATED TRANSCRIPTIONAL ACTIVATION; TATA-BINDING PROTEIN; HMG-BOX PROTEINS; NF-KAPPA-B; IN-VITRO; LINKER HISTONES; ARCHITECTURAL ELEMENTS; PREINTEGRATION COMPLEXES; STRUCTURAL FEATURES; HMGI(Y) EXPRESSION C1 NCI, Prot Sect, Mol Carcinogenesis Lab, Div Basic Sci,NIH, Bethesda, MD 20892 USA. RP Bustin, M (reprint author), NCI, Prot Sect, Mol Carcinogenesis Lab, Div Basic Sci,NIH, Bldg 37,Room 3D-12, Bethesda, MD 20892 USA. RI Bustin, Michael/G-6155-2015 NR 132 TC 627 Z9 667 U1 0 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 1999 VL 19 IS 8 BP 5237 EP 5246 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 217RY UT WOS:000081513800001 PM 10409715 ER PT J AU Gary, R Park, MS Nolan, JP Cornelius, HL Kozyreva, OG Tran, HT Lobachev, KS Resnick, MA Gordenin, DA AF Gary, R Park, MS Nolan, JP Cornelius, HL Kozyreva, OG Tran, HT Lobachev, KS Resnick, MA Gordenin, DA TI A novel role in DNA metabolism for the binding of Fen1/Rad27 to PCNA and implications for genetic risk SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CELL NUCLEAR ANTIGEN; NUCLEOTIDE EXCISION-REPAIR; SACCHAROMYCES-CEREVISIAE; ENDONUCLEASE ACTIVITY; FLAP ENDONUCLEASE-1; MUTATION AVOIDANCE; POLYMERASE-DELTA; REPLICATION FORK; MISMATCH REPAIR; STRANDED-DNA AB Fen1/Rad27 nuclease activity, which is important in DNA metabolism, is stimulated by proliferating cell nuclear antigen (PCNA) in vitro. The in vivo role of the PCNA interaction,vas investigated in the yeast Rad27. A nuclease-defective rad27 mutation had a dominant-negative effect that was suppressed by a mutation in the PCNA binding site, thereby demonstrating the importance of the Rad27-PCNA interaction. The PCNA-binding defect alone had little effect on mutation, recombination, and the methyl methanesulfonate (MMS) response in repair-competent cells, but it greatly amplified the MMS sensitivity of a rad51 mutant. Furthermore, the PCNA binding mutation resulted in lethality when combined with a homozygous or even a heterozygous pol3-01 mutation in the 3' --> 5' exonuclease domain of DNA polymerase delta. These results suggest that phenotypically mild polymorphisms in DNA metabolic proteins can have dramatic consequences when combined. C1 Univ Calif Los Alamos Natl Lab, Div Life Sci, Los Alamos, NM 87545 USA. RP Gordenin, DA (reprint author), NIEHS, Mol Genet Lab, Mail Drop D3-01,101 TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. RI Gary, Ronald/A-8650-2008; OI Gary, Ronald/0000-0001-5079-1953; Gordenin, Dmitry/0000-0002-8399-1836 FU NCI NIH HHS [CA71630] NR 56 TC 80 Z9 81 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 1999 VL 19 IS 8 BP 5373 EP 5382 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 217RY UT WOS:000081513800014 PM 10409728 ER PT J AU Sella, O Gerlitz, G Le, SY Elroy-Stein, O AF Sella, O Gerlitz, G Le, SY Elroy-Stein, O TI Differentiation-induced internal translation of c-sis mRNA: Analysis of the cis elements and their differentiation-linked binding to the hnRNP C protein SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID NUCLEAR RIBONUCLEOPROTEIN-C; RIBOSOME ENTRY SITE; MESSENGER-RNA LEADER; SWINE FEVER VIRUS; 5'-NONCODING REGION; PICORNAVIRUS RNA; POLIOVIRUS RNA; FUNCTIONAL-CHARACTERIZATION; ALTERNATIVE TRANSLATION; STRUCTURAL ELEMENT AB In previous reports we showed that the long 5' untranslated region (5' UTR) of c-sis, the gene encoding the B chain of platelet-derived growth factor, has translational modulating activity due to its differentiation-activated internal ribosomal entry site (D-IRES). Here we show that the 5' UTR contains three regions with a computer-predicted Y-shaped structure upstream of an AUG codon, each of which can confer some degree of internal translation by itself In nondifferentiated cells, the entire 5' UTR is required for maximal basal IRES activity. The elements required for the differentiation-sensing ability (i.e., D-IRES) were mapped to a 630-nucleotide fragment within the central portion of the 5' UTR. Even though the region responsible for IRES activation is smaller, the full-length 5' UTR is capable of mediating the maximal translation efficiency in differentiated cells, since only the entire 5' UTR is able to confer the maximal basal IRES activity. Interestingly, a 43-kDa protein, identified as hnRNP C, binds in a differentiation-induced manner to the differentiation-sensing region. Using UV cross-linking experiments, we show that while hnRNP C is mainly a nuclear protein, its binding activity to the D-IRES is mostly nuclear in nondifferentiated cells, whereas in differentiated cells such binding activity is associated with the ribosomal fraction. Since the c-sis 5' UTR is a translational modulator in response to cellular changes, it seems that the large number of cross-talking structural entities and the interactions,vith regulated trans-acting factors are important for the strength of modulation in response to cellular changes. These characteristics may constitute the major difference between strong IRESs, such as those seen in some viruses, and IRESs that serve as translational modulators in response to developmental signals, such as that of c-sis. C1 Tel Aviv Univ, George S Wise Fac Life Sci, Dept Cell Res & Immunol, IL-69978 Tel Aviv, Israel. NCI, Lab Expt & Computat Biol, DBS, NIH, Frederick, MD 21702 USA. RP Elroy-Stein, O (reprint author), Tel Aviv Univ, George S Wise Fac Life Sci, Dept Cell Res & Immunol, IL-69978 Tel Aviv, Israel. NR 59 TC 92 Z9 92 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 1999 VL 19 IS 8 BP 5429 EP 5440 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 217RY UT WOS:000081513800019 PM 10409733 ER PT J AU Srivastava, RK Sollott, SJ Khan, L Hansford, R Lakatta, EG Longo, DL AF Srivastava, RK Sollott, SJ Khan, L Hansford, R Lakatta, EG Longo, DL TI Bcl-2 and Bcl-X-L block thapsigargin-induced nitric oxide generation, c-Jun NH2-terminal kinase activity, and apoptosis SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PROGRAMMED CELL-DEATH; MITOCHONDRIAL PERMEABILITY TRANSITION; CYTOCHROME-C; ENDOPLASMIC-RETICULUM; PROTEIN-KINASE; GAMMA-RADIATION; JNK ACTIVATION; CALCIUM; BCL-X(L); PATHWAY AB The proteins Bcl-2 and Bcl-X-L prevent apoptosis, but their mechanism of action is unclear. We examined the role of Bcl-2 and Bcl-X-L in the regulation of cytosolic Ca2+, nitric oxide production (NO), c-Jun NH2-terminal kinase (JNK) activation, and apoptosis in Jurkat T cells. Thapsigargin (TG), an inhibitor of the endoplasmic reticulum-associated Ca2+ ATPase, was used to disrupt Ca2+ homeostasis. TG acutely elevated intracellular free Ca2+ and mitochondrial Ca2+ levels and induced NO production and apoptosis in Jurkat cells transfected with vector (JT/Neo). Buffering of this Ca2+ response with 1,2-bis (o-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester (BAPTA-AM) or inhibiting NO synthase activity with N-G-nitro-L-arginine methyl ester hydrochloride (L-NAR IE) blocked TG-induced NO production and apoptosis in JT/Neo cells. By contrast, while TG produced comparable early changes in the Ca2+ level (i.e., within 3 h) in Jurkat cells overexpressing Bcl-2 and Bcl-X-L (JT/Bcl-2 or JT/Bcl-X-L), NO production, late (36-h) Ca2+ accumulation, and apoptosis were dramatically reduced compared to those in JT/Neo cells. Exposure of JT/Bcl-2 and JT/Bcl-X-L, cells to the NO donor, S-nitroso-N-acetylpenacillamine (SNAP) resulted in apoptosis comparable to that seen in JT/Neo cells. TG also activated the JNK pathway, which was blocked by L-NAME. Transient expression of a dominant negative mutant SEK1 (Lys --> Arg), an upstream kinase of JNK, prevented both TG-induced JNK activation and apoptosis. A dominant negative c-Jun mutant also reduced TG-induced apoptosis. Overexpression of Bcl-2 or Bcl-X-L inhibited TG-induced loss in mitochondrial membrane potential, release of cytochrome c, and activation of caspase-3 and JNK. Inhibition of caspase-3 activation blocked TG-induced JNK activation, suggesting that JNK activation occurred downstream of caspase-3. Thus, TG-induced Ca2+ release leads to NO generation followed by mitochondrial changes including cytochrome c release and caspase-3 activation. Caspase-3 activation leads to activation of the JNK pathway and apoptosis. In summary, Ca2+-dependent activation of NO production mediates apoptosis after TG exposure in JT/Neo cells. JT/Bcl-2 and JT/Bcl-X-L, cells are susceptible to NO-mediated apoptosis, but Bcl-2 and Bcl-X-L protect the cells against TG-induced apoptosis by negatively regulating Ca2+-sensitive NO synthase activity or expression. C1 NIA, Immunol Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. NIA, Lab Cardiovasc Sci, Intramural Res Program, NIH, Baltimore, MD 21224 USA. NIA, Genet Mol Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Srivastava, RK (reprint author), NIA, Immunol Lab, Intramural Res Program, NIH, 5600 Nathan Shock Dr,Box 9, Baltimore, MD 21224 USA. NR 72 TC 135 Z9 139 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 1999 VL 19 IS 8 BP 5659 EP 5674 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 217RY UT WOS:000081513800041 PM 10409755 ER PT J AU Balasundaram, D Benedik, MJ Morphew, M Dang, VD Levin, HL AF Balasundaram, D Benedik, MJ Morphew, M Dang, VD Levin, HL TI Nup124p is a nuclear pore factor of Schizosaccharomyces pombe that is important for nuclear import and activity of retrotransposon Tf1 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; SPINDLE POLE BODY; FISSION YEAST; SACCHAROMYCES-CEREVISIAE; NUCLEOCYTOPLASMIC TRANSPORT; REVERSE-TRANSCRIPTASE; LOCALIZATION SIGNAL; POLY(A)(+) RNA; MESSENGER-RNA; NONDIVIDING CELLS AB The long terminal repeat (LTR)-containing retrotransposon Tf1 propagates within the fission yeast Schizosaccharomyces pombe as the result of several mechanisms that are typical of both retrotransposons and retroviruses. To identify host factors that contribute to the transposition process, we mutagenized cultures of S. pombe and screened them for strains that were unable to support Tf1 transposition. One such strain contained a mutation in a gene we named nup124. The product of this gene contains 11 FXFG repeats and is a component of the nuclear pore complex. In addition to the reduced levels of Tf1 transposition, the nup124-1 allele. caused a significant reduction in the nuclear localization of Tf1 Gag. Surprisingly, the mutation in nup124-1 did not cause any reduction in the growth rate, the nuclear localization of specific nuclear localization signal-containing proteins, or the cytoplasmic localization of poly(A) mRNA. A two-hybrid analysis and an in vitro precipitation assay both identified an interaction between Tf1 Gag and the N terminus of Nup124p. These results provide evidence for an unusual mechanism of nuclear import that relies on a direct interaction between a nuclear pore factor and Tf1 Gag. C1 NICHHD, Lab Eukaryot Gene Regulat, NIH, Bethesda, MD 20892 USA. Univ Houston, Houston, TX USA. Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA. RP NICHHD, Lab Eukaryot Gene Regulat, NIH, Bethesda, MD 20892 USA. EM Henry_Levin@nih.gov RI Benedik, Michael/H-2478-2011 OI Benedik, Michael/0000-0002-7435-0092 FU NCRR NIH HHS [RR-0592, P41 RR000592] NR 69 TC 29 Z9 30 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 1999 VL 19 IS 8 BP 5768 EP 5784 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 217RY UT WOS:000081513800050 PM 10409764 ER PT J AU Gonzalez-Villasenor, LI AF Gonzalez-Villasenor, LI TI A duplex PCR assay for detection and genotyping of Herpes simplex virus in cerebrospinal fluid SO MOLECULAR AND CELLULAR PROBES LA English DT Article DE Herpes simplex virus; genotyping; PCR; cerebrospinal fluid; encephalitis; infants ID POLYMERASE CHAIN-REACTION; LABORATORY DIAGNOSIS; RAPID DIAGNOSIS; VIRAL-DNA; ENCEPHALITIS; TYPE-2; ANTIBODIES; SPECIMENS; CSF AB A duplex polymerase chain reaction (PCR) assay for the detection and genotyping of Herpes simplex virus (HSV) 1 and 2 from cerebrospinal fluid (CFS) of infants was developed. The glycoprotein D (gD) gene of HSV was selected as a target for amplification. The assay is highly specific, sensitive and reproducible. Herpes simplex virus detection is performed by agarose gel electrophoresis and Southern blot using a chemiluminescent probe. The probe hybridizes to sequences common to both HSV-1 and 2. A DNA fragment of HSV go gene was cloned and used as positive control and to determine the specificity and sensitivity of the assay. The PCR assay is user-friendly and unambiguously differentiates in one-step both herpes virus strains. The assay is useful to screen CFS specimens from infants exposed to HSV during birth and at risk of developing encephalitis. (C) 1999 Academic Press. C1 BBI Biotech Res Labs, Gaithersburg, MD 20877 USA. RP Gonzalez-Villasenor, LI (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 25 TC 5 Z9 5 U1 0 U2 0 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0890-8508 J9 MOL CELL PROBE JI Mol. Cell. Probes PD AUG PY 1999 VL 13 IS 4 BP 309 EP 314 DI 10.1006/mcpr.1999.0253 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology GA 226BD UT WOS:000081999700009 PM 10441204 ER PT J AU Balajee, AS Machwe, A May, A Gray, MD Oshima, J Martin, GM Nehlin, JO Brosh, R Orren, DK Bohr, VA AF Balajee, AS Machwe, A May, A Gray, MD Oshima, J Martin, GM Nehlin, JO Brosh, R Orren, DK Bohr, VA TI The Werner syndrome protein is involved in RNA polymerase II transcription SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID SYNDROME CELL-LINES; SYNDROME GENE; DNA-REPAIR; COCKAYNE-SYNDROME; HELICASE; TOPOISOMERASE; EXTRACTS; CLONING; NUCLEI AB Werner syndrome (WS) is a human progeroid syndrome characterized by the early onset of a large number of clinical features associated with the normal aging process. The complex molecular and cellular phenotypes of WS involve characteristic features of genomic instability and accelerated replicative senescence. The gene involved (WRN) was recently cloned, and its gene product (WRNp) was biochemically characterized as a helicase. Helicases play important roles in a variety of DNA transactions, including DNA replication, transcription, repair, and recombination. We have assessed the role of the WRN gene in transcription by analyzing the efficiency of basal transcription in WS lymphoblastoid cell lines that carry homozygous WRN mutations. Transcription was measured in permeabilized cells by [H-3]UTP incorporation and in vitro by using a plasmid template containing the RNA polymerase II (RNA pol II)-dependent adenovirus major late promoter. With both of these approaches, we find that the transcription efficiency in different WS cell lines is reduced to 40-60% of the transcription in cells from normal individuals. This defect can be complemented by the addition of normal cell extracts to the chromatin of WS cells. Addition of purified wild-type WRNp but not mutated WRNp to the in vitro transcription assay markedly stimulates RNA pol II-dependent transcription carried out by nuclear extracts. A nonhelicase domain (a direct repeat of 27 amino acids) also appears to have a role in transcription enhancement, as revealed by a yeast hybrid-protein reporter assay. This is further supported by the lack of stimulation of transcription when mutant WRNp lacking this domain was added to the in vitro assay. We have thus used several approaches to show a role for WRNp in RNA pol II transcription, possibly as a transcriptional activator. A deficit in either global or regional transcription in WS cells may be a primary molecular defect responsible for the WS clinical phenotype. C1 NIA, Mol Genet Lab, NIH, Baltimore, MD 21224 USA. Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98195 USA. RP Bohr, VA (reprint author), NIA, Mol Genet Lab, NIH, Baltimore, MD 21224 USA. FU NCI NIH HHS [R24 CA078088, R24-CA-78088]; NIA NIH HHS [AG-01751, AG-14446, P01 AG001751] NR 33 TC 97 Z9 100 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA PUBL OFFICE, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD AUG PY 1999 VL 10 IS 8 BP 2655 EP 2668 PG 14 WC Cell Biology SC Cell Biology GA 227BC UT WOS:000082057100016 PM 10436020 ER PT J AU Kohn, KW AF Kohn, KW TI Molecular interaction map of the mammalian cell cycle control and DNA repair systems SO MOLECULAR BIOLOGY OF THE CELL LA English DT Review ID REPLICATION PROTEIN-A; SINGLE-STRANDED-DNA; NUCLEOTIDE EXCISION-REPAIR; RNA-POLYMERASE-II; UBIQUITIN-PROTEASOME PATHWAY; TRANSCRIPTION FACTOR AP-2; CARBOXYL-TERMINAL DOMAIN; NUCLEAR ANTIGEN PROMOTER; MOBILITY GROUP PROTEIN-1; PHOSPHORYLATED IN-VITRO AB Eventually to understand the integrated function of the cell cycle regulatory network, we must organize the known interactions in the form of a diagram, map, and/or database. A diagram convention was designed capable of unambiguous representation of networks containing multiprotein complexes, protein modifications, and enzymes that are substrates of other enzymes. To facilitate linkage to a database, each molecular species is symbolically represented only once in each diagram. Molecular species can be located on the map by means of indexed grid coordinates. Each interaction is referenced to an annotation list where pertinent information and references can be found. Parts of the network are grouped into functional subsystems. The map shows how multiprotein complexes could assemble and function at gene promoter sites and at sites of DNA damage. It also portrays the richness of connections between the p53-Mdm2 subsystem and other parts of the network. C1 NCI, Div Basic Sci, Mol Pharmacol Lab, Bethesda, MD 20892 USA. RP Kohn, KW (reprint author), NCI, Div Basic Sci, Mol Pharmacol Lab, Bethesda, MD 20892 USA. NR 262 TC 338 Z9 345 U1 2 U2 13 PU AMER SOC CELL BIOLOGY PI BETHESDA PA PUBL OFFICE, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD AUG PY 1999 VL 10 IS 8 BP 2703 EP 2734 PG 32 WC Cell Biology SC Cell Biology GA 227BC UT WOS:000082057100019 PM 10436023 ER PT J AU Fischer, SM Lo, HH Gordon, GB Seibert, K Kelloff, G Lubet, RA Conti, CJ AF Fischer, SM Lo, HH Gordon, GB Seibert, K Kelloff, G Lubet, RA Conti, CJ TI Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, and indomethacin against ultraviolet light-induced skin carcinogenesis SO MOLECULAR CARCINOGENESIS LA English DT Article DE ultraviolet tight; cyclooxygenase; skin carcinogenesis ID FAMILIAL ADENOMATOUS POLYPOSIS; COLON CARCINOGENESIS; MOUSE SKIN; PROSTAGLANDIN SYNTHESIS; VASCULAR-PERMEABILITY; SELECTIVE-INHIBITION; TUMOR PROMOTION; PROLIFERATION; MECHANISMS; APOPTOSIS AB Epidemiological and dietary studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colon cancer, possibly through a mechanism involving inhibition of cyclooxygenase (COX)-2, which is overexpressed in premalignant adenomatous polyps and colon cancer. Because ultraviolet light (UV) can induce COX-2 and nonspecific NSAIDs can decrease UV-induced skin cancer, we evaluated the ability of two compounds, celecoxib (a specific COX-2 inhibitor) and indomethacin (a nonspecific NSAID), to block UV-induced skin tumor development in SKH:HR-1-hrBr hairless mice. Mice fed 150 or 500 ppm celecoxib showed a dose-dependent reduction (60% and 89%, respectively) in tumor yield. Indomethacin (4 ppm) reduced tumor yield by 78%. Although both acute and chronic UV exposure increased cell proliferation and edema, neither compound reduced these parameters. In contrast, UV-induced prostaglandin synthesis in the epidermis was effectively blocked by both compounds. UV-induced increases in COX-2 expression in skin were also not altered in any of the treatment groups. Similarly, tumors that constitutively express high levels of COX-2 displayed no reduction by treatment with celecoxib or indomethacin. The dramatic protective effects of celecoxib suggests that specific COX-2 inhibitors may offer a way to safely reduce the risk of skin cancer in humans. (C) 1999 Wiley-Liss, Inc. C1 Univ Texas, MD Anderson Canc Ctr, Div Res, Smithville, TX 78957 USA. Searle Res & Dev, St Louis, MO USA. NIH, Div Canc Prevent & Control, Bethesda, MD 20892 USA. RP Fischer, SM (reprint author), Univ Texas, MD Anderson Canc Ctr, Div Res, Sci Pk,POB 389,Pk Rd 1C, Smithville, TX 78957 USA. FU NCI NIH HHS [CA 34443, CN 65110-72, CA 16672] NR 41 TC 301 Z9 311 U1 1 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD AUG PY 1999 VL 25 IS 4 BP 231 EP 240 PG 10 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 223BF UT WOS:000081819300001 PM 10449029 ER PT J AU Tanaka, H Horikawa, I Kugoh, H Shimizu, M Barrett, JC Oshimura, M AF Tanaka, H Horikawa, I Kugoh, H Shimizu, M Barrett, JC Oshimura, M TI Telomerase-independent senescence of human immortal cells induced by microcell-mediated chromosome transfer SO MOLECULAR CARCINOGENESIS LA English DT Article DE telomere; telomerase; senescence; chromosome transfer; tumor cells ID CELLULAR SENESCENCE; CATALYTIC SUBUNIT; GROWTH ARREST; TUMOR-CELLS; MAMMALIAN TELOMERASE; REPEAT POLYMORPHISM; HUMAN FIBROBLASTS; CARCINOMA-CELLS; RNA COMPONENT; GENE AB Maintenance of telomeres, commonly through expression of telomerase activity, is necessary but may not be sufficient for human cells to escape from the cellular senescence program and become immortal. We report here that human tumor cells could undergo cellular senescence in the presence of telomerase activity when a specific normal human chromosome was introduced via microcell-mediated chromosome transfer. The cell models studied include SiHa (uterine cervical carcinoma cells expressing E6 and E7 oncoproteins of human papillomavirus type 16) with a transferred chromosome 2, CC1 (choriocarcinoma cells expressing an amino-terminally truncated p53 protein) with a transferred chromosome 7, and JTC-32 (bladder carcinoma cells) with a transferred chromosome 11. The microcell hybrids with the indicated chromosomes ceased to divide after five to 10 population doublings and showed senescence-associated B-galactosidase activity but still expressed the genes encoding three components of human telomerase, consistent with the retention of telomerase activity. These results are evidence for barriers to human cell immortalization, which involve activation of unidentified senescence-inducing genes that function independently of inactivation of telomerase. (C) 1999 Wiley-Liss, Inc. C1 Tottori Univ, Fac Med, Sch Life Sci, Dept Mol & Cell Genet, Yonago, Tottori 6838503, Japan. NIEHS, Mol Carcinogenesis Lab, Triangle Pk, NC USA. Nippon Dent Univ, Sch Dent, Dept Pharmacol, Tokyo, Japan. RP Oshimura, M (reprint author), Tottori Univ, Fac Med, Sch Life Sci, Dept Mol & Cell Genet, Nishimachi 86, Yonago, Tottori 6838503, Japan. NR 46 TC 12 Z9 12 U1 0 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD AUG PY 1999 VL 25 IS 4 BP 249 EP 255 DI 10.1002/(SICI)1098-2744(199908)25:4<249::AID-MC3>3.0.CO;2-Z PG 7 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 223BF UT WOS:000081819300003 PM 10449031 ER PT J AU Rice, PL Porter, SE Koski, KM Ramakrishna, G Chen, A Schrump, D Kazlauskas, A Malkinson, AM AF Rice, PL Porter, SE Koski, KM Ramakrishna, G Chen, A Schrump, D Kazlauskas, A Malkinson, AM TI Reduced receptor expression for platelet-derived growth factor and epidermal growth factor in dividing mouse lung epithelial cells SO MOLECULAR CARCINOGENESIS LA English DT Article DE cell proliferation; serum deprivation; transformation; lung adenocarcinoma; protein regulation ID DEPENDENT PROTEIN-KINASE; MESSENGER-RNA LEVELS; EGF-RECEPTOR; TYPE-2 PNEUMOCYTE; RAS; PDGF; LINES; FIBROBLASTS; ACTIVATION; ONCOGENES AB The roles of growth factors in mouse lung neoplasia were investigated by examining receptors for platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) in epithelial cell lines. Whereas nontumorigenic lung cells expressed mRNA and protein for PDGF receptor (PDGFR)-alpha, PDGFR-beta, and EGF receptor (EGFR), five of six neoplastic lines did not. Because this exceptional tumorigenic cell line grows slowly, we hypothesized that receptor levels increased with cell stasis. To test this hypothesis, serum concentrations were manipulated, and log-phase and postconfluent cells were compared. Consistent with our hypothesis, PDGFR-alpha and EGFR contents, but not PDGFR-beta contents, increased at stasis. Ki-ras mutation initiates lung tumorigenesis in mice, but activation of Ki-ras did not affect receptor expression. This was determined both by transfecting nontumorigenic cells with activated Ki-ras and neoplastic cells with a Ki-ras antisense construct and by diminishing Ki-ras activation by using a farnesyltransferase inhibitor. Stasis-associated upregulation of growth-factor receptor expression suggests a function in lung cell differentiation that is abrogated during neoplastic growth. (C) 1999 Wiley-Liss, Inc. C1 Univ Colorado, Hlth Sci Ctr, Sch Pharm, Dept Pharmaceut Sci, Denver, CO 80262 USA. NCI, Frederick Canc Res & Dev Ctr, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. NCI, Surg Branch, Thorac Oncol Sect, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA 02115 USA. RP Malkinson, AM (reprint author), Univ Colorado, Hlth Sci Ctr, Sch Pharm, Dept Pharmaceut Sci, 4200 E 9th Ave,Campus Box C238, Denver, CO 80262 USA. NR 53 TC 11 Z9 12 U1 0 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD AUG PY 1999 VL 25 IS 4 BP 285 EP 294 DI 10.1002/(SICI)1098-2744(199908)25:4<285::AID-MC7>3.0.CO;2-F PG 10 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 223BF UT WOS:000081819300007 PM 10449035 ER PT J AU Thoene, J Lemons, R Anikster, Y Mullet, J Paelicke, K Lucero, C Gahl, W Schneider, J Shu, SG Campbell, HT AF Thoene, J Lemons, R Anikster, Y Mullet, J Paelicke, K Lucero, C Gahl, W Schneider, J Shu, SG Campbell, HT TI Mutations of CTNS causing intermediate cystinosis SO MOLECULAR GENETICS AND METABOLISM LA English DT Article ID FIBROBLASTS; TRANSPORT; PROTEIN; CELLS AB Six patients with the intermediate form of cystinosis are described. Two have new mutations not previously described. The disease occurs due either to the combination of one mild mutation and one which is known to cause nephropathic cystinosis or to homozygosity for a predicted mild mutation. Par tial phenotypic correction of cystinotic fibroblasts by transfection with normal cDNA or a cDNA derived from a mutation causing intermediate cystinosis is demonstrated. (C) 1999 Academic Press. C1 Univ Michigan, Dept Pediat, Div Biochem Genet & Metab, Ann Arbor, MI 48109 USA. NICHD, Sect Human Biochem Genet, Heritable Disorders Branch, NIH, Bethesda, MD USA. Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA. Taichung Vet Gen Hosp, Dept Pediat, Taichung, Taiwan. Marshfield Clin Fdn Med Res & Educ, Dept Hypertens & Nephrol, Marshfield, WI USA. RP Thoene, J (reprint author), Univ Michigan, Dept Pediat, Div Biochem Genet & Metab, 300 N Ingalls Bldg,Room 1192SE, Ann Arbor, MI 48109 USA. NR 15 TC 42 Z9 48 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD AUG PY 1999 VL 67 IS 4 BP 283 EP 293 DI 10.1006/mgme.1999.2876 PG 11 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 232TH UT WOS:000082385700003 PM 10444339 ER PT J AU Brody, LC Baker, PJ Chines, PS Musick, A Molloy, AM Swanson, DA Kirke, PN Ghosh, S Scott, JM Mills, JL AF Brody, LC Baker, PJ Chines, PS Musick, A Molloy, AM Swanson, DA Kirke, PN Ghosh, S Scott, JM Mills, JL TI Methionine synthase: High-resolution mapping of the human gene and evaluation as a candidate locus for neural tube defects SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE methionine synthase; folate metabolism; neural tube defects; gene mapping; transmission disequilibrium test ID METHYLENETETRAHYDROFOLATE REDUCTASE MUTATION; 185DELAG BRCA1 MUTATION; LINKAGE DISEQUILIBRIUM; SPINA-BIFIDA; 5,10-METHYLENETETRAHYDROFOLATE REDUCTASE; TRANSMISSION/DISEQUILIBRIUM TEST; VITAMIN SUPPLEMENTATION; THERMOLABILE VARIANT; VASCULAR-DISEASE; CDNA CLONING AB Periconceptual folate supplementation has been found to prevent the occurrence of many neural tube defects (NTDs). Consequently, genetic variation in folate metabolism genes is expected to contribute to the risk for neural tube defects. Methionine synthase catalyzes the vitamin B-12-dependent conversion of homocysteine and 5-methyltetrahydrofolate to methionine and tetrahydrofolate. The observation that homocysteine and vitamin B-12 levels are independent predictors of NTD risk suggested that methionine synthase could be a candidate gene for NTDs. To assess the role of the MS gene in NTDs, we performed high-resolution physical mapping of the MS locus, isolated highly polymorphic markers linked to the MS gene, and tested for an association between specific MS alleles and NTDs. We mapped the MS gene to a position between 909 and 913 cR(1000) on chromosome 1 by radiation hybrid mapping. Polymorphic markers D1S1567 and D1S1568 map to locations no more than 900 and 194 kb from the MS gene, respectively. The segregation of these polymorphic markers was measured in 85 Irish NTD families. No allele of either marker showed a significant association with NTDs using the transmission disequilibrium test. A lack of association was also observed for the D1919G; missense mutation within the gene. Our results suggest that inherited variation in the MS gene does not contribute to NTD risk in this population. (C) 1999 Academic Press. C1 Natl Human Genome Res Inst, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. Trinity Coll, Dept Biochem, Dublin, Ireland. Hlth Res Board Ireland, Dublin, Ireland. NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. RP Brody, LC (reprint author), Natl Human Genome Res Inst, Genet & Mol Biol Branch, NIH, 49 Convent Dr,Room 3A14, Bethesda, MD 20892 USA. RI Addington, Anjene/C-3460-2008 NR 60 TC 18 Z9 20 U1 0 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 AUG PY 1999 VL 67 IS 4 BP 324 EP 333 DI 10.1006/mgme.1999.2881 PG 10 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 232TH UT WOS:000082385700007 PM 10444343 ER PT J AU Joe, B Wilder, RL AF Joe, B Wilder, RL TI Animal models of rheumatoid arthritis SO MOLECULAR MEDICINE TODAY LA English DT Article C1 NIAMSD, Inflammatory Joint Dis Sect, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. RP Joe, B (reprint author), NIAMSD, Inflammatory Joint Dis Sect, Arthrit & Rheumatism Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 9N240, Bethesda, MD 20892 USA. NR 5 TC 40 Z9 45 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1357-4310 J9 MOL MED TODAY JI Mol. Med. Today PD AUG PY 1999 VL 5 IS 8 BP 367 EP 369 DI 10.1016/S1357-4310(99)01528-2 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 224XB UT WOS:000081924300013 PM 10475714 ER PT J AU Scidmore-Carlson, MA Shaw, EI Dooley, CA Fischer, ER Hackstadt, T AF Scidmore-Carlson, MA Shaw, EI Dooley, CA Fischer, ER Hackstadt, T TI Identification and characterization of a Chlamydia trachomatis early operon encoding four novel inclusion membrane proteins SO MOLECULAR MICROBIOLOGY LA English DT Article ID ELECTRON-MICROSCOPY; ENDOCYTIC PATHWAY; INFECTED-CELLS; PSITTACI; GENE; SPHINGOLIPIDS; MACROPHAGES; VACUOLE; HUMANS; ENTRY AB Chlamydia trachomatis is a bacterial obligate intracellular parasite that replicates within a vacuole, termed an inclusion, that does not fuse with lysosomes. Within 2 h after internalization, the C. trachomatis inclusion ceases to interact with the endocytic pathway and, instead, becomes fusogenic with exocytic vesicles containing exogenously synthesized NBD-sphingomyelin. Both fusion of exocytic vesicles and longterm avoidance of lysosomal fusion require early chlamydial gene expression. Modification of the chlamydial inclusion probably occurs through the expression and insertion of chlamydial protein(s) into the inclusion membrane. To identify candidate inclusion membrane proteins, antisera were raised against a total membrane fraction purified from C. trachomatis-infected HeLa cells. By indirect immunofluorescence, this antisera recognized the inclusion membrane and, by immunoblot analysis, recognized three chlamydial-specific antigens of approximate molecular weights 15, 18 and 21 kDa. IncG, encoding an 18 kDa and 21 kDa doublet chlamydial antigen, was identified by screening a C. trachomatis, serovar L2, genomic expression library. Three additional genes, incD, incE and incF, were co-transcribed with incG. Monospecific antisera against each of the four genes of this operon demonstrated that the gene products were localized to the chlamydial inclusion membrane. Immediately downstream from the operon containing incD-G was the C. trachomatis homologue of incA. Like IncD, E, F and G, C. trachomatis IncA is also localized to the inclusion membrane. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis demonstrated that IncD-G, but not incA, are transcribed within the first 2 h after internalization, making them candidates for chlamydial factors required for the modification of the nascent chlamydial inclusion. C1 NIAID, Rocky Mt Labs, Host Parasite Interact Sect, Intracellular Parasites Lab, Hamilton, MT 59840 USA. NIAID, Rocky Mt Labs, Microscopy Branch, Hamilton, MT 59840 USA. RP Hackstadt, T (reprint author), NIAID, Rocky Mt Labs, Host Parasite Interact Sect, Intracellular Parasites Lab, Hamilton, MT 59840 USA. NR 33 TC 118 Z9 127 U1 1 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD AUG PY 1999 VL 33 IS 4 BP 753 EP 765 DI 10.1046/j.1365-2958.1999.01523.x PG 13 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 234HF UT WOS:000082478000009 PM 10447885 ER PT J AU Luo, YQ Hattori, A Munoz, J Qin, ZH Roth, GS AF Luo, YQ Hattori, A Munoz, J Qin, ZH Roth, GS TI Intrastriatal dopamine injection induces apoptosis through oxidation-involved activation of transcription factors AP-1 and NF-kappa B in rats SO MOLECULAR PHARMACOLOGY LA English DT Article ID C-JUN; SUBSTANTIA-NIGRA; NUCLEAR TRANSLOCATION; SYMPATHETIC NEURONS; STRIATAL NEURONS; CELL-DEATH; PHOSPHORYLATION; INHIBITION; EXPRESSION; ISCHEMIA AB More and more evidence suggests that increases in dopamine (DA) in striata may participate in neurodegenerative processes during acute ischemia, hypoxia, and excitotoxicity. With a rat model of intrastriatal DA injection, we studied the molecular events involved in DA toxicity. Intrastriatal injections of DA in amounts from 1 to 2 mu mol result in apoptotic cell death, as indicated by terminal deoxynucleotidyl transferase labeling of DNA strand breaks and Klenow polymerase-catalyzed [P-32]deoxycytidine triphosphate-labeled DNA laddering, Injections of DA produce a strong and prolonged activated protein 1 (AP-1) activity that contains c-fos, c-jun, and phosphorylated c-jun protein. DA injections also stimulate the activity of nuclear factor-kappa B (NF-kappa B), an oxidative stress-responsive transcription factor. Injection of curcumin at a dose that selectively inhibits AP-1 activation without affecting NF-kappa B activity attenuates DNA laddering induced by DA, Preinjection with SN50, a specific permeable recombinant NF-kappa B translocation inhibitor peptide, reduces DA-induced NF-kappa B activation and apoptosis. Moreover, preinjection of the antioxidant GSH significantly inhibits both DA-induced activation of transcription factors AP-I and NF-kappa B and subsequent apoptosis, Thus, our data suggest that DA-oxidative stress-induced apoptosis in vivo is mediated by activation of transcription factors AP-1 and NF-kappa B. C1 NIA, Mol Physiol & Genet Sect, Gerontol Res Ctr, Baltimore, MD 21224 USA. NINCDS, Expt Therapeut Branch, Bethesda, MD 20892 USA. RP Luo, YQ (reprint author), NIA, Mol Physiol & Genet Sect, Gerontol Res Ctr, 4C01,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 44 TC 95 Z9 98 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 AUG PY 1999 VL 56 IS 2 BP 254 EP 264 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 220CG UT WOS:000081646500002 PM 10419543 ER PT J AU Gutmann, H Fricker, G Drewe, J Toeroek, M Miller, DS AF Gutmann, H Fricker, G Drewe, J Toeroek, M Miller, DS TI Interactions of HIV protease inhibitors with ATP-dependent drug export proteins SO MOLECULAR PHARMACOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS PROTEASE; RESISTANCE GENE-PRODUCT; ORGANIC ANION SECRETION; P-GLYCOPROTEIN; PROXIMAL TUBULES; BRUSH-BORDER; RITONAVIR; SAQUINAVIR; TRANSPORT; COMBINATION AB We used renal proximal tubules from a teleost fish (killifish; Fundulus heteroclitus), fluorescent substrates and confocal microscopy to study the interactions between human immunodeficiency virus protease inhibitors and drug-transporting ATPases. Both saquinavir and ritonavir inhibited luminal accumulation of a fluorescent cyclosporin A derivative (a substrate for P-glycoprotein) and of fluorescein methotrexate [a substrate for multidrug resistance-associated protein 2 (Mrp2)]. Of the two protease inhibitors, ritonavir was the more potent inhibitor of transport by a factor of at least 20. Ritonavir was at least as good an inhibitor of P-glycoprotein- and Mrp2-mediated transport as cyclosporin A and leukotriene C4, respectively. Inhibition of P-glycoprotein- and Mrp2-mediated transport was not due to toxicity or impaired metabolism, because neither saquinavir nor ritonavir inhibited transport of fluorescein on the renal organic anion system. Experiments with a fluorescent saquinavir derivative showed strong secretion into the tubular lumen that was inhibited by verapamil, leukotriene C4, saquinavir, and ritonavir. Together, the data demonstrate that saquinavir, and especially ritonavir, are potent inhibitors of P-glycoprotein- and Mrp2-mediated transport. The experiments with the fluorescent saquinavir derivative suggest that these protease inhibitors may also be substrates for both P-glycoprotein and Mrp2. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. Kantonsspital, Childrens Hosp, Univ Clin, Div Gastroenterol, Basel, Switzerland. Kantonsspital, Childrens Hosp, Univ Clin, Div Clin Pharmacol, Basel, Switzerland. Kantonsspital, Childrens Hosp, Univ Clin, Dept Internal Med, Basel, Switzerland. Kantonsspital, Childrens Hosp, Univ Clin, Dept Res, Basel, Switzerland. Univ Heidelberg, Inst Pharmaceut Technol & Biopharm, Heidelberg, Germany. Mt Desert Isl Biol Lab, Salsbury Cove, ME USA. RP Miller, DS (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. FU NIEHS NIH HHS [ES03828] NR 34 TC 141 Z9 144 U1 1 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 AUG PY 1999 VL 56 IS 2 BP 383 EP 389 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 220CG UT WOS:000081646500017 PM 10419558 ER PT J AU Lin, ZC Wang, WF Kopajtic, T Revay, RS Uhl, GR AF Lin, ZC Wang, WF Kopajtic, T Revay, RS Uhl, GR TI Dopamine transporter: Transmembrane phenylalanine mutations can selectively influence dopamine uptake and cocaine analog recognition SO MOLECULAR PHARMACOLOGY LA English DT Article ID NOREPINEPHRINE TRANSPORTERS; STRUCTURAL DOMAINS; NUCLEUS-ACCUMBENS; BINDING; INHIBITION; SUBSTRATE; EXPRESSION; MECHANISM; RECEPTOR; 1-METHYL-4-PHENYLPYRIDINIUM AB Cocaine blocks the normal role of the dopamine transporter (DAT) in terminating dopamine signaling through molecular interactions that are only partially understood. Cocaine analog structure-activity studies have suggested roles for both cationic and aromatic interactions among DAT, dopamine, and cocaine. We hypothesized that phenylalanine residues lying in putative DAT transmembrane (TM) domains were good candidates to contribute to aromatic and/or cationic interactions among DAT, dopamine, and cocaine. To test this idea, we characterized the influences of alanine substitution for each of 29 phenylalanine residues lying in or near a putative DAT TM domain. Cells express 22 mutants at near wild-type levels, manifest by DAT immunohistochemistry and binding of the radiolabeled cocaine analog [H-3](-)-2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane (CFT). Seven mutants fail to express at normal levels. Four mutations selectively reduce cocaine analog affinities. Alanine substitutions at Phe(76), Phe(98), Phe(390), and Phe(361) located in TM domains 1 and 2, the fourth extracellular loop near TM 4 and in TM 7, displayed normal affinities for dopamine but 3- to 8-fold reductions in affinities for CFT. One TM 3 mutation, F(155)A, selectively decreased dopamine affinity to less than 3% of wild-type levels while reducing CFT affinity less than 3-fold. In a current DAT structural model, each of the residues at which alanine substitution selectively reduces cocaine analog or dopamine affinities faces a central transporter cavity, whereas mutations that influence expression levels are more likely to lie at potential helix/helix interfaces. Specific, overlapping sets of phenylalanine residues contribute selectively to DAT recognition of dopamine and cocaine. C1 NIDA, Mol Neurobiol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Uhl, GR (reprint author), NIDA, Mol Neurobiol Branch, Intramural Res Program, NIH, 5500 Nathan Shock Dr,POB 5180, Baltimore, MD 21224 USA. NR 40 TC 74 Z9 75 U1 1 U2 8 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 AUG PY 1999 VL 56 IS 2 BP 434 EP 447 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 220CG UT WOS:000081646500024 PM 10419565 ER PT J AU Felsenfeld, DP Schwartzberg, PL Venegas, A Tse, R Sheetz, MP AF Felsenfeld, DP Schwartzberg, PL Venegas, A Tse, R Sheetz, MP TI Selective regulation of integrin-cytoskeleton interactions by the tyrosine kinase Src SO NATURE CELL BIOLOGY LA English DT Article ID EXTRACELLULAR-MATRIX; FOCAL ADHESIONS; CELL-MIGRATION; C-SRC; FIBRONECTIN; BINDING; ALPHA(V)BETA(3); ASSOCIATION; FIBROBLASTS; PP125(FAK) AB Cell motility on extracellular-matrix (ECM) substrates depends on the regulated generation of force against the substrate through adhesion receptors known as integrins, Here we show that integrin-mediated traction forces can be selectively modulated by the tyrosine kinase Src, In Src-deficient fibroblasts, cell spreading on the ECM component vitronectin is inhibited, while the strengthening of linkages between integrin vitronectin receptors and the force-generating cytoskeleton in response to substrate rigidity is dramatically increased. In contrast, Src deficiency has no detectable effects on fibronectin-receptor function. Finally, truncated Src (lacking the kinase domain) co-localizes to focal-adhesion sites with alpha(v) but not with beta(1) integrins, These data are consistent with a selective, functional interaction between Src and the vitronectin receptor that acts at the integrin-cytoskeleton interface to regulate cell spreading and migration. C1 Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Sheetz, MP (reprint author), Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. NR 36 TC 206 Z9 208 U1 0 U2 3 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD AUG PY 1999 VL 1 IS 4 BP 200 EP 206 DI 10.1038/12021 PG 7 WC Cell Biology SC Cell Biology GA 245HZ UT WOS:000083102700014 PM 10559917 ER PT J AU Rust, S Rosier, M Funke, H Real, J Amoura, Z Piette, JC Deleuze, JF Brewer, HB Duverger, N Denefle, P Assmann, G AF Rust, S Rosier, M Funke, H Real, J Amoura, Z Piette, JC Deleuze, JF Brewer, HB Duverger, N Denefle, P Assmann, G TI Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1 SO NATURE GENETICS LA English DT Article ID FAMILIAL INTRAHEPATIC CHOLESTASIS; ABC TRANSPORTERS; A-I; RECEPTOR; CHOLESTEROL; CLONING; 9Q31 AB Tangier disease (TD) was first discovered nearly 40 years ago in two siblings living on Tangier Island(1). This autosomal co-dominant condition is characterized in the homozygous state by the absence of HDL-cholesterol (HDL-C) from plasma, hepatosplenomegaly, peripheral neuropathy and frequently premature coronary artery disease(1) (CAD). In heterozygotes, HDL-C levels are about one-half those of normal individuals(1). Impaired cholesterol efflux from macrophages leads to the presence of foam cells throughout the body, which may explain the increased risk of coronary heart disease in some TD families(2). We report here refining of our previous linkage of the TD gene(3) to a 1-cM region between markers D9S271 and D9S1866 on chromosome 9q31, in which we found the gene encoding human ATP cassette-binding transporter 1 (ABC1). We also found a change in ABC1 expression level on cholesterol loading of phorbol ester-treated THP1 macrophages, substantiating the role of ABC1 in cholesterol efflux. We cloned the full-length cDNA and sequenced the gene in two unrelated families with four TD homozygotes. In the first pedigree, a 1-bp deletion in exon 13, resulting in truncation of the predicted protein to approximately one-fourth of its normal size, co-segregated with the disease phenotype. An in-frame insertion-deletion in exon 12 was found in the second family. Our findings indicate that defects in ABC1, encoding a member of the ABC transporter superfamily, are the cause of TD. C1 Univ Munster, Inst Arterioskleroseforsch, D-48149 Munster, Germany. Rhone Poulenc Rorer, Core Genom Biotechno Dept, F-91006 Evry, France. Rhone Poulenc Rorer, Dept Cardiovasc, F-91006 Evry, France. Univ Munster, Inst Klin Chem & Lab Med, D-48149 Munster, Germany. Univ Valencia, Dept Med, Hosp Clin, Valencia 46010, Spain. Hop La Pitie Salpetriere, Serv Med Interne, Paris, France. NHLBI, NIH, Bethesda, MD 20892 USA. RP Rust, S (reprint author), Univ Munster, Inst Arterioskleroseforsch, Domagkstr 3, D-48149 Munster, Germany. NR 22 TC 1072 Z9 1113 U1 5 U2 25 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 AUG PY 1999 VL 22 IS 4 BP 352 EP 355 DI 10.1038/11921 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 222FH UT WOS:000081772500016 PM 10431238 ER PT J AU Van Etten, WJ Steen, RG Nguyen, H Castle, AB Slonim, DK Ge, B Nusbaum, C Schuler, GD Lander, ES Hudson, TJ AF Van Etten, WJ Steen, RG Nguyen, H Castle, AB Slonim, DK Ge, B Nusbaum, C Schuler, GD Lander, ES Hudson, TJ TI Radiation hybrid map of the mouse genome SO NATURE GENETICS LA English DT Article AB Radiation hybrid (RH) maps are a useful tool for genome analysis, providing a direct method for localizing genes and anchoring physical maps and genomic sequence along chromosomes, The construction of a comprehensive RH map for the human genome(1) has resulted in gene maps reflecting the location of more than 30,000 human genes(2,3). Here we report the first comprehensive RH map of the mouse genome. The map contains 2,486 loci screened against an RH panel of 93 cell lines(4). Most loci (93%) are simple sequence length polymorphisms (SSLPs) taken from the mouse genetic map, thereby providing direct integration between these two key maps, We performed RH mapping by a new and efficient approach in which we replaced traditional gel- or hybridization-based assays by a homogeneous 5'-nuclease assay(5) involving a single common probe for all genetic markers. The map provides essentially complete connectivity and coverage across the genome, and good resolution for ordering loci, with 1 centiRay (cR) corresponding to an average of approximately 100 kb, The RH map, together with an accompanying World-Wide Web server, makes it possible for any investigator to rapidly localize sequences in the mouse genome. Together with the previously constructed genetic map(6) and a YAC-based physical map reported in a companion paper(7), the fundamental maps required for mouse genomics are now available. C1 MIT, Whitehead Inst Biomed Res, Ctr Genome Res, Cambridge, MA 02142 USA. McGill Univ, Montreal Gen Hosp, Res Inst, Montreal, PQ H3G 1A4, Canada. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. MIT, Dept Biol, Cambridge, MA 02139 USA. RP Lander, ES (reprint author), MIT, Whitehead Inst Biomed Res, Ctr Genome Res, Cambridge, MA 02142 USA. FU NHGRI NIH HHS [HG01806] NR 10 TC 91 Z9 92 U1 0 U2 2 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 AUG PY 1999 VL 22 IS 4 BP 384 EP 387 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 222FH UT WOS:000081772500023 PM 10431245 ER PT J AU Nusbaum, C Slonim, DK Harris, KL Birren, BW Steen, RG Stein, LD Miller, J Dietrich, WF Nahf, R Wang, V Merport, O Castle, AB Husain, Z Farino, G Gray, D Anderson, MO Devine, R Horton, LT Ye, WJ Wu, XY Kouyoumjian, V Zemsteva, IS Wu, Y Collymore, AJ Courtney, DF Tam, J Cadman, M Haynes, AR Heuston, C Marsland, T Southwell, A Trickett, P Strivens, MA Ross, MT Makalowski, W Xu, YX Boguski, MS Carter, NP Denny, P Brown, SDM Hudson, TJ Lander, ES AF Nusbaum, C Slonim, DK Harris, KL Birren, BW Steen, RG Stein, LD Miller, J Dietrich, WF Nahf, R Wang, V Merport, O Castle, AB Husain, Z Farino, G Gray, D Anderson, MO Devine, R Horton, LT Ye, WJ Wu, XY Kouyoumjian, V Zemsteva, IS Wu, Y Collymore, AJ Courtney, DF Tam, J Cadman, M Haynes, AR Heuston, C Marsland, T Southwell, A Trickett, P Strivens, MA Ross, MT Makalowski, W Xu, YX Boguski, MS Carter, NP Denny, P Brown, SDM Hudson, TJ Lander, ES TI A YAC-based physical map of the mouse genome SO NATURE GENETICS LA English DT Article ID RESOLUTION; SYSTEM AB A physical map of the mouse genome is an essential tool for both positional cloning and genomic sequencing in this key model system for biomedical research, Indeed, the construction of a mouse physical map with markers spaced at an average interval of 300 kb is one of the stated goals of the Human Genome Project(1). Here we report the results of a project at the Whitehead Institute/MIT Center for Genome Research to construct such a physical map of the mouse. We built the map by screening sequenced-tagged sites (STSs) against a large-insert yeast artificial chromosome (YAC) library and then integrating the STS-content information with a dense genetic map. The integrated map shows the location of 9,787 loci, providing landmarks with an average spacing of approximately 300 kb and affording YAC coverage of approximately 92% of the mouse genome. We also report the results of a project at the MRC UK Mouse Genome Centre targeted at chromosome X. The project produced a YAC-based map containing 619 loci (with 121 loci in common with the Whitehead map and 498 additional loci), providing especially dense coverage of this sex chromosome. The YAC-based physical map directly facilitates positional cloning of mouse mutations by providing ready access to most of the genome. More generally, use of this map in addition to a newly constructed radiation hybrid (RH) map(2) provides a comprehensive framework for mouse genomic studies. C1 Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. MRC, UK Mouse Genome Ctr, Harwell OX11 0RD, Berks, England. MRC, Mammalian Genet Unit, Harwell OX11 0RD, Berks, England. Sanger Ctr Wellcome Trust Genome Campus, Cambridge CB10 1SA, England. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. Johns Hopkins Univ, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21205 USA. McGill Univ, Montreal Gen Hosp, Res Inst, Montreal, PQ H3G 1A4, Canada. MIT, Dept Biol, Cambridge, MA 02139 USA. RP Lander, ES (reprint author), Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. RI Makalowski, Wojciech/I-2843-2016; OI Hudson, Thomas/0000-0002-1376-4849 FU Wellcome Trust NR 15 TC 55 Z9 58 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 AUG PY 1999 VL 22 IS 4 BP 388 EP 393 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 222FH UT WOS:000081772500024 PM 10431246 ER PT J AU Hoe, NP Nakashima, K Lukomski, S Grigsby, D Liu, MY Kordari, P Dou, SJ Pan, X Vuopio-Varkila, J Salmelinna, S McGeer, A Low, DE Schwartz, B Schuchat, A Naidich, S De Lorenzo, D Fu, YX Musser, JM AF Hoe, NP Nakashima, K Lukomski, S Grigsby, D Liu, MY Kordari, P Dou, SJ Pan, X Vuopio-Varkila, J Salmelinna, S McGeer, A Low, DE Schwartz, B Schuchat, A Naidich, S De Lorenzo, D Fu, YX Musser, JM TI Rapid selection of complement-inhibiting protein variants in group A Streptococcus epidemic waves SO NATURE MEDICINE LA English DT Article ID GROUP-A STREPTOCOCCUS; MOLECULAR EPIDEMIOLOGY; SIZE MUTANTS; INFECTIONS; SEROTYPE; DISEASE; GLYCOPROTEIN; ATLANTA; STRAINS; SPREAD AB Serotype M1 group A Streptococcus strains cause epidemic waves of human infections long thought to be mono- or pauciclonal. The gene encoding an extracellular group A Streptococcus protein (streptococcal inhibitor of complement) that inhibits human complement was sequenced in 1,132 M1 strains recovered from population-based surveillance of infections in Canada, Finland and the United States. Epidemic waves are composed of strains expressing a remarkably heterogeneous array of variants of streptococcal inhibitor of complement that arise very rapidly by natural selection on mucosal surfaces. Thus, our results enhance the understanding of pathogen population dynamics in epidemic waves and infectious disease reemergence. C1 Natl Publ Hlth Inst, Dept Bacteriol, FIN-00300 Helsinki, Finland. Mt Sinai Hosp, Dept Microbiol, Toronto, ON M5G 1X5, Canada. Univ Toronto, Toronto, ON M5G 1X5, Canada. Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. Genomics, New York, NY 10013 USA. Univ Texas, Hlth Sci Ctr, Ctr Human Genet, Houston, TX 77030 USA. RP Musser, JM (reprint author), NIAID, Rocky Mt Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. RI Low, Donald/B-1726-2012; mcgeer, allison /H-7747-2014 OI mcgeer, allison /0000-0001-5647-6137 FU NIAID NIH HHS [AI-33119]; NIGMS NIH HHS [GM-50428] NR 34 TC 62 Z9 62 U1 0 U2 4 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 AUG PY 1999 VL 5 IS 8 BP 924 EP 929 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 220TR UT WOS:000081684000037 PM 10426317 ER PT J AU Brennan, C Rivas-Plata, K Landis, SC AF Brennan, C Rivas-Plata, K Landis, SC TI The p75 neurotrophin receptor influences NT-3 responsiveness of sympathetic neurons in vivo SO NATURE NEUROSCIENCE LA English DT Article ID NERVE GROWTH-FACTOR; FOREBRAIN CHOLINERGIC NEURONS; AFFINITY NGF RECEPTOR; MICE LACKING; CELL-DEATH; SIGNAL-TRANSDUCTION; SURVIVAL; TRKA; EXPRESSION; ACTIVATION AB To determine the role of the p75 neurotrophin receptor (p75(NTR)) in sympathetic neuron development, we crossed transgenic mice with mutations in p75(NTR), nerve growth factor (NGF) and neurotrophin-3 (NT-3). Neuron number is normal in sympathetic ganglia of adult p75(NTR-/-) mice. Mice heterozygous for a NGF deletion (NGF(+/-)) have 50% fewer sympathetic neurons. In the absence of p75(NTR) (P75(NTR-/-) NGF(+/-)), however, neuron number is restored to wild-type levels. When NT-3 levels are reduced (p75(NTR-/-) NGF(+/-) NT3(+/-)), neuron number decreases compared to p75(NTR-/-) NGF(+/-) NT3(+/+). Thus, without p75(NTR), NT3 substitutes for NGF, suggesting that p75 alters the neurotrophin specificity of TrkA in vivo. C1 NINDS, Neural Dev Sect, NIH, Bethesda, MD 20892 USA. RP Brennan, C (reprint author), NINDS, Neural Dev Sect, NIH, 36 Convent Dr,Bldg 36,Rm 2B08, Bethesda, MD 20892 USA. NR 50 TC 87 Z9 90 U1 0 U2 1 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 AUG PY 1999 VL 2 IS 8 BP 699 EP 705 DI 10.1038/11158 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 259FA UT WOS:000083882800008 PM 10412058 ER PT J AU De Weerd, P Peralta, MR Desimone, R Ungerleider, LG AF De Weerd, P Peralta, MR Desimone, R Ungerleider, LG TI Loss of attentional stimulus selection after extrastriate cortical lesions in macaques SO NATURE NEUROSCIENCE LA English DT Article ID INFERIOR TEMPORAL CORTEX; AREA V4; INFEROTEMPORAL CORTEX; VISUAL-SEARCH; SHAPE-DISCRIMINATION; NEURAL MECHANISMS; CEREBRAL-CORTEX; NEURONS; MONKEY; COLOR AB Many objects in natural visual scenes compete for attention. To identify the neural mechanisms necessary for visual attention, we made restricted lesions, affecting different quadrants of the visual field but leaving one quadrant intact, in extrastriate cortical areas V4 and TEO of two monkeys. Monkeys were trained to discriminate the orientation of a target grating surrounded by distracters. As distracter contrast increased, performance deteriorated in quadrants affected by V4 and TEO lesions, but not in the normal quadrant. Performance in affected quadrants was restored by increasing the contrast of the target relative to distracters. Thus, without V4 and TEO, visual attention is 'captured' by strong stimuli, regardless of their behavioral relevance. C1 NIMH, Lab Brain Cognit, Bethesda, MD 20892 USA. NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. RP De Weerd, P (reprint author), Univ Arizona, Coll Social & Behav Sci, Dept Psychol, POB 210068, Tucson, AZ 85721 USA. NR 50 TC 98 Z9 100 U1 1 U2 2 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 AUG PY 1999 VL 2 IS 8 BP 753 EP 758 DI 10.1038/11234 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 259FA UT WOS:000083882800016 PM 10412066 ER PT J AU Bushara, KO Weeks, RA Ishii, K Catalan, MJ Tian, B Rauschecker, JP Hallett, M AF Bushara, KO Weeks, RA Ishii, K Catalan, MJ Tian, B Rauschecker, JP Hallett, M TI Modality-specific frontal and parietal areas for auditory and visual spatial localization in humans SO NATURE NEUROSCIENCE LA English DT Article ID POSITRON EMISSION TOMOGRAPHY; WORKING-MEMORY; SOUND-LOCALIZATION; VISUOSPATIAL ATTENTION; PREFRONTAL CORTEX; PET; NEURONS; NEGLECT; MONKEY; MECHANISMS AB Although the importance of the posterior parietal and prefrontal regions in spatial localization of visual stimuli is well established, their role in auditory space perception is less clear. Using positron emission tomography (PET) during auditory and visual spatial localization in the same subjects, modality-specific areas were identified in the superior parietal lobule, middle temporal and lateral prefrontal cortices. These findings suggest that, similar to the visual system, the hierarchical organization of the auditory system extends beyond the temporal lobe to include areas in the posterior parietal and prefrontal regions specialized in auditory spatial processing. Our results may explain the dissociation of visual and auditory spatial localization deficits following lesions involving these regions. C1 NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Inst Cognit & Computat Sci, Washington, DC 20007 USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10,Room 5N226,10 Center MSC 1428, Bethesda, MD 20892 USA. RI Rauschecker, Josef/A-4120-2013 NR 50 TC 271 Z9 275 U1 1 U2 5 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 AUG PY 1999 VL 2 IS 8 BP 759 EP 766 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 259FA UT WOS:000083882800017 PM 10412067 ER PT J AU Karamychev, VN Zhurkin, VB Garges, S Neumann, RD Panyutin, IG AF Karamychev, VN Zhurkin, VB Garges, S Neumann, RD Panyutin, IG TI Detecting the DNA kinks in a DNA-CRP complex in solution with iodine-125 radioprobing SO NATURE STRUCTURAL BIOLOGY LA English DT Article ID BINDING; I-125; DECAY; TRIPLEX; DAMAGE; CAP; PROMOTER; PROTEINS; REGIONS; SYSTEM AB Auger-electron-emitting radioisotopes such as I-125 produce DNA strand breaks within nanometer range of the decay site. Here we analyze these breaks in order to study changes in DNA conformation upon binding with cyclic AMP receptor protein (CRP) in solution. The clear difference we found in break frequency in the CRP-DNA complex, as compared to the naked DNA duplex, correlates with the increased distances between the deoxyriboses and the radioiodine atom caused by the CRP-induced kink observed in the cocrystal. Thus, we demonstrate that I-125 radioprobing can be used to study fine conformational changes of DNA within DNA-protein complexes. C1 NIH, Dept Nucl Med, Bethesda, MD 20892 USA. Novosibirsk Bioorgan Chem Inst, Novosibirsk 630090, Russia. NCI, NIH, Bethesda, MD 20892 USA. RP Panyutin, IG (reprint author), NIH, Dept Nucl Med, Bethesda, MD 20892 USA. NR 26 TC 19 Z9 19 U1 0 U2 0 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 AUG PY 1999 VL 6 IS 8 BP 747 EP 750 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 220TP UT WOS:000081683800014 PM 10426952 ER PT J AU Weight, FF Li, CY Peoples, RW AF Weight, FF Li, CY Peoples, RW TI Alcohol action on membrane ion channels gated by extracellular ATP (P2X receptors) SO NEUROCHEMISTRY INTERNATIONAL LA English DT Review DE alcohol; ethanol; neuron; receptor; ion channel; ATP; P2X receptor ID NODOSE GANGLION NEURONS; RAT HIPPOCAMPAL SLICES; LONG-CHAIN ALCOHOLS; ACTIVATED CURRENT; SYNAPTIC TRANSMISSION; ETHANOL INHIBITION; MAMMALIAN NEURONS; SENSORY NEURONS; NERVOUS-SYSTEM; BRAIN AB Extracellular adenosine 5'-triphosphate (ATP) has been reported to produce excitatory actions in the nervous system, such as excitatory postsynaptic potentials or currents in both central and peripheral neurons, via activation of a class of ATP-gated membrane ion channels designated P2X receptors. This article reviews studies of alcohol effects on these receptor-channels. Ethanol has been found to inhibit ATP-gated ion channel function by shifting the agonist concentration-response curve to the right in a parallel manner, increasing the EC50 without affecting E-max of this curve. To distinguish whether this inhibition involves competitive antagonism of agonist action or a decrease in the affinity of the agonist binding site,the kinetics of activation and deactivation of agonist-activated current were studied. Ethanol was found to decrease the time-constant of deactivation of ATP-gated ion channels without affecting the time-constant of activation, indicating that ethanol inhibits the function of these receptors by an allosteric decrease in the affinity of the agonist binding site. The inhibition of ATP-gated ion channel function by a number of alcohols was found to exhibit a distinct cutoff effect that appeared to be related to the molecular volume of the alcohols. For alcohols with a molecular volume of less than or equal to 42.2 ml/mol, potency for inhibiting ATP-activated current was correlated with lipid solubility (order of potency: 1-propanol = trifluoroethanol > monochloroethanol > ethanol > methanol). However, despite increased lipid solubility, alcohols with a molecular volume of greater than or equal to 46.1 ml/mol (1-butanol, 1-pentanol, trichloroethanol, and dichloroethanol) were without effect on the ATP-activated current. This cutoff effect has been interpreted as evidence that alcohols inhibit the function of ATP-gated ion channels by interacting with a hydrophobic pocket of circumscribed dimensions on the receptor protein. To evaluate the localization of this presumed alcohol binding site, the effect of the intracellular application of ethanol was studied on the inhibition of ATP-activated current by extracellularly applied ethanol. The intracellular application of 100 mM ethanol did not affect the inhibition of current by 100 mM extracellular ethanol, suggesting that the alcohol inhibition of ATP-gated ion channel function involves the extracellular domain of the receptor. Finally, recent studies suggest that the alcohol sensitivity of ATP-gated channels may be regulated by physiological mechanisms. Published by Elsevier Science Ltd. C1 NIAAA, Mol & Cellular Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Weight, FF (reprint author), NIAAA, Mol & Cellular Neurobiol Lab, NIH, Bethesda, MD 20892 USA. NR 64 TC 39 Z9 40 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0197-0186 J9 NEUROCHEM INT JI Neurochem. Int. PD AUG PY 1999 VL 35 IS 2 BP 143 EP 152 DI 10.1016/S0197-0186(99)00056-X PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 212LP UT WOS:000081218400008 PM 10405998 ER PT J AU Thaler, J Harrison, K Sharma, K Lettieri, K Kehrl, J Pfaff, SL AF Thaler, J Harrison, K Sharma, K Lettieri, K Kehrl, J Pfaff, SL TI Active suppression of interneuron programs within developing motor neurons revealed by analysis of homeodomain factor HB9 SO NEURON LA English DT Article ID IN-SITU HYBRIDIZATION; SPINAL-CORD; HOMEOBOX GENE; SONIC HEDGEHOG; TAIL MUTATION; FLOOR PLATE; EXPRESSION; ZEBRAFISH; IDENTITY; CELLS AB Sonic hedgehog (Shh) specifies the identity of both motor neurons (MNs) and interneurons with morphogen-like activity. Here, we present evidence that the homeodomain factor HB9 is critical for distinguishing MN and interneuron identity in the mouse. Presumptive MN progenitors and postmitotic MNs express HB9, whereas interneurons never express this factor. This pattern resembles a composite of the avian homologs MNR2 and HB9. In mice lacking Hb9, the genetic profile of MNs is significantly altered, particularly by upregulation of Chx10, a gene normally restricted to a class of ventral interneurons. This aberrant gene expression is accompanied by topological disorganization of motor columns, loss of the phrenic and abducens nerves, and intercostal nerve pathfinding defects. Thus, MNs actively suppress interneuron genetic programs to establish their identity. C1 Salk Inst Biol Studies, Gene Express Lab, La Jolla, CA 92037 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Pfaff, SL (reprint author), Salk Inst Biol Studies, Gene Express Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. OI Kehrl, John/0000-0002-6526-159X FU NINDS NIH HHS [NS37116] NR 53 TC 233 Z9 237 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD AUG PY 1999 VL 23 IS 4 BP 675 EP 687 DI 10.1016/S0896-6273(01)80027-1 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 230ZE UT WOS:000082280900012 PM 10482235 ER PT J AU Gleason, TC Dreiling, JL Crawley, JN AF Gleason, TC Dreiling, JL Crawley, JN TI Rat strain differences in response to galanin on the Morris water task SO NEUROPEPTIDES LA English DT Article ID NONMATCHING-TO-SAMPLE; NUCLEUS BASALIS MAGNOCELLULARIS; ALZHEIMERS-DISEASE; DIAGONAL BAND; ACETYLCHOLINE INTERACTIONS; SPATIAL MEMORY; MEDIAL SEPTUM; VERTICAL LIMB; SWIM MAZE; AGED RATS AB Galanin acts as an inhibitory modulator of cholinergic transmission in the septohippocampal pathway of the rat. Centrally administered galanin induces performance deficits on rodent learning and memory tasks, including delayed non-matching to position, T-maze delayed alternation, passive avoidance, starbust radial maze acquisition, and the Morris water task. The present study investigates differences in responsiveness to intraventricularly administered galanin across three strains of laboratory rat on acquisition of spatial learning in the Morris water task. Sprague-Dawley rats showed normal performance during training, but lack of selective quadrant search on the probe trial in response to galanin treatment. Long-Evans rats showed no effects of galanin on performance during training or probe trial. Wistar rats showed longer latencies to reach the hidden platform during training, and lack of selective quadrant search on the probe trial in response to galanin. Performance on the visible platform task and on locomotor activity in the open field was normal in rats treated with galanin. These results are consistent with an interpretation of strain differences in sensitivity to the inhibitory actions of galanin on learning and memory. C1 NIMH, Sect Behav Neuropharmacol, ETB, Bethesda, MD 20892 USA. RP Crawley, JN (reprint author), NIMH, Sect Behav Neuropharmacol, ETB, Bldg 10,Room 4D11, Bethesda, MD 20892 USA. NR 36 TC 31 Z9 33 U1 0 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4179 J9 NEUROPEPTIDES JI Neuropeptides PD AUG PY 1999 VL 33 IS 4 BP 265 EP 270 DI 10.1054/npep.1999.0044 PG 6 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 248QG UT WOS:000083286400003 PM 10657502 ER PT J AU Shen, FS Aguilera, G Loh, YP AF Shen, FS Aguilera, G Loh, YP TI Altered biosynthesis and secretion of pro-opiomelanocortin in the intermediate and anterior pituitary of carboxpyeptidase E-deficient, Cpe(fat)/Cpe(fat) mice SO NEUROPEPTIDES LA English DT Article ID CARBOXYPEPTIDASE-E MUTATION; PATHWAY SORTING RECEPTOR; OBESE FAT/FAT MICE; CPE(FAT) MICE; FAT MUTATION; CELLS; HORMONE; RELEASE; ADRENOCORTICOTROPIN; DOPAMINE AB The biosynthesis and secretion of pro-opiolelanocortin (POMC) was examined in the pituitary of Cpe(fat)/Cpe(fat) mice, which are deficient in carboxypeptidase E, a sorting receptor for the regulated secretory pathway (Cool D R, Normant E, Shen F S, et al. Cell 1997; 83: 73-83). Dopamine inhibited forskolin-stimulated accumulation of cAMP in the intermediate lobe of Cpe(fat)/Cpe(fat) mice, showing that their dopamine receptors were fully functional. This result indicates that the elevated, dopamine-insensitive POMC secretion previously observed in the intermediate pituitary of Cpe(fat)/Cpe(fat) mice was constitutive, rather than due to defective dopamine receptors. Concomitant with the increase in POMC secretion was a twofold increase in POMC mRNA levels and [S-35]-methionine incorporation into POMC. In the anterior pituitary of Cpe(fat)/Cpe(fat) mice, a 1.6-fold increase in basal release of POMC was accompanied by a similar increase in [S-35]-methionine incorporation into POMC, although POMC mRNA levels were unchanged. Thus, the intermediate and anterior pituitary of Cpe(fat)/Cpe(fat) mice compensate for the constitutive secretion of POMC by upregulating biosynthesis. C1 NICHHD, Cellular Neurobiol Sect, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Loh, YP (reprint author), NICHHD, Cellular Neurobiol Sect, Dev Neurobiol Lab, NIH, Bldg 49,Rm 5A38,MSC 4480, Bethesda, MD 20892 USA. NR 20 TC 10 Z9 10 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 0143-4179 J9 NEUROPEPTIDES JI Neuropeptides PD AUG PY 1999 VL 33 IS 4 BP 276 EP 280 DI 10.1054/npep.1999.0045 PG 5 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 248QG UT WOS:000083286400005 PM 10657504 ER PT J AU Rishi, AK Sun, RJ Gao, YP Hsu, CKA Gerald, TM Sheikh, MS Dawson, MI Reichert, U Shroot, B Fornace, AJ Brewer, G Fontana, JA AF Rishi, AK Sun, RJ Gao, YP Hsu, CKA Gerald, TM Sheikh, MS Dawson, MI Reichert, U Shroot, B Fornace, AJ Brewer, G Fontana, JA TI Post-transcriptional regulation of the DNA damage-inducible gadd45 gene in human breast carcinoma cells exposed to a novel retinoid CD437 SO NUCLEIC ACIDS RESEARCH LA English DT Article ID MESSENGER-RNA STABILITY; MAMMALIAN-CELLS; GROWTH-ARREST; APOPTOSIS; PROTEINS; PATHWAY; MYD; P53 AB The biologically active synthetic retinoid CD437 (6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene, AHPN) and different human breast carcinoma (HBC) cell lines were used to examine the possible mechanism(s) of gadd45 induction. Northern blot analysis of mRNA isolated from MCF-7, MDA-MB-468 and MDA-MB-231 HBC cell lines demonstrated a progressive increase in the 1.4 kb gadd45 transcript after exposure to 1 mu M CD437, Western blot analysis showed increased gadd45 protein levels in MDA-MB-468 HBC cells following exposure to CD437, CD437 increased gadd45 mRNA levels by similar to 20-fold in MDA-MB-468 cells, however, the transcriptional activity was increased similar to 2-3-fold as demonstrated by the human gadd45 promoter-luciferase reporter construct and nuclear run-off assays. Sublines of MDA-MB-468 HBC cells expressing stably integrated GADD45 cDNA fragments were obtained and CD437-dependent induction of GADD45 analyzed. We report that similar to 300 nt located in the 5'-untranslated region (5'-UTR) of gadd45 mRNA are involved in the CD437-dependent 4-fold enhanced stability of gadd45 transcripts, MDA-MB-468 cells were stably transfected with either a plasmid having a CMV promoter-driven rabbit beta-globin gene or plasmids having a CMV promoter-driven chimeric gadd45 5'-UTR-rabbit beta-globin gene, where the entire gadd45 5'-UTR (from +1 to +298) or a 45 bp subfragment of the gadd45 5'-UTR (from +10 to +55) was positioned at the 5-end of the rabbit beta-globin gene. CD437 was found to up-regulate expression of both the chimeric gadd45-rabbit beta-globin transcripts, suggesting that cis element(s) involved in the CD437-dependent enhanced stability of gadd45 mRNA are contained in the 45 nt of the 5'-UTR of the gadd45 mRNA. C1 Wayne State Univ, Dept Internal Med, Detroit, MI 48201 USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI 48201 USA. Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. SRI Int, Div Life Sci, Menlo Park, CA 94025 USA. Ctr Int Rech Dermatol Galderma, Valbonne, France. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC 27157 USA. RP Rishi, AK (reprint author), VA Med Ctr, Res 151,Room B4270,4646 John R, Detroit, MI 48201 USA. RI Fornace, Albert/A-7407-2008; OI Fornace, Albert/0000-0001-9695-085X; Fontana, Joseph/0000-0003-3829-3358 FU NCI NIH HHS [CA-63335, CA51993] NR 27 TC 36 Z9 39 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD AUG 1 PY 1999 VL 27 IS 15 BP 3111 EP 3119 DI 10.1093/nar/27.15.3111 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 223GQ UT WOS:000081832900016 PM 10454607 ER PT J AU Lipinski, LJ Hoehr, N Mazur, SJ Dianov, GL Senturker, S Dizdaroglu, M Bohr, VA AF Lipinski, LJ Hoehr, N Mazur, SJ Dianov, GL Senturker, S Dizdaroglu, M Bohr, VA TI Repair of oxidative DNA base lesions induced by fluorescent light is defective in xeroderma pigmentosum group A cells SO NUCLEIC ACIDS RESEARCH LA English DT Article ID CHROMATOGRAPHY-MASS-SPECTROMETRY; TRANSCRIPTION-COUPLED REPAIR; NUCLEOTIDE EXCISION-REPAIR; COLI ENDONUCLEASE-III; IN-VITRO REPAIR; MAMMALIAN-CELLS; SACCHAROMYCES-CEREVISIAE; SUBSTRATE-SPECIFICITY; IONIZING-RADIATION; MOLECULAR-CLONING AB Fluorescent light (FL) has been shown to generate free radicals within cells, however, the specific chemical nature of DNA damage induced by FL has not previously been determined. Using gas chromatography/isotope dilution mass spectrometry, we have detected induction of the oxidative DNA lesions 5-hydroxycytosine (5-OH-Cyt), 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyGua) and 4,6-diamino-5-formamidopyrimidine (FapyAde) in cultured cells irradiated with FL, We followed the repair of these lesions in normal and xeroderma pigmentosum group A (XP-A) cells. 5-OH-Cyt and FapyGua were repaired efficiently in normal cells within 6 h following FL exposure. XP-A cells were unable to repair these oxidative DNA base lesions. Additionally, to compare the repair of oxidative lesions induced by various sources, in vitro repair studies were performed using plasmid DNA damaged by FL, gamma-irradiation or OsO4 treatment. Whole cell extracts from normal cells repaired damaged substrates efficiently, whereas there was little repair in XP-A extracts, Our data demonstrate defective repair of oxidative DNA base lesions in XP-A cells in vivo and in vitro. C1 NIA, Mol Genet Lab, NIH, Baltimore, MD 21224 USA. Natl Inst Stand & Technol, Chem Sci & Technol Lab, Gaithersburg, MD 20899 USA. RP Bohr, VA (reprint author), NIA, Mol Genet Lab, NIH, Baltimore, MD 21224 USA. NR 47 TC 36 Z9 36 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD AUG 1 PY 1999 VL 27 IS 15 BP 3153 EP 3158 DI 10.1093/nar/27.15.3153 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 223GQ UT WOS:000081832900021 PM 10454612 ER PT J AU Baris, D Liner, MS Tarone, RE Kleinerman, RA Hatch, EE Kaune, WT Robison, LL Lubin, J Wacholder, S AF Baris, D Liner, MS Tarone, RE Kleinerman, RA Hatch, EE Kaune, WT Robison, LL Lubin, J Wacholder, S TI Residential exposure to magnetic fields: an empirical examination of alternative measurement strategies SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article DE residential exposure; magnetic field; missing data; imputations ID LUNG-CANCER; RISK AB Objectives-To investigate the impact of measuring a single home then imputing information from another home among subjects who lived in two homes in a subset of the National Cancer Institute/Children's Cancer Group (NCI/CCG) investigation of residential exposure to magnetic fields and risk of childhood leukaemia. Methods-Each subject's summary time weighted average (TWA) exposure was derived from measurements or two homes, weighted by the fraction of the reference period lived in the residence. The three cost efficient field work strategies examined were measuring: (a) the longer lived in home; (b) the currently lived in home; and (c) the former lived in home. Two different methods were used for imputing the missing values: (a) control mean imputation, (b) status specific mean imputation. The subject's summary exposure to magnetic fields estimated with each approach was compared with the subject's TWA calculated from measurements in both homes. The association between estimated exposure to magnetic fields and the risk of leukaemia under different approaches was examined with unconditional logistic regression analysis. Results-The Pearson correlation coefficient between the two measurements within subjects was 0.31 (p<10(-4)), indicating a lack of independence of measurements. Differences were found between mean exposures in current and former homes of cases, and between longer and shorter lived in homes of controls. All methods with measurements from one of the homes in conjunction with imputation of measurements for the second home led to marked attenuation of risk estimates at the highest exposure category, particularly when measurements from current homes were used and those from former homes were imputed. Conclusion-Results argue against attempting to estimate lifetime magnetic field exposure from imputed values derived from current residences to fill in gaps caused by unmeasured residences previously lived in. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EMF Factors, Richland, WA USA. Univ Minnesota, Div Pediat Epidemiol Clin Res, Minneapolis, MN USA. RP Baris, D (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Execut Plaza S,Room 8122, Bethesda, MD 20892 USA. OI Kleinerman, Ruth/0000-0001-7415-2478 NR 13 TC 2 Z9 2 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD AUG PY 1999 VL 56 IS 8 BP 562 EP 566 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 221AD UT WOS:000081701300011 PM 10492656 ER PT J AU Kheifets, LI Gilbert, ES Sussman, SS Guenel, P Sahl, JD Savitz, DA Theriault, G AF Kheifets, LI Gilbert, ES Sussman, SS Guenel, P Sahl, JD Savitz, DA Theriault, G TI Comparative analyses of the studies of magnetic fields and cancer in electric utility workers: studies from France, Canada, and the United States SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article DE cancer; electromagnetic fields; epidemiological methods ID OCCUPATIONAL EXPOSURE; BRAIN CANCER; LEUKEMIA; METAANALYSIS; MORTALITY; ONTARIO; TUMORS; COHORT AB Objectives-To summarise and to facilitate comparison of three major studies of electric utility workers that examined the relation between quantitative measurements of occupational exposure to magnetic fields and risk of brain cancer and leukaemia. These studies have been interpreted as providing conflicting evidence. Methods-A common analytical approach was applied to data from the five cohorts included in the three studies based on original data from four of the cohorts, and published data from one additional cohort. A nested case-control design with conditional logistic regression was used to estimate the relative risk/10 microtesla-years (mu T-years) for each of the contributing cohorts and for the combined data. The homogeneity of these estimates among the studies was also evaluated. Results-Apparent inconsistencies in the findings of these studies can be explained by statistical variation. Overall, the studies suggest a small increase in risk of both brain cancer and leukaemia. Different methodological choices had little impact on the results. Based on a combined analysis of data from all five studies, the relative risk/10 mu T-years was 1.12 (95% confidence interval (95% CI) 0.98 to 1.28) for brain cancer, and 1.09 (95% CI 0.98 to 1.21) for leukaemia. Conclusions-The combined estimates seem to provide the best summary measures of the data from all studies. However, fluctuations in risks among studies may reflect real differences, and the exposure measurements in different studies may not be entirely comparable. C1 Elect Power Res Inst, Environm Div, EMF Business Area, Palo Alto, CA 94304 USA. NCI, Radiat Epidemiol Branch, Rockville, MD USA. INSERM, U88, Paris, France. So Calif Edison Co, Rosemead, CA USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. McGill Univ, Fac Med, Dept Occupat Hlth, Montreal, PQ, Canada. RP Kheifets, LI (reprint author), Elect Power Res Inst, Environm Div, EMF Business Area, 3412 Hillview Ave, Palo Alto, CA 94304 USA. NR 19 TC 32 Z9 33 U1 1 U2 2 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD AUG PY 1999 VL 56 IS 8 BP 567 EP 574 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 221AD UT WOS:000081701300012 PM 10492657 ER PT J AU Li, SZ Xu, JJ He, MG Wu, KL Munoz, SR Ellwein, LB AF Li, SZ Xu, JJ He, MG Wu, KL Munoz, SR Ellwein, LB TI A survey of blindness and cataract surgery in Doumen County, China SO OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT Global China Ophthalmology Congress CY AUG, 1998 CL BEIJING, PEOPLES R CHINA ID OF-LIFE OUTCOMES; SHUNYI COUNTY; PREVALENCE; NEPAL AB Purpose: To assess blindness prevalence and that caused specifically by cataract in rural southern China. Design: Population-based, cross-sectional study. Participants: A total of 5342 persons older than 50 years of age. Methods: Visual acuity and eye examinations were performed in the summer of 1997 in a random sample of villages in Doumen County. Differences in blindness prevalence associated with age, gender, and education were explored using logistic regression, The survey was preceded by a pilot study in which operational methods were refined and quality assurance measures were performed. Main Outcome Measures: Distance visual acuity and lens status. Results: Bilateral blindness (presenting visual acuity < 0.10) was found in 4.37% (95% confidence interval, 3.67%-5.06%). Blindness was associated with increasing age (P < 0.001) and with the lack of education (P < 0.01). Cataract was the principal cause of blindness in at least one eye in 61.5% of blind people, with refractive error responsible for another 10%. An estimated 40% of the cataract blind were operated on; surgical coverage was lowest among the elderly, women, and those without schooling, although not at statistically significant levels. Conclusions: Despite the increased attention given to eye care in Doumen County, blindness remains a major public health problem. Cataract surgery is reaching fewer than half of those who could benefit from it. C1 NEI, NIH, Bethesda, MD 20892 USA. Sun Yat Sen Univ Med Sci, Zongshan Ophthalm Ctr, Guangzhou, Peoples R China. Univ La Frontera, Unidad Epidemiol Clin, Temuco, Chile. RP Ellwein, LB (reprint author), NEI, NIH, 31 Ctr Dr, Bethesda, MD 20892 USA. RI wu, kaili/A-1227-2011; OI He, Mingguang/0000-0002-6912-2810; Wu, Kaili/0000-0003-3606-683X FU NEI NIH HHS [N01-EY-2103] NR 9 TC 98 Z9 112 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD AUG PY 1999 VL 106 IS 8 BP 1602 EP 1608 DI 10.1016/S0161-6420(99)90459-1 PG 7 WC Ophthalmology SC Ophthalmology GA 221NC UT WOS:000081732300040 PM 10442910 ER PT J AU He, MG Xu, JJ Li, SZ Wu, KL Munoz, SR Ellwein, LB AF He, MG Xu, JJ Li, SZ Wu, KL Munoz, SR Ellwein, LB TI Visual acuity and quality of life in patients with cataract in Doumen County, China SO OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT Global China Ophthalmology Congress CY AUG, 1998 CL BEIJING, PEOPLES R CHINA ID MADURAI INTRAOCULAR-LENS; OF-LIFE; OUTCOMES; BLINDNESS; INDIA AB Purpose: To evaluate the effectiveness of cataract surgery in achieving sight restoration and vision-related quality-of-rife (QOL) in patients from rural southern China. Design: Population-based, cross-sectional study. Participants: A total of 109 cataract operated persons (152 eyes) and 654 unoperated persons. Methods: Cluster sampling was used in identifying a random sample of 5342 persons 50 years of age and older for visual acuity and eye examinations. Visual functioning (VF) and QOL questionnaires were administered to aphakic and pseudophakic individuals, unoperated persons with presenting visual acuity less than 0.10 in either eye, and a sample of those with normal vision. Main Outcome Measures: Distance visual acuity, VF, and QOL questionnaire scores. Results: Among the cataract operated participants, 43 (39.4%) were bilaterally operated on, 32.1% had presenting visual acuity less than 0.10 in both eyes with 8.3% greater than or equal to 0.32 in both eyes. Of operated eyes, 52.6% presented with visual acuity less than 0.10, 23.7% greater than or equal to 0.32; with best correction, the corresponding percentages were 21.1% and 42.1%. Uncorrectable aphakia due to surgical complications was common. In a multivariate regression model, better visual acuity outcomes were associated with higher level surgeon practice settings and recent surgery. On a 0 to 100 scale, mean VF and QOL scores for the cataract operated population were 41.6 and 54.5, respectively. Mean scores ranged from 84.4 and 93.4, respectively, for the unoperated persons with normal vision, to 14.6 and 31.2, respectively, for those with visual acuity less than 0.05 in both eyes, The VF and QOL scores were closely correlated with presenting visual acuity in both cataract operated and unoperated populations (r = 0.49-0.64). Scores among the cataract operated population were not influenced by age, gender, or education level. Among the unoperated population, lack of education was associated with lower VF and QOL scores (P = 0.017 and P = 0.005, respectively), and older age was associated with lower QOL scores (P < 0.001). Conclusion: Patients in rural southern China are not realizing the full sight-restoring potential of modern-day cataract surgery, Remedial efforts are needed to improve the performance of local eye surgeons. C1 NEI, NIH, Bethesda, MD 20892 USA. Sun Yat Sen Univ Med Sci, Zhongshan Ophthalm Ctr, Guangzhou, Peoples R China. Univ La Frontera, Clin Epidemiol Unit, Temuco, Chile. RP Ellwein, LB (reprint author), NEI, NIH, 31 Ctr Dr, Bethesda, MD 20892 USA. RI wu, kaili/A-1227-2011; OI He, Mingguang/0000-0002-6912-2810; Wu, Kaili/0000-0003-3606-683X FU NEI NIH HHS [N01-EY-2103] NR 10 TC 68 Z9 83 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD AUG PY 1999 VL 106 IS 8 BP 1609 EP 1615 DI 10.1016/S0161-6420(99)90460-8 PG 7 WC Ophthalmology SC Ophthalmology GA 221NC UT WOS:000081732300041 PM 10442911 ER PT J AU Harris, LF Sullivan, MR Hatfield, DL AF Harris, LF Sullivan, MR Hatfield, DL TI Directed molecular evolution SO ORIGINS OF LIFE AND EVOLUTION OF BIOSPHERES LA English DT Article ID ELEMENT DNA-SEQUENCE; GLUCOCORTICOID RECEPTOR PROTEIN; SITE-SPECIFIC RECOGNITION; MAMMARY-TUMOR VIRUS; GENETIC-CODE; AMINO-ACIDS; DYNAMICS SIMULATION; BINDING DOMAIN; ALPHA-HELICES; COMPLEX AB We propose the existence of a relationship of stereochemical complementarity between gene sequences that code for interacting components: nucleic acid-nucleic acid, protein-protein and protein-nucleic acid. Such a relationship would impose evolutionary constraints on the DNA sequences themselves, thus retaining these sequences and governing the direction of the evolutionary process. Therefore, we propose that prebiotic, template-directed autocatalytic synthesis of mutally cognate peptides and polynucleotides resulted in their amplification and evolutionary conservation in contemporary prokaryotic and eukaryotic organisms as a genetic regulatory apparatus. If this proposal is correct, then the relationships between the sequences in DNA coding for these interactions constitute a life code of which the genetic code is only one aspect of the many related interactions encoded in DNA. C1 Abbott NW Hosp, David F Hickok Mem Canc Res Lab, Minneapolis, MN 55407 USA. NCI, Sect Mol Biol Selenium, Lab Basic Sci, NIH, Bethesda, MD 20892 USA. RP Harris, LF (reprint author), Abbott NW Hosp, David F Hickok Mem Canc Res Lab, 800 E 28th St, Minneapolis, MN 55407 USA. EM harrislf@sp.msl.umn.edu; hatfield@dc37a.nci.nih.gov NR 42 TC 1 Z9 1 U1 1 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0169-6149 J9 ORIGINS LIFE EVOL B JI Orig. Life Evol. Biosph. PD AUG PY 1999 VL 29 IS 4 BP 425 EP 435 DI 10.1023/A:1006683409144 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 215ZJ UT WOS:000081415500007 PM 10472630 ER PT J AU Reichling, DB Levine, JD AF Reichling, DB Levine, JD TI The primary afferent nociceptor as pattern generator SO PAIN LA English DT Article DE gate control theory; stimulus transduction; pain; polymodal nerve fiber ID ROOT GANGLION NEURONS; RAT SENSORY NEURONS; PROTEIN-KINASE-C; HYPERPOLARIZATION-ACTIVATED CURRENT; RESISTANT SODIUM-CHANNELS; NERVE GROWTH-FACTOR; ADULT-RAT; IN-VITRO; PHORBOL ESTERS; CA2+ CHANNELS AB One of the most important advances in our understanding of the pain experience was the introduction of the 'gate control' theory which stimulated analysis of activity pattern in nociceptive pathways and its modulation. Advances in cellular and molecular biology have recently begun to provide detailed information on the mechanisms of stimulus transduction within primary afferent nociceptors as well as mechanisms that modulate the transduction process. From these new insights into the sensory physiology of the nociceptive nerve ending emerges a concept of the primary afferent as the first site of pattern generation in the nociceptive pathway, in which dynamic tuning of gain in the mosaic of inputs to individual primary afferents occurs. The electrical properties of the nociceptor membrane that converts the generator potential to a pattern of action potentials is also actively adjusted. Our present understanding of the intracellular mechanisms that modulate the pattern of activity in nociceptive primary afferents is summarized, and implications for future efforts to unravel the meaning of patterning in nociceptor activity are discussed. (C) 1999 International Association for the Study of Pain. Published by Elsevier Science B.V. C1 Univ Calif San Francisco, NIH, Pain Ctr, San Francisco, CA 94143 USA. RP Reichling, DB (reprint author), Univ Calif San Francisco, NIH, Pain Ctr, San Francisco, CA 94143 USA. NR 100 TC 2 Z9 2 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD AUG PY 1999 SU 6 BP S103 EP S109 PG 7 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 233EH UT WOS:000082412200014 ER PT J AU Anderson, TJC Su, XZ Bockarie, M Lagog, M Day, KP AF Anderson, TJC Su, XZ Bockarie, M Lagog, M Day, KP TI Twelve microsatellite markers for characterization of Plasmodium falciparum from finger-prick blood samples SO PARASITOLOGY LA English DT Article DE microsatellite; Plasmodium falciparum; heterozygosity ID PAPUA-NEW-GUINEA; MEROZOITE SURFACE-ANTIGEN; POPULATION-STRUCTURE; CLINICAL IMMUNITY; POSITIVE SELECTION; NATURAL-SELECTION; MALARIA PARASITES; HUMORAL RESPONSE; PROTEIN; ANTIBODIES AB Multiple, selectively neutral genetic markers are the most appropriate tools for analysis of parasite population structure and epidemiology, but yet existing methods for characterization of malaria field samples utilize a limited number of antigen encoding genes, which appear to be under strong selection. We describe protocols for characterization of 12 microsatellite markers from finger-prick blood samples infected with Plasmodium falciparum. A two-step, heminested strategy was used to amplify all loci, and products were visualized by fluorescent end-labelling of internal primers. This procedure allows amplification from low levels of template, while eliminating the problem of spurious products due to primer carry over from the primary round of PCR. The loci can be conveniently multiplexed, while accurate sizing and quantification of PCR products can be automated using the GENOTYPER software. The primers do not amplify co-infecting malaria species such as P. vivax and P. malariae. To demonstrate the utility of these markers, we characterized 57 infected finger-prick blood samples from the village of Mebat in Papua New Guinea for all 12 loci, and all samples were genotyped a second time to measure reproducibility. Numbers of alleles per locus range from 4 to 10 in this population, while heterozygosities range from 0.21 to 0.87. Reproducibility (measured as concordance between predominant alleles detected in replicate samples) ranged from 92 to 98 % for the 12 loci. The composition of PCR products from infections containing multiple malaria clones could also be defined using strict criteria and scored in a highly repeatable manner. C1 Univ Oxford, Dept Zool, Wellcome Trust Ctr Epidemiol Infect Dis, Oxford OX1 3PS, England. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Papua New Guinea Inst Med Res, Madang, Papua N Guinea. RP Anderson, TJC (reprint author), SW Fdn Biomed Res, Dept Genet, POB 760549, San Antonio, TX 78245 USA. RI Day, Karen/F-3697-2015; OI Day, Karen/0000-0002-6115-6135; Su, Xinzhuan/0000-0003-3246-3248 FU Wellcome Trust NR 46 TC 202 Z9 206 U1 0 U2 6 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0031-1820 J9 PARASITOLOGY JI Parasitology PD AUG PY 1999 VL 119 BP 113 EP 125 DI 10.1017/S0031182099004552 PN 2 PG 13 WC Parasitology SC Parasitology GA 228KV UT WOS:000082136400001 PM 10466118 ER PT J AU Walsh, TJ Seibel, NL Arndt, C Harris, RE Dinubile, MJ Reboli, A Hiemenz, J Chanock, SJ AF Walsh, TJ Seibel, NL Arndt, C Harris, RE Dinubile, MJ Reboli, A Hiemenz, J Chanock, SJ TI Amphotericin B lipid complex in pediatric patients with invasive fungal infections SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE candidiasis; aspergillosis; fusariosis; zygomycosis; amphotericin B; amphotericin B lipid complex ID HUMAN-IMMUNODEFICIENCY-VIRUS; EXTRAPULMONARY CRYPTOCOCCOSIS; ANTIFUNGAL THERAPY; CHILDREN; ASPERGILLOSIS; MENINGITIS; EXPERIENCE; FUSARIUM; LEUKEMIA; TOXICITY AB Background Lipid formulations of amphotericin B have been recently introduced for treatment of invasive fungal infections. However, little is known about their role in pediatric populations. Methods. We studied the safety and antifungal efficacy of amphotericin B lipid complex (ABLC, Abelcet) in 111 treatment episodes in pediatric patients through an open label, emergency use multicenter study. Patients with invasive fungal infections were enrolled if they had mycoses refractory to conventional antifungal therapy, if they were intolerant of previous systemic antifungal agents or concomitant nephrotoxic drugs or if they had preexisting renal disease. Results. All 111 treatment episodes were evaluable for safety and 54 were evaluable for efficacy. The mean serum creatinine for the study population did not significantly change between baseline (1.23 +/- 0.11 mg/dl) and cessation of ABLC therapy (1.32 +/- 0.12 mg/dl) during 6 weeks. There were no significant differences observed between initial and end-of-therapy levels of serum potassium, magnesium, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and hemoglobin. However, there was an increase in mean total bilirubin (3.66 +/- 0.73 to 5.31 +/- 1.09 mg/dl) at the end of therapy (P = 0.054). Among 54 cases fulfilling criteria for evaluation of antifungal efficacy, a complete or partial therapeutic response was obtained in 38 patients (70%) after ABLC therapy, Complete or partial therapeutic response was documented in 56% of cases with aspergillosis (n = 25) and in 81% (n = 27) with candidiasis. Among premature infants (n = 8) and allogeneic marrow recipients (n = 14), response rates were 88 and 57%, respectively. Response was similar in those patients enrolled because of intolerance to previous antifungal therapy or because of progressive infection. Conclusions. These data support the use of ABLC for treatment of invasive fungal infections in pediatric patients who are intolerant of or refractory to conventional antifungal therapy. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. Childrens Hosp, Med Ctr, Cincinnati, OH 45229 USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Camden, NJ 08103 USA. Cooper Hosp Univ Med Ctr, Camden, NJ 08103 USA. Walt Disney Med Ctr, Orlando, FL USA. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bldg 10,Room 13N-240, Bethesda, MD 20892 USA. NR 30 TC 86 Z9 95 U1 0 U2 1 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 AUG PY 1999 VL 18 IS 8 BP 702 EP 708 DI 10.1097/00006454-199908000-00010 PG 7 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 226CR UT WOS:000082003200009 PM 10462340 ER PT J AU Guttler, F Azen, C Guldberg, P Romstad, A Hanley, WB Levy, HL Matalon, R Rouse, BM Trefz, F de la Cruz, F Koch, R AF Guttler, F Azen, C Guldberg, P Romstad, A Hanley, WB Levy, HL Matalon, R Rouse, BM Trefz, F de la Cruz, F Koch, R TI Relationship among genotype, biochemical phenotype, and cognitive performance in females with phenylalanine hydroxylase deficiency: Report from the Maternal Phenylketonuria Collaborative Study SO PEDIATRICS LA English DT Article DE phenylalanine hydroxylase; phenylketonuria; genotype-phenotype correlation; hyperphenylalaninemia; maternal phenylketonuria ID MUTATION GENOTYPE; GENE; POPULATION AB Objective. To examine the relationship of phenylalanine hydroxylase (PAH) genotypes to biochemical phenotype and cognitive development in maternal phenylketonuria (PKU). Methodology. PAH gene mutations were examined in 222 hyperphenylalaninemic females enrolled in the Maternal PKU Collaborative Study (MPKUCS). A total of 84 different mutations were detected, and complete genotype was obtained in 199 individuals. Based on previous knowledge about mutation-phenotype associations, 78 of the mutations could be assigned to one of four classes of severity (severe PKU, moderate PKU, mild PKU, and mild hyperphenylalaninemia [MHP]). Then, 189 MPKUCS subjects were grouped according to the various combinations of mutation classifications. The sample sizes were large enough for statistical testing in four groups with at least one mutation that completely abolishes enzyme activity. These patients are considered functionally hemizygous. Results. The biochemical phenotype predicted from the genotype in functionally hemizygous patients was related significantly to the assigned phenylalanine level. Cognitive performance (IQ) was also significantly related to genotype. The IQ of PAH-deficient mothers with a severe PKU mutation in combination with a MHP mutation or a mild PKU mutation was 99 and 96, respectively, whereas the IQ of PKU mothers with two severe PKU mutations or with one severe and one moderate PKU mutation was 83 and 84, respectively. Of the patients with PKU, 92% had been treated during childhood. Those who were untreated or treated late had lower than average IQ scores for their group of mutation combinations. Females with moderate or mild PKU who were treated early and treated for >6 years showed IQ scores 10 points above average for their group. Conclusions. The reproductive outcome in maternal phenylketonuria is dependent on prenatal metabolic control and postnatal environmental circumstances. Both factors depend on the intellectual resources of the mother with PKU. The significant relationship among genotype, biochemical phenotype, and cognitive performance observed in the present study is of importance for the development of an optimal strategy for future treatment of females with PKU who plan pregnancy. C1 John F Kennedy Inst, DK-2600 Glostrup, Denmark. Univ So Calif, Los Angeles, CA USA. Childrens Hosp, Div Med Genet, Los Angeles, CA 90027 USA. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. Childrens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. Univ Texas, Med Branch, Childrens Hosp, Galveston, TX 77550 USA. Univ Tubingen, Reutlingen, Germany. NICHHD, Bethesda, MD 20892 USA. RP Koch, R (reprint author), John F Kennedy Inst, GI Landevej 7, DK-2600 Glostrup, Denmark. FU BHP HRSA HHS [1-DH-2-3155]; NICHD NIH HHS [1-HD-2-3148, 1-HD-2-3149] NR 29 TC 44 Z9 47 U1 0 U2 4 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD AUG PY 1999 VL 104 IS 2 BP 258 EP 262 DI 10.1542/peds.104.2.258 PG 5 WC Pediatrics SC Pediatrics GA 222EP UT WOS:000081770700012 PM 10429004 ER PT J AU Ehrenkranz, RA Younes, N Lemons, JA Fanarof, AA Donovan, EF Wright, LL Katsikiotis, V Tyson, JE Oh, W Shankaran, S Bauer, CR Korones, SB Stoll, BJ Stevenson, DK Papile, LA AF Ehrenkranz, RA Younes, N Lemons, JA Fanarof, AA Donovan, EF Wright, LL Katsikiotis, V Tyson, JE Oh, W Shankaran, S Bauer, CR Korones, SB Stoll, BJ Stevenson, DK Papile, LA TI Longitudinal growth of hospitalized very low birth weight infants SO PEDIATRICS LA English DT Article; Proceedings Paper CT 65th Annual Meeting of the Society-for-Pediatric-Research CY MAY 02-10, 1996 CL WASHINGTON, D.C. SP Soc Pediat Res DE very low birth weight infant; growth curves; National Institute of Child Health and Human Development Neonatal Research Network ID DEVELOPMENT NEONATAL NETWORK; POSTNATAL-GROWTH; PREMATURE-INFANTS; MULTICENTER TRIAL; PRETERM INFANTS; FETAL GROWTH; OUTCOMES; DEXAMETHASONE; NUTRITION; STANDARD AB Background. The interpretation of growth rates for very low birth weight infants is obscured by limited data, recent changes in perinatal care, and the uncertain effects of multiple therapies. Objectives. To develop contemporary postnatal growth curves for very low birth weight preterm infants and to relate growth velocity to birth weight, nutritional practices, fetal growth status (small- or appropriate-for-gestational-age), and major neonatal morbidities (chronic lung disease, nosocomial infection or late-onset infection, severe intraventricular hemorrhage, and necrotizing enterocolitis). Design. Large, multicenter, prospective cohort study. Methods. Growth was prospectively assessed for 1660 infants with birth weights between 501 to 1500 g admitted by 24 hours of age to 1 of the 12 National Institute of Child Health and Human Development Neonatal Research Network centers between August 31, 1994 and August 9, 1995. Infants were included if they survived >7 days (168 hours) and were free of major congenital anomalies. Anthropometric measures (body weight, length, head circumference, and midarm circumference) were performed from birth until discharge, transfer, death, age 120 days, or a body weight of 2000 g. To obtain representative data, nutritional practices were not altered by the study protocol. Results. Postnatal growth curves suitable for clinical and research use were constructed for body weight, length, head circumference, and midarm circumference. Once birth weight was regained, weight gain (14.4-16.1 g/kg/d) approximated intrauterine rates. However, at hospital discharge, most infants born between 24 and 29 weeks of gestation had not achieved the median birth weight of the reference fetus at the same postmenstrual age. Gestational age, race, and gender had no effect on growth within 100-g birth weight strata. Appropriate-for-gestational age infants who survived to hospital discharge without developing chronic lung disease, severe intraventricular hemorrhage, necrotizing enterocolitis, or late onset-sepsis gained weight faster than comparable infants with those morbidities. More rapid weight gain was also associated with a shorter duration of parenteral nutrition providing at least 75% of the total daily fluid volume, an earlier age at the initiation of enteral feedings, and an earlier age at achievement of full enteral feedings. Conclusions. These growth curves may be used to better understand postnatal growth, to help identify infants developing illnesses affecting growth, and to aid in the design of future research. They should not be taken as optimal. Randomized clinical trials should be performed to evaluate whether different nutritional management practices will permit birth weight to be regained earlier and result in more rapid growth, more appropriate body composition, and improved short- and long-term outcomes. C1 Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06520 USA. George Washington Univ, Ctr Biostat, Rockville, MD USA. Indiana Univ, Indianapolis, IN 46204 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Cincinnati, Cincinnati, OH USA. NICHHD, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Brown Univ, Women & Infants Hosp, Providence, RI USA. Wayne State Univ, Detroit, MI USA. Univ Miami, Miami, FL 33152 USA. Univ Tennessee, Memphis, TN USA. Emory Univ, Atlanta, GA 30322 USA. Stanford Univ, Stanford, CA 94305 USA. Univ New Mexico, Albuquerque, NM 87131 USA. RP Ehrenkranz, RA (reprint author), Yale Univ, Sch Med, Dept Pediat, POB 208064,333 Cedar St, New Haven, CT 06520 USA. FU NCRR NIH HHS [MO1 RR 08084]; NICHD NIH HHS [U10 HD21364, U10 HD27853] NR 38 TC 397 Z9 428 U1 0 U2 15 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 AUG PY 1999 VL 104 IS 2 BP 280 EP 289 DI 10.1542/peds.104.2.280 PG 10 WC Pediatrics SC Pediatrics GA 222EP UT WOS:000081770700017 PM 10429008 ER PT J AU Wilfert, CM Aronson, JE Beck, DT Fleischman, AR Kline, MW Mofenson, LM Scott, GB Wara, DW Whitley-Williams, PN Lindegren, ML Halsey, NA Abramson, JS Chesney, PJ Fisher, MC Gerber, MA Marcy, SM Murray, DL Overturf, GD Prober, CG Saari, TN Weiner, LB Whitley, RJ Baker, CJ Peter, G Pickering, LK Hirsch, A Jacobs, RF MacDonald, NE Myers, MG Orenstein, WA Patriarca, PA Rabinovich, NR Schwartz, B AF Wilfert, CM Aronson, JE Beck, DT Fleischman, AR Kline, MW Mofenson, LM Scott, GB Wara, DW Whitley-Williams, PN Lindegren, ML Halsey, NA Abramson, JS Chesney, PJ Fisher, MC Gerber, MA Marcy, SM Murray, DL Overturf, GD Prober, CG Saari, TN Weiner, LB Whitley, RJ Baker, CJ Peter, G Pickering, LK Hirsch, A Jacobs, RF MacDonald, NE Myers, MG Orenstein, WA Patriarca, PA Rabinovich, NR Schwartz, B CA Comm Pediat AIDS Comm Infect Dis TI Issues related to human immunodeficiency virus transmission in schools, child care, medical settings, the home, and community SO PEDIATRICS LA English DT Article ID HEPATITIS-B VIRUS; INFECTED CHILDREN; HIV-INFECTION; TYPE-1 HIV-1; WORKERS; BLOOD; RISK; SURVEILLANCE; PERSONNEL; EXPOSURE AB Current recommendations of the American Academy of Pediatrics (AAP) for infection control practices to prevent transmission of blood-borne pathogens, including human immunodeficiency virus (HIV) in hospitals, other medical settings, schools, and child care facilities, are reviewed and explained. Hand-washing is essential, whether or not gloves are used, and gloves should be used when contact with blood or blood-containing body fluids may occur. In hospitalized children, the 1996 recommendations of the Centers for Disease Control and Prevention (CDC) should be implemented as modified in the 1997 Red Book. The generic principles of Standard Precautions in the CDC guidelines generally are applicable to children in all health care settings, schools, child care facilities, and the home. However, gloves are not required for routine changing of diapers or for wiping nasal secretions of children in most circumstances. This AAP recommendation differs from that in the CDC guidelines. Current US Public Health Service guidelines for the management of potential occupational exposures of health care workers to HIV are summarized. As previously recommended by the AAP, HIV-infected children should be admitted without restriction to child care centers and schools and allowed to participate in all activities to the extent that their health and other recommendations for management of contagious diseases permit. Because it is not required that the school be notified of HIV infection, it may be helpful if the pediatrician notify the school that he or she is operating under a policy of nondisclosure of infection with blood-borne pathogens. Thus, it is possible that the pediatrician will not report the presence of such infections on the form. Because HIV infection occurs in persons throughout the United States, these recommendations for prevention of HIV transmission should be applied universally. C1 Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. Amer Thorac Soc, New York, NY USA. Canadian Paediat Soc, Ottawa, ON, Canada. Natl Vaccine Program Off, Atlanta, GA USA. US FDA, Rockville, MD 20857 USA. NIH, Bethesda, MD 20892 USA. RP Wilfert, CM (reprint author), Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. OI Mofenson, Lynne/0000-0002-2818-9808 NR 55 TC 4 Z9 4 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD AUG PY 1999 VL 104 IS 2 BP 318 EP 324 PG 7 WC Pediatrics SC Pediatrics GA 222EP UT WOS:000081770700039 ER PT J AU Desposito, F Desposito, F Cunniff, C Frias, JL Panny, SR Trotter, TL Wappner, RS Hanson, JW Elias, S Moore, CA Lloyd-Puryear, M de la Cruz, F Pletcher, BA Cho, SC AF Desposito, F Desposito, F Cunniff, C Frias, JL Panny, SR Trotter, TL Wappner, RS Hanson, JW Elias, S Moore, CA Lloyd-Puryear, M de la Cruz, F Pletcher, BA Cho, SC CA Comm Genetics TI Folic acid for the prevention of neural tube defects SO PEDIATRICS LA English DT Article ID VITAMIN SUPPLEMENTATION AB The American Academy of Pediatrics endorses the US Public Health Service (USPHS) recommendation that all women capable of becoming pregnant consume 400 mu g of folic acid daily to prevent neural tube defects (NTDs). Studies have demonstrated that periconceptional folic acid supplementation can prevent 50% or more of NTDs such as spina bifida and anencephaly. For women who have previously had an NTD-affected pregnancy, the Centers for Disease Control and Prevention (CDC) recommends increasing the intake of folic acid to 4000 mu g per day beginning at least 1 month before conception and continuing through the first trimester. Implementation of these recommendations is essential for the primary prevention of these serious and disabling birth defects. Because fewer than 1 in 3 women consume the amount of folic acid recommended by the USPHS, the Academy notes that the prevention of NTDs depends on an urgent and effective campaign to close this prevention gap. C1 Amer Coll Med Genet, Bethesda, MD USA. Amer Coll Obstetricians & Gynecologists, Washington, DC 20024 USA. Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. US Hlth Resources & Serv Adm, Rockville, MD 20857 USA. NIH, Bethesda, MD 20892 USA. RP Desposito, F (reprint author), Amer Coll Med Genet, Bethesda, MD USA. NR 18 TC 50 Z9 55 U1 0 U2 2 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 AUG PY 1999 VL 104 IS 2 BP 325 EP 327 PG 3 WC Pediatrics SC Pediatrics GA 222EP UT WOS:000081770700040 ER PT J AU Etzel, RA Balk, SJ Bearer, CF Miller, MD Shannon, MW Shea, KM Falk, H Goldman, LR Miller, RW Rogan, W Coven, B AF Etzel, RA Balk, SJ Bearer, CF Miller, MD Shannon, MW Shea, KM Falk, H Goldman, LR Miller, RW Rogan, W Coven, B CA Comm Environm Hlth TI Ultraviolet light: A hazard to children SO PEDIATRICS LA English DT Article ID CUTANEOUS MALIGNANT-MELANOMA; SUN EXPOSURE; SKIN-CANCER; FASHION MAGAZINES; SUNSCREEN USE; PROTECTION; TRENDS; NEVI; PHOTOPROTECTION; MORTALITY C1 Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. US EPA, Washington, DC 20460 USA. NCI, Bethesda, MD 20892 USA. NIEHS, Bethesda, MD 20892 USA. RP Etzel, RA (reprint author), Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. RI Goldman, Lynn/D-5372-2012; OI Miller, Mark/0000-0002-9301-0093 NR 45 TC 58 Z9 62 U1 0 U2 4 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD AUG PY 1999 VL 104 IS 2 BP 328 EP 333 PG 6 WC Pediatrics SC Pediatrics GA 222EP UT WOS:000081770700041 ER PT J AU Starc, TJ Lipshultz, SE Kaplan, S Easley, KA Bricker, JT Colan, SD Lai, WW Gersony, WM Sopko, G Moodie, DS Schluchter, MD AF Starc, TJ Lipshultz, SE Kaplan, S Easley, KA Bricker, JT Colan, SD Lai, WW Gersony, WM Sopko, G Moodie, DS Schluchter, MD CA Natl Heart Lung Blood Inst TI Cardiac complications in children with human immunodeficiency virus infection SO PEDIATRICS LA English DT Article; Proceedings Paper CT 64th Annual Meeting of the Society-for-Pediatric-Research CY MAY 05-11, 1995 CL SAN DIEGO, CALIFORNIA SP Soc Pediat Res DE HIV; cardiac disease; pediatrics ID P(2)C(2) HIV MULTICENTER; HEART; ABNORMALITIES; CONTRACTILITY; ZIDOVUDINE; DISEASE; INFANTS AB Objective. Although numerous cardiac abnormalities have been reported in HIV-infected children, precise estimates of the incidence of cardiac disease in these children are not well-known. The objective of this report is to describe the 2-year cumulative incidence of cardiac abnormalities in HIV-infected children. Methodology: Design. Prospective cohort (Group I) and inception cohort (Group II) study design. Setting. A volunteer sample from 10 university and public hospitals. Participants. Group I consisted of 205 HIV vertically infected children enrolled at a median age of 22 months. This group was comprised of infants and children already known to be HIV-infected at the time of enrollment in the study. Most of the children were African-American or Hispanic and 89% had symptomatic HIV infection at enrollment. The second group included 611 neonates born to HIV-infected mothers, enrolled during fetal life or before 28 days of age (Group II). In contrast to the older Group I children, all the Group II children were enrolled before their HIV status was ascertained. Interventions. According to the study protocol, children underwent a series of cardiac evaluations including two-dimensional echocardiogram and Doppler studies of cardiac function every 4 to 6 months. They also had a 12- or 15-lead surface electrocardiogram (ECG), 24-hour ambulatory ECG monitoring, and a chest radiograph every 12 months. Outcome Measures. Main outcome measures were the cumulative incidence of an initial episode of left ventricular (LV) dysfunction, cardiac enlargement, and congestive heart failure (CHF). Because cardiac abnormalities tended to cluster in the same patients, we also determined the number of children who had cardiac impairment which we defined as having either left ventricular fractional shortening (LV FS) less than or equal to 25% after 6 months of age, CHF, or treatment with cardiac medications. Results: Cardiac Abnormalities. In Group I children (older cohort), the prevalence of decreased LV function (FS less than or equal to 25%) was 5.7% and the 2-year cumulative incidence (excluding prevalent cases) was 15.3%. The prevalence of echocardiographic LV enlargement (LV end-diastolic dimension z score >2) at the time of the first echocardiogram was 8.3%. The cumulative incidence of LV end-diastolic enlargement was 11.7% after 2 years. The cumulative incidence of CHF and/or the use of cardiac medications was 10.0% in Group I children. There were 14 prevalent cases of cardiac impairment (LV FS less than or equal to 25% after 6 months of age, CHF, or treatment with cardiac medications) in Group I. After excluding these prevalent cases, the 2-year cumulative incidence of cardiac impairment was 19.1% among Group I children and 80.9% remained free of cardiac impairment after 2 years of follow-up. Within Group II (neonatal cohort), the 2-year cumulative incidence of decreased LV FS was 10.7% in the HIV-infected children compared with 3.1% in the HIV-uninfected children. LV dilatation was also more common in Group II infected versus uninfected children (8.7% vs 2.1%). The cumulative incidence of CHF and/or the use of cardiac medications was 8.8% in Group II infected versus 0.5% in uninfected subjects. The 1- and 2-year cumulative incidence rates of cardiac impairment for Group II infected children were 10.1% and 12.8%, respectively, with 87.2% free of cardiac impairment after the first 2 years of life. Mortality. In the Group I cohort, the 2-year cumulative death rate from all causes was 16.9% [95% CI: 11.7%-22.1%]. The 1- and 2-year mortality rates after the diagnosis of CHF (Kaplan-Meier estimates) were 69% and 100%:, respectively. In the Group II cohort, the 2-year cumulative death rate from all causes was 16.3% [95% CI: 8.8%-23.9%] in the HIV-infected children compared with no deaths among the 463 uninfected Group II children. Two of the 4 Group II children with CHF died during the 2-year observation period and 1 more died within 2 years of the diagnosis of CHF. The 2-year mortality rate after the diagnosis of CHF was 75%. Conclusions. This study reports that in addition to subclinical cardiac abnormalities previously reported by the (PC2)-C-2 Study Group, an important number of HIV-infected children develop clinical heart disease. Over a 2-year period, approximately 10% of HIV-infected children had CHF or were treated with cardiac medications. In addition, approximately 20% of HIV-infected children developed depressed LV function or LV dilatation and it is likely that these abnormalities are hallmarks of future clinically important cardiac dysfunction. Cardiac abnormalities were found in both the older (Group I) as well as the neonatal cohort (Group II) (whose HIV infection status was unknown before enrollment) thereby minimizing potential selection bias based on previously known heart disease. Based on these findings, we recommend that clinicians need to maintain a high degree of suspicion for heart disease in HIV-infected children. All HIV-infected infants and children should have a thorough baseline cardiac evaluation. Patients who develop symptoms of heart or lung disease should undergo more detailed cardiac examinations including ECG and cardiac ultrasound. C1 Columbia Univ, Sch Med, Presbyterian Hosp, Dept Pediat,Div Pediat Cardiol, New York, NY USA. Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA. Univ Calif Los Angeles, Dept Pediat, Div Pediat Cardiol, Los Angeles Med Ctr, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90024 USA. Cleveland Clin, Dept Biostat, Cleveland, OH 44106 USA. Cleveland Clin, Dept Epidemiol, Cleveland, OH 44106 USA. Cleveland Clin, Dept Pediat, Cleveland, OH 44106 USA. Cleveland Clin, Div Pediat Cardiol, Cleveland, OH 44106 USA. Baylor Coll Med, Dept Pediat, Div Pediat Cardiol, Houston, TX 77030 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Mt Sinai Sch Med, Dept Pediat, Div Pediat Cardiol, New York, NY USA. RP Starc, TJ (reprint author), Columbia Presbyterian Med Ctr, Babies & Childrens Hosp 2 N, 630 W 168th St, New York, NY 10032 USA. FU NCRR NIH HHS [M01 RR000071, M01 RR000188, M01 RR000645, M01 RR000865, M01 RR002172, K01 RR000188, M01 RR000533, M01 RR000043]; NHLBI NIH HHS [N01 HR096037, N01 HR096043] NR 22 TC 25 Z9 26 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD AUG PY 1999 VL 104 IS 2 AR e14 DI 10.1542/peds.104.2.e14 PG 9 WC Pediatrics SC Pediatrics GA 222EP UT WOS:000081770700018 PM 10429132 ER PT J AU Machalek, AZ AF Machalek, AZ TI Communicating with the public - It's in your best interest SO PHARMACEUTICAL RESEARCH LA English DT News Item C1 NIGMS, Off Commun & Publ Liaison, NIH, Bethesda, MD 20892 USA. RP Machalek, AZ (reprint author), NIGMS, Off Commun & Publ Liaison, NIH, 45 Ctr Dr,Room 1AS-25, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 J9 PHARMACEUT RES JI Pharm. Res. PD AUG PY 1999 VL 16 IS 8 BP 1147 EP 1148 DI 10.1023/A:1011972808230 PG 2 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 226XF UT WOS:000082047800001 PM 10468012 ER PT J AU Rogan, WJ Ragan, NB Damokosh, AI Davoli, C Shaffer, TR Jones, RL Wilkens, S Heenehan, MC Ware, JH Henretig, F AF Rogan, WJ Ragan, NB Damokosh, AI Davoli, C Shaffer, TR Jones, RL Wilkens, S Heenehan, MC Ware, JH Henretig, F TI Recall of a lead-contaminated vitamin and mineral supplement in a clinical trial SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE succimer; lead poisoning; mineral supplements; children; clinical trials AB Purpose - The Treatment of Lead-exposed Children (TLC) trial tested whether developmental outcome differed between children treated for lead poisoning with succimer or placebo. On 7 July 1997, TLC was informed that the vitamin and mineral supplements it gave to ail children were contaminated with about 35 mu g of lead per tablet. Methods - TLC recalled the contaminated supplements and measured the children's exposure. Results - The families of 96% of the children were contacted with 30 days. Among the 571 children to whom the contaminated supplements were dispensed, the mean increase in blood lead was 0.06 +/- 0.01 mu mol/L (1.2 +/- 0.2 mu g/dL); among 78 children to whom they were not, it was 0.09 +/- 0.03 mu mol/L (1.8 +/- 0.7 mu g/dL). There was no evidence of a dose-response relation between estimated supplement consumption and increase in blood lead concentration. Conclusions-The children's blood lead concentrations were not detectably affected by the contamination. Since the association of cognitive delay with lead exposure is best described for blood lead, we believe that the trial's inference about the effect of drug therapy on lead induced cognitive delay should be unaffected. Copyright (C) 1999 John Wiley & Sons, Ltd. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Kennedy Krieger Inst, Baltimore, MD USA. US Dept HHS, Program Support Ctr, Perry Point, MD USA. Ctr Dis Control & Prevent, Nutr Biochem Branch, Atlanta, GA USA. Univ Cincinnati, Cincinnati, OH USA. Univ Med & Dent New Jersey, Newark, NJ 07103 USA. Childrens Hosp, Philadelphia, PA 19104 USA. RP Rogan, WJ (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. RI Jones, Robert/E-1170-2011; Rogan, Walter/I-6034-2012 OI Rogan, Walter/0000-0002-9302-0160 NR 2 TC 9 Z9 9 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG-SEP PY 1999 VL 8 IS 5 BP 343 EP 350 PG 8 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 239XC UT WOS:000082794500005 PM 15073911 ER PT J AU Hansen, PL Svensek, D Parsegian, VA Podgornik, R AF Hansen, PL Svensek, D Parsegian, VA Podgornik, R TI Buckling, fluctuations, and collapse in semiflexible polyelectrolytes SO PHYSICAL REVIEW E LA English DT Article ID RODLIKE POLYELECTROLYTES; RENORMALIZATION-GROUP; PERSISTENCE LENGTH; TETHERED MEMBRANES; DNA; TRANSITIONS; ATTRACTION; LIMIT AB We present a systematic statistical mechanical analysis of the conformational properties of a stiff polyelectrolyte chain with intrachain attractions that are due to counterion correlations. We show that the mean-field solution corresponds to an Euler-like buckling instability. The effect of the conformational fluctuations on the buckling instability is investigated, first, qualitatively, within the harmonic ("semiclassical") theory, then, systematically, within a 1/d expansion, where d denotes the dimension of embedding space. Within the "semiclassical" approximation, we predict that the effect of fluctuations is to renormalize the effective persistence length to smaller values, but not to change thenature of the mean-field (i.e., buckling) behavior. Based on the 1/d expansion we are, however, led to conclude that thermal fluctuations are responsible for a change of the buckling behavior which is turned into polymer collapse. A phase diagram is constructed in which a sequence of collapse transitions terminates at a buckling instability that occurs at a place that varies with the magnitude of the bare persistence length of the polymer chain, as well as with the strength and range of the attractive potential. [S1063-651X(99)04708-X]. C1 Univ Calif Santa Barbara, Inst Theoret Phys, Santa Barbara, CA 93106 USA. NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. Univ Ljubljana, Fac Math & Phys, Dept Phys, SI-1000 Ljubljana, Slovenia. Jozef Stefan Inst, Dept Theoret Phys, SI-1000 Ljubljana, Slovenia. RP Podgornik, R (reprint author), Univ Calif Santa Barbara, Inst Theoret Phys, Santa Barbara, CA 93106 USA. RI Podgornik, Rudolf/C-6209-2008 OI Podgornik, Rudolf/0000-0002-3855-4637 NR 36 TC 38 Z9 38 U1 0 U2 4 PU AMERICAN PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1063-651X J9 PHYS REV E JI Phys. Rev. E PD AUG PY 1999 VL 60 IS 2 BP 1956 EP 1966 DI 10.1103/PhysRevE.60.1956 PN B PG 11 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 230CW UT WOS:000082235100041 PM 11969988 ER PT J AU Venkatesh, B Ramasamy, S Swarnalatha, V Santhanalakshmi, J Asokan, R Rifkind, JM Manoharan, PT AF Venkatesh, B Ramasamy, S Swarnalatha, V Santhanalakshmi, J Asokan, R Rifkind, JM Manoharan, PT TI Surfactant-induced stabilization of four-coordinated hemes in reconstituted hemoglobins SO PROCEEDINGS OF THE INDIAN ACADEMY OF SCIENCES-CHEMICAL SCIENCES LA English DT Article DE surface-induced stabilization; 4-coordinated hemes; reconstituted hemoglobins; hemoglobin-surfactant interaction ID HYBRID HEMOGLOBINS; CYTOCHROME-C; CONFORMATION; EQUILIBRIUM; SPECTRA AB A transition from 5-coordination to 4-coordination metal centres of porphyrins in carbonmonoxy Fe(II), Cu(II) and Ni(II) hemoglobins is observed as a consequence of ionic surfactant interactions with metalloproteins through UV-Vis studies. SDS (anionic) and CTAB (cationic) surfactants are used. Values of heme partition coefficient (K) between globin and surfactant show that, in both CTAB and SDS, partitioning increases proportionately with surfactant concentration for a fixed concentration of hemoglobin. The interactions seem to be mainly hydrophobic in nature with metalloproteins, though coordination and coulombic interactions may also play a minor role in CTAB and SDS respectively. The present study provides new insight into reconstituted hemoglobin-surfactant interaction. C1 Indian Inst Technol, Dept Chem, Chennai 600036, India. Indian Inst Technol, Reg Sophisticated Instrumentat Ctr, Chennai 600036, India. Univ Madras, Dept Phys Chem, Chennai 600025, India. Natl Inst Hlth, Inst Aging, Cellular & Mol Biol Lab, Mol Dynam Sect, Baltimore, MD 21224 USA. RP Manoharan, PT (reprint author), Indian Inst Technol, Dept Chem, Chennai 600036, India. NR 27 TC 2 Z9 2 U1 0 U2 2 PU INDIAN ACADEMY SCIENCES PI BANGALORE PA P B 8005 C V RAMAN AVENUE, BANGALORE 560 080, INDIA SN 0253-4134 J9 P INDIAN AS-CHEM SCI JI Proc. Indian Acad. Sci.-Chem. Sci. PD AUG PY 1999 VL 111 IS 4 BP 547 EP 554 PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA 244FN UT WOS:000083041300001 ER PT J AU Oriji, GK AF Oriji, GK TI Angiotensin II-induced ET and PGI(2) release in rat aortic endothelial cells is meditated by PKC SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article ID PROTEIN-KINASE-C; IMMUNOREACTIVE ENDOTHELIN; PROSTAGLANDINS; INCREASES; MECHANISM; RABBIT AB Angiotensin II (Ang II) has been shown to stimulate the release of immunoreactive endothelin (ET) from cultured bovine ECs. Also, Ang II activates phospholipase A(2) (PLA(2)) in various tissues, resulting in the release of arachidonic acid and formation of prostaglandins. We used rat aortic endothelial cells to investigate the role of protein kinase C (PKC) in Ang II-induced release of both ET and prostacyclin (PGI(2)). The amount of ET and PGI(2) produced were determined by radioimmunoassay. Ang Ii-induced the release of both ET and PGI(2). Pretreatment with 10(-6)M of any one of the PKC inhibitors: 1-(5-isoquinolinesulfonyl) piperazine(CL), staurosporine, 1-(5-isoquinolinesulfonylmethyl)piperazine(H7), and calphostin C blocked AII-induced release of both ET and PGI(2). In rat aortic endothelial cells that were treated with either AII or PDBu, PKC enzyme assay showed PKC was translocated from the cytosol to the membrane which indicates activation. This suggests that PKC mediates All-induced ET and PGI(2) release. In summary, All activates PKC which inhibits rat aortic endothelial cells ET and PGI(2) formation, and this inhibition can be overcome by pretreatment with PKC inhibitors. C1 William Paterson Univ, Coll Sci & Hlth, Dept Biol, Wayne, NJ 07470 USA. NHLBI, Hypertens Endocrine Branch, NIH, Bethesda, MD 20892 USA. RP Oriji, GK (reprint author), William Paterson Univ, Coll Sci & Hlth, Dept Biol, Wayne, NJ 07470 USA. NR 27 TC 15 Z9 16 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 0952-3278 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD AUG PY 1999 VL 61 IS 2 BP 113 EP 117 DI 10.1054/plef.1999.0079 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 242WA UT WOS:000082963600006 PM 10509866 ER PT J AU Oriji, GK AF Oriji, GK TI Cyclosporine A-induced prostacyclin release is maintained by extracellular calcium in rat aortic endothelial cells: role of protein kinase C SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article ID SMOOTH-MUSCLE CELLS; VASCULAR RELAXATION; CONTRACTION; ANGIOTENSIN; RESPONSES; RABBIT AB Chronic treatment with the immunosuppressive drug Cyclosporine A (CsA) is associated with increased intracellular calcium in vascular smooth muscle cells, which may activate phospholipase A(2). We used rat aortic endothelial cells to investigate the role of protein kinase C (PKC) in CsA-induced prostacyclin (PGI(2)) release. CsA (10(-9)M) produced a significant increase in PGI(2) release. CsA-induced PGI(2) release were inhibited 80-85% by 10(-9)M, and 99-100% by 10(-6)M pretreatment doses of any of three different PKC inhibitors, i.e. 1-(5-isoquinolinesulfonylmethyl)piperazine(H7), staurosporine or 1-(5-isoquinolinesulfonyl)piperazine. Pretreatment with (10(-9)M) of diltiazem (a voltage-sensitive L-type calcium channel blocker) completely inhibited both CsA-induced PGI(2) release. Conversely, pretreatment with (10(-9)M) of thapsigargin (an intracellular calcium channel blocker) did not alter the action of CsA. These results strongly suggest that PKC, in association with an influx of extracellular calcium, mediates CsA-induced PGI(2) release in rat aortic endothelial cells. C1 William Paterson Univ, Coll Sci & Hlth, Dept Biol, Wayne, NJ 07470 USA. NHLBI, Hypertens Endocrine Branch, NIH, Bethesda, MD 20892 USA. RP Oriji, GK (reprint author), William Paterson Univ, Coll Sci & Hlth, Dept Biol, Wayne, NJ 07470 USA. NR 24 TC 5 Z9 5 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 AUG PY 1999 VL 61 IS 2 BP 119 EP 123 DI 10.1054/plef.1999.0080 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 242WA UT WOS:000082963600007 PM 10509867 ER PT J AU Hui, R Kameda, H Risinger, JI Angerman-Stewart, J Han, B Barrett, JC Eling, TE Glasgow, WC AF Hui, R Kameda, H Risinger, JI Angerman-Stewart, J Han, B Barrett, JC Eling, TE Glasgow, WC TI The linoleic acid metabolite, 13-HpODE augments the phosphorylation of EGF receptor and SHP-2 leading to their increased association SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article ID EPIDERMAL GROWTH-FACTOR; PROTEIN-TYROSINE-PHOSPHATASE; HAMSTER EMBRYO FIBROBLASTS; PHOSPHOTYROSINE PHOSPHATASE; MITOGENIC RESPONSE; ARACHIDONIC-ACID; BREAST-CANCER; SH-PTP2; DEPHOSPHORYLATION; PHENOTYPES AB In previous studies with Syrian hamster embryo fibroblasts, we found that a specific lipoxygenase metabolite of linoleic acid, 13(S)-hydroperoxyoctadecadienoic acid (HpODE), enhanced epidermal growth factor (EGF) signal transduction in a tumor suppressor gene plus phenotype (supB(+)); with a diminished response to 13(S)-HpODE in a tumor suppressor gene minus phenotype (supB(-)). This differential response was attributed to differences in the rate of EGF receptor (EGFR) dephosphorylation. To further define the molecular basis for these observations, in this report we examine the interaction of phosphorylated EGFR with the SH2 domain-containing protein tyrosine phosphatase, SHP-2, a positive modulator of EGF dependent cell growth. SHP-2 associated with phosphorylated EGFR to a greater extent in supB+ cells when compared to supB-. This differential association could not be accounted for by differences between suppressor gene phenotypes in SHP-2 protein level or mutations in the molecular sequence, The addition of 13(S)-HpODE stimulated a concentration-dependent increase in EGF-dependent phosphorylation of SHP-2 and its association with EGFR. A more dramatic response was observed in the supB(+) cells. Differences in SHP-2 interaction with EGFR may account, in part, for phenotypic differences in the growth rates and responsiveness to EGF between the supB(+) and supB(-) cells, EGFR-SHP-2 association appears to play an important role in the regulation of EGFR signal transduction. C1 NIEHS, Mol Carcinogenesis Lab, Eicosanoid Biochem Sect, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Carcinogenesis Lab, Canc & Aging Sect, Res Triangle Pk, NC 27709 USA. Mercer Univ, Sch Med, Div Basic Med Sci, Macon, GA 31207 USA. RP Eling, TE (reprint author), NIEHS, Mol Carcinogenesis Lab, Eicosanoid Biochem Sect, POB 12233, Res Triangle Pk, NC 27709 USA. NR 19 TC 8 Z9 8 U1 0 U2 3 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 AUG PY 1999 VL 61 IS 2 BP 137 EP 143 DI 10.1054/plef.1999.0083 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 242WA UT WOS:000082963600010 PM 10509870 ER PT J AU Tsai, CJ Maizel, JV Nussinov, R AF Tsai, CJ Maizel, JV Nussinov, R TI Distinguishing between sequential and nonsequentially folded proteins: Implications for folding and misfolding SO PROTEIN SCIENCE LA English DT Article DE building block; funnels; hydrophobic folding unit; misfolding; protein folding; sequential folding ID SECONDARY STRUCTURE PREDICTION; IN-VIVO; FRAGMENT COMPLEMENTATION; SUPERSECONDARY STRUCTURE; PEPTIDE-FRAGMENTS; INITIATION SITES; COMPACT UNITS; DATA-BANK; BETA; MODELS AB We describe here an algorithm for distinguishing sequential from nonsequentially folding proteins. Several experiments have recently suggested that most of the proteins that are synthesized in the eukaryotic cell may fold sequentially. This proposed folding mechanism in vivo is particularly advantageous to the organism. In the absence of chaperones, the probability that a sequentially folding protein will misfold is reduced significantly. The problem we address here is devising a procedure that would differentiate between the two types of folding patterns. Footprints of sequential folding may be found in structures where consecutive fragments of the chain interact with each other. In such cases, the folding complexity may be viewed as being lower. On the other hand, higher folding complexity suggests that at least a portion of the polypeptide backbone folds back upon itself to form three-dimensional (3D) interactions with noncontiguous portion(s) of the chain. Hence, we look at the mechanism of folding of the molecule via analysis of its complexity, that is, through the 3D interactions formed by contiguous segments on the polypeptide chain. To computationally splice the structure into consecutively interacting fragments, we either cut it into compact hydrophobic folding units or into a set of hypothetical, transient, highly populated, contiguous :fragments ("building blocks" of the structure). In sequential folding, successive building blocks interact with each other from the amino to the carboxy terminus of the polypeptide chain. Consequently, the results of the parsing differentiate between sequentially vs. nonsequentially folded chains. The automated assessment of the folding complexity provides insight into both the likelihood of misfolding and the kinetic folding rate of the given protein. In terms of the funnel free energy landscape theory, a protein that truly follows the mechanism of sequential folding, in principle, encounters smoother free energy barriers. A simple sequentially folded protein should, therefore, be less error prone and fold faster than a protein with a complex folding pattern. C1 NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, SAIC,Intramural Res Support Program, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Frederick Canc Res Facil, Bldg 469,Room 151, Frederick, MD 21702 USA. FU NCI NIH HHS [1-CO-74102] NR 57 TC 18 Z9 19 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 1999 VL 8 IS 8 BP 1591 EP 1604 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 224PT UT WOS:000081908000002 PM 10452603 ER PT J AU Zhang, H Grishin, NV AF Zhang, H Grishin, NV TI The alpha-subunit of protein prenyltransferases is a member of the tetratricopeptide repeat family SO PROTEIN SCIENCE LA English DT Article DE helix packing; protein evolution; protein-protein interactions; protein prenyltransferases; tetratricopeptide repeat ID RAB GERANYLGERANYL TRANSFERASE; LEUCINE-RICH REPEAT; CRYSTAL-STRUCTURE; FARNESYLTRANSFERASE; MOTIFS; TPR; EXPRESSION; ALIGNMENT; DISTANCE; MATRICES AB Lipidation catalyzed by protein prenyltransferases is essential for the biological function of a number of eukaryotic proteins, many of which are involved in signal transduction and vesicular traffic regulation. Sequence similarity searches reveal that the alpha-subunit of protein prenyltransferases (PT alpha) is a member of the tetratricopeptide repeat (TPR) superfamily. This finding makes the three-dimensional structure of the rat protein farnesyltransferase the first structural model of a TPR protein interacting with its protein partner. Structural comparison of the two TPR domains in protein farnesyltransferase and protein phosphatase 5 indicates that variation in TPR consensus residues may affect protein binding specificity through altering the overall shape of the TPR superhelix. A general approach to evolutionary analysis of proteins with repetitive sequence motifs has been developed and applied to the protein prenyltransferases and other TPR proteins. The results suggest that all members in PT alpha family originated from a common multirepeat ancestor, while the common ancestor of PT alpha and other members of TPR superfamily is likely to be a single repeat protein. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Univ Maryland, Inst Biotechnol, Rockville, MD 20850 USA. Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. RP Grishin, NV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM grishin@ncbi.nlm.nih.gov FU NIGMS NIH HHS [GM7890-01] NR 40 TC 17 Z9 17 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 1999 VL 8 IS 8 BP 1658 EP 1667 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 224PT UT WOS:000081908000009 PM 10452610 ER PT J AU Kapust, RB Waugh, DS AF Kapust, RB Waugh, DS TI Escherichia coli maltose-binding protein is uncommonly effective at promoting the solubility of polypeptides to which it is fused SO PROTEIN SCIENCE LA English DT Article DE aggregation; fusion protein; glutathione S-transferase; inclusion bodies; maltose-binding protein; protein folding; solubility; thioredoxin ID GREEN-FLUORESCENT PROTEIN; HIGH-LEVEL EXPRESSION; SOLUBLE RECOMBINANT PROTEINS; FUSION PROTEIN; PURIFICATION; DOMAIN; GENE; THIOREDOXIN; BACTERIAL; RECEPTOR AB Although it is usually possible to achieve a favorable yield of a recombinant protein in Escherichia coli, obtaining the protein in a soluble, biologically active form continues to be a major challenge. Sometimes this problem can be overcome by fusing an aggregation-prone polypeptide to a highly soluble partner. To study this phenomenon in greater detail, we compared the ability of three soluble fusion partners-maltose-binding protein (MBP), glutathione S-transferase; (GST), and thioredoxin (TRX)-to inhibit the aggregation of six diverse proteins that normally accumulate in an insoluble form. Remarkably, we found that MEP is a far more effective solubilizing agent than the other two fusion partners. Moreover. we demonstrated that in some cases fusion to MEP can promote the proper folding of the attached protein into its biologically active conformation. Thus, MBP seems to be capable of functioning as a general molecular chaperone in the context of a fusion protein. A model is proposed to explain how MBP promotes the solubility and influences the folding of its fusion partners. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. RP Waugh, DS (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, POB B, Frederick, MD 21702 USA. NR 46 TC 569 Z9 604 U1 6 U2 63 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 1999 VL 8 IS 8 BP 1668 EP 1674 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 224PT UT WOS:000081908000010 PM 10452611 ER PT J AU Xie, D Gulnik, S Gustchina, E Yu, B Shao, W Qoronfleh, W Nathan, A Erickson, JW AF Xie, D Gulnik, S Gustchina, E Yu, B Shao, W Qoronfleh, W Nathan, A Erickson, JW TI Drug resistance mutations can affect dimer stability of HIV-1 protease at neutral pH SO PROTEIN SCIENCE LA English DT Article DE dimer stability; drug resistant; HIV-1 protease; sedimentation equilibrium ID IMMUNODEFICIENCY VIRUS PROTEASE; MUTAGENESIS; INHIBITORS; DISSOCIATION; PROTEINASES; MUTANTS AB The monomer-dimer equilibrium for the human immunodeficiency virus type 1 (HIV-1) protease has been investigated under physiological conditions. Dimer dissociation at pH 7.0 was correlated with a loss in beta-sheet structure and a lower degree of ANS binding. An autolysis-resistant mutant, Q7K/L33I/L63I, was used to facilitate sedimentation equilibrium studies at neutral pH where the wild-type enzyme is typically unstable in the absence of bound inhibitor. The dimer dissociation constant (K-D) of the triple mutant was 5.8 mu M at pH 7.0 and was below the limit of measurement (similar to 100 nM) at pH 4.5. Similar studies using the catalytically inactive D25N mutant yielded a K-D value of 1.0 mu M at pH 7.0. These values differ significantly from a previously reported value of 23 nM obtained indirectly from inhibitor binding measurements (Darke et al., 1994). We show that the discrepancy may result from the thermodynamic linkage between the monomer-dimer and inhibitor binding equilibria. Under conditions wheres significant degree of monomer is present, both substrates and competitive inhibitors will shift the equilibrium toward the dimer, resulting in apparent increases in dimer stability and decreases in ligand binding affinity. Sedimentation equilibrium studies were also carried out on several drug-resistant HIV-I protease mutants: V82F, V82F/I84V, V82T/I84V, and L90M. All four mutants exhibited reduced dimer stability relative to the autolysis-resistant mutant at pH 7.0. Our results indicate that: reductions in drug affinity may be due to the combined effects of mutations on both dimer stability and inhibitor binding. C1 NCI, Frederick Canc Res & Dev Ctr, SAIC, Struct Biochem Program, Frederick, MD 21702 USA. RP NCI, Frederick Canc Res & Dev Ctr, SAIC, Struct Biochem Program, Bldg 322,Room 27C, Frederick, MD 21702 USA. EM xie@ncifcrf.gov FU NCI NIH HHS [N01 CO-56000] NR 29 TC 65 Z9 66 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD AUG PY 1999 VL 8 IS 8 BP 1702 EP 1707 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 224PT UT WOS:000081908000014 PM 10452615 ER PT J AU Makarova, KS Aravind, L Koonin, EV AF Makarova, KS Aravind, L Koonin, EV TI A superfamily of archaeal, bacterial, and eukaryotic proteins homologous to animal transglutaminases SO PROTEIN SCIENCE LA English DT Article DE catalytic triad; evolution of enzymes; iterative database search; thiol protease; transglutaminase ID COAGULATION-FACTOR-XIII; GTP-BINDING PROTEIN; CATALYTIC ACTIVITY; SEQUENCE; CLONING; LOCALIZATION; EXPRESSION; ENVELOPE; ENZYME; RHO AB Computer analysis using profiles generated by the PSI-BLAST program identified a superfamily of proteins homologous to eukaryotic transglutaminases. The members of the new protein superfamily are found in all archaea, show a sporadic distribution among bacteria, and were detected also in eukaryotes, such as two yeast species and the nematode Caenorhabditis elegans. Sequence conservation in this superfamily primarily involves three motifs that center around conserved cysteine, histidine, and aspartate residues that form the catalytic triad in the structurally characterized transglutaminase, the human blood clotting factor XIIIa'. On the basis of the experimentally demonstrated activity of the Methanobacterium phage pseudomurein endoisopeptidase, it is proposed that many, if not all, microbial homologs of the transglutaminases are proteases and that the eukaryotic transglutaminases have evolved from an ancestral protease. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Pathol, Bethesda, MD 20814 USA. Texas A&M Univ, Dept Biol, College Stn, TX 77843 USA. RP Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM koonin@ncbi.nih.gov NR 35 TC 113 Z9 114 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD AUG PY 1999 VL 8 IS 8 BP 1714 EP 1719 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 224PT UT WOS:000081908000017 PM 10452618 ER PT J AU Ausseil, J Soyer-Gobillard, MO Geraud, ML Bhaud, Y Baines, I Preston, T Moreau, H AF Ausseil, J Soyer-Gobillard, MO Geraud, ML Bhaud, Y Baines, I Preston, T Moreau, H TI Characterization of p80, a novel nuclear and cytoplasmic protein in dinoflagellates SO PROTIST LA English DT Article ID HEAVY-CHAIN GENE; COMPLEX CELL-CYCLE; MYOSIN-I ISOFORMS; ACANTHAMOEBA-CASTELLANII; CRYPTHECODINIUM-COHNII; NEURODEGENERATIVE DISEASES; UNCONVENTIONAL MYOSINS; TOXOPLASMA-GONDII; GLUTAMINE REPEATS; LOCALIZATION AB The presence of myosin in dinoflagellates was tested using an anti-Acanthamoeba castellanii myosin II polyclonal antibody on the heterotrophic dinoflagellate Crypthecodinium cohnii Seligo. Western blots revealed the presence of a unique band of 80 kDa in total protein extracts and after immunoprecipitation. Expression of this 80 kDa protein appeared constant during the different phases of the cell cycle. In protein extracts from various other dinoflagellates, this 80 kDa protein was defected only in the autotrophic species Prorocentrum micans Ehr. Screening of a C. cohnii cDNA expression library with this antibody revealed a cDNA coding for an amino acid sequence without homology in the databases. However, particular regions were detected : - a polyglutamine repeat domain in the N-terminal part of the protein, - four peptide sequences associated with GTP-binding sites, - a sequence with slight homology to the rod tail of Caenorhabditis elegans myosin II, - a sequence with homology to a human kinesin motor domain. Immunocytolocalization performed on C. cohnii thin sections with a polyclonal antibody raised against the recombinant protein showed p80 to be present both within the nucleus and in the cytoplasm. Labelling was widespread in the nucleoplasm and more concentrated at the periphery of the permanently condensed chromosomes. In the cytoplasm, labelling appeared in a punctate region close to the nucleus and in the flagellum. Potential functions of this novel protein are discussed. C1 Univ Paris 06, Lab Arago, Observ Oceanol Banyuls sur Mer, CNRS,UMR 7628, F-66651 Banyuls sur Mer, France. NIH, Bethesda, MD 20892 USA. UCL, London, England. RP Ausseil, J (reprint author), Univ Paris 06, Lab Arago, Observ Oceanol Banyuls sur Mer, CNRS,UMR 7628, BP 44, F-66651 Banyuls sur Mer, France. EM ausseil@arago.obs-banyuls.fr NR 58 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 1434-4610 J9 PROTIST JI Protist PD AUG PY 1999 VL 150 IS 2 BP 197 EP 211 PG 15 WC Microbiology SC Microbiology GA 236GU UT WOS:000082592500009 PM 10505419 ER PT J AU Brechtel, A Buchanan, TW Sollers, JJ Lovallo, WR AF Brechtel, A Buchanan, TW Sollers, JJ Lovallo, WR TI Effects of exogenous cortisol on the acoustic startle reflex SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract C1 Univ Dusseldorf, D-4000 Dusseldorf, Germany. Univ Oklahoma, Norman, OK 73019 USA. NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD AUG PY 1999 VL 36 SU 1 BP S37 EP S37 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 222QZ UT WOS:000081797400143 ER PT J AU Duncan, CC Gabbay, FH Mirsky, AF AF Duncan, CC Gabbay, FH Mirsky, AF TI Auditory and visual P300 in men and women: Within- and between-session stability SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract C1 Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NIMH, Intramural Res Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD AUG PY 1999 VL 36 SU 1 BP S48 EP S48 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 222QZ UT WOS:000081797400188 ER PT J AU Gabbay, FH Duncan, CC Mirsky, AF AF Gabbay, FH Duncan, CC Mirsky, AF TI Sex differences in amphetamine effects on the P300 elicited in an auditory novelty oddball task SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract C1 Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NIMH, Intramural Res Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD AUG PY 1999 VL 36 SU 1 BP S52 EP S52 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 222QZ UT WOS:000081797400202 ER PT J AU Junghoefer, M Perlstein, WM Russmann, T May, JC Cuthbert, B Bradley, MM Lang, PJ AF Junghoefer, M Perlstein, WM Russmann, T May, JC Cuthbert, B Bradley, MM Lang, PJ TI Arousal sensitive slow wave in high-density EEG SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract C1 Univ Florida, Gainesville, FL 32611 USA. NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD AUG PY 1999 VL 36 SU 1 BP S64 EP S64 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 222QZ UT WOS:000081797400251 ER PT J AU Sabatinelli, D Bradley, MM King, WM Desai, P Fitzsimmons, JR Cuthbert, BN Lang, PJ AF Sabatinelli, D Bradley, MM King, WM Desai, P Fitzsimmons, JR Cuthbert, BN Lang, PJ TI Functional activity in visual cortex: Pleasure and arousal SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract C1 Univ Florida, Gainesville, FL 32611 USA. NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD AUG PY 1999 VL 36 SU 1 BP S99 EP S99 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 222QZ UT WOS:000081797400390 ER PT J AU Sloan, DM Strauss, CC Cuthbert, BN Sullivan, E Bradley, MM Lang, PJ AF Sloan, DM Strauss, CC Cuthbert, BN Sullivan, E Bradley, MM Lang, PJ TI Facial EMG activity in comorbid anxiety and depression SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract C1 Univ Florida, Gainesville, FL 32611 USA. NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD AUG PY 1999 VL 36 SU 1 BP S106 EP S106 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 222QZ UT WOS:000081797400420 ER PT J AU Sollers, JJ Thayer, JF Pearson, MA Faith, ML Costa, PT AF Sollers, JJ Thayer, JF Pearson, MA Faith, ML Costa, PT TI Personality correlates of autonomic activity and mood at rest SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract C1 NIA, Bethesda, MD 20892 USA. Univ Missouri, Columbia, MO USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD AUG PY 1999 VL 36 SU 1 BP S109 EP S109 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 222QZ UT WOS:000081797400429 ER PT J AU Thayer, JF AF Thayer, JF TI Perseverative thinking and health: Neurovisceral concomitants SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract C1 NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD AUG PY 1999 VL 36 SU 1 BP S9 EP S9 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 222QZ UT WOS:000081797400034 ER PT J AU Bertheau, P Steinberg, SM Cowan, K Merino, MJ AF Bertheau, P Steinberg, SM Cowan, K Merino, MJ TI Breast cancer in young women: Clinicopathologic correlation SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Article DE breast cancer; young women; clinicopathologic correlation ID PATHOLOGICAL PROGNOSTIC FACTORS; TERM FOLLOW-UP; FAMILY HISTORY; AGED 35; CARCINOMA; SURVIVAL; HISTOPATHOLOGY; LESS; DIAGNOSIS; FEATURES AB It has been suggested that early-onset breast carcinomas may be different from those that occur in older women. The clinicopathologic characteristics of 191 young female patients (under 40 years of age) diagnosed with breast carcinoma (BC) were studied. Clinical history, staging, treatment and outcome were reviewed. Histology was assessed for tumor subtypes, invasive and in situ components, nuclear and histologic grades and lymph node status. Adjacent nontumoral breast tissue was evaluated. Clinically, 11 patients were stage 0, 21 stage I, 94 stage II, 38 stage III, 6 stage IV, and in 21 no information was obtained. Sixty five percent of patients had positive lymph nodes at diagnosis; 102 patients (54%) relapsed at a median of 29 months after diagnosis. Histologically, 180 cases were infiltrating BC, 150 ductal (83%), 19 lobular (11%) and 11 of special types (6%); 11 cases were ductal carcinoma in situ, We found no cases of medullary carcinoma. High nuclear grade and vascular invasions were frequent (68% and 67%, respectively) even in patients who remained disease-free at least 5 years after diagnosis (61% and 60%, respectively). Our study demonstrates that the histologic types of early-onset breast cancer are not different from other BC. However, BC in young women is often associated with histologic features of high-grade malignancy even in patients with better survival. Our results suggest that BCs in young women are different from those that occur in older women. This is a US government work. There are no restrictions on its use. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. St Louis Hosp, Lab Surg Pathol, Paris, France. NCI, Biostat & Data Management Sect, Div Clin Sci, NIH, Bethesda, MD 20892 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. RP Merino, MJ (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Room 2N212,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 57 TC 23 Z9 26 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 0740-2570 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD AUG PY 1999 VL 16 IS 3 BP 248 EP 256 PG 9 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 232VY UT WOS:000082391700006 PM 10490201 ER PT J AU Love, PE Shores, EW AF Love, PE Shores, EW TI Antigen receptor signalling in T cell development and selection - Introduction SO SEMINARS IN IMMUNOLOGY LA English DT Editorial Material C1 NICHHD, Sect Cellular & Dev Biol, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. RP Love, PE (reprint author), NICHHD, Sect Cellular & Dev Biol, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD AUG PY 1999 VL 11 IS 4 BP 225 EP 226 DI 10.1006/smim.1999.0178 PG 2 WC Immunology SC Immunology GA 228CB UT WOS:000082117700001 ER PT J AU Hayday, AC Barber, DF Douglas, N Hoffman, ES AF Hayday, AC Barber, DF Douglas, N Hoffman, ES TI Signals involved in gamma/delta T cell versus alpha/beta T cell lineage commitment SO SEMINARS IN IMMUNOLOGY LA English DT Review DE development; lineage commitment; preTCR; signalling; thymocyte ID RECEPTOR-BETA-CHAIN; GAMMA-DELTA LINEAGES; THYMOCYTE DEVELOPMENT; GENE REARRANGEMENT; ALLELIC EXCLUSION; MICE LACKING; LIGHT-CHAIN; V(D)J RECOMBINATION; IMMATURE THYMOCYTES; TYROSINE KINASES AB In seeking an explanation for the complexity of tissue development, biologists are obliged to explain lineage commitment, the events that dictate whether or not a progenitor . cell will differentiate into one cell type or another. Such explanations have been sought across a broad spectrum of biological systems, although in no case has a full understanding been developed. For immunologists, attention has been focused on the lineage commitment of a T cell progenitor to becoming either a gamma delta T cell or an ap T cell. In this review, we compare the signals that thymocytes may receive from om the pre T cell receptor (preTCR) with signalling from TCR gamma delta. These signals may determine, co-determine, facilitate, or cement the alpha beta/gamma delta lineage decision, in, concert with signals from additional molecules, such as Notch and cytokine receptors. Elucidating the pleiotropic signalling eve nts, particularly those elicited by the preTCR, may in the near future contribute to a molecular ddefinition of lineage commitment. C1 Univ London, Guys Kings St Thomas Sch Med, Dept Immunobiol, London SE1 9RT, England. Yale Univ, Dept Mol Cell & Dev Biol, New Haven, CT 06520 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Hayday, AC (reprint author), Univ London, Guys Kings St Thomas Sch Med, Dept Immunobiol, Guys Hosp Campus, London SE1 9RT, England. RI Barber, Domingo/G-1257-2010 OI Barber, Domingo/0000-0001-8824-5405 NR 80 TC 38 Z9 38 U1 0 U2 0 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD AUG PY 1999 VL 11 IS 4 BP 239 EP 249 DI 10.1006/smim.1999.0180 PG 11 WC Immunology SC Immunology GA 228CB UT WOS:000082117700003 PM 10441210 ER PT J AU Singer, A Bosselut, R Bhandoola, A AF Singer, A Bosselut, R Bhandoola, A TI Signals involved in CD4/CD8 lineage commitment: Current concepts and potential mechanisms SO SEMINARS IN IMMUNOLOGY LA English DT Review DE thymus; T cell development; coreceptor; signaling ID T-CELL RECEPTOR; P56(LCK) TYROSINE KINASE; IMMATURE CD4+CD8+ THYMOCYTES; POSITIVE SELECTION; THYMIC SELECTION; ANTIGEN RECEPTOR; TRANSGENIC MICE; CD8 LINEAGE; NEGATIVE SELECTION; CD4(+)CD8(+) THYMOCYTES AB A competent immune system requires that mature T cells express TCR and CD4/CD8 coreceptors with matching MHC specificities. Such matching of TCR and coreceptor specificity is induced in the thymus at the CD4(+)8(+) stage of development and is referred ed to as lineage commitment. The process by which immature CD4(+)8(+) thymocytes are signaled to undergo lineage commitment continues to be the subject of intense investigation and discussion. Here, we review the major models by which lineage commitment is thought to occur and discuss the experimental results on which they were based. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10 Room 4B36, Bethesda, MD 20892 USA. NR 62 TC 20 Z9 20 U1 0 U2 0 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD AUG PY 1999 VL 11 IS 4 BP 273 EP 281 DI 10.1006/smim.1999.0183 PG 9 WC Immunology SC Immunology GA 228CB UT WOS:000082117700006 PM 10441213 ER PT J AU Piper, MA Severin, ST Wiktor, SZ Unger, ER Ghys, PD Miller, DL Horowitz, IR Greenberg, AE Reeves, WC Vernon, SD AF Piper, MA Severin, ST Wiktor, SZ Unger, ER Ghys, PD Miller, DL Horowitz, IR Greenberg, AE Reeves, WC Vernon, SD TI Association of human papillomavirus with HIV and CD4 cell count in women with high or low numbers of sex partners SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Article; Proceedings Paper CT 9th International AIDS Conference on AIDS and STD in Africa CY DEC 10-14, 1995 CL KAMPALA, UGANDA DE human papillomavirus; HIV; CD4 count ID HUMAN-IMMUNODEFICIENCY-VIRUS; CERVICAL INTRAEPITHELIAL NEOPLASIA; HPV INFECTION; RISK; IMMUNOSUPPRESSION; PROSTITUTES; CANCER AB Objective: To explore whether HIV serostatus (HIV-1, HIV-2, and dual (HIV-D) reactivity) and CD4 cell count affect human papillomavirus (HPV) in two groups of women from Cote d'Ivoire. Methods: We conducted a cross sectional study of two groups of women. One group had low numbers of lifetime sex partners (maternal women, n=258) and were enrolled based on HIV serostatus. The other group had high numbers of sex partners (female sex workers, n=278) and all consenting self identified sex workers were admitted to this study. We collected epidemiological and clinical data, and cervicovaginal lavage for HPV testing. Results: The groups had different distributions of HIV seroreactivity, but the rates of HPV DNA detection were similar. Most of the HPV DNAs detected in both groups were high risk types. A strong association of high risk HPV DNA and HIV-1 seropositivity was found in both maternal women (adjusted odds ratio (OR) 7.5 (95% CI 3.2-17.4)) and in sex workers (OR 5.0 (2.1-12.0)). The maternal group also showed an association of high risk HPV DNA detection with HIV-2 (OR 3.7 (1.6-8.5)) and HIV-D (OR 12.7 (4.3-37.5)) that was not observed in the sex workers. In addition, the association of high risk HPV DNA with HIV-1 in the maternal group was independent of low CD4 cell count, while in the sex workers the association depended on CD4: cell counts less than or equal to 500 x 10(6)/l. Conclusions: We found that an association between HPV and HIV varied depending on the sexual behaviour and CD4 cell count of the population examined. C1 Ctr Dis Control & Prevent, Publ Hlth Serv, US Dept Hlth & Human Serv, Atlanta, GA 30333 USA. NCI, Rockville, MD USA. CHU Treichville, Projet RETROCI, Abidjan, Cote Ivoire. Inst Trop Med, B-2000 Antwerp, Belgium. Emory Univ, Emory Sch Med, Atlanta, GA USA. RP Vernon, SD (reprint author), Ctr Dis Control & Prevent, Publ Hlth Serv, US Dept Hlth & Human Serv, 1600 Clifton Rd NE,MS G18, Atlanta, GA 30333 USA. OI Unger, Elizabeth/0000-0002-2925-5635 NR 27 TC 11 Z9 12 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD AUG PY 1999 VL 75 IS 4 BP 253 EP 257 PG 5 WC Infectious Diseases SC Infectious Diseases GA 232YE UT WOS:000082396900011 PM 10615312 ER PT J AU Vernon, SD Unger, ER Piper, MA Severin, ST Wiktor, SZ Ghys, PD Miller, DL Horowitz, IR Greenberg, AE Reeves, WC AF Vernon, SD Unger, ER Piper, MA Severin, ST Wiktor, SZ Ghys, PD Miller, DL Horowitz, IR Greenberg, AE Reeves, WC TI HIV and human papillomavirus as independent risk factors for cervical neoplasia in women with high or low numbers of sex partners SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Article DE HIV; human papillomavirus; cervical neoplasia ID INTRAEPITHELIAL NEOPLASIA; INFECTION; PREVALENCE; CANCER; VIRUS AB Objective: To explore whether HIV types 1 and 2 and CD4 cell count affect cervical neoplasia independent of human papillomavirus (HPV) in women with high or low numbers of sexual partners residing in Abidjan, Cote d'Ivoire. Methods: The study population and methods are described in the companion paper. Additional methods include a Papanicolaou smear for cytological diagnosis and statistical analysis. Results: In maternal women, both HIV-1 and high risk HPV were significant independent risk factors for squamous intraepithelial lesions (SIL) (adjusted odds ratio (OR) 11.0 (95% CI 1.1-112) and 5.4 (1.5-18.8), respectively). Only high levels of HPV DNA in the lavage were associated with SIL (OR 13.2 (3.6-47.8)) in the maternal group. In female sex workers, high risk HPV was significantly associated with SIL (OR 23.7 (4.4-126)); HN seropositivity was not. Any positive level (high or low amounts) of HPV DNA was significantly associated with SIL in sex workers (ORs 15.9 (3.3-76) and 12.7 (3.6-44), respectively). There was no association of SIL with CD4 cell counts less than or equal to 500 x 10(6)/l in HN seropositive women from either group. Conclusion: HPV or HIV-1 infection independently affect cervical neoplasia in women with low numbers of sex partners. C1 Ctr Dis Control & Prevent, Publ Hlth Serv, US Dept Hlth & Human Serv, Atlanta, GA 30333 USA. NCI, Canc Prevent Fellowship Off, Rockville, MD USA. CHU Treichville, Projet RETROCI, Abidjan, Cote Ivoire. Inst Trop Med, B-2000 Antwerp, Belgium. Emory Univ, Emory Sch Med, Atlanta, GA 30322 USA. RP Vernon, SD (reprint author), Ctr Dis Control & Prevent, Publ Hlth Serv, US Dept Hlth & Human Serv, 1600 Clifton Rd,MSG18, Atlanta, GA 30333 USA. OI Unger, Elizabeth/0000-0002-2925-5635 NR 12 TC 12 Z9 12 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD AUG PY 1999 VL 75 IS 4 BP 258 EP 260 PG 3 WC Infectious Diseases SC Infectious Diseases GA 232YE UT WOS:000082396900012 PM 10615313 ER PT J AU Park, BC Lee, YC Strott, CA AF Park, BC Lee, YC Strott, CA TI Testosterone sulfotransferase: Evidence in the guinea pig that this reaction is carried out by 3 alpha-hydroxysteroid sulfotransferase SO STEROIDS LA English DT Article DE 3 alpha-/3 beta-hydroxysteroid; 17 beta-hydroxysteroid; sulfotransferase; androsterone; testosterone; estradiol ID CONJUGATED NEUTRAL STEROIDS; ESTROGEN SULFOTRANSFERASE; MOLECULAR-CLONING; HYDROXYSTEROID SULFOTRANSFERASE; RAT-LIVER; DEHYDROEPIANDROSTERONE SULFOTRANSFERASE; HUMAN TESTIS; EXPRESSION; PURIFICATION; DISTINCT AB During the course of isolating, characterizing, and cloning estrogen and 3-hydroxysteroid sulfotransferases from the guinea pig adrenal gland, it was noted that cytosolic preparations from this tissue would also sulfonate testosterone. Therefore, we set: out to isolate and clone the enzyme that performs this reaction. Testosterone sulfotransferase (TST) was isolated from the guinea Dig adrenal by using the standard procedures of ion exchange, affinity, and high-performance liquid chromatography. When purified, TST was examined by liquid-phase nondenaturing isoelectric focusing, it was found that the TST activity profile completely overlapped with the activity profile of the 3 alpha-hydroxysteroid sulfotransferase (3 alpha HST) isoform, but not the 3 beta-hydroxysteroid sulfotransferase (3 beta HST) isoform. This finding was further investigated by overexpressing the cDNAs for 3 alpha HST and 3 beta HST in Escherichia coli and examining the expressed proteins for TST activity. This experiment confirmed that 3 alpha HST does indeed function as a TST. In addition, 3 alpha HST was also found to sulfonate estradiol but not estrone, a finding that further suggested that 3 alpha HST may function as a general 17 beta-hydroxysteroid sulfotransferase. Published by Elsevier Science Inc. C1 NICHHD, Sect Steroid Regulat, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Strott, CA (reprint author), NICHHD, Sect Steroid Regulat, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Rm 6A36, Bethesda, MD 20892 USA. NR 37 TC 0 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0039-128X J9 STEROIDS JI Steroids PD AUG PY 1999 VL 64 IS 8 BP 510 EP 517 DI 10.1016/S0039-128X(99)00027-6 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 234ER UT WOS:000082472000002 PM 10493595 ER PT J AU Grotta, JC Chin, D Lu, M Patel, S Levine, SR Tilley, BC Brott, TG Haley, EC Lyden, PD Kothari, R Frankel, M Lewandowski, CA Libman, R Kwiatkowski, T Broderick, JP Marler, JR Corrigan, J Huff, S Mitsias, P Talati, S Tanne, D AF Grotta, JC Chin, D Lu, M Patel, S Levine, SR Tilley, BC Brott, TG Haley, EC Lyden, PD Kothari, R Frankel, M Lewandowski, CA Libman, R Kwiatkowski, T Broderick, JP Marler, JR Corrigan, J Huff, S Mitsias, P Talati, S Tanne, D CA NINDS rt-PA Stroke Trial Study Grp TI Agreement and variability in the interpretation of early CT changes in stroke patients qualifying for intravenous rtPA therapy SO STROKE LA English DT Article DE cerebral infarction; statistics; stroke; tissue plasminogen activator; tomography, emission-computed ID ACUTE ISCHEMIC STROKE; THROMBOLYTIC THERAPY; COMPUTED-TOMOGRAPHY; KAPPA; RELIABILITY; ECASS; BRAIN; CATS; MRI AB Background and Purpose-Ischemic changes identified on CT scans performed in the first few hours after stroke onset, which are thought to possibly represent early cytotoxic edema and development of irreversible injury, may have important implications for subsequent treatment However, insecurity and conflicting data exist over the ability of clinicians to correctly recognize and interpret these changes. We performed a detailed review of selected baseline CT scans from the NINDS rt-PA Stroke Trial to test agreement among experienced stroke specialists and other physicians on the presence of early CT ischemic changes. Methods-Seventy baseline CT scans from the NINDS Stroke Trial were read and classified for the presence or absence of various early findings of ischemia by 16 individuals, including NINDS trial investigators, other neurologists, other emergency medicine physicians, and radiology or stroke fellows. CT scans included normal scans and scans from patients who later developed symptomatic intracranial hemorrhage, as well, as scans on which the NINDS rt-PA Stroke Trial neuroradiologist identified clear-cut early CT changes. For each CT finding, kappa-statistics were used to assess the proportion of agreement beyond chance. Results-kappa-Values (95% confidence interval [CI]) ranged from 0.20 (-0.20, 0.61) (fair agreement) to 0.42 (0.37, GAS) (moderate agreement) among the 16 viewers, and the kappa-value was only 0.39 (0.29, 0.49) (fair) in answer to the question "do early CT changes involve more than one third of the MCA [middle cerebral artery] territory?" There was substantial variability within each specialty group and between groups. kappa-Values were only fair to moderate even among physicians experienced in selecting and treating acute stroke patients with rtPA, Observed agreement ranged from 68% to 85%. Physicians agreed on the finding of early CT changes involving >33% of the MCA territory 77% of the time, although the kappa-value of 0.39 suggested only moderate: agreement beyond chance. Conclusions-There is considerable lack of agreement, even among experienced clinicians, in recognizing and quantifying early CT changes. Improved methods of recognizing and quantifying early ischemic brain damage are needed. C1 Univ Texas, Sch Med, Dept Neurol, Stroke Program, Houston, TX 77030 USA. Henry Ford Hlth Sci Ctr, Dept Biostat & Res Epidemiol, Detroit, MI USA. Henry Ford Hlth Sci Ctr, Dept Radiol, Detroit, MI USA. Henry Ford Hlth Sci Ctr, Dept Neurol, Detroit, MI USA. Henry Ford Hlth Sci Ctr, Dept Emergency Med, Detroit, MI USA. Univ Cincinnati, Med Ctr, Dept Neurol, Cincinnati, OH 45267 USA. Univ Cincinnati, Med Ctr, Dept Emergency Med, Cincinnati, OH 45267 USA. Univ Virginia, Dept Neurol, Charlottesville, VA USA. Univ Virginia, Dept Emergency Med, Charlottesville, VA USA. Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. Long Isl Jewish Med Ctr, Dept Neurol, New Hyde Park, NY 11042 USA. Long Isl Jewish Med Ctr, Dept Emergency Med, New Hyde Park, NY 11042 USA. NINDS, Div Stroke & Trauma, Bethesda, MD 20892 USA. RP Grotta, JC (reprint author), Univ Texas, Sch Med, Dept Neurol, Stroke Program, 6431 Fannin, Houston, TX 77030 USA. RI Tanne, David/F-2560-2010 OI Tanne, David/0000-0002-6699-2220 FU NINDS NIH HHS [N01-NS-02374, N01-NS-02377, N01-NS-02382] NR 26 TC 169 Z9 173 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD AUG PY 1999 VL 30 IS 8 BP 1528 EP 1533 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 224JM UT WOS:000081894300006 PM 10436095 ER PT J AU Rusa, R Alkayed, NJ Crain, BJ Traystman, RJ Kimes, AS London, ED Klaus, JA Hurn, PD AF Rusa, R Alkayed, NJ Crain, BJ Traystman, RJ Kimes, AS London, ED Klaus, JA Hurn, PD TI 17 beta-estradiol reduces stroke injury in estrogen-deficient female animals SO STROKE LA English DT Article DE cerebral blood flow; cerebral ischemia; 17 beta-estradiol; estrogen replacement therapy; stroke; rats ID CEREBRAL-ARTERY OCCLUSION; NITRIC-OXIDE SYNTHASE; MESSENGER-RNA; VESSEL WALL; RAT; RECEPTOR; BRAIN; EXPRESSION; CYCLE; IDENTIFICATION AB Background and Purpose-The importance of postmenopausal estrogen replacement therapy for stroke in females remains controversial. We previously showed that female rats sustain less infarction in reversible middle cerebral artery occlusion (MCAO) than their ovariectomized counterparts and that vascular mechanisms are partly responsible for improved tissue outcomes. Furthermore, exogenous estrogen strongly protects the male brain, even when administered in a single injection before MCAO injection. The present study examined the hypothesis that replacement of 17 beta-estradiol to physiological levels improves stroke outcome in ovariectomized, estrogen-deficient female rats, acting through blood flow-mediated mechanisms. Methods-Age-matched, adult female Wistar rats were ovariectomized and treated with 0, 25, or 100 mu g of 17 beta-estradiol administered through a subcutaneous implant or with a single Premarin (USP) injection(1 mg/kg) given immediately before ischemia was induced (n = 10 per group). Each animal subsequently underwent 2 hours of MCAO by the intraluminal filament technique, followed by 22 hours of reperfusion. Ipsilateral parietal cortex perfusion was monitored by laser-Doppler flowmetry throughout ischemia. Cortical and caudate-putamen infarction. volumes were determined by 2,3,5-triphenyltetrazolium chloride staining and digital image analysis. End-ischemic regional cerebral blood flow was measured in ovariectomized females with 0- or 25-mu g implants (n=4 per group) by C-14-iodoantipyrine quantitative autoradiography. Results-Plasma estradiol levels were 3.0+/-0.6, 20+/-8, and 46+/-10 pg/mL in the 0-, 25-, and 100-mu g groups, respectively. Caudate-putamen infarction (% of ipsilateral caudate-putamen) was reduced by long-term, 25-mu g estrogen treatment (13+/-4% versus 31+/-6% in the 0-mu g group, P<0.05, and 22+/-3% in the 100-mu g group). Similarly, cortical infarction (% of ipsilateral cortex) was reduced only in the 25-mu g group (3+/-2% versus 12+/-3% in the 0-mu g group, P<0.05, and 6+/-3% in the 100-mu g group. End-ischemic striatal or cortical blood flow was not altered by estrogen treatment at the neuroprotective dose. Infarction volume was unchanged by acute treatment before MCAO when estrogen-treated animals were compared with saline vehicle-treated animals. Conclusions-Long-term estradiol replacement within a low physiological range ameliorates ischemic brain injury in previously ovariectomized female rats. The neuroprotective mechanism is flow-independent, not through preservation of residual ischemic regional cerebral blood flow. Furthermore, the therapeutic range is narrow, because the benefit of estrogen in transient vascular occlusion is diminished at larger doses, which yield high, but still physiologically relevant, plasma 17 beta-estradiol levels. Lastly, unlike in the male brain, single-injection estrogen exposure does not salvage ischemic tissue in the female brain. Therefore, although exogenous steroid therapy protects both male and female estrogen-deficient brain, the mechanism may not be identical and depends on long-term hormone augmentation in the female. C1 Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. NIDA, Baltimore, MD 21224 USA. RP Hurn, PD (reprint author), Johns Hopkins Med Inst, Dept Anesthesiol & Crit Care Med, 600 N Wolfe St,Blalock 1404, Baltimore, MD 21287 USA. FU NINDS NIH HHS [NS3368, NS20020]; NINR NIH HHS [NR03521] NR 39 TC 226 Z9 230 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD AUG PY 1999 VL 30 IS 8 BP 1665 EP 1669 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 224JM UT WOS:000081894300031 PM 10436119 ER PT J AU Riker, A Cormier, J Panelli, M Kammula, U Wang, E Abati, A Fetsch, P Lee, KH Steinberg, S Rosenberg, S Marincola, F AF Riker, A Cormier, J Panelli, M Kammula, U Wang, E Abati, A Fetsch, P Lee, KH Steinberg, S Rosenberg, S Marincola, F TI Immune selection after antigen-specific immunotherapy of melanoma SO SURGERY LA English DT Article; Proceedings Paper CT 60th Annual Meeting of the Society-of-University-Surgeons CY FEB 11-13, 1999 CL NEW ORLEANS, LOUISIANA SP Soc Univ Surgeons ID TUMOR-INFILTRATING LYMPHOCYTES; METASTATIC MELANOMA; IN-VIVO; MONOCLONAL-ANTIBODIES; T-CELLS; EXPRESSION; PEPTIDE; GP100; PATIENT; MART-1 AB Background. Melanoma antigen (MA)-specific vaccination strongly enhances antitumor reactivity in vivo and is capable of producing strong cytotoxic T lymphocyte responses in vitro. Furthermore, specific human leukocyte antigen-restricted T cell activation is hypothesized to occur in response to peptide-based immunotherapy, which may lead to the preferential killing of tumor cells bearing the relevant MA. The development of melanoma antigen-loss variants may subsequently occur in vivo. Methods. Analysis of 532 melanoma lesions from 204 patients was performed on fine-needle aspiration biopsy specimens. Lesions were graded for the expression of the MAs gp100 and MART-1 with use of immunocytochemistry. A total of 351 melanoma lesions were divided into cohorts on the basis of the treatment received. The pretreatment group, (n = 175) consisted of lesions obtained before any form of gp100 immunotherapy, with the posttreatment group (n = 176) consisting of lesions obtained after vaccination With a modified gp100 epitope, gp209-2M +/- interleukin 2 (IL-2). Results. The percentage of lesions not expressing the gp100 antigen is greater than the percentage not expressing MART-1 (26% vs 14%). The frequency of lesions with highly expression (>75%) of gp100 significantly decreased with therapy (47% vs 34%) and conversely negative lesions increased (18% vs 29%). Treatment of lesions with peptide alone (no IL-2) revealed a significant decrease in gp100 expression (47% vs 32%), enhanced with the addition of IL-2 to therapy (47% vs 35%). The expression of MART-1 remained essentially unchanged unless IL-2 was added (54 % vs 54 %, MART-1 peptide alone, 54% vs 43%, MART-1 peptide + IL-2). Of 94 patients (181 lesions) assessed for gp100 express ion before treatment, 10 patients responded to therapy. Pretreatment lesions in responding patients expressed some level of gp100 in all cases compared with 27% of nonresponding lesions, which were negative for gp100 expression. Conclusion. This study indirectly demonstrates that vaccination with an MA-derived peptide can result in immune selection in vivo. Furthermore, it provides strong immunologic evidence for the specificity MA vaccines and to the relevance of MA expression in predicting the response to vaccination. C1 NIH, Surg Branch, Biostat & Data Management Sect, Pathol Lab,Div Clin Sci,NCI, Bethesda, MD 20892 USA. RP Marincola, F (reprint author), NIH, Surg Branch, Biostat & Data Management Sect, Pathol Lab,Div Clin Sci,NCI, 10 Ctr Dr,Bldg 10,Room 2B58, Bethesda, MD 20892 USA. RI Riker, Adam/A-6065-2011 NR 24 TC 136 Z9 137 U1 2 U2 6 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0039-6060 J9 SURGERY JI Surgery PD AUG PY 1999 VL 126 IS 2 BP 112 EP 120 DI 10.1016/S0039-6060(99)70143-1 PG 9 WC Surgery SC Surgery GA 226NJ UT WOS:000082025800002 PM 10455872 ER PT J AU Manganiello, VC Degerman, E AF Manganiello, VC Degerman, E TI Cyclic nucleotide phosphodiesterases: Diverse regulators of cyclic nucleotide signals and inviting molecular targets for novel therapeutic agents SO THROMBOSIS AND HAEMOSTASIS LA English DT Article ID CGMP-STIMULATED PHOSPHODIESTERASE; AMP PHOSPHODIESTERASE; INHIBITORS; CAMP; ROLIPRAM; CELLS; PROLIFERATION; COMPARTMENTALIZATION; ACTIVATION; ISOFORMS C1 NHLBI, PCCMB, NIH, Bethesda, MD 20892 USA. Univ Lund, Dept Cell & Mol Biol, Lund, Sweden. RP Manganiello, VC (reprint author), NHLBI, PCCMB, NIH, Bldg 10,Room 5N-307,10 Ctr DR,MSC1434, Bethesda, MD 20892 USA. NR 40 TC 80 Z9 82 U1 0 U2 0 PU F K SCHATTAUER VERLAG GMBH PI STUTTGART PA P O BOX 10 45 43, LENZHALDE 3, D-70040 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD AUG PY 1999 VL 82 IS 2 BP 407 EP 411 PG 5 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 246QN UT WOS:000083176200032 PM 10605731 ER PT J AU Koh, KK Horne, MK Cannon, RO AF Koh, KK Horne, MK Cannon, RO TI Effects of hormone replacement therapy on coagulation, fibrinolysis, and thrombosis risk in postmenopausal women SO THROMBOSIS AND HAEMOSTASIS LA English DT Article ID PLASMINOGEN-ACTIVATOR INHIBITOR; PROTEIN ALPHA-2-MACROGLOBULIN RECEPTOR; CORONARY HEART-DISEASE; BREAST-CANCER; VENOUS THROMBOEMBOLISM; CARDIOVASCULAR-DISEASE; ENDOTHELIAL-CELLS; MENOPAUSAL STATUS; FACTOR-VII; MYOCARDIAL-INFARCTION C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. NIH, Dept Clin Pathol, Hematol Sect, Bethesda, MD 20892 USA. Gachon Med Coll, Ctr Heart, Dept Internal Med, Inchon, South Korea. RP Cannon, RO (reprint author), NHLBI, Cardiol Branch, NIH, Bldg 10,Room 7B15,10 Ctr Dr MSC-1650, Bethesda, MD 20892 USA. NR 58 TC 59 Z9 60 U1 0 U2 0 PU F K SCHATTAUER VERLAG GMBH PI STUTTGART PA P O BOX 10 45 43, LENZHALDE 3, D-70040 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD AUG PY 1999 VL 82 IS 2 BP 626 EP 633 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 246QN UT WOS:000083176200061 PM 10605760 ER PT J AU Mendoza, J Catlett, J Williams, S Rivera, C AF Mendoza, J Catlett, J Williams, S Rivera, C TI Plasma thrombopoietin levels and glycocalicin indexes in thrombocytopenic patients with alcoholic liver disease SO THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 Washington Hosp Ctr, Washington, DC 20010 USA. NIH, Warren Grant Magnuson Clin Ctr, Hematol Serv, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU F K SCHATTAUER VERLAG GMBH PI STUTTGART PA P O BOX 10 45 43, LENZHALDE 3, D-70040 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD AUG PY 1999 SU S MA 25 BP 9 EP 9 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 290FP UT WOS:000085665900026 ER PT J AU Lozier, J Metzger, M Donahue, R Morgan, R AF Lozier, J Metzger, M Donahue, R Morgan, R TI Anti-factor IX antibodies in rhesus macaques after human factor IX adenovirus vector gene transfer SO THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 NHGRI, Bethesda, MD USA. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU F K SCHATTAUER VERLAG GMBH PI STUTTGART PA P O BOX 10 45 43, LENZHALDE 3, D-70040 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD AUG PY 1999 SU S MA 85 BP 29 EP 29 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 290FP UT WOS:000085665900086 ER PT J AU Falanga, A Toma, S Consonni, R Palombo, R Raffo, P Marziali, S Barbui, T AF Falanga, A Toma, S Consonni, R Palombo, R Raffo, P Marziali, S Barbui, T TI All-trans-retinoic acid affects the hypercoagulable state in patients with breast cancer SO THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 Osped Riuniti Bergamo, Dept Hematol, I-24100 Bergamo, Italy. Natl Canc Inst, CBA, Genoa, Italy. OI Falanga, Anna/0000-0001-6906-9020 NR 0 TC 0 Z9 0 U1 0 U2 0 PU F K SCHATTAUER VERLAG GMBH PI STUTTGART PA P O BOX 10 45 43, LENZHALDE 3, D-70040 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD AUG PY 1999 SU S MA 169 BP 57 EP 57 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 290FP UT WOS:000085665900170 ER PT J AU Krizek, DR Rick, ME AF Krizek, DR Rick, ME TI A rapid, simple method for gel electrophoresis and western blotting for determination of von willebrand factor (vWF) multimers SO THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU F K SCHATTAUER VERLAG GMBH PI STUTTGART PA P O BOX 10 45 43, LENZHALDE 3, D-70040 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD AUG PY 1999 SU S MA 271 BP 89 EP 89 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 290FP UT WOS:000085665900272 ER PT J AU Mondoro, TH Ryan, BB Hrinczenko, B Schechter, A Vostal, J Vostal, J Alayash, A AF Mondoro, TH Ryan, BB Hrinczenko, B Schechter, A Vostal, J Vostal, J Alayash, A TI Biological action of no donor compounds on platelets from patients with sickle cell disease SO THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU F K SCHATTAUER VERLAG GMBH PI STUTTGART PA P O BOX 10 45 43, LENZHALDE 3, D-70040 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD AUG PY 1999 SU S MA 728 BP 231 EP 232 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 290FP UT WOS:000085665900727 ER PT J AU Horne, M Merryman, P Cullinane, A AF Horne, M Merryman, P Cullinane, A TI Histidine-rich glycoprotein binding to platelets depends upon plasminogen or certain divalent cations SO THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU F K SCHATTAUER VERLAG GMBH PI STUTTGART PA P O BOX 10 45 43, LENZHALDE 3, D-70040 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD AUG PY 1999 SU S MA 1017 BP 322 EP 322 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 290FP UT WOS:000085665901017 ER PT J AU Holada, K Mondoro, TH Gahl, WA Vostal, JG AF Holada, K Mondoro, TH Gahl, WA Vostal, JG TI Up-regulation of platelet prion protein after platelet activation does not correlate with up-regulation of lysosomal GP-53 SO THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 US FDA, Ctr Biol Evaluat & Res, Div Hematol, Bethesda, MD 20892 USA. NICHD, Metab Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU F K SCHATTAUER VERLAG GMBH PI STUTTGART PA P O BOX 10 45 43, LENZHALDE 3, D-70040 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD AUG PY 1999 SU S MA 1137 BP 358 EP 358 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 290FP UT WOS:000085665901138 ER PT J AU Horne, MK Cannon, RO Chen, CC Shawker, TH Chang, R AF Horne, MK Cannon, RO Chen, CC Shawker, TH Chang, R TI Treatment of leg deep venous thrombosis with pulse-sprayed TPA SO THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU F K SCHATTAUER VERLAG GMBH PI STUTTGART PA P O BOX 10 45 43, LENZHALDE 3, D-70040 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD AUG PY 1999 SU S MA 1439 BP 455 EP 455 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 290FP UT WOS:000085665901441 ER PT J AU Wong, ECC Oblitas, J Stewart, MW Leitman, SF Stroncek, D AF Wong, ECC Oblitas, J Stewart, MW Leitman, SF Stroncek, D TI Evaluation of platelet function in volunteer apheresis donors and plateletpheresis products produced by three different apheresis instruments SO THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 NIH, Dept Transfus Med, Bethesda, MD 20892 USA. Thrombot Inc, Edmonton, AB, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU F K SCHATTAUER VERLAG GMBH PI STUTTGART PA P O BOX 10 45 43, LENZHALDE 3, D-70040 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD AUG PY 1999 SU S MA 2624 BP 828 EP 828 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 290FP UT WOS:000085665902635 ER PT J AU Han, M Hannick, LI DiBrino, M Robinson, MA AF Han, M Hannick, LI DiBrino, M Robinson, MA TI Polymorphism of human CD1 genes SO TISSUE ANTIGENS LA English DT Article DE CD1; cell surface molecules; MHC class I; molecular biology ID ANTIGEN-PRESENTING MOLECULES; KILLER T-CELLS; MYCOBACTERIUM-TUBERCULOSIS; MOUSE CD1; FAMILY; RECOGNITION AB Human CD1 genes have been reported to be invariant or to show limited polymorphism. Recently, certain functions of CD1 antigens have been described to include the presentation lipid and glycolipid antigens. These observations prompted a thorough survey of the genetic polymorphism in the five human CD1 genes (CD1a-CD1e). Using polymerase chain reaction-single stranded conformational polymorphism (PCR-SSCP) combined with sequence analyses, exons 2 and 3 from CD1a-CD1e were characterized from a total of 110 unrelated healthy donors. Results showed that all five genes (CD1a-CD1e) are polymorphic in exon 2. Substitutions in CD1b and CD1e are silent, whereas, substitutions in CD1a, CD1d and CD1e result in amino acid replacements in the deduced protein products. CD1a and CD1e polymorphisms are prevalent in the population. The substitutions in CD1a have characteristics that may influence interactions with beta(2)-microglobulin (beta(2)-m) or accessory molecules. The substitution in CD1e is located in the region predicted to interact with ligands and may differentially impact the ability of CD1e alleles to bind antigen. C1 NIAID, Immunogenet Lab, Twinbrook Facil 2, NIH, Rockville, MD 20852 USA. RP Robinson, MA (reprint author), NIAID, Immunogenet Lab, Twinbrook Facil 2, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. NR 30 TC 62 Z9 67 U1 0 U2 2 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 AUG PY 1999 VL 54 IS 2 BP 122 EP 127 DI 10.1034/j.1399-0039.1999.540202.x PG 6 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 232WJ UT WOS:000082392700002 PM 10488738 ER PT J AU Jahnke, G Marr, M Myers, C Wilson, R Travlos, G Price, C AF Jahnke, G Marr, M Myers, C Wilson, R Travlos, G Price, C TI Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats SO TOXICOLOGICAL SCIENCES LA English DT Article DE melatonin; prenatal toxicity; development; mammary gland; pregnancy ID PINEAL-GLAND; SEXUAL-MATURATION; MOUSE-EMBRYOS; SUCKLING RATS; PREIMPLANTATION; METABOLISM; DYNAMICS; INDOLES; SITES; LIGHT AB Melatonin (MEL) is a widely used, over-the-counter sleep aid, and it has putative contraceptive, antioxidant, antiaging, and anticancer effects. The developmental toxicity potential for repeated oral doses of MEL had not previously been evaluated. In the present studies, time-mated, Sprague-Dawley-derived (CD(R)) rats were administered MEL or vehicle by gavage on gestation days (gd) 6-19. MEL-treated groups received 1-, 10-, 100-, 150-, or 200-mg/kg body weight/day in the screening study (15 rats/group), and 50, 100, or 200 mg/kg/day in the definitive study (25 rats/group). In both studies, maternal food/water consumption, body weight, and clinical signs were monitored at regular intervals throughout gestation. At termination (gd 20, both studies:), maternal liver and gravid uterine weights, number of ovarian corpora lutea, conceptus survival, fetal sex, and fetal body weight were evaluated. Fetal morphological examination included external structures (both studies) as well as visceral and skeletal structures (definitive study). In the screening study, maternal serum levels of 17 beta-estradiol, progesterone, prolactin, and luteinizing hormone were determined by radioimmunoassay, and mammary tissue was fixed, stained, and evaluated for percent glandular area within the fat pad. No maternal morbidity/mortality was found In either study. In the screening study, aversion to treatment (greater than or equal to 100 mg/kg/day) and reduced maternal weight gain (greater than or equal to 150 mg/kg/day) were noted, but reproductive/endocrine parameters and fetal development were not affected. In the definitive study, aversion to treatment was noted at greater than or equal to 50 mg/kg/day, and mild sedation, reduced maternal food intake, and reduced body weight gain were found during initial treatment with 200 mg/kg/day. MEL had no effect on prenatal survival, fetal body weight, or incidences of fetal malformations/variations. Thus, in the definitive study, the maternal toxicity NOAEL and LOAEL were 100 and 200 mg/kg/day, respectively, and the developmental toxicity NOAEL was greater than or equal to 200 mg/kg/day. C1 NIEHS, Reprod Toxicol Grp, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. Res Triangle Inst, Ctr Life Sci & Toxicol, Res Triangle Pk, NC 27709 USA. RP NIEHS, Reprod Toxicol Grp, MD B3-05,Bldg 101,Alexander Dr, Res Triangle Pk, NC 27709 USA. EM Jahnke@NIEHS.NIH.gov FU NIEHS NIH HHS [N01-ES-35370, N01-ES-55395, N01-ES-65405] NR 68 TC 154 Z9 159 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD AUG PY 1999 VL 50 IS 2 BP 271 EP 279 DI 10.1093/toxsci/50.2.271 PG 9 WC Toxicology SC Toxicology GA 251QA UT WOS:000083455300014 PM 10478864 ER PT J AU El-Masri, HA Bell, DA Portier, CJ AF El-Masri, HA Bell, DA Portier, CJ TI Effects of glutathione transferase theta polymorphism on the risk estimates of dichloromethane to humans SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE polymorphism; PBPK; Monte Carlo ID S-TRANSFERASE; METHYLENE-CHLORIDE; GENETIC-POLYMORPHISM; HUMAN-ERYTHROCYTES; METABOLISM; LIVER; PHARMACOKINETICS; FORMALDEHYDE; GSTT1; T1 AB The carcinogenic potential of dichloromethane (DCM) has been linked to its metabolism to formaldehyde by glutathione-S-transferase theta 1 (GSTT1), GSTT1 is polymorphic in humans. The frequency of the GSTT1 homozygous null genotype ranges from 10 to 60% in different ethnic and racial populations around the world, We investigated how varying GSTT1 genotype frequencies would impact cancer risk estimates for DCM by the application of Monte Carlo simulation methods in combination with physiologically based pharmacokinetic (PBPK) models. The PBPK model was used to estimate the DNA-protein cross links (DPX) caused by metabolism of DCM based on an earlier model. Cancer potency of DCM was obtained by the application of the estimated DPX amounts to the results of a carcinogenicity study by National Toxicology Program in B6C3F(1) mice. Human risks were estimated based on the carcinogenic potency of DCM to mice and PBPK-predicted amounts of DPX formed in humans. The Monte Carlo simulations were used to provide distributions of risk estimates for a sample of 1000 PBPK runs, each run representing a collection of biochemical and physiological parameters for a single person (with and without polymorphism included in the model). Our results show that average and median risk estimates were 23-30% higher when GSTT1 polymorphism was not included at inhalation DCM doses of 1000, 100, 10, and 1 ppm. This increase in risk was significantly reduced when it was based on the 95th percentile measure for all the doses, The specific effect of this polymorphism on population risk was further investigated by varying the probability that an individual may have a nonfunctional form of the enzyme at a constant dose level of 10 ppm of DCM, Higher values of this probability resulted in a corresponding decrease in risk. Again, this drop in population risk was not as significant when the 95th percentile measure was used. C1 Novigen Sci Inc, Washington, DC 20036 USA. NIEHS, Lab Computat Biol & Risk Anal, Res Triangle Pk, NC 27709 USA. RP El-Masri, HA (reprint author), Novigen Sci Inc, Washington, DC 20036 USA. RI Portier, Christopher/A-3160-2010 OI Portier, Christopher/0000-0002-0954-0279 NR 18 TC 48 Z9 49 U1 0 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD AUG 1 PY 1999 VL 158 IS 3 BP 221 EP 230 DI 10.1006/taap.1999.8715 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 227VX UT WOS:000082101600003 PM 10438655 ER PT J AU Cowan, EP Nemo, GJ Williams, AE Alexander, RK Vallejo, A Hewlett, IK Lal, RB Dezzutti, CS Gallahan, D George, K Pancake, BA Zucker-Franklin, D McCurdy, PR Tabor, E AF Cowan, EP Nemo, GJ Williams, AE Alexander, RK Vallejo, A Hewlett, IK Lal, RB Dezzutti, CS Gallahan, D George, K Pancake, BA Zucker-Franklin, D McCurdy, PR Tabor, E TI Absence of human T-lymphotropic virus type I tax sequences in a population of normal blood donors in the Baltimore, MD/Washington, DC, area: results from a multicenter study SO TRANSFUSION LA English DT Article ID MYCOSIS-FUNGOIDES; MYELOPATHY; PROVIRUS AB BACKGROUND: It was reported recently that sequences corresponding to the human T-lymphotropic virus type I (HTLV-I) tax gene were detected in peripheral blood mononuclear cells from 8 to 11 percent of healthy blood donors without detectable antibodies to HTLV-I. A multicenter blind study was conducted to determine if these results could be independently confirmed. STUDY DESIGN AND METHODS: Specimens were collected from 100 anti-HTLV-I-negative healthy blood donors and from 11 anti-HTLV-I- or anti-HTLV-II-positive individuals. All samples were coded and distributed to each of four independent testing laboratories for polymerase chain reaction analysis to detect sequences of the HTLV-I or HTLV-II fax gene, using detailed procedures specified by the laboratory reporting the original observation. Each laboratory also tested a dilution panel of a plasmid containing HTLV-I tax to determine the analytical sensitivity of the procedure. RESULTS: The analytical sensitivity of the screening methods permitted detection of as few as 1 to 10 copies of the fax gene. However, HTLV-I tax sequences could not be detected in any of the anti-HTLV-I-negative blood donors at more than one test site. CONCLUSION: HTLV-I tax sequences appear not to be present in this population of 100 blood donors negative for anti-HTLV-I. C1 NHLBI, Transfus Med Sci Res Grp, Bethesda, MD 20892 USA. US FDA, Div Transfus Transmitted Dis, Atlanta, GA 30333 USA. Ctr Dis Control & Prevent, HIV & Retrovirus Dis Branch, Atlanta, GA 30333 USA. Amer Red Cross, Jerome H Holland Lab, Transmissible Dis Dept, Rockville, MD USA. Retrovirus Epidemiol Donor Study, Rockville, MD USA. NYU Med Ctr, Dept Med, New York, NY 10016 USA. RP Cowan, EP (reprint author), 1401 Rockville Pike,HFM-320, Rockville, MD 20852 USA. RI Vallejo, Alejandro/I-5881-2015 OI Vallejo, Alejandro/0000-0001-5360-878X NR 15 TC 12 Z9 12 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 AUG PY 1999 VL 39 IS 8 BP 904 EP 909 DI 10.1046/j.1537-2995.1999.39080904.x PG 6 WC Hematology SC Hematology GA 226ZH UT WOS:000082052700018 PM 10504129 ER PT J AU Hampshire, V Davis, J AF Hampshire, V Davis, J TI Inside the mouse hospital: science, animal welfare and strife in the drive for AAALAC accreditation SO TRANSGENIC RESEARCH LA English DT Letter C1 NINDS, NIH, Bethesda, MD 20892 USA. RP Hampshire, V (reprint author), NINDS, NIH, Bldg 35 Rm B125,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0962-8819 J9 TRANSGENIC RES JI Transgenic Res. PD AUG PY 1999 VL 8 IS 4 BP 251 EP 252 DI 10.1023/A:1008994416860 PG 2 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 246QX UT WOS:000083177000001 PM 10621972 ER PT J AU Williams-Simons, L Westphal, H AF Williams-Simons, L Westphal, H TI EIIaCre - Utility of a general deleter strain SO TRANSGENIC RESEARCH LA English DT Letter ID SITE-SPECIFIC RECOMBINATION; TRANSGENIC MICE C1 NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Westphal, H (reprint author), NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. NR 8 TC 4 Z9 4 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0962-8819 J9 TRANSGENIC RES JI Transgenic Res. PD AUG PY 1999 VL 8 IS 4 BP 253 EP 254 DI 10.1023/A:1008994831937 PG 2 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 246QX UT WOS:000083177000002 ER PT J AU Amero, SA AF Amero, SA TI Careers-perspective interview - Sally A. Amero SO TRENDS IN CELL BIOLOGY LA English DT Editorial Material C1 NIH, Ctr Sci Review, Bethesda, MD 20205 USA. RP Amero, SA (reprint author), NIH, Ctr Sci Review, Bethesda, MD 20205 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD AUG PY 1999 VL 9 IS 8 BP 333 EP 333 DI 10.1016/S0962-8924(99)01583-4 PG 1 WC Cell Biology SC Cell Biology GA 220JL UT WOS:000081661800008 PM 10407413 ER PT J AU Aravind, L Tatusov, RL Wolf, YI Walker, DR Koonin, EV AF Aravind, L Tatusov, RL Wolf, YI Walker, DR Koonin, EV TI Archaeal and bacterial hyperthermophiles - horizontal gene exchange or common ancestry? Reply SO TRENDS IN GENETICS LA English DT Editorial Material C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. NR 8 TC 11 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD AUG PY 1999 VL 15 IS 8 BP 299 EP 300 DI 10.1016/S0168-9525(99)01786-2 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 223CN UT WOS:000081822600004 ER PT J AU Brody, T AF Brody, T TI The Interactive Fly: gene networks, development and the Internet SO TRENDS IN GENETICS LA English DT Article C1 NINDS, LNC, NIH, Bethesda, MD 20892 USA. RP Brody, T (reprint author), NINDS, LNC, NIH, Bethesda, MD 20892 USA. NR 0 TC 33 Z9 39 U1 1 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD AUG PY 1999 VL 15 IS 8 BP 333 EP 334 DI 10.1016/S0168-9525(99)01775-8 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 223CN UT WOS:000081822600010 PM 10431196 ER PT J AU Nickel, JC Nyberg, LM Hennenfent, M AF Nickel, JC Nyberg, LM Hennenfent, M CA Int Prostatitis Collaborative Network TI Research guidelines for chronic prostatitis: Consensus report from the first National Institutes of Health International Prostatitis Collaborative Network SO UROLOGY LA English DT Article ID NONBACTERIAL PROSTATITIS; PROSTATODYNIA; QUESTIONNAIRE AB Objectives. The National Institutes of Health (NIH) organized the first International Prostatitis Collaborative Network workshop (November 5 and 6, 1998, Washington, DC) to address the confusion surrounding the diagnostic and treatment strategies in chronic prostatitis. Methods. A panel of North American and international urologic researchers, interested physicians, medical industry representatives, and patients were invited to participate and reviewed current definitions, classification systems, and recent epidemiologic and both published and "in progress" treatment studies. Results. A general concensus was developed for adoption of the following criteria for clinical studies in chronic prostatitis/chronic pelvic pain syndrome: (a) the NIH definition of chronic prostatitis/chronic pelvic pain syndrome; (b) the 1995 NIH Classification System; (c) the eligibility (inclusion/exclusion) criteria developed by the NIH Chronic Prostatitis Clinical Research Network; (d) the NIH Chronic Prostatitis Symptom Index. It was agreed that clinical treatment trials involving presently available, experimental, and theoretical therapeutic modalities be prioritized according to maximum potential benefits and that regulatory authorities (ie, Food and Drug Administration in the United States) consider major changes in the approval process for treatment modalities in chronic prostatitis. Conclusions. Chronic prostatitis is a major health care issue. Standardization of definitions, classification, study design, and outcome parameters will promote rational and comparative evaluation of diagnostic and therapeutic strategies. (C) 1999, Elsevier Science Inc. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. Prostatitis Fdn, Chicago, IL USA. Queens Univ, Dept Urol, Kingston, ON, Canada. RP Nickel, JC (reprint author), Queens Univ, Kingston Gen Hosp, Dept Urol, Kingston, ON K7L 2V7, Canada. NR 14 TC 116 Z9 157 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD AUG PY 1999 VL 54 IS 2 BP 229 EP 233 DI 10.1016/S0090-4295(99)00205-8 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 221RL UT WOS:000081740000007 PM 10443716 ER PT J AU Lu-Yao, GL Albertsen, P Warren, J Yao, SL AF Lu-Yao, GL Albertsen, P Warren, J Yao, SL TI Effect of age and surgical approach on complications and short-term mortality after radical prostatectomy - A population-based study SO UROLOGY LA English DT Article ID LYMPH-NODE DISSECTION; PERINEAL PROSTATECTOMY; RETROPUBIC PROSTATECTOMY; CANCER; LYMPHADENECTOMY; CLAIMS AB Objectives. To use population-based data to accurately delineate the types and incidence of complications, risk of readmission, and influence of age and surgical approach on short-term mortality after radical prostatectomy. Methods. Medicare claims from 1991 to 1994 were used to identify and quantify the types and risks of complications, rehospitalization within 90 days, and mortality at 30 and 90 days after perineal or retropubic prostatectomy. Logistic regression was used to determine the relationships between age, surgical approach, and short-term outcomes while adjusting for potential confounders. Results. On the basis of data from 101,604 men, complications affected 25.0% to 28.8% of patients treated with the perineal or retropubic approach. The retropubic approach had a higher risk of respiratory complications (relative risk [RR] = 1.53, 95% confidence interval [CI] 1.37 to 1.71)and miscellaneous medical complications (RR = 1.77, 95% CI 1.60 to 1.97) and a lower risk of miscellaneous surgical complications (RR = 0.86, 95% CI 0.78 to 0.94). Differences in medically related gastrointestinal complications partially accounted for the differences in miscellaneous medical complications. Rectal injury with the perineal approach was only similar to 1% to 2%. Readmission within 90 days was necessary for 8.5% to 8.7% of patients who underwent the retropubic or perineal approach. The 30-day mortality was less than 0.5% for men aged 65 to 69; it approached 1% for men aged 75 and older. Conclusions. Complications and readmission after prostatectomy are substantially more common than previously recognized. Notable differences exist in the incidence of respiratory and nonsurgical gastrointestinal complications, although many short-term outcomes are comparable for the two approaches. Older age is associated with elevated surgical mortality and complications. (C) 1999, Elsevier Science Inc. C1 Merck Res Labs, Rahway, NJ 07065 USA. HealthStat, Princeton, NJ USA. Univ Connecticut, Dept Urol, Farmington, CT USA. NCI, Bethesda, MD 20892 USA. RP Yao, SL (reprint author), Merck Res Labs, POB 2000,RY33-640, Rahway, NJ 07065 USA. NR 25 TC 64 Z9 64 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD AUG PY 1999 VL 54 IS 2 BP 301 EP 307 DI 10.1016/S0090-4295(99)00100-4 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 221RL UT WOS:000081740000020 PM 10443729 ER PT J AU Nagai, Y Metter, EJ Fleg, JL AF Nagai, Y Metter, EJ Fleg, JL TI Increased carotid artery intimal-medial thickness: risk factor for exercise-induced myocardial ischemia in asymptomatic older individuals SO VASCULAR MEDICINE LA English DT Review DE carotid arteries; coronary artery disease; exercise testing; risk factors; ultrasound ID CORONARY HEART-DISEASE; B-MODE ULTRASOUND; WALL THICKNESS; ATHEROSCLEROSIS RISK; FOLLOW-UP; MEN; COMMUNITIES; POPULATION; EVENTS; ECG AB Asymptomatic coronary artery disease (CAD) is prevalent in the general population and has been associated with an increased risk for symptomatic CAD. Although the diagnosis of asymptomatic CAD is currently dependent on exercise testing and coronary angiography, other vascular diagnostic techniques could potentially be of aid in the assessment. Increased intimal-medial thickness (IMT) of the common carotid artery as assessed by B-mode ultrasonography is a purported index of atherosclerosis, and is associated with symptomatic CAD. Based on a recent report, this article will focus on the relationship between IMT and asymptomatic CAD as evidenced by exercise ECG, and in combination with exercise thallium scintigraphy. It was found that exercise-induced ST segment depression was associated with increased IMT independent of age, coronary risk factors and manifest CAD. After adjustment for age, IMT progressively increased from healthy subjects to asymptomatic subjects with positive exercise ECG alone, to those with concordant positive ECG and thallium scintigraphic findings who had IMT virtually identical to that in subjects with manifest CAD. Each 0.1 mm increase in IMT was associated with a 1.91-fold (95% Cl 1.46-2.50) increased risk for concordant positive exercise tests or manifest CAD, independent of other coronary risk factors. These findings and the review of the literature suggest the potential utility of carotid ultrasonography in identifying asymptomatic individuals at higher risk for CAD. C1 NIA, NIH, Intramural Res Program, Gerontol Res Ctr,Lab Clin Invest, Baltimore, MD 21224 USA. Osaka Univ, Sch Med, Dept Med, Osaka, Japan. RP Metter, EJ (reprint author), NIA, NIH, Intramural Res Program, Gerontol Res Ctr,Lab Clin Invest, Box 06,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 70 TC 8 Z9 8 U1 0 U2 0 PU ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 1358-863X J9 VASC MED JI Vasc. Med. PD AUG PY 1999 VL 4 IS 3 BP 181 EP 186 DI 10.1177/1358836X9900400309 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 233ZU UT WOS:000082457700009 PM 10512598 ER PT J AU Hirsch, MS Wilfert, C Ammann, A Coovadia, HM Cu-Uvin, S Dabis, F Ekpini, RAE Kallings, LO Mofenson, L Tess, B Bryson, Y Cao, Y Chotpitayasunondh, T Nduati, R Solomon, S AF Hirsch, MS Wilfert, C Ammann, A Coovadia, HM Cu-Uvin, S Dabis, F Ekpini, RAE Kallings, LO Mofenson, L Tess, B Bryson, Y Cao, Y Chotpitayasunondh, T Nduati, R Solomon, S TI IAS position paper on prevention of HIV1 mother-to-child transmission SO AIDS LA English DT Article ID ZIDOVUDINE C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Infect Dis Unit, Boston, MA 02114 USA. Glaser Pediat AIDS Fdn, Durham, NC USA. Duke Univ, Med Ctr, Durham, NC USA. Global Strategies HIV Prevent, San Rafael, CA USA. Univ Natal, Dept Pediat & Child Hlth, ZA-4001 Durban, South Africa. Brown Univ, Miriam Hosp, Providence, RI USA. Univ Victor Segalen, Bordeaux, France. Project RETEO CI, Abidjan, Cote Ivoire. Int AIDS Soc, Stockholm, Sweden. NICHHD, Pediat Adolescent & Maternal AIDS Branch, NIH, Rockville, MD USA. Minist Publ Hlth, Brasilia, DF, Brazil. Univ Calif Los Angeles, Los Angeles, CA 90024 USA. Natl Ctr AIDS Prevent & Control, Dept Clin Virol, Beijing, Peoples R China. Queen Sirikit Natl Inst Child Hlth, Childrens Hosp, Bangkok, Thailand. Univ Nairobi, Dept Pediat, Nairobi, Kenya. Ctr AIDS Res & Educ, Chennai, India. RP Hirsch, MS (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Infect Dis Unit, Boston, MA 02114 USA. NR 22 TC 1 Z9 1 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 JUL 30 PY 1999 VL 13 IS 11 BP A5 EP A9 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 221JD UT WOS:000081723200035 ER PT J AU Bogi, K Lorenzo, PS Acs, P Szallasi, Z Wagner, GS Blumberg, PM AF Bogi, K Lorenzo, PS Acs, P Szallasi, Z Wagner, GS Blumberg, PM TI Comparison of the roles of the C1a and C1b domains of protein kinase C alpha in ligand induced translocation in NIH 3T3 cells SO FEBS LETTERS LA English DT Article DE phorbol 12-myristate 13-acetate; PMA; tumor promotion; sn-1,2-diacylglycerol ID ESTER-INDUCED TRANSLOCATION; ACTIVATOR-BINDING DOMAIN; PHORBOL ESTER; PKC-DELTA; IN-VIVO; CALCIUM; SELECTIVITY; EXPRESSION; AFFINITY; ISOZYMES AB To explore the relative roles of the two C1 domains of protein kinase C alpha (PKC alpha) in the response to phorbol esters and related analogs, we mutated the individual C1 domains, expressed the mutated PKC alpha in NIH 3T3 cells, and then examined the ability of ligands to induce its translocation to the membrane, The C1a and C1b domains play equivalent roles for translocation in response to phorbol 12-myristate 13-acetate, mezerein, and (-)octylindolactam V, These results contrast with those previously reported for PKC delta, suggesting that the domains play different roles in different PKC isoforms, (C) 1999 Federation of European Biochemical Societies. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. RP Blumberg, PM (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bldg 37, Bethesda, MD 20892 USA. NR 20 TC 31 Z9 31 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUL 30 PY 1999 VL 456 IS 1 BP 27 EP 30 DI 10.1016/S0014-5793(99)00927-8 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 224QQ UT WOS:000081910100006 PM 10452523 ER PT J AU Keller, JE Neale, EA Oyler, G Adler, M AF Keller, JE Neale, EA Oyler, G Adler, M TI Persistence of botulinum neurotoxin action in cultured spinal cord cells SO FEBS LETTERS LA English DT Article DE botulinum neurotoxin; synaptosomal-associated protein of 25 kDa (SNAP-25); spinal cord culture ID RAT NEUROMUSCULAR-JUNCTION; CLOSTRIDIAL NEUROTOXINS; SEROTYPE-A; SNAP-25; PROTEINS; TETANUS; RELEASE; TOXIN; ASTROCYTES; TERMINALS AB Primary dissociated fetal mouse spinal cord cultures were used to study the mechanisms underlying the differences in persistence of botulinum neurotoxin A (BoNT/A) and botulinum neurotoxin/E (BoNT/E) activities. Spinal cord cultures were exposed to BoNT/A (0.4 pM) for 2-3 days, which converted approximately half of the SNAP-25 to an altered form lacking the final nine C-terminal residues. The distribution of toxin-damaged to control SNAP-25 remained relatively unchanged for up to 80 days thereafter. Application of a high concentration of BoNT/E (250 pM) either 25 or 60 days following initial intoxication with BoNT/A converted both normal and BoNT/ A-truncated SNAP-25 into a single population lacking the final 26 C-terminal residues. Excess BoNT/E was removed by washout, and recovery of intact SNAP-25 was monitored by Western blot analysis. The BoNT/E-truncated species gradually diminished during the ensuing 18 days, accompanied by the reappearance of both normal and BoNT/A-truncated SNAP-25, Return of BoNT/A-truncated SNAP-25 was observed in spite of the absence of BoNT/A in the culture medium during all but the first 3 days of exposure. These results indicate that proteolytic activity associated with the BoNT/A light chain persists inside cells for >11 weeks, while recovery from BoNT/E is complete in <3 weeks. This longer duration of enzymatic activity appears to account for the persistence of serotype A action. (C) 1999 Federation of European Biochemical Societies. C1 USA, Med Res Inst Chem Def, Neurotoxicol Branch, Div Pharmacol, Aberdeen Proving Ground, MD 21010 USA. NICHHD, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Publ Hlth & Human Hyg, Baltimore, MD 21287 USA. RP Keller, JE (reprint author), USA, Med Res Inst Chem Def, Neurotoxicol Branch, Div Pharmacol, 3100 Ricketts Point Rd, Aberdeen Proving Ground, MD 21010 USA. NR 28 TC 105 Z9 107 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUL 30 PY 1999 VL 456 IS 1 BP 137 EP 142 DI 10.1016/S0014-5793(99)00948-5 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 224QQ UT WOS:000081910100028 PM 10452545 ER PT J AU Coudray, C Charon, C Komas, N Mory, G Diot-Dupuy, F Manganiello, V Ferre, P Bazin, R AF Coudray, C Charon, C Komas, N Mory, G Diot-Dupuy, F Manganiello, V Ferre, P Bazin, R TI Evidence for the presence of several phosphodiesterase isoforms in brown adipose tissue of Zucker rats: modulation of PDE2 by the fa gene expression SO FEBS LETTERS LA English DT Article DE type 3 phosphodiesterase; type 4 phosphodiesterase; obesity; cyclic GMP ID CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; AMP PHOSPHODIESTERASE; UNCOUPLING PROTEIN; FA/FA RATS; BINDING; IDENTIFICATION; CELLS; PUPS AB The present study was undertaken to characterise the phosphodiesterases (PDEs) present in brown adipose tissue (BAT) of Zucker rat pups and to determine whether the capacity for degradation of cyclic nucleotides was affected hy the fatty genotype, Regardless of the genotype, PDE2-4 contributed to total PDE activity, the PDE3 activity equalling the sum of PDE2 and 4 activities. In fa/fa compared to Fa/fa rats, (a) PDE2 activity was significantly increased, (b) Western blot analysis of PDE2 revealed two signals at 71 and 105 kDa, with changes in protein being in good parallelism with changes in activity, (c) the PDE2 mRNA concentration was also significantly increased. In good agreement, the cGMP concentration was decreased in BAT from fa/fa pups, (C) 1999 Federation of European Biochemical Societies. C1 INSERM, U465, F-75006 Paris, France. Biotechnol Res Inst, NRC, Montreal, PQ H4P 2R2, Canada. NHLBI, Pulm Branch, Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Bazin, R (reprint author), INSERM, U465, 15 Rue Ecole Med, F-75006 Paris, France. RI Ferre, Pascal/K-1250-2013 NR 24 TC 11 Z9 11 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUL 30 PY 1999 VL 456 IS 1 BP 207 EP 210 DI 10.1016/S0014-5793(99)00934-5 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 224QQ UT WOS:000081910100042 PM 10452559 ER PT J AU Potischman, N Swanson, CA Coates, RJ Gammon, MD Brogan, DR Curtin, J Brinton, LA AF Potischman, N Swanson, CA Coates, RJ Gammon, MD Brogan, DR Curtin, J Brinton, LA TI Intake of food groups and associated micronutrients in relation to risk of early-stage breast cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID VITAMIN-A; DIETARY FIBER; NUTRITION; QUESTIONNAIRE; CONSUMPTION; GREECE; WOMEN; FAT AB Epidemiologic studies have evaluated the risk of breast cancer related to dietary fat intake, but only recently have other dietary factors received attention. Frequent intakes of fruit, vegetables and fiber have been associated with low risk of the disease in some studies but results are inconsistent. In a large case-control study of early-onset breast cancer, we evaluated risk related to a variety of food groups, associated micronutrients and non-nutritive constituents. Cases treated with chemotherapy appeared to have altered reporting of food intake and were excluded. Analyses were restricted to 568 cases with in situ and localized disease and 1,451 population-based controls. Reduced risks were observed for high intake of cereals and grains [odds ratio (OR) = 0.84, 95% confidence interval (CI) = 0.6-1.1 for highest compared with lowest quartile], vegetables (OR = 0.86, 95% CI = 0.6-1.1), beans (OR = 0.87, 95% CI = 0.7-1.2) and fiber from beans (OR = 0.88, 95% CI = 0.7-1.2). However, no trends of decreasing risk across quartiles of increasing intake were observed. Risk was not associated with dietary constituents related to these food groups including dietary fiber, carotenoids, vitamins A, C and E and folate. Incorporation of information from vitamin supplements did not alter the results for micronutrients. Our data suggest that intakes of cereals and grains, vegetables and beans are associated with minimal, if any, reduction in risk of early-stage breast cancer among young women. Int. J. Cancer 82:315-321, 1999. Published 1999 Wiley-Liss, Inc.dagger C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Div Canc Prevent & Control, Atlanta, GA USA. Columbia Univ, Sch Publ Hlth, Div Epidemiol, New York, NY USA. Emory Univ, Dept Epidemiol, Atlanta, GA 30322 USA. Informat Management Syst, Silver Spring, MD USA. RP Brinton, LA (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Room 7068, Bethesda, MD 20892 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 32 TC 100 Z9 101 U1 2 U2 12 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 JUL 30 PY 1999 VL 82 IS 3 BP 315 EP 321 DI 10.1002/(SICI)1097-0215(19990730)82:3<315::AID-IJC1>3.0.CO;2-N PG 7 WC Oncology SC Oncology GA 211YJ UT WOS:000081189200001 PM 10399945 ER PT J AU Thomas, GR Chen, Z Oechsli, MN Hendler, FJ Van Waes, C AF Thomas, GR Chen, Z Oechsli, MN Hendler, FJ Van Waes, C TI Decreased expression of CD80 is a marker for increased tumorigenicity ln a new murine model of oral squamous-cell carcinoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID B7-1 CD80; CO-STIMULATION; T-CELLS; COSTIMULATION; KERATINOCYTES; RESPONSES; INDUCTION; MECHANISM; GROWTH; ANERGY AB We established a new syngeneic murine model of oral squamous-cell carcinoma (SCC) to analyze the potential role of immune recognition determinants in the early development of oral cancer. In this study, we examined whether SCC that undergo transformation and development in the absence of specific immunity exhibit differences in tumorigenicity that relate to differences in expression of CD80, CD86 or MHC class I. Mucosal keratinocytes from BALB/c mice were transformed in vitro with 4-nitroquinolone-1-oxide (4-NQO) and inoculated into SCID mice to obtain tumorigenic cell lines. Five SCC cell lines were re-isolated from tumors, and 4 retained cytokeratin and beta 4-integrin markers of epithelial origin. Their growth was compared in BALB/c and in congenic SCID mice to establish whether the cell lines exhibit differences in immunogenicity. Three lines that showed slower growth or completely regressed when implanted in immune competent hosts retained or developed increased expression of CD80 during development in SCID mice. Conversely, 2 SCC lines that lost expression of CD80 after passage in vivo grew progressively in immune-competent hosts. MHC-class-l and CD86 expression did not correlate with tumorigenicity. These observations provide evidence that decreased expression of CD80 may serve as a marker for increased tumorigenicity during early development of oral SCC. The development of this new murine oral SCC model should prove useful in determining the potential effects of CD80 expression on the immune pathogenesis and therapy of SCC. Int. J. Cancer 82:377-384, 1999. (C) 1999 Wiley-Liss, Inc. C1 NIDCD, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD 20892 USA. Univ Louisville, J Graham Brown Canc Inst, Dept Med, Louisville, KY 40292 USA. Univ Louisville, J Graham Brown Canc Inst, Dept Biochem & Mol Biol, Louisville, KY 40292 USA. Louisville Vet Adm Hosp, Louisville, KY USA. RP Van Waes, C (reprint author), NIDCD, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bldg 10,Room 5D55,10 Ctr Dr, Bethesda, MD 20892 USA. FU NIDCD NIH HHS [Z01-DC-00016] NR 21 TC 26 Z9 27 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 JUL 30 PY 1999 VL 82 IS 3 BP 377 EP 384 DI 10.1002/(SICI)1097-0215(19990730)82:3<377::AID-IJC11>3.0.CO;2-9 PG 8 WC Oncology SC Oncology GA 211YJ UT WOS:000081189200011 PM 10399955 ER PT J AU Nieves-Neira, W Pommier, Y AF Nieves-Neira, W Pommier, Y TI Apoptotic response to camptothecin and 7-hydroxystaurosporine (UCN-01) in the 8 human breast cancer cell lines of the NCI anticancer drug screen: Multifactorial relationships with topoisomerase I, protein kinase C, Bcl-2, p53, MDM-2 and caspase pathways SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID DNA FRAGMENTATION; EXPRESSION; CYTOTOXICITY; INHIBITOR; DEATH AB Derivatives of camptothecins, topoisomerase I inhibitors and 7-hydroxystaurosporine (UCN-01), a protein kinase C (PKC) inhibitor and cell cycle checkpoint abrogator, are promising anticancer drugs, We characterized the apoptotic response to camptothecin and UCN-01 for the 8 human breast carcinoma cell lines (MCF-7, MCF-7/ADR, T47D, HS578T, BT549, MDA-N, MDA MB231, MDA435) from the National Cancer Institute (NCI) Anticancer Drug Screen. MCF-7 and T47D cells exhibited marked resistance to apoptosis, whereas MCF-7/ADR (NCI/ADR-RES) and HS578T cells exhibited the most pronounced apoptotic response. Apoptotic response was not correlated with growth inhibition measured by sulforhodamine B (SRB) assay, indicating that apoptosis is not the only mechanism of drug-induced cell death, Measurements of topoisomerase I levels and cleavage complexes and of PKC isoforms demonstrated that primary target inhibition was not correlated with apoptotic response. Several key apoptotic pathways were evaluated. Only MCF-7 cells had wild-type p53, indicating that p53 is not required for drug-induced apoptosis, MCF-7 cells also showed the highest MDM-2 expression (along with T47D cells, which were also resistant to apoptosis), Bcl-2, Mcl-1 and caspases 2 and 3 protein levels varied widely, whereas Bar expression was comparable among cell lines. Interestingly, Bcl-2, Mcl-1 and Bcl-X-L cumulative expressions were inversely correlated with apoptotic response. Our results provide a comparative molecular characterization for the breast cancer cell lines of the NCI Anticancer Drug Screen and demonstrate the diversity of cellular responses to drugs (apoptosis vs. cell cycle arrest) and the importance of multifactorial analyses for modulating/ predicting the apoptotic response to chemotherapy. Int. J. Cancer 82:396-404, 1999. Published 1999 Wiley-Liss, Inc.dagger C1 NCI, Mol Pharmacol Lab, Div Basic Sci, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Div Basic Sci, Bldg 37,Room 5D02, Bethesda, MD 20892 USA. NR 26 TC 96 Z9 99 U1 0 U2 8 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 JUL 30 PY 1999 VL 82 IS 3 BP 396 EP 404 DI 10.1002/(SICI)1097-0215(19990730)82:3<396::AID-IJC13>3.0.CO;2-Z PG 9 WC Oncology SC Oncology GA 211YJ UT WOS:000081189200013 PM 10399957 ER PT J AU Muth, JN Yamaguchi, H Mikala, G Grupp, IL Lewis, W Cheng, HP Song, LS Lakatta, EG Varadi, G Schwartz, A AF Muth, JN Yamaguchi, H Mikala, G Grupp, IL Lewis, W Cheng, HP Song, LS Lakatta, EG Varadi, G Schwartz, A TI Cardiac-specific overexpression of the alpha(1) subunit of the L-type voltage-dependent Ca2+ channel in transgenic mice - Loss of isoproterenol-induced contraction SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; ADENYLYL-CYCLASE; CALCIUM CHANNELS; HEART; CELLS; RECEPTOR; FAILURE; ENTRY AB The L-type voltage-dependent calcium channel (L-VDCC) regulates calcium influx in cardiac myocytes, Activation of the P-adrenergic receptor (PAR) pathway causes phosphorylation of the L-VDCC and that in turn increases Ca2+ influx. Targeted expression of the L-VDCC a, subunit in transgenic (Tg) mouse ventricles resulted in marked blunting of the PAR pathway. Inotropic and lusitropic responses to isoproterenol and forskolin in Tg hearts were significantly reduced. Likewise, Ca2+ current augmentation induced by isoproterenol and forskolin was markedly depressed in Tg cardiomyocytes. Despite no change in PAR number, isoproterenol-stimulated adenylyl cyclase activity was absent in Tg membranes and NaF and forskolin responses were reduced. We postulate an important pathway for regulation of the PAR by Ca2+ channels. C1 Univ Cincinnati, Coll Med, Inst Mol Pharmacol & Biophys, Cincinnati, OH 45267 USA. Univ Cincinnati, Coll Med, Dept Cell Biol Neurobiol & Anat, Cincinnati, OH 45267 USA. Univ Cincinnati, Coll Med, Dept Pathol & Lab Med, Cincinnati, OH 45267 USA. Univ Cincinnati, Coll Med, Dept Pharmacol & Cell Biophys, Cincinnati, OH 45267 USA. NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Schwartz, A (reprint author), Univ Cincinnati, Coll Med, Inst Mol Pharmacol & Biophys, POB 670828, Cincinnati, OH 45267 USA. RI Song, Long-Sheng/D-5899-2012 FU NHLBI NIH HHS [P01 HL22619, R01 R37HL43231, T32 HL 07382] NR 25 TC 50 Z9 51 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 JUL 30 PY 1999 VL 274 IS 31 BP 21503 EP 21506 DI 10.1074/jbc.274.31.21503 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 221HF UT WOS:000081721100004 PM 10419451 ER PT J AU Park, BC Lee, YC Strott, CA AF Park, BC Lee, YC Strott, CA TI Identification by chimera formation and site-selected mutagenesis of a key amino acid residue involved in determining stereospecificity of guinea pig 3-hydroxysteroid sulfotransferase isoforms SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MOLECULAR-CLONING; 3-ALPHA-HYDROXYSTEROID SULFOTRANSFERASE; STEROID SULFOTRANSFERASES; ESTROGEN SULFOTRANSFERASE; EXPRESSION; DISTINCT; PROTEIN; BINDING AB The 3-hydroxysteroid sulfotransferases that have been isolated and cloned from humans and rodents ap pear to have broad substrate specificities. In the guinea pig, however, two 3-hydroxysteroid sulfotransferases have been isolated that function according to an innate stereospecificity: the alpha-isoform acts on steroids with a 3-hydroxyl group oriented in the alpha position, whereas the beta-isoform acts on steroids where the 3-hydroxyl group is in a beta orientation. To examine the structural basis for this remarkable stereoselectivity, chimeras of the two enzymes, which are 87% identical, were constructed. A chimera consisting of the NH2-terminal 91 amino acids of the alpha-isoform and the COOH-terminal 196 amino acids of the beta-isoform displayed activity similar to that of the alpha-isoform. Site-selected mutagenesis of this 3 alpha/beta hydroxysteroid sulfotransferase chimera involving the 12 amino acid differences that exist between the two isoforms within the 91 amino acid NH2-terminal region revealed that the amino acid residue at position 51 plays a fundamental role in determining the stereospecificity exhibited by the alpha- and beta-isoforms, i.e. if residue 51 is an asparagine, alpha activity predominates, whereas if an isoleucine is in that position, beta activity prevails. C1 NICHD, Sect Steriod Regulat, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Strott, CA (reprint author), NICHD, Sect Steriod Regulat, Endocrinol & Reprod Res Branch, NIH, Bldg 10,Rm 6A36, Bethesda, MD 20892 USA. NR 12 TC 7 Z9 7 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 JUL 30 PY 1999 VL 274 IS 31 BP 21562 EP 21568 DI 10.1074/jbc.274.31.21562 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 221HF UT WOS:000081721100014 PM 10419461 ER PT J AU Safrany, ST Ingram, SW Cartwright, JL Falck, JR McLennan, AG Barnes, LD Shears, SB AF Safrany, ST Ingram, SW Cartwright, JL Falck, JR McLennan, AG Barnes, LD Shears, SB TI The diadenosine hexaphosphate hydrolases from Schizosaccharomyces pombe and Saccharomyces cerevisiae are homologues of the human diphosphoinositol polyphosphate phosphohydrolase - Overlapping substrate specificities in a MutT-type protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INOSITOL HEXAKISPHOSPHATE; KINASE; CELL; ATP; PENTAKISPHOSPHATE; INHIBITION; CLONING; FAMILY; PURIFICATION; EXPRESSION AB Aps1 from Schizosaccharomyces pombe (Ingram, S. W., Stratemann, S, A., and Barnes, L, D, (1999) Biochemistry 38, 3649-3655) and YOR163w from Saccharomyces cerevisiae (Cartwright, J, L., and McLennan, A. G, (1999) J. Biol. Chem. 274, 8604-8610) have both previously been characterized as MutT family hydrolases with high specificity for diadenosine hexa- and pentaphosphates (Ap(6)A and Ap(5)A). Using purified recombinant preparations of these enzymes, we have now discovered that they have an important additional function, namely, the efficient hydrolysis of diphosphorylated inositol polyphosphates, This overlapping specificity of an enzyme for two completely different classes of substrate is not only of enzymological significance, but in addition, this finding provides important new information pertinent to the structure, function, and evolution of the MutT motif. Moreover, we report that the human protein previously characterized as a diphosphorylated inositol phosphate phosphohydrolase represents the first example, in any animal, of an enzyme that degrades Ap(6)A and Ap(5)A, in preference to other diadenosine polyphosphates, The emergence of Ap(6)A and Ap(5)A as extracellular effecters and intracellular ion-channel ligands points not only to diphosphorylated inositol phosphate phosphohydrolase as a candidate for regulating signaling by diadenosine polyphosphates, but also suggests that diphosphorylated inositol phosphates may competitively inhibit this process. C1 NIEHS, Inositide Signaling Grp, NIH, Res Triangle Pk, NC 27709 USA. Univ Texas, Hlth Sci Ctr, Dept Biochem, San Antonio, TX 78284 USA. Univ Liverpool, Sch Biol Sci, Liverpool L69 7ZB, Merseyside, England. Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75235 USA. Univ Texas, SW Med Ctr, Dept Pharmacol, Dallas, TX 75235 USA. RP Shears, SB (reprint author), NIEHS, Inositide Signaling Grp, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. FU NIGMS NIH HHS [GM31278] NR 46 TC 76 Z9 80 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 JUL 30 PY 1999 VL 274 IS 31 BP 21735 EP 21740 DI 10.1074/jbc.274.31.21735 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 221HF UT WOS:000081721100039 PM 10419486 ER PT J AU Watari, H Blanchette-Mackie, EJ Dwyer, NK Watari, M Neufeld, EB Patel, S Pentchev, PG Strauss, JF AF Watari, H Blanchette-Mackie, EJ Dwyer, NK Watari, M Neufeld, EB Patel, S Pentchev, PG Strauss, JF TI Mutations in the leucine zipper motif and sterol-sensing domain inactivate the Niemann-Pick C1 glycoprotein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHOLESTEROL HOMEOSTASIS; DISEASE; COMPLEMENTATION; ACCUMULATION; FIBROBLASTS; TRANSPORT; MUTANTS; GENE AB Niemann-Pick type C (NPC) disease, characterized by accumulation of low density lipoprotein-derived free cholesterol in lysosomes, is caused by mutations in the NPC1 gene. We examined the ability of wild-type NPC1 and NPC1 mutants to correct the NPC sterol trafficking defect and their subcellular localization in CT60 cells. Cells transfected with wild-type NPC1 expressed 170- and 190-kDa proteins. Tunicamycin treatment resulted in a 140-kDa protein, the deduced size of NPC1, suggesting that NPC1 is N-glycosylated, Mutation of all four asparagines in potential N-terminal N-glycosylation sites to glutamines resulted in a 20-kDa reduction of the expressed protein. Proteins with a single N-glycosylation site mutation localized to late endosome/lysosomal compartments, as did wild-type NPC1, and each corrected the cholesterol trafficking defect. However, mutation of all four potential N-glycosylation sites reduced ability to correct the NPC phenotype commensurate with reduced expression of the protein. Mutations in the putative sterol-sensing domain resulted in inactive proteins targeted to lysosomal membranes encircling cholesterol-laden cores. N-terminal leucine zipper motif mutants could not correct the NPC defect, although they accumulated in lysosomal membranes. We conclude that NPC1 is a glycoprotein that must have an intact sterol-sensing domain and leucine zipper motif for cholesterol-mobilizing activity. C1 Univ Penn, Med Ctr, Dept Obstet & Gynecol, Ctr Res Reprod & Womens Hlth, Philadelphia, PA 19104 USA. Dept Vet Affairs Connecticut Healthcare Syst, Neurol Res Lab, Newington, CT 06111 USA. NIDDK, Sect Lipid Cell Biol, NIH, Newington, CT 06111 USA. NINDS, Cellular & Mol Pathophysiol Sect, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Strauss, JF (reprint author), 1354 BRBII-III,421 Curie Blvd, Philadelphia, PA 19104 USA. FU NICHD NIH HHS [HD06274]; NINDS NIH HHS [NS34339] NR 23 TC 74 Z9 76 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 JUL 30 PY 1999 VL 274 IS 31 BP 21861 EP 21866 DI 10.1074/jbc.274.31.21861 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 221HF UT WOS:000081721100057 PM 10419504 ER PT J AU Bortner, CD Cidlowski, JA AF Bortner, CD Cidlowski, JA TI Caspase independent/dependent regulation of K+, cell shrinkage, and mitochondrial membrane potential during lymphocyte apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SIGNALING COMPLEX DISC; PERMEABILITY TRANSITION; CYTOCHROME-C; THYMOCYTE APOPTOSIS; FLOW-CYTOMETRY; IN-VIVO; DEATH; BCL-2; ACTIVATION; INHIBITION AB The loss of cell volume is a fundamental feature of apoptosis. We have previously shown that DNA degradation and caspase activity occur only in cells which have shrunken as a result of potassium and sodium efflux (Bortner, C. D., Hughes, F. M., Jr., and Cidlowski, J. A. (1997) J. Biol Chem. 272, 32436-32442). Furthermore, maintaining a normal intracellular potassium concentration represses the cell death process by inhibiting the activity of apoptotic nucleases and suppressing the activation of effector caspases (Hughes, F, M., Jr., Bortner, C. D. Purdy, G. D., and Cidlowski, J. A. (1997) J. Biol. Chem. 272, 30567-30576). We have now investigated the relationship between cell shrinkage, ion efflux, and changes in the mitochondrial membrane potential, in addition to the role of caspases in these apoptotic events. Treatment of Jurkat cells with a series of inducers which act via distinct signal transduction pathways, resulted in all of the cell death characteristics including loss of cell viability, cell shrinkage, K+ efflux, altered mitochondrial membrane potential, and DNA fragmentation Interestingly, only cells which shrunk had a loss of mitochondrial membrane potential and the other apoptotic characteristics. Treatment of Jurkat cells with an anti-Pas antibody in the presence of the general caspase inhibitor z-VAD, abrogated these features. In contrast, when Jurkat cells were treated with either the calcium ionophore A23187 or thapsigargin, z-VAD failed to prevent cell shrinkage, K+ efflux, or changes in the mitochondrial membrane potential, while effectively inhibiting DNA degradation. Treatment of Jurkat cells with various apoptotic agents in the presence of either the caspase-3 inhibitor DEVD, or the caspase-8 inhibitor IETD also blocked DNA degradation, but failed to prevent other characteristics of apoptosis, Together these data suggest that the cell shrinkage, K+ efflux, and changes in the mitochondrial membrane potential are tightly coupled, but occur independent of DNA degradation, and can be largely caspase independent depending on the particular signal transduction pathway. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 50 TC 241 Z9 249 U1 1 U2 7 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 JUL 30 PY 1999 VL 274 IS 31 BP 21953 EP 21962 DI 10.1074/jbc.274.31.21953 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 221HF UT WOS:000081721100071 PM 10419518 ER PT J AU Kuschel, M Zhou, YY Cheng, HP Zhang, SJ Chen, Y Lakatta, EG Xiao, RP AF Kuschel, M Zhou, YY Cheng, HP Zhang, SJ Chen, Y Lakatta, EG Xiao, RP TI G(1) protein-mediated functional compartmentalization of cardiac beta(2)-adrenergic signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOSPHOLAMBAN PHOSPHORYLATION; CALCIUM CHANNELS; HEART-CELLS; CA2+ CHANNELS; INTACT HEART; RAT-HEART; STIMULATION; MYOCYTES; CAMP; CONTRACTILITY AB In contrast to beta(1)-adrenoreceptor (beta(1)-AR) signaling, beta(2)-AR stimulation in cardiomyocytes augments L-type Ca2+ current in a cAMP-dependent protein kinase (PKA)dependent manner but fails to phosphorylate phospholamban, indicating that the beta(2)-AR-induced cAMP/PKA signaling is highly localized. Here we show that inhibition of G(i) proteins with pertussis toxin (PTX) permits a full phospholamban phosphorylation and a de novo relaxant effect following beta(2)-AR stimulation, converting the localized beta(2)-AR signaling to a global signaling mode similar to that of beta(1)-AR. Thus, beta(2)-AR-mediated G(i) activation constricts the cAMP signaling to the sarcolemma. PTX treatment did not significantly affect the beta(2)-AR-stimulated PKA activation. Similar to G(i) inhibition, a protein phosphatase inhibitor, calyculin A (3 x 10(-8) M), selectively enhanced the beta(2)-AR but not beta(1)-AR-mediated contractile response. Furthermore, PTX and calyculin A treatment had a non-additive potentiating effect on the beta(2)-AR-mediated positive inotropic response. These results suggest that the interaction of the beta(2)-AR-coupled G(i), and G(s) signaling affects the local balance of protein kinase and phosphatase activities. Thus, the additional coupling of beta(2)-AR to G(i) proteins is a key factor causing the compartmentalization of beta(2)-AR-induced cAMP signaling. C1 NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Xiao, RP (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 32 TC 117 Z9 123 U1 0 U2 6 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 JUL 30 PY 1999 VL 274 IS 31 BP 22048 EP 22052 DI 10.1074/jbc.274.31.22048 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 221HF UT WOS:000081721100084 PM 10419531 ER PT J AU Jordan, DB Bacot, KO Carlson, TJ Kessel, M Viitanen, PV AF Jordan, DB Bacot, KO Carlson, TJ Kessel, M Viitanen, PV TI Plant riboflavin biosynthesis - Cloning, chloroplast localization expression, purification, and partial characterization of spinach lumazine synthase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CRYSTAL-STRUCTURE ANALYSIS; GTP CYCLOHYDROLASE-II; BACILLUS-SUBTILIS; ESCHERICHIA-COLI; SACCHAROMYCES-CEREVISIAE; CLONED DNA; GENE; SUBUNIT; INTEGRATION; RESOLUTION AB Lumazine synthase, which catalyzes the penultimate step of riboflavin biosynthesis, has been cloned from three higher plants (spinach, tobacco, and arabidopsis) through functional complementation of an Escherichia coli auxotroph. Whereas the three plant proteins exhibit some structural similarities to known microbial homologs, they uniquely possess N-terminal polypeptide extensions that resemble typical chloroplast transit peptides. In vitro protein import assays with intact chloroplasts and immunolocalization experiments verify that higher plant lumazine synthase is synthesized in the cytosol as a larger molecular weight precursor protein, which is post-translationally imported into chloroplasts where it is proteolytically cleaved to its mature size. The authentic spinach enzyme is estimated to constitute <0.02% of the total chloroplast protein. Recombinant "mature" spinach lumazine synthase is expressed in E. coli at levels exceeding 30% of the total soluble protein and is readily purified to homogeneity using a simple two-step procedure. Apparent V-max and K-m values obtained with the purified plant protein are similar to those reported for microbial lumazine synthases. Electron microscopy and hydrodynamic studies reveal that native plant lumazine synthase is a hollow capsid-like structure comprised of 60 identical 16.5-kDa subunits, resembling its icosahedral counterparts in E. coli and Bacillus subtilis. C1 Dupont Co, Life Sci, Expt Stn, Wilmington, DE 19880 USA. Dupont Co, Agr Prod, Stine Haskell Res Ctr, Newark, DE 19714 USA. Dupont Co, Agr Prod, Expt Stn, Wilmington, DE 19880 USA. NIH, Struct Biol Lab, Bethesda, MD 20892 USA. RP Viitanen, PV (reprint author), Dupont Co, Life Sci, Expt Stn, Wilmington, DE 19880 USA. NR 36 TC 49 Z9 53 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 JUL 30 PY 1999 VL 274 IS 31 BP 22114 EP 22121 DI 10.1074/jbc.274.31.22114 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 221HF UT WOS:000081721100094 PM 10419541 ER PT J AU Sharma, M Marshall, P Hinton, DM AF Sharma, M Marshall, P Hinton, DM TI Binding of the bacteriophage T4 transcriptional activator, MotA, to T4 middle promoter DNA: Evidence for both major and minor groove contacts SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE activation; AsiA; bacteriophage; MotA; transcription ID COLI RNA-POLYMERASE; SIGMA(70) SUBUNIT; CRYSTAL-STRUCTURE; PROTEIN CONTACTS; GEL RETARDATION; ASIA PROTEIN; TATA ELEMENT; RECOGNITION; COMPLEXES; IDENTIFICATION AB During infection, the bacteriophage T4 transcriptional activator MotA, the co-activator AsiA, and host RNA polymerase are needed to transcribe from T4 middle promoters. Middle promoters contain a -10 region recognized by the sigma(70) subunit of RNA polymerase and a MotA box centered at -30 that is bound by MotA. We have investigated how the loss or modification of base determinants within the MotA box sequence 5'TTTGCTTTA3' (positions -34 to -26 of a middle promoter) affects MotA function. Gel retardation assays with mutant MotA boxes are consistent with the idea that MotA uses minor groove contacts upstream and major groove contacts downstream of the center GC, and does not require any specific base feature at the CG base-pair at position -30. Ln particular, the 5-methyl residue on the thymine residue at position -29, a major groove contact, contributes to MotA binding, while converting the TA at -32 to a C . I base-pair, a change that affects the major but nor the minor groove, yields a MotA box that is similar to wild-type. However, methylation interference analyses indicate that neither the binding of MotA nor the binding of polymerase/MotA/AsiA to the middle promoter P-uvs chi is inhibited by premethylation of guanine and adenine residues, suggesting that binding does not require minor groove contact with any specific TA base-pair. Using gel retardation analyses, we calculate an apparent dissociation constant of 130 nM for MotA binding to the wild-type MotA box. Previous work has shown that the N-terminal region of MotA is needed for an interaction between MotA and sigma(70). We suggest that this MotA-sigma(70) interaction helps to stabilize the relatively weak interaction of MotA with the -30 region of middle promoter DNA. (C) 1999 Academic Press. C1 NIDDKD, Mol & Cellular Biol Lab, Bethesda, MD 20892 USA. RP Hinton, DM (reprint author), NIDDKD, Mol & Cellular Biol Lab, Bethesda, MD 20892 USA. NR 42 TC 20 Z9 20 U1 0 U2 0 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUL 30 PY 1999 VL 290 IS 5 BP 905 EP 915 DI 10.1006/jmbi.1999.2928 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 221HL UT WOS:000081721600001 PM 10438591 ER PT J AU Croteau, DL Stierum, RH Bohr, VA AF Croteau, DL Stierum, RH Bohr, VA TI Mitochondrial DNA repair pathways SO MUTATION RESEARCH-DNA REPAIR LA English DT Article DE mitochondrial DNA repair pathways; base excision repair; nucleotide excision repair ID COLI ENDONUCLEASE-III; BASE EXCISION-REPAIR; HAMSTER OVARY CELLS; ESCHERICHIA-COLI; OXIDATIVE DAMAGE; SACCHAROMYCES-CEREVISIAE; MAMMALIAN MITOCHONDRIA; NUCLEAR-DNA; RAT-LIVER; IONIZING-RADIATION AB DNA repair mechanisms are fairly well characterized for nuclear DNA while knowledge regarding the repair mechanisms operable in mitochondria is limited. Several lines of evidence suggest that mitochondria contain DNA repair mechanisms. DNA lesions are removed from mtDNA in cells exposed to various chemicals. Protein activities that process damaged DNA have been detected in mitochondria. As will be discussed, there is evidence for base excision repair (BER), direct damage reversal, mismatch repair, and recombinational repair mechanisms in mitochondria, while nucleotide excision repair (NER), as we know it from nuclear repair, is not present. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIA, Mol Genet Lab, NIH, Baltimore, MD 21224 USA. Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. RP Bohr, VA (reprint author), NIA, Mol Genet Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 73 TC 140 Z9 145 U1 4 U2 9 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 JUL 30 PY 1999 VL 434 IS 3 BP 137 EP 148 DI 10.1016/S0921-8777(99)00025-7 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 229VD UT WOS:000082215700002 PM 10486588 ER PT J AU Alberts, BM Ayala, FJ Botstein, D Frank, E Holmes, EW Lee, RD Macagno, ER Marrack, P Oparil, S Orkin, SH Rubenstein, AH Slayman, CW Sparling, PF Squire, LR von Hippel, PH Yamamoto, KR AF Alberts, BM Ayala, FJ Botstein, D Frank, E Holmes, EW Lee, RD Macagno, ER Marrack, P Oparil, S Orkin, SH Rubenstein, AH Slayman, CW Sparling, PF Squire, LR von Hippel, PH Yamamoto, KR TI Science policy - Proposed changes for NIH's Center for Scientific Review SO SCIENCE LA English DT Editorial Material C1 NIH, Ctr Sci Review Advisory Comm, Bethesda, MD 20892 USA. RP Alberts, BM (reprint author), NIH, Ctr Sci Review Advisory Comm, Bethesda, MD 20892 USA. NR 1 TC 6 Z9 6 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 JUL 30 PY 1999 VL 285 IS 5428 BP 666 EP 667 DI 10.1126/science.285.5428.666 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 222CD UT WOS:000081765100026 PM 10454921 ER PT J AU Brustle, O Jones, KN Learish, RD Karram, K Choudhary, K Wiestler, OD Duncan, ID McKay, RDG AF Brustle, O Jones, KN Learish, RD Karram, K Choudhary, K Wiestler, OD Duncan, ID McKay, RDG TI Embryonic stem cell-derived glial precursors: A source of myelinating transplants SO SCIENCE LA English DT Article ID IN-VITRO DIFFERENTIATION; CENTRAL-NERVOUS-SYSTEM; NEURAL PRECURSORS; TARGETED MUTATION; PROGENITOR CELLS; NEURONS; BRAIN; ESTABLISHMENT; ASTROCYTE; LETHALITY AB Self-renewing, totipotent embryonic stem (ES) cells may provide a virtually unlimited donor source for transplantation. A protocol that permits the in vitro generation of precursors for oligodendrocytes and astrocytes from ES cells was devised. Transplantation in a rat model of a human myelin disease shows that these ES cell-derived precursors interact with host neurons and efficiently myelinate axons in brain and spinal cord. Thus, ES cells can serve as a valuable source of cell type-specific somatic precursors for neural transplantation. C1 Univ Bonn, Med Ctr, Dept Neuropathol, D-53105 Bonn, Germany. NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Wisconsin, Sch Vet Med, Dept Med Sci, Madison, WI 53706 USA. RP Brustle, O (reprint author), Univ Bonn, Med Ctr, Dept Neuropathol, Sigmund Freud Str 25, D-53105 Bonn, Germany. FU NINDS NIH HHS [NS33710] NR 32 TC 685 Z9 745 U1 1 U2 25 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 JUL 30 PY 1999 VL 285 IS 5428 BP 754 EP 756 DI 10.1126/science.285.5428.754 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 222CD UT WOS:000081765100060 PM 10427001 ER PT J AU Schultz, C Link, A Leost, M Zaharevitz, DW Gussio, R Sausville, EA Meijer, L Kunick, C AF Schultz, C Link, A Leost, M Zaharevitz, DW Gussio, R Sausville, EA Meijer, L Kunick, C TI Paullones, a series of cyclin-dependent kinase inhibitors: Synthesis, evaluation of CDK1/cyclin B inhibition, and in vitro antitumor activity SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID TUMOR-CELL-LINES; ANTICANCER DRUG SCREEN; CHEMICAL INHIBITORS; CRYSTAL-STRUCTURES; PURINE ANALOGS; DIVERSE PANEL; CANCER CELLS; CDK2; FLAVOPIRIDOL; ROSCOVITINE AB The paullones represent a novel class of small molecule cyclin-dependent kinase (CDK) inhibitors. To investigate structure-activity relationships and to develop paullones with antitumor activity, derivatives of the lead structure kenpaullone (9-bromo-7,12-dihydroindolo-[3,2-d][1]benzazepin-6(5H)-one, 4a) were synthesized. Paullones with different substituents in the 2-, 3-, 4-, 9-, and 11-positions were prepared by a Fischer indole reaction starting from 1H-[1]benzazepine-2,5(3H,4H)-diones 5. Selective substitutions at either the lactam or the indole nitrogen atom were accomplished by treating kenpaullone with alkyl halides in the presence of sodium hydride/THF or potassium hydroxide/acetone, respectively. S-Methylation of the kenpaullone-derived thiolactam 18 yielded the methylthioimidate 19, which gave the hydroxyamidine 20 upon reaction with hydroxylamine. The new paullones were tested both in a CDK1/ cyclin B inhibition assay and in the in vitro antitumor cell line-screening program of the National Cancer Institute (NCI). With respect to the CDK1/cyclin B inhibition, electron-withdrawing substituents in the 9-position as well as a 2,3-dimethoxy substitution on the paullone basic scaffold turned out to be favorable. A 9-trifluoromethyl substituent was found to be equivalent to the 9-bromo substituent of kenpaullone. Replacement of the 9-bromo substituent of kenpaullone by a 9-cyano or 9-nitro group produced a substantial increase in enzyme-inhibiting potency. Substitutions in other positions or the replacement of the lactam moiety led to decreased CDK1 inhibition. Noteworthy in vitro antitumor activities (GI(50) values between 1 and 10 mu M) were found with the 9-bromo-2,3-dimethoxy-7,12-dihydroindolo[3,2-d]-[1]benzazepin-6(5H)-one (4t), its 9-trifluoromethyl analogue 4u, the 12-Boc-substituted paullone 15, and the methylthioimidate 19, respectively. The 9-nitro-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-one (4j, named alsterpaullone) showed a high CDK1/cyclin B inhibitory activity (IC50 = 0.035 mu M) and exceeded the in vitro antitumor potency of the other paullones by 1 order of magnitude (log GI(50) mean graph midpoint = -6.4 M). C1 Univ Hamburg, Inst Pharm, Abt Pharmazeut Chem, D-20146 Hamburg, Germany. CNRS, Biol Stn, F-29682 Roscoff, France. NCI, Div Canc Treatment & Diag, Dev Therapeut Program, Rockville, MD 20852 USA. RP Kunick, C (reprint author), Univ Hamburg, Inst Pharm, Abt Pharmazeut Chem, Bundesstr 45, D-20146 Hamburg, Germany. RI Link, Andreas/H-5067-2013 OI Link, Andreas/0000-0003-1262-6636 NR 46 TC 236 Z9 240 U1 2 U2 18 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 JUL 29 PY 1999 VL 42 IS 15 BP 2909 EP 2919 DI 10.1021/jm9900570 PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 222CJ UT WOS:000081765600019 PM 10425100 ER PT J AU Deal, KA Davis, IA Mirzadeh, S Kennel, SJ Brechbiel, MW AF Deal, KA Davis, IA Mirzadeh, S Kennel, SJ Brechbiel, MW TI Improved in vivo stability of actinium-225 macrocyclic complexes SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID POLYAMINO POLYCARBOXYLIC MACROCYCLES; AQUEOUS-SOLUTION; IN-VIVO; LIGAND; IONS; RADIOIMMUNOTHERAPY; RADIOLANTHANIDES; BIODISTRIBUTION; DISSOCIATION; AC-225 AB The favorable nuclear properties of actinium-225 (Ac-225) have led to proposal of this isotope for use in radioimmunotherapy. In an effort to reduce the toxicity of free Ac-225, a series of ligands were evaluated for stability in vivo. Loss of Ac-225 from acyclic chelating agents resulted in high liver uptake and poor whole body clearance. The macrocyclic ligands c-DOTA, PEPA, and HEHA were evaluated, and Ac-225-HEHA showed exceptional stability in vivo. Ac-225 chelated with EDTA, DTPA, DOTA, or PEPA permitted substantial accumulation of the radionuclide to the Liver, while the Ac-225-HEHA complex was essentially excreted within minutes of administration. The preparation of the ligands and radiolabeled complexes and the biodistribution results will be discussed. C1 NCI, NIH, Bethesda, MD 20892 USA. Oak Ridge Natl Lab, Div Life Sci, Oak Ridge, TN 37831 USA. RP Brechbiel, MW (reprint author), NCI, NIH, 9000 Rockville Pike,Bldg 10 Room B3B69, Bethesda, MD 20892 USA. NR 36 TC 27 Z9 27 U1 2 U2 7 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 JUL 29 PY 1999 VL 42 IS 15 BP 2988 EP 2992 DI 10.1021/jm990141f PG 5 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 222CJ UT WOS:000081765600027 PM 10425108 ER PT J AU Freifeld, A Marchigiani, D Walsh, T Chanock, S Lewis, L Hiemenz, J Hiemenz, S Hicks, JE Gill, V Steinberg, SM Pizzo, PP AF Freifeld, A Marchigiani, D Walsh, T Chanock, S Lewis, L Hiemenz, J Hiemenz, S Hicks, JE Gill, V Steinberg, SM Pizzo, PP TI A double-blind comparison of empirical oral and intravenous antibiotic therapy for low-risk febrile patients with neutropenia during cancer chemotherapy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RANDOMIZED TRIAL; FEVER; MANAGEMENT; CIPROFLOXACIN; CEFTAZIDIME; EPISODES AB Background Among patients with fever and neutropenia during cancer chemotherapy who have a low risk of complications, oral administration of empirical broad-spectrum antibiotics may be an acceptable alternative to intravenous treatment. Methods We conducted a randomized, double-blind, placebo-controlled study of patients (age, 5 to 74 years) who had fever and neutropenia during chemotherapy for cancer. Neutropenia was expected to be present for no more than 10 days in these patients, and they had to have no other underlying conditions. Patients were assigned to receive either oral ciprofloxacin plus amoxicillin-clavulanate or intravenous ceftazidime. They were hospitalized until fever and neutropenia resolved. Results A total of 116 episodes were included in each group (84 patients in the oral-therapy group and 79 patients in the intravenous-therapy group). The mean neutrophil counts at admission were 81 per cubic millimeter and 84 per cubic millimeter, respectively; the mean duration of neutropenia was 3.4 and 3.8 days, respectively. Treatment was successful without the need for modifications in 71 percent of episodes in the oral-therapy group and 67 percent of episodes in the intravenous-therapy group (difference between groups, 3 percent; 95 percent confidence interval, -8 percent to 15 percent; P=0.48). Treatment was considered to have failed because of the need for modifications in the regimen in 13 percent and 32 percent of episodes, respectively (P<0.001) and because of the patient's inability to tolerate the regimen in 16 percent and 1 percent of episodes, respectively (P<0.001). There were no deaths. The incidence of intolerance of the oral antibiotics was 16 percent, as compared with 8 percent for placebo (P=0.07). Conclusions In hospitalized low-risk patients who have fever and neutropenia during cancer chemotherapy, empirical therapy with oral ciprofloxacin and amoxicillin-clavulanate is safe and effective. (N Engl J Med 1999;341:305-11.) (C) 1999, Massachusetts Medical Society. C1 NCI, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. RP Freifeld, A (reprint author), Univ Nebraska, Med Ctr, Infect Dis Sect, 985400 Nebraska Med Ctr, Omaha, NE 68198 USA. RI Lee, Yee Mei/H-1143-2011 NR 23 TC 237 Z9 248 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 29 PY 1999 VL 341 IS 5 BP 305 EP 311 DI 10.1056/NEJM199907293410501 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 220LF UT WOS:000081666900001 PM 10423464 ER PT J AU Grimbacher, B Holland, SM Puck, JM AF Grimbacher, B Holland, SM Puck, JM TI Hyper-IgE syndrome - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Natl Human Genome Res Inst, Bethesda, MD 20892 USA. NIAID, Bethesda, MD 20892 USA. RP Grimbacher, B (reprint author), Natl Human Genome Res Inst, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 1 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 29 PY 1999 VL 341 IS 5 BP 376 EP 377 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 220LF UT WOS:000081666900027 ER PT J AU Riley, GF Potosky, AL Klabunde, CN Warren, JL Ballard-Barbash, R AF Riley, GF Potosky, AL Klabunde, CN Warren, JL Ballard-Barbash, R TI Increase in the use of breast-conserving surgery - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 Hlth Care Financing Adm, Baltimore, MD USA. NCI, Bethesda, MD 20892 USA. RP Riley, GF (reprint author), Hlth Care Financing Adm, Baltimore, MD USA. NR 2 TC 0 Z9 0 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 JUL 28 PY 1999 VL 282 IS 4 BP 326 EP 327 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 219FG UT WOS:000081596800022 ER PT J AU Corey, L Langenberg, AGM Ashley, R Sekulovich, RE Izu, AE Douglas, JM Handsfield, HH Warren, T Marr, L Tyring, S DiCarlo, R Adimora, AA Leone, P Dekker, CL Burke, RL Leong, WP Straus, SE AF Corey, L Langenberg, AGM Ashley, R Sekulovich, RE Izu, AE Douglas, JM Handsfield, HH Warren, T Marr, L Tyring, S DiCarlo, R Adimora, AA Leone, P Dekker, CL Burke, RL Leong, WP Straus, SE CA Chiron HSV Vaccine Study Grp TI Recombinant glycoprotein vaccine for the prevention of genital HSV-2 infection - Two randomized controlled trials SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article; Proceedings Paper CT 37th Interscience Conference on Antimicrobial Agents and Chemotherapy CY SEP 28-OCT 03, 1997 CL TORONTO, CANADA ID HERPES-SIMPLEX VIRUS; WESTERN IMMUNOBLOT; GUINEA-PIGS; TYPE-2; RISK; ACQUISITION; PROTECTION; ANTIBODY; AIDS; PREGNANCY AB Context In the last 3 decades, herpes simplex virus type 2 (HSV-2) infection seroprevalence and neonatal herpes have increased substantially. An effective vaccine for the prevention of genital herpes could help control this epidemic. Objective To evaluate the efficacy of a vaccine for prevention of HSV-2 infection. Design Two randomized, double-blind, placebo-controlled multicenter trials of a recombinant subunit vaccine containing 30 mu g each of 2 major HSV-2 surface glycoproteins (gB(2) and gD(2)) against which neutralizing antibodies are directed, administered at months 0, 1, and 6. Control subjects were given a citrate buffer vehicle. Participants were followed up for 1 year after the third immunization. Setting and Participants We enrolled 2393 persons from December 10, 1993, to April 4, 1995, who were HSV-2 and human immunodeficiency virus seronegative. One trial with 18 centers enrolled 531 HSV-2-seronegative partners of HSV-2-infected persons; the other, with 22 centers, enrolled 1862 persons attending sexually transmitted disease clinics. A total of 2268 (94.8%) met inclusion criteria and were included in the analysis with 1135 randomized to placebo and 2012 to vaccine. Main Outcome Measure Time to acquisition of HSV-2 infection, defined by seroconversion or isolation of HSV-2 in culture during the study period by randomization group. Results Time-to-event curves indicated a 50% lower acquisition rate among vaccine vs placebo recipients during the initial 5 months of the trial; however, overall vaccine efficacy was 9% (95% confidence interval, -29% to 36%). Acquisition rates of HSV-2 were 4.6 and 4.2 per 100 patient-years in the placebo and vaccine recipients, respectively (P = .58). Follow-up of vaccine recipients acquiring HSV-2 infection showed vaccination had no significant influence on duration of clinical first genital HSV-2 episodes (vaccine, median of 7.1 days; placebo, 6.5 days; P > .10) or subsequent frequency of reactivation (median monthly recurrence rate with vaccine, 0.2; with placebo, 0.3; P > .10). The vaccine induced high levels of HSV-2-specific neutralizing antibodies in vaccinated persons who did and did not develop genital herpes. Conclusions Efficient and sustained protection from sexual acquisition of HSV-2 infection will require more than high titers of specific neutralizing antibodies. Protection against sexually transmitted viruses involving exposure over a prolonged period will require a higher degree of vaccine efficacy than that achieved in this study. C1 Univ Washington, Harborview Med Ctr, Seattle, WA 98104 USA. Childrens Hosp & Reg Med Ctr, Seattle, WA USA. Denver Dis Control Serv, Denver, CO USA. Westover Hts Clin, Portland, OR USA. Univ Texas, Med Branch, Galveston, TX 77550 USA. Louisiana State Univ, New Orleans, LA USA. Univ N Carolina, Sch Med, Chapel Hill, NC USA. Wake Cty Hlth Dept, Raleigh, NC USA. NIH, Bethesda, MD 20892 USA. Chiron Corp, HSV Vaccine Study Grp, Emeryville, CA 94608 USA. RP Corey, L (reprint author), 1100 Fairview Ave E,D3-100,POB 19024, Seattle, WA 98109 USA. FU NIAID NIH HHS [AI-30731] NR 45 TC 296 Z9 308 U1 0 U2 5 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 JUL 28 PY 1999 VL 282 IS 4 BP 331 EP 340 DI 10.1001/jama.282.4.331 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 219FG UT WOS:000081596800028 PM 10432030 ER PT J AU Mills, JL DerSimonian, R Raymond, E Morrow, JD Roberts, LJ Clemens, JD Hauth, JC Catalano, P Sibai, B Curet, LB Levine, RJ AF Mills, JL DerSimonian, R Raymond, E Morrow, JD Roberts, LJ Clemens, JD Hauth, JC Catalano, P Sibai, B Curet, LB Levine, RJ TI Prostacyclin and thromboxane changes predating clinical onset of preeclampsia - A multicenter prospective study SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID LOW-DOSE ASPIRIN; CHROMATOGRAPHY MASS-SPECTROMETRY; PREVENT PREECLAMPSIA; POSTPARTUM PERIOD; RANDOMIZED TRIAL; PREGNANT-WOMEN; QUANTIFICATION; HYPERTENSION; METABOLITES; DELIVERY AB Context An imbalance in vasodilating (prostacyclin [PGI(2)]) and vasoconstricting (thromboxane A(2) [TxA(2)]) eicosanoids may be important in preeclampsia, but prospective data from large studies needed to resolve this issue are lacking. Because most trials using aspirin to reduce TxA(2) production have failed to prevent preeclampsia, it is critical to determine whether eicosanoid changes occur before the onset of clinical disease or are secondary to clinical manifestations of preeclampsia, Objective To determine whether PGI(2) or TxA(2) changes occur before onset of clinical signs of preeclampsia. Design, Setting, and Participants Multicenter prospective study from 1992 to 1995 of subjects from the placebo arm of the Calcium for Preeclampsia Prevention Trial. Women who developed preeclampsia (n =134) were compared with matched normotensive control women (n = 139), Main Outcome Measures Excretion of urinary metabolites of PGI(2) (PGI-M) and TxA(2) (Tx-M) as measured from timed urine collections obtained prospectively before 22 weeks', between 26 and 29 weeks', and at 36 weeks' gestation. Results Women who developed preeclampsia had significantly lower PCI-M levels throughout pregnancy, even at 13 to 16 weeks' gestation (long before the onset of clinical disease); their gestational age-adjusted levels were 17% lower than those of controls (95% confidence interval [CI], 6%-27%; P = 005). The Tx-M levels of preeclamptic women were not significantly higher overall (9% higher than those of controls; 95% CI, -3% to 23%; P = .14). The ratio of Tx-M to PGI-M, used to express relative vasoconstricting vs vasodilating effects, was 24% higher (95% CI, 6% -45%) n preeclamptic women throughout pregnancy (P = .007). Conclusions Our results show that reduced PGI(2) production, but not increased TxA(2) production, occurs many months before clinical onset of preeclampsia, Aspirin trials may have failed because an increase in thromboxane production is not the initial anomaly. Future interventions should make correcting prostacyclin deficiency a major part of the strategy to balance the abnormal vasoconstrictor-vasodilator ratio present in preeclampsia. C1 NICHHD, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. NICHHD, Biometry & Stat Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. Family Hlth Int, Clin Trials Div, Durham, NC USA. Vanderbilt Univ, Dept Clin Pharmacol, Nashville, TN USA. Vanderbilt Univ, Dept Med, Nashville, TN USA. Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. Metrohlth Med Ctr, Dept Obstet & Gynecol, Cleveland, OH USA. Univ Tennessee, Dept Obstet & Gynecol, Memphis, TN 38103 USA. Univ New Mexico, Dept Obstet & Gynecol, Albuquerque, NM 87131 USA. RP Mills, JL (reprint author), NICHD, Pediat Epidemiol Sect, DESPR, NIH, 6100 Execut Blvd,Room 7B03, Bethesda, MD 20892 USA. FU NICHD NIH HHS [N01-HD-3122, N01-HD-3123, N01-HD-3121] NR 23 TC 101 Z9 107 U1 1 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 28 PY 1999 VL 282 IS 4 BP 356 EP 362 DI 10.1001/jama.282.4.356 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 219FG UT WOS:000081596800031 PM 10432033 ER PT J AU Viragh, C Kovach, IM Pannell, L AF Viragh, C Kovach, IM Pannell, L TI Small molecular products of dealkylation in soman-inhibited electric eel acetylcholinesterase SO BIOCHEMISTRY LA English DT Article ID PHOSPHYLATED HUMAN ACETYLCHOLINESTERASE; PHOSPHONATE ESTER ADDUCTS; PUSH-PULL MECHANISM; CATALYTIC RECRUITMENT; SERINE PROTEASES; ACTIVE-CENTER; CHOLINESTERASES; STEREOISOMERS; INACTIVATION; HYDROLYSIS AB product analysis of dealkylation in P(S)C(S)-soman-inhibited electric eel acetylcholinesterase (AChE) by GC-MS using the selected ion monitoring mode has been carried out. The instrument was calibrated with pure standards of 2,3-dimethyl-1-butene and 2,3-dimethyl-2-butene in the gas phase and methylene chloride extracts of 2,3-dimethyl-2-butanol and 3,3-dimethyl-2-butanol from the aqueous phase. The dealkylation in soman-inhibited AChE at pH 5.0 +/- 0.2 and 25 degrees C produces close to 40% alkenes and 50-60% 2,3-dimethyl-2-butanol. No 3,3-dimethyl-2-butanol could be detected to provide direct evidence of the intervention of a secondary carbenium ion in the reaction path. All the products of the reaction originate from a tertiary carbenium ion. These findings are in good agreement with the results of Michel et al. [(1967) Arch. Biochem. Biophys. 121, 29], which were obtained by countercurrent distribution of tritium-labeled products and their identification by scintillation counting. The early experiments were performed with the mixture of the four soman diastereomers, all labeled with tritium in C alpha. C1 Catholic Univ Amer, Dept Chem, Washington, DC 20064 USA. NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Kovach, IM (reprint author), Catholic Univ Amer, Dept Chem, Washington, DC 20064 USA. NR 50 TC 23 Z9 23 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 27 PY 1999 VL 38 IS 30 BP 9557 EP 9561 DI 10.1021/bi991112+ PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 222DV UT WOS:000081768900001 PM 10423232 ER PT J AU Verhaar, MC Wever, RMF Kastelein, JJP van Loon, D Milstien, S Koomans, HA Rabelink, TJ AF Verhaar, MC Wever, RMF Kastelein, JJP van Loon, D Milstien, S Koomans, HA Rabelink, TJ TI Effects of oral folic acid supplementation on endothelial function in familial hypercholesterolemia - A randomized placebo-controlled trial SO CIRCULATION LA English DT Article DE endothelium; nitric oxide; folate; hypercholesterolemia ID METHYLENETETRAHYDROFOLATE REDUCTASE; SERUM FOLATE; FOREARM; DISEASE; RISK AB Background-Folates have been suggested to be of benefit in reducing cardiovascular risk. The present study was designed to examine whether oral folic acid supplementation could improve endothelial function as an intermediate end point for cardiovascular risk in patients with increased risk of atherosclerosis due to familial hypercholesterolemia (FH). Methods and Results-In a prospective, randomized, double-blind, placebo-controlled study with crossover design, we evaluated the effects of 4 weeks of treatment with oral folic acid (5 mg PO) on endothelial function in FH. In 20 FH patients, forearm vascular function was assessed at baseline, after 4 weeks of folic acid treatment, and after 4 weeks of placebo treatment by venous occlusion plethysmography, with serotonin and sodium nitroprusside used as endothelium-dependent and -independent vasodilators. In addition, we examined the vasoconstrictor response to the NO synthase inhibitor NG-monomethyl-L-arginine to assess basal NO activity. In FH patients, folic acid supplementation restored the impaired endothelium-dependent vasodilation, whereas it did not significantly influence endothelium-independent vasodilation or basal forearm vasomotion. There was a trend toward improvement in basal NO activity. Conclusions-These data demonstrate that oral supplementation of folic acid can improve endothelial function in patients with increased risk of atherosclerotic disease due to hypercholesterolemia, without changes in plasma lipids. C1 Univ Utrecht Hosp, Dept Hypertens & Nephrol, NL-3508 GA Utrecht, Netherlands. Univ Utrecht Hosp, Dept Clin Chem, NL-3508 GA Utrecht, Netherlands. Acad Med Ctr, Dept Vasc Med, Amsterdam, Netherlands. Antonius Hosp, Dept Clin Chem, Nieuwegein, Netherlands. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD USA. RP Rabelink, TJ (reprint author), Univ Utrecht Hosp, Dept Hypertens & Nephrol, POB 85500, NL-3508 GA Utrecht, Netherlands. RI Verhaar, Marianne/A-6577-2008; Rabelink, Ton/A-5316-2008; OI Rabelink, Ton/0000-0001-6780-5186; Verhaar, Marianne/0000-0002-3276-6428 NR 13 TC 142 Z9 145 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 27 PY 1999 VL 100 IS 4 BP 335 EP 338 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 220UV UT WOS:000081686600005 PM 10421591 ER PT J AU Franklin, SS Khan, SA Wong, ND Larson, MG Levy, D AF Franklin, SS Khan, SA Wong, ND Larson, MG Levy, D TI Is pulse pressure useful in predicting risk for coronary heart disease? The Framingham Heart Study SO CIRCULATION LA English DT Article DE blood pressure; hypertension; coronary disease ID BLOOD-PRESSURE; CARDIOVASCULAR MORTALITY; MYOCARDIAL-INFARCTION; HYPERTENSION AB Background-Current definitions of hypertension are based on levels of systolic blood pressure (SBP) and diastolic blood pressure (DBP), but not on pulse pressure (PP). We examined whether PP adds useful information for predicting coronary heart disease (CHD) in the population-based Framingham Heart Study, Methods and Results-We studied 1924 men and women between 50 and 79 years of age at baseline with no clinical evidence of CHD and not taking antihypertensive drug therapy. Cox regression, adjusted for age, sex, and other risk factors, was used to assess the relations between blood pressure components and CHD risk over a 20-year follow-up. The association with CHD risk was positive for SEP, DBP, and PP, considering each pressure individually; of the 3, PP yielded the largest chi(2) statistic. When SEP and DBP were jointly entered into the multivariable model, the association with CHD risk was positive for SEP (HR, 1.22; 95% CI, 1.15 to 1.30) and negative for DBP (HR, 0.86; 95% CI, 0.75 to 0.98). Four subgroups were defined according to SEP levels (<120, 120 to 139, 140 to 159, and greater than or equal to 160 mm Hg). Within each subgroup, the association with CHD risk was negative for DBP and positive for PP. A cross-classification of SBP-DBP levels confirmed these results. Conclusions-In the middle-aged and elderly, CHD risk increased with lower DBP at any level of SBP greater than or equal to 120 mm Hg, suggesting that higher PP was an important component of risk. Neither SEP nor DBP was superior to PP in predicting CHD risk. C1 Univ Calif Irvine, Heart Dis Prevent Program, Irvine, CA 92697 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. NHLBI, Bethesda, MD 20892 USA. RP Franklin, SS (reprint author), Univ Calif Irvine, Heart Dis Prevent Program, C420 Med Sci, Irvine, CA 92697 USA. FU NHLBI NIH HHS [N01-HC-38038] NR 29 TC 1012 Z9 1137 U1 1 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 27 PY 1999 VL 100 IS 4 BP 354 EP 360 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 220UV UT WOS:000081686600008 PM 10421594 ER PT J AU Kosmidis, MH Breier, A Fantie, BD AF Kosmidis, MH Breier, A Fantie, BD TI Avoidance learning in schizophrenia: a dissociation between the effects of aversive and non-aversive stimuli SO SCHIZOPHRENIA RESEARCH LA English DT Article DE learning; operant conditioning; schizophrenia ID CLOSED-HEAD-INJURY; ANTICIPATORY BEHAVIOR DEFICITS; ONSET SCHIZOPHRENIA; PREFRONTAL CORTEX; PERFORMANCE; DYSFUNCTION; DEMENTIA; TESTS; AGE AB Patients with schizophrenia did not take significantly more trials than normal controls to learn to use a visual warning signal to avoid a non-aversive stimulus on a simple computer-administered avoidance learning task. When the stimulus to be avoided was aversive (i.e. a loud buzzer), however, the schizophrenic group could be divided into two subgroups based upon their performance; almost one half of the schizophrenic group failed to learn how to avoid this task successfully. The other half, like the normal controls and the closed head injury group in our previous studies, benefited from the aversiveness of the stimulus to be avoided, and learned to avoid more quickly than in the non-aversive condition. A post-hoc analysis of the differences between these two subgroups of the patients suggested that the discrepancy in learning was related to the age of onset of illness. (C) 1999 Elsevier Science B.V. All rights reserved. C1 American Univ, Dept Psychol, Human Neuropsychol Lab, Washington, DC 20016 USA. NIMH, Expt Therapeut Branch, Bethesda, MD 20892 USA. RP Fantie, BD (reprint author), American Univ, Dept Psychol, Human Neuropsychol Lab, 4400 Massachusetts Ave NW, Washington, DC 20016 USA. NR 41 TC 14 Z9 15 U1 2 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD JUL 27 PY 1999 VL 38 IS 1 BP 51 EP 59 DI 10.1016/S0920-9964(98)00181-9 PG 9 WC Psychiatry SC Psychiatry GA 216BC UT WOS:000081419800006 PM 10427610 ER PT J AU Contreras, JL Eckhoff, DE Cartner, S Frenette, L Thomas, FT Robbin, ML Neville, DM Thomas, JM AF Contreras, JL Eckhoff, DE Cartner, S Frenette, L Thomas, FT Robbin, ML Neville, DM Thomas, JM TI Tolerability and side effects of anti-CD3-immunotoxin in preclinical testing in kidney and pancreatic islet transplant recipients (Retracted article. See vol 86, pg. 482, 2008) SO TRANSPLANTATION LA English DT Article; Retracted Publication ID IMMUNOTOXIN; TOLERANCE; PERITRANSPLANT; ALLOGRAFTS; INDUCTION; BLOOD AB Introduction, Anti-CD3-immunotoxin (alpha-CD3-IT) promotes allograft tolerance in nonhuman primates owing to efficient depletion of sessile and circulating T cells. Common side effects of vascular leak syndrome, hepatotoxicity, and nephrotoxicity have limited tolerability of other immunotoxins. We report on preclinical studies of alpha-CD3-IT-related side effects. Methods. Normal rhesus monkeys received a kidney transplant and alpha-CD3-IT alone (on day -to +2) or in combination with brief peritransplant adjunctive immunosuppressive therapy. Some received donor CD34(+) cells. Blood chemistries, complete blood count, weight, liver, and kidney biopsies were examined for immunotoxin-related changes. Five spontaneously diabetic primates also received alpha-CD3-IT, three of whom had a pancreas islet transplant. Results. The main side effect of alpha-CD3-IT, vascular leak syndrome, was entirely prevented by adjunctive immunosuppressive therapy. Renal and liver function tests and biopsies revealed a lack of nephrotoxicity and hepatotoxicity, All had transient weight loss (14+/-5%). Without infusion of donor CD34(+) cells, 97% had full weight recovery. Of those given donor CD34(+) cells, 50% were euthanized for wasting. Conclusions. Side effects of alpha-CD3-IT are manageable and should not prevent therapeutic application. C1 Univ Alabama, Dept Surg, Div Transplantat Immunol, Birmingham, AL 35294 USA. Univ Alabama, Dept Comparat Med, Birmingham, AL 35294 USA. Univ Alabama, Dept Anesthesia, Birmingham, AL 35294 USA. Univ Alabama, Dept Radiol, Birmingham, AL 35294 USA. NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Thomas, JM (reprint author), Univ Alabama, Dept Surg, Div Transplantat Immunol, BDB 802,1808 7th Ave S, Birmingham, AL 35294 USA. FU NIAID NIH HHS [R0I AI39793, R0I AII22293] NR 13 TC 20 Z9 20 U1 3 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JUL 27 PY 1999 VL 68 IS 2 BP 215 EP 219 DI 10.1097/00007890-199907270-00009 PG 5 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 224RB UT WOS:000081911100009 PM 10440390 ER PT J AU Smith, NL Psaty, BM Furberg, CD White, R Lima, JAC Newman, AB Manolio, TA AF Smith, NL Psaty, BM Furberg, CD White, R Lima, JAC Newman, AB Manolio, TA TI Temporal trends in the use of anticoagulants among older adults with atrial fibrillation SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID MYOCARDIAL-INFARCTION; WARFARIN USE; CARDIOVASCULAR HEALTH; NATIONAL PATTERNS; PREVALENCE; ASPIRIN; PREVENTION; REGISTRY; FAILURE; STROKE AB Background: Several recent randomized clinical trials have demonstrated that warfarin sodium treatment, and to a lesser extent aspirin, reduces risk of stroke and death compared with placebo in persons with atrial fibrillation. Insufficient documentation exists on the extent to which the use of these therapies following trial publications has continued to increase in the elderly with atrial fibrillation. Methods: We used data from the Cardiovascular Health Study, a study of 5888 community-dwelling adults aged 65 years or older, to determine the prevalence of warfarin and aspirin use in persons with electrocardiogram-identified atrial fibrillation. Electrocardiogram examinations were conducted at baseline from 1989 through 1990, and at 6 subsequent annual examinations through 1995-1996. Medication data were collected by inventory methods at each examination. Temporal change in use of anticoagulants was analyzed by comparing percentage use in 1990 to use in each year through 1996. Results: The use of warfarin increased 4-fold from 13% in 1990 to 50% in 1996 among participants with prevalent atrial fibrillation (P < .001). Daily use of aspirin did not increase over time. Participants younger than 80 years were 4 times more likely to use warfarin in 1996 (P < .001) than those 80 years and older. Use of aspirin did not vary significantly with age. Conclusions: Warfarin use in community-dwelling elderly persons with electrocardiogram-documented atrial fibrillation increased steadily following the first publication of its treatment benefit, reaching 50% by 1996. In contrast, use of aspirin was unchanged during this same period. Continued efforts to promote appropriate antil coagulation therapy to physicians and their patients may still be needed. C1 Univ Washington, Dept Med, Seattle, WA USA. Univ Washington, Dept Epidemiol, Seattle, WA USA. Univ Washington, Hlth Serv, Seattle, WA USA. Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Winston Salem, NC USA. Univ Calif Davis, Div Gen Med, Davis, CA 95616 USA. Johns Hopkins Univ, Div Cardiol, Hagerstown, MD USA. Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Smith, NL (reprint author), Cardiovasc Hlth Res Unit, 1730 Minor Ave,Suite 1360, Seattle, WA 98101 USA. RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU NHLBI NIH HHS [N01-HC-85079, N01-HC-85080, N01-HC-85081] NR 29 TC 77 Z9 78 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUL 26 PY 1999 VL 159 IS 14 BP 1574 EP 1578 DI 10.1001/archinte.159.14.1574 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 217QF UT WOS:000081509900007 PM 10421280 ER PT J AU Klebanoff, MA Secher, NJ Mednick, BR Schulsinger, C AF Klebanoff, MA Secher, NJ Mednick, BR Schulsinger, C TI Maternal size at birth and the development of hypertension during pregnancy - A test of the Barker hypothesis SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID INTRAUTERINE GROWTH-RETARDATION; INSULIN-RESISTANCE; RISK-FACTORS; PREECLAMPSIA; WOMEN; DISEASE; WEIGHT; FETAL; PREVENTION; PRETERM AB Background: Whether individuals who were small at birth are at increased risk of developing cardiovascular disease (the Barker hypothesis) is a topic of great controversy. Although an increased risk has been suggested by several reports, the reports have been criticized for being based on ill-defined populations, for the large numbers of subjects who were unavailable for follow-up, and for inadequate control of socioeconomic status. Objective: To determine whether a woman's weight and gestational age at birth predict the development of hypertension during her subsequent pregnancies. Design: Prospective observational study. Subjects: Women born in Copenhagen, Denmark, as subjects in the Danish Perinatal Study (1959-1961) were traced through the Danish Population Register. Information was obtained on their pregnancies from 1974 to 1989. Main Outcome Measures: Onset of hypertension in pregnancy, defined by the presence of a systolic blood pressure of 140 mm Hg or greater or a diastolic blood pressure of 90 mm Hg or greater on 2 visits at or after 140 days gestation. Results: Hypertension developed in 11.3% of the pregnant women who were small for gestational age at birth, compared with 7.2% of the pregnant women who were not small for gestational age at birth (odds ratio [OR], 1.7, 95% confidence interval [CI], 1.1-2.6), and in 9.4% of the pregnancies in women who were preterm at birth, compared with 7.6% of pregnancies in women who were not preterm at birth (OR, 1.3; 95% CI, 0.8-2.0), After adjustment for adult body mass index, smoking, birth order, and hypertension in the subjects' own mothers, the ORs for small-for-gestational-age women and preterm women to develop hypertension during pregnancy were 1.8 (95% CI, 1.1-2.8) and 1.5 (95% CI, 0.96-2.5), respectively. Conclusion: These results support the Barker hypothesis, while addressing many of the methodological criticisms of previous investigations. C1 NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. Univ Aarhus, Dept Obstet & Gynecol, Aarhus, Denmark. Univ So Calif, Dept Educ Psychol, Los Angeles, CA USA. Univ Copenhagen, Inst Sygdomsforebyggelse, Copenhagen, Denmark. RP Klebanoff, MA (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, NIH, 6100 Bldg,Room 7B03, Bethesda, MD 20892 USA. FU NICHD NIH HHS [N01-HD-7-2902] NR 27 TC 36 Z9 39 U1 2 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUL 26 PY 1999 VL 159 IS 14 BP 1607 EP 1612 DI 10.1001/archinte.159.14.1607 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 217QF UT WOS:000081509900011 PM 10421284 ER PT J AU Soussan, L Burakov, D Daniels, MP Toister-Achituv, M Porat, A Yarden, Y Elazar, Z AF Soussan, L Burakov, D Daniels, MP Toister-Achituv, M Porat, A Yarden, Y Elazar, Z TI ERG30, a VAP-33-related protein, functions in protein transport mediated by COPI vesicles SO JOURNAL OF CELL BIOLOGY LA English DT Article DE endoplasmic reticulum; Golgi; coated vesicles; secretion; transport intermediates ID ENDOPLASMIC-RETICULUM; MEMBRANE-PROTEIN; GOLGI MEMBRANES; IN-VITRO; FUSION; DOCKING; COMPLEX; COATOMER; SEQUENCE; CELLS AB Intracellular transport of newly synthesized and mature proteins via vesicles is controlled by a large group of proteins. Here we describe a ubiquitous rat protein-endoplasmic reticulum (ER) and Golgi 30-kD protein (ERG30)-which shares structural characteristics with VAP-33, a 33-kD protein from Aplysia californica which was shown to interact with the synaptic protein VAMP. The transmembrane topology of the 30-kD ERG30 corresponds to a type II integral membrane protein, whose cytoplasmic NH2 terminus contains a predicted coiled-coil motif. We localized ERG30 to the ER and to pre-Golgi intermediates by biochemical and immunocytochemical methods. Consistent with a role in vesicular transport, anti-ERG30 antibodies specifically inhibit intra-Golgi transport in vitro, leading to significant accumulation of COPI-coated vesicles. It appears that ERG30 functions early in the secretory pathway, probably within the Golgi and between the Golgi and the ER. C1 Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. Weizmann Inst Sci, Dept Regulat Biol, IL-76100 Rehovot, Israel. NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Elazar, Z (reprint author), Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. RI YARDEN, YOSEF/K-1467-2012 FU NCI NIH HHS [R37 CA072981, CA 72981, R01 CA072981] NR 50 TC 71 Z9 73 U1 0 U2 2 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 JUL 26 PY 1999 VL 146 IS 2 BP 301 EP 311 DI 10.1083/jcb.146.2.301 PG 11 WC Cell Biology SC Cell Biology GA 221KF UT WOS:000081725700004 PM 10427086 ER PT J AU Drgonova, J Drgon, T Roh, DH Cabib, E AF Drgonova, J Drgon, T Roh, DH Cabib, E TI The GTP-binding protein Rho1p is required for cell cycle progression and polarization of the yeast cell SO JOURNAL OF CELL BIOLOGY LA English DT Article DE Saccharomyces cerevisiae; G proteins; cell polarity; actin; cell cycle ID SACCHAROMYCES-CEREVISIAE; ACTIN CYTOSKELETON; KINASE-C; S-PHASE; RAS TRANSFORMATION; BUD EMERGENCE; POLARITY; G(1); IDENTIFICATION; MORPHOGENESIS AB Previous work showed that the GTP-binding protein Rho1p is required in the yeast, Saccharomyces cerevisiae, for activation of protein kinase C (Pkc1p) and for activity and regulation of beta(1-->3)glucan synthase. Here we demonstrate a hitherto unknown function of Rho1p required for cell cycle progression and cell polarization. Cells of mutant rho1(E45I) in the G1 stage of the cell cycle did not bud at 37 degrees C. In those cells actin reorganization and recruitment to the presumptive budding site did not take place at the nonpermissive temperature. Two mutants in adjacent amino acids, rho1(E43T) and rho1(F44Y), showed a similar behavior, although some budding and actin polarization occurred at the nonpermissive temperature. This was also the case for rho1(E45I) when placed in a different genetic background. Cdc42p and Spa2p, two proteins that normally also move to the bud site in a process independent from actin organization, failed to localize properly in rho1(E45I). Nuclear division did not occur in the mutant at 37 degrees C, although replication of DNA proceeded slowly. The rho1 mutants were also defective in the formation of mating projections and in congregation of actin at the projections in the presence of mating pheromone. The in vitro activity of beta(1-->3)glucan synthase in rho1(E45I), although diminished at 37 degrees C, appeared sufficient for normal in vivo function and the budding defect was not suppressed by expression of a constitutively active allele of PKC1. Reciprocally, when Pkc1p function was eliminated by the use of a temperature-sensitive mutation and beta(1-->3)glucan synthesis abolished by an echinocandin-like inhibitor, a strain carrying a wild-type RHO1 allele was able to produce incipient buds. Taken together, these results reveal a novel function of Rho1p that must be executed in order for the yeast cell to polarize. C1 NIDDKD, Lab Biochem & Genet, Bethesda, MD 20892 USA. RP NIH, 8 Ctr Dr,MSC 0851, Bethesda, MD 20892 USA. EM enricoc@bdg10.niddk.nih.gov RI Drgonova, Jana/B-2903-2008; OI Drgonova, Jana/0000-0002-4623-8466 NR 62 TC 42 Z9 45 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD JUL 26 PY 1999 VL 146 IS 2 BP 373 EP 387 DI 10.1083/jcb.146.2.373 PG 15 WC Cell Biology SC Cell Biology GA 221KF UT WOS:000081725700010 PM 10427091 ER PT J AU Gu, JG Tamura, M Pankov, R Danen, EHJ Takino, T Matsumoto, K Yamada, KM AF Gu, JG Tamura, M Pankov, R Danen, EHJ Takino, T Matsumoto, K Yamada, KM TI Shc and FAK differentially regulate cell motility and directionality modulated by PTEN SO JOURNAL OF CELL BIOLOGY LA English DT Article DE Shc; focal adhesion kinase; integrin; cell migration; PTEN ID FOCAL ADHESION KINASE; ACTIVATED PROTEIN-KINASE; TUMOR-SUPPRESSOR PTEN; MAP KINASE; SIGNALING PATHWAYS; PHOSPHATIDYLINOSITOL 3-KINASE; GLIOBLASTOMA CELLS; EPITHELIAL-CELLS; TYROSINE KINASES; PROSTATE-CANCER AB Cell migration is modulated by regulatory molecules such as growth factors, oncogenes, and the tumor suppressor PTEN. We previously described inhibition of cell migration by PTEN and restoration of motility by focal adhesion kinase (FAK.) and p130 Crk-associated substrate (p130(Cas)). We now report a novel pathway regulating random cell motility involving Shc and mitogen-activated protein (MAP) kinase, which is downmodulated by PTEN and additive to a FAK pathway regulating directional migration. Overexpression of Shc or constitutively activated MEK1 in PTEN-reconstituted U87-MG cells stimulated integrin-mediated MAP kinase activation and cell migration. Conversely, overexpression of dominant negative Shc inhibited cell migration; Akt appeared uninvolved. PTEN directly dephosphorylated Shc. The migration induced by FAK or p130(Cas) was directionally persistent and involved extensive organization of actin microfilaments and focal adhesions. In contrast, Shc or MEK1 induced a random type of motility associated with less actin cytoskeletal and focal adhesion organization. These results identify two distinct, additive pathways regulating cell migration that are downregulated by tumor suppressor PTEN: one involves Shc, a MAP kinase pathway, and random migration, whereas the other involves FAK, p130(Cas), more extensive actin cytoskeletal organization, focal contacts, and directionally persistent cell motility. Integration of these pathways provides an intracellular mechanism for regulating the speed and the directionality of cell migration. C1 Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. RP Yamada, KM (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bldg 30,Room 421,30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. RI Pankov, Roumen/B-3284-2014; TAKINO, Takahisa/D-8460-2015; OI Pankov, Roumen/0000-0002-3157-3659; Yamada, Kenneth/0000-0003-1512-6805 NR 76 TC 307 Z9 333 U1 2 U2 6 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 JUL 26 PY 1999 VL 146 IS 2 BP 389 EP 403 DI 10.1083/jcb.146.2.389 PG 15 WC Cell Biology SC Cell Biology GA 221KF UT WOS:000081725700011 PM 10427092 ER PT J AU Mouro, C Bondon, A Jung, C Hoa, GHB De Certaines, JD Spencer, RGS Simonneaux, G AF Mouro, C Bondon, A Jung, C Hoa, GHB De Certaines, JD Spencer, RGS Simonneaux, G TI Proton nuclear magnetic resonance study of the binary complex of cytochrome P450cam and putidaredoxin: interaction and electron transfer rate analysis SO FEBS LETTERS LA English DT Article DE cytochrome P450; putidaredoxin; electron transfer; nuclear magnetic resonance; isocyanide ID SELF-EXCHANGE; CAMPHOR; BINDING; MUTAGENESIS; P-450(CAM); SURFACE; H-1-NMR; MODEL AB A H-1 nuclear magnetic resonance study of the complex of cytochrome P450cam-putidaredoxin has been performed. Isocyanide is bound to cytochrome p450cam in order to increase the stability of the protein both in the reduced and the oxidized state. Diprotein complex formation was detected through variation of the heme methyl proton resonances which have been assigned in the two redox states. The electron transfer rate at equilibrium was determinated by magnetization transfer experiments. The observed rate of oxidation of reduced cytochrome P450 by the oxidized putidaredoxin is 27 (+/- 7) per s, (C) 1999 Federation of European Biochemical Societies. C1 Univ Rennes 1, CNRS, UMR 6509, Lab Chim Organomet & Biol, F-35042 Rennes, France. Max Delbruck Ctr Mol Med, D-13092 Berlin, Germany. Inst Biol Physicochim, F-75005 Paris, France. Univ Rennes 1, UPRES EA 2230, Lab Resonance Magnet Biol & Med, F-35043 Rennes, France. NIA, Nucl Magnet Resonance Unit, NIH, Baltimore, MD 21224 USA. RP Bondon, A (reprint author), Univ Rennes 1, CNRS, UMR 6509, Lab Chim Organomet & Biol, Campus Beaulieu, F-35042 Rennes, France. OI RONDEAU-MOURO, Corinne/0000-0002-8573-1050 NR 33 TC 19 Z9 19 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUL 23 PY 1999 VL 455 IS 3 BP 302 EP 306 DI 10.1016/S0014-5793(99)00898-4 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 221XU UT WOS:000081753500022 PM 10437793 ER PT J AU Tcherkasskaya, O Ptitsyn, OB AF Tcherkasskaya, O Ptitsyn, OB TI Molten globule versus variety of intermediates: influence of anions on pH-denatured apomyoglobin SO FEBS LETTERS LA English DT Article DE apomyoglobin; fluorescence energy transfer; molten globule; protein folding ID HORSE HEART METMYOGLOBIN; FOLDING INTERMEDIATE; STRUCTURAL CHARACTERIZATION; 3-DIMENSIONAL STRUCTURE; ALPHA-LACTALBUMIN; PROTEIN MOLECULES; COMPACT STATE; STABILITY; STABILIZATION; TRANSITIONS AB The molten globule state was shown to be the third thermodynamic state of protein molecules in addition to their native and unfolded states. On the other hand, it was reported that optical and hydrodynamic properties of pH-denatured apomyoglobin depend on the nature of anions added to the protein solution, This observation was used to conclude that there are many 'partly folded' intermediates between the native and unfolded states rather than one distinct molten globule state, However, little is known on the structures of pH-denatured apomyoglobin in the presence of different anions, Two tyrosine residues in horse apomyoglobin have been successively modified by the reaction with tetranitromethane, This approach was employed to measure the distances between tryptophans and modified tyrosines in different states of apomyoglobin by the method of direct energy transfer. Experimental data show that the distance between the middle of the A-helix and the beginning of the G-helix and/or the end of the H-helix in 'anion-induced' states are very close to those in the native holo- and apomyoglobins. This suggests that the AGH helical complex, being the most structured part of apomyoglobin in the molten globule state, exists also in pH-denatured apomyoglobin in the presence of different anions, Consequently, all non-native forms of apomyoglobin studied so far share the common important feature of its native structure, (C) 1999 Federation of European Biochemical Societies. C1 NCI, Lab Expt & Computat Biol, NIH, Bethesda, MD 20892 USA. Russian Acad Sci, Inst Macromol Cpds, St Petersburg 199004, Russia. Russian Acad Sci, Inst Prot Res, Pushchino 142292, Moscow Region, Russia. RP Tcherkasskaya, O (reprint author), NCI, Lab Expt & Computat Biol, NIH, MSC 5677,Bldg 12B,Room B116, Bethesda, MD 20892 USA. NR 43 TC 24 Z9 24 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUL 23 PY 1999 VL 455 IS 3 BP 325 EP 331 DI 10.1016/S0014-5793(99)00792-9 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 221XU UT WOS:000081753500027 PM 10437798 ER PT J AU Osheroff, WP Beard, WA Wilson, SH Kunkel, TK AF Osheroff, WP Beard, WA Wilson, SH Kunkel, TK TI Base substitution specificity of DNA polymerase beta depends on interactions in the DNA minor groove SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CRYSTAL-STRUCTURES; EXCISION-REPAIR; B-DNA; FIDELITY; REPLICATION; MECHANISM; PROCESSIVITY; MISMATCHES; RESOLUTION; MUTATIONS AB To examine the hypothesis that interactions between a DNA polymerase and the DNA minor groove are critical for accurate DNA synthesis, we studied the fidelity of DNA polymerase beta mutants at residue Arg(283), where arginine, which interacts with the minor groove at the active site, is replaced by alanine or lysine. Alanine substitution, removing minor groove interactions, strongly reduces polymerase selectivity for all single-base mispairs examined. In contrast, the lysine substitution, which retains significant interactions with the minor groove, has wild-type-like selectivity for T.dGMP and A.dGMP mispairs but reduced selectivity for T.dCMP and A.dCMP mispairs, Examination of DNA crystal structures of these four mispairs indicates that the two mispairs excluded by the lysine mutant have an atom (N2) in an unfavorable position in the minor groove, while the two mispairs permitted by the lysine mutant do not. These results suggest that unfavorable interactions between an active site amino acid side chain and mispair-specific atoms in the minor groove contribute to DNA polymerase specificity. C1 NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Kunkel, TK (reprint author), NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. NR 32 TC 57 Z9 57 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 23 PY 1999 VL 274 IS 30 BP 20749 EP 20752 DI 10.1074/jbc.274.30.20749 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 219NJ UT WOS:000081613100002 PM 10409611 ER PT J AU Lamzin, VS Morris, RJ Dauter, Z Wilson, KS Teeter, MM AF Lamzin, VS Morris, RJ Dauter, Z Wilson, KS Teeter, MM TI Experimental observation of bonding electrons in proteins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RAY-DIFFRACTION DATA; DENSITY PARAMETERS; ATOMIC-RESOLUTION; CRYSTAL-STRUCTURE; CRAMBIN; POLYPEPTIDES; REFINEMENT AB We demonstrate with two examples the success and potential of recent developments in x-ray protein crystallography at ultra high resolution. Our preliminary structural analyses using diffraction data collected for the two proteins crambin and savinase show meaningful deviations from the conventional independent spherical atom approximation. A noise-reduction averaging technique enables bonding details of electron distributions in proteins to be revealed experimentally for the first time. We move one step closer to imaging directly the fine details of the electronic structure on which the biological function of a protein is based. C1 European Mol Biol Lab, D-22603 Hamburg, Germany. NCI, Upton, NY 11973 USA. Univ York, York YO1 5DD, N Yorkshire, England. Boston Coll, Dept Chem, Chestnut Hill, MA 02167 USA. RP Lamzin, VS (reprint author), European Mol Biol Lab, D-22603 Hamburg, Germany. OI Lamzin, Victor/0000-0002-6058-7793 NR 19 TC 17 Z9 17 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 23 PY 1999 VL 274 IS 30 BP 20753 EP 20755 DI 10.1074/jbc.274.30.20753 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 219NJ UT WOS:000081613100003 PM 10409612 ER PT J AU Pellegrini, L Passer, BJ Tabaton, M Ganjei, JK D'Adamio, L AF Pellegrini, L Passer, BJ Tabaton, M Ganjei, JK D'Adamio, L TI Alternative, non-secretase processing of Alzheimer's beta-amyloid precursor protein during apoptosis by caspase-6 and-8 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MISSENSE MUTATIONS; FAMILY PROTEASES; CELL-DEATH; DISEASE; GENE; CLEAVAGE; PEPTIDE; MUTANT; PRESENILIN-1; INVOLVEMENT AB Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Although the pathogenesis of AD is unknown, it is widely accepted that AD is caused by extracellular accumulation of a neurotoxic peptide, known as A beta, Mutations in the beta-amyloid precursor protein (APP), from which A beta arises by proteolysis, are associated with some forms of familial AD (FAD) and result in increased A beta production. Two other FAD genes, presenilin-1 and -2, have also been shown to regulate A beta production; however, studies examining the biological role of these FAD genes suggest an alternative theory for the pathogenesis of AD. In fact, all three genes have been shown to regulate programmed cell death, hinting at the possibility that dysregulation of apoptosis plays a primary role in causing neuronal loss in AD. In an attempt to reconcile these two hypotheses, we investigated APP processing during apoptosis and found that APP is processed by the cell death proteases caspase-6 and -8. APP is cleaved by caspases in the intracellular portion of the protein, in a site distinct from those processed by secretases. Moreover, it represents a general effect of apoptosis, because it occurs during cell death induced by several stimuli both in T cells and in neuronal cells. C1 NIAID, T Cell Apoptopsis Unit, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. Univ Genoa, Ist Anat Umana, I-16132 Genoa, Italy. Univ Genoa, Dipartimento Neurosci, I-16132 Genoa, Italy. RP D'Adamio, L (reprint author), NIAID, T Cell Apoptopsis Unit, Cellular & Mol Immunol Lab, NIH, Bldg 4-431, Bethesda, MD 20892 USA. NR 45 TC 119 Z9 125 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 23 PY 1999 VL 274 IS 30 BP 21011 EP 21016 DI 10.1074/jbc.274.30.21011 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 219NJ UT WOS:000081613100041 PM 10409650 ER PT J AU Li, RX Blanchette-Mackie, EJ Ladisch, S AF Li, RX Blanchette-Mackie, EJ Ladisch, S TI Induction of endocytic vesicles by exogenous C-6-ceramide SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GOLGI-APPARATUS; CERAMIDE ANALOG; PATHWAY; PROTEIN; STRESS; CELLS; DIFFERENTIATION; ARREST; KINASE; CYCLE AB Ceramide is a newly discovered second messenger that has been shown to cause cell growth arrest and apoptosis, Here, we present evidence that exogenously added C-6-ceramide induces enlargement of late endosomes and lysosomes, 10 mu M C-6-ceramide caused the formation of numerous vesicles of varying sizes (2-10 mu m) in fibroblasts (3T3-L1 and 3T3-F442A), without toxic effects. Vesicle formation induced by C-6-ceramide was time- and dose-dependent, rapid, and reversible. Numerous small vesicles appeared within 8 h of treatment with 10 mu M C-6-ceramide, They enlarged with time, with large vesicles found in the perinuclear region and small ones observed at the cell periphery. Within 24 h of treatment, similar to 30% of the cells exhibited these vesicles. Removal of ceramide from the culture medium caused disappearance of the vesicles, which reappeared upon readdition of ceramide, Confocal immunofluorescence microscopic analysis using an anti-lysosome-associated membrane protein antibody identified the enlarged vesicles as late endosomes/lysosomes. The fluorescent C-6-NBD-ceramide, a vital stain for the Golgi apparatus, did not stain these vesicles. The effect on vesicle formation was influenced by ceramide structure; D-erythro-C-6-ceramide was the most active ceramide analogue tested. Short chain ceramide metabolites, such as sphingosine, sphingosine 1-phosphate, N-hexanoyl-sphingosylphosphorylcholine, N-acetylpsychosine, and C-2-ceramide G(M3), (G(M3), N-acetylneuraminosyl-alpha(2,3)-galactosyl-beta (1,4)-glucosylceramide), were inactive in causing vesicle formation when added exogenously, Together, these studies demonstrate that exogenous C-6-ceramide induces endocytic vesicle formation and causes enlarged late endosomes and lysosomes in mouse fibroblasts. C1 Childrens Res Inst, Ctr Canc & Transplant Biol, Glycobiol Program, Washington, DC 20010 USA. George Washington Univ, Sch Med, Dept Pediat, Washington, DC 20052 USA. George Washington Univ, Sch Med, Dept Biochem Mol Biol, Washington, DC 20052 USA. NIDDK, Lipid Cell Biol Sect, NIH, Bethesda, MD 20892 USA. RP Li, RX (reprint author), Childrens Res Inst, Ctr Canc & Transplant Biol, Glycobiol Program, 111 Michigan Ave NW, Washington, DC 20010 USA. FU NCI NIH HHS [CA61010] NR 29 TC 45 Z9 45 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 23 PY 1999 VL 274 IS 30 BP 21121 EP 21127 DI 10.1074/jbc.274.30.21121 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 219NJ UT WOS:000081613100056 PM 10409665 ER PT J AU Kirsch, DG Doseff, A Chau, BN Lim, DS de Souza-Pinto, NC Hansford, R Kastan, MB Lazebnik, YA Hardwick, JM AF Kirsch, DG Doseff, A Chau, BN Lim, DS de Souza-Pinto, NC Hansford, R Kastan, MB Lazebnik, YA Hardwick, JM TI Caspase-3-dependent cleavage of Bcl-2 promotes release of cytochrome c SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DRUG-INDUCED APOPTOSIS; CELL-DEATH; MORPHOLOGICAL-CHANGES; DNA FRAGMENTATION; CASPASE FAMILY; PROTEIN; BAX; ACTIVATION; PATHWAY; MITOCHONDRIA AB Caspases are cysteine proteases that mediate apoptosis by proteolysis of specific substrates, Although many caspase substrates have been identified, for most substrates the physiologic caspase(s) required for cleavage is unknown. The Bcl-2 protein, which inhibits apoptosis, is cleaved at Asp-34 by caspases during apoptosis and by recombinant caspase-3 in vitro. In the present study, we show that endogenous caspase-3 is a physiologic caspase for Bcl-2, Apoptotic extracts from 293 cells cleave Bcl-2 but not Bax, even though Bax is cleaved to an 18-kDa fragment in SK-NSH cells treated with ionizing radiation. In contrast to Bcl-2, cleavage of Bax was only partially blocked by caspase inhibitors. Inhibitor profiles indicate that Bax may be cleaved by more than one type of noncaspase protease, Immunodepletion of caspase-3 from 293 extracts abolished cleavage of Bcl-2 and caspase-7, whereas immunodepletion of caspase-7 had no effect on Bcl-2 cleavage. Furthermore, MCF-7 cells, which lack caspase-3 expression, do not cleave Bcl-2 following staurosporine-induced cell death. However, transient transfection of caspase-3 into MCF-7 cells restores Bcl-2 cleavage after staurosporine treatment. These results demonstrate that in these models of apoptosis, specific cleavage of Bcl-2 requires activation of caspase-3, When the pro-apoptotic caspase cleavage fragment of Bcl-2 is transfected into baby hamster kidney cells, it localizes to mitochondria and causes the release of cytochrome c into the cytosol. Therefore, caspase-3-dependent cleavage of Bcl-2 appears to promote further caspase activation as part of a positive feedback loop for executing the cell. C1 Johns Hopkins Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. Johns Hopkins Sch Publ Hlth, Ctr Oncol, Baltimore, MD 21205 USA. Johns Hopkins Sch Publ Hlth, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. Johns Hopkins Sch Publ Hlth, Dept Neurol, Baltimore, MD 21205 USA. Johns Hopkins Sch Med, Ctr Oncol, Baltimore, MD 21205 USA. Johns Hopkins Sch Med, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. Johns Hopkins Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD 21205 USA. Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. NIA, NIH, Baltimore, MD 21224 USA. RP Hardwick, JM (reprint author), Johns Hopkins Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. RI Souza-Pinto, Nadja/C-3462-2013; Doseff, Andrea/E-2991-2011; Lim, Dae-Sik/C-1599-2011 OI Souza-Pinto, Nadja/0000-0003-4206-964X; Lim, Dae-Sik/0000-0003-2356-7555 FU NCI NIH HHS [CA77715]; NIEHS NIH HHS [ES05777]; NIGMS NIH HHS [GM07309] NR 46 TC 342 Z9 368 U1 3 U2 13 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 23 PY 1999 VL 274 IS 30 BP 21155 EP 21161 DI 10.1074/jbc.274.30.21155 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 219NJ UT WOS:000081613100060 PM 10409669 ER PT J AU Wingfield, PT Sax, JK Stahl, SJ Kaufman, J Palmer, I Chung, V Corcoran, ML Kleiner, DE Stetler-Stevenson, WG AF Wingfield, PT Sax, JK Stahl, SJ Kaufman, J Palmer, I Chung, V Corcoran, ML Kleiner, DE Stetler-Stevenson, WG TI Biophysical and functional characterization of full-length, recombinant human tissue inhibitor of metalloproteinases-2 (TIMP-2) produced in Escherichia coli - Comparison of wild type and amino-terminal alanine appended variant with implications for the mechanism of TIMP functions SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN SECONDARY STRUCTURE; MATRIX METALLOPROTEINASES; CIRCULAR-DICHROISM; GELATINASE-A; 72-KDA GELATINASE; KINETIC-ANALYSIS; IV COLLAGENASE; B-CELLS; DOMAIN; EXPRESSION AB Matrix metalloproteinases (MMPs) function in the remodeling of the extracellular matrix that is integral for many normal and pathological processes. The tissue inhibitor of metalloproteinases family, including tissue inhibitor of metalloproteinases-2 (TIMP-2), regulates the activity of these multifunctional metalloproteinases. TIMP family members are proteinase inhibitors that contain six conserved disulfide bonds, one involving an amino-terminal cysteine residue that is critical for MMP inhibitor activity. TIMP-2 has been expressed in Escherichia coli, folded from insoluble protein, and functionally characterized. The wild type protein inhibited gelatinase A (MMP-2), whereas a variant with an alanine appended to the amino terminus (Ala+TIMP-2) was inactive. Removal of amino-terminal alanine by exopeptidase digestion restored protease inhibitor activity. This confirms the mechanistic importance of the amino-terminal amino group in the metalloproteinase inhibitory activity, as originally suggested from the x-ray structure of a complex of MMP-3 with TIMP-1 and a complex of TIMP-2 with MT-1-MMP. The Ala+-TIMP-2 variant exhibited conformational, pro-MMP-2 complex formation and fibroblast growth modulating properties of the wild type protein. These findings demonstrate that Ala+TIMP-2 is an excellent biochemical tool for examining the specific role of MMP inhibition in the multiple functions ascribed to TIMPs. C1 NCI, ECMPS, Pathol Lab, NIH, Bethesda, MD 20892 USA. NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. RP Stetler-Stevenson, WG (reprint author), NCI, ECMPS, Pathol Lab, NIH, Bldg 10,Rm 2A33,MSC 1500,10 Ctr Dr, Bethesda, MD 20892 USA. RI Stetler-Stevenson, William/H-6956-2012 OI Stetler-Stevenson, William/0000-0002-5500-5808 NR 31 TC 76 Z9 78 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 23 PY 1999 VL 274 IS 30 BP 21362 EP 21368 DI 10.1074/jbc.274.30.21362 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 219NJ UT WOS:000081613100088 PM 10409697 ER PT J AU Barr, VA Lane, K Taylor, SI AF Barr, VA Lane, K Taylor, SI TI Subcellular localization and internalization of the four human leptin receptor isoforms SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SIGNAL TRANSDUCER GP130; LIGAND-INDUCED ENDOCYTOSIS; OB-R; ERYTHROPOIETIN RECEPTOR; ENDOPLASMIC-RETICULUM; EXTRACELLULAR DOMAIN; MEDIATED ENDOCYTOSIS; PROTEIN-DEGRADATION; DOWN-REGULATION; IL-6 RECEPTOR AB There are four known isoforms of the human leptin receptor (HLR) with different C-terminal cytoplasmic domains (designated by the number of unique C-terminal amino acids). In cells expressing HLR-5, -15, or -274, 15-25% of the leptin binding sites were located at the plasma membrane. In contrast, in cells expressing HLR-67, only 5% of the total binding sites were at the plasma membrane. Immunofluorescent microscopy showed that all four isoforms partially co-localized with calnexin and beta-COP, markers of the endoplasmic reticulum and the Golgi, respectively. All isoforms were also detected in an unidentified punctate compartment. AU isoforms were internalized via clathrin-mediated endocytosis, but at different rates. After 20 min at 37 degrees C, 45% of a bound cohort of labeled ligand had been internalized by HLR-15, 30% by HLR-67, 25% by HLR-274, and 15% by HLR-5. Degradation of internalized leptin occurred in lysosomes. Overnight exposure to leptin down-regulated all isoforms, but to a variable extent. HLR-274 displayed the greatest down-regulation and also appeared to reach lysosomes more quickly than the other isoforms. The faster degradation of HLR-274 may help to terminate leptin signaling. C1 NIDDK, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Taylor, SI (reprint author), NIDDK, Diabet Branch, NIH, Bldg 10 9S213,10 Ctr Dr, Bethesda, MD 20892 USA. NR 54 TC 98 Z9 102 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 23 PY 1999 VL 274 IS 30 BP 21416 EP 21424 DI 10.1074/jbc.274.30.21416 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 219NJ UT WOS:000081613100095 PM 10409704 ER PT J AU Wang, SQ Zhou, ZQ AF Wang, SQ Zhou, ZQ TI Alpha-stat calibration of indo-1 fluorescence and measurement of intracellular free calcium in rat ventricular cells at different temperatures SO LIFE SCIENCES LA English DT Article DE alpha-stat pH management; intracellular free calcium; fluorescent Ca2+ probe; temperature; cardiac myocute ID MYOCYTES; INDICATOR; PROTEIN; BINDING; RABBIT; PROBES AB To explore how to manage pH when calibrating Ca2+ probes at different temperatures, the dissociation constant (K-d) of indo-1 was determined both in pH-stat (pH is fixed despite the temperature) and in alpha-stat (pH changes with temperature as in cells). The results showed that the K-d was much more sensitive to temperature in pH-stat than in alpha-stat, demonstrating that alpha-stat calibration should be preferred when using a Ca2+ probe to measure intracellular free calcium ([Ca2+](i)) at different temperatures. Based on the calibration in situ and in alpha-stat, we showed a striking increase of [Ca2+](i) from 141+/-8 nM at 30 degrees C to 218+/-22 nM at 10 degrees C in indo-1 loaded rat ventricular cells, which supports that intracellular calcium overload takes place in cardiac myocytes of non-hibernating mammals during hypothermia. C1 Peking Univ, Coll Life Sci, Beijing 100871, Peoples R China. RP Wang, SQ (reprint author), NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. NR 16 TC 17 Z9 20 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD JUL 23 PY 1999 VL 65 IS 9 BP 871 EP 877 DI 10.1016/S0024-3205(99)00317-3 PG 7 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 224BJ UT WOS:000081876000004 PM 10465347 ER PT J AU Gawley, RE Zhang, QH Higgs, PI Wang, SP Leblanc, RM AF Gawley, RE Zhang, QH Higgs, PI Wang, SP Leblanc, RM TI Anthracylmethyl crown ethers as fluorescence sensors of saxitoxin SO TETRAHEDRON LETTERS LA English DT Article ID ELECTRON-TRANSFER SENSORS; NEUTRAL MOLECULES; RECOGNITION; 18-CROWN-6; CHEMISTRY; BINDING; COMPLEX; TOXINS AB Anthracylmethyl crowns 1 and 2 show up to 30-fold increase in fluorescence emission intensity in the presence of saxitoxin in ethanol, and sixfold enhancement in 80% ethanol. The binding constant between saxitoxin and 1 is 3880 M-1 in ethanol and 1100 M-1 in 80% ethanol. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 Univ Miami, Dept Chem, Coral Gables, FL 33124 USA. Univ Miami, NIEHS, Marine & Freshwater Biomed Sci Ctr, Coral Gables, FL 33124 USA. RP Leblanc, RM (reprint author), Univ Miami, Dept Chem, Coral Gables, FL 33124 USA. NR 41 TC 18 Z9 19 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD JUL 23 PY 1999 VL 40 IS 30 BP 5461 EP 5465 DI 10.1016/S0040-4039(99)01066-7 PG 5 WC Chemistry, Organic SC Chemistry GA 216EC UT WOS:000081427400008 ER PT J AU Kondrashov, AS Kondrashov, FA AF Kondrashov, AS Kondrashov, FA TI Interactions among quantitative traits in the course of sympatric speciation SO NATURE LA English DT Article ID SEXUAL SELECTION; LAKE-VICTORIA; MODEL; EVOLUTION; CICHLIDS; BARBS AB Sympatric speciation, the origin of two or more species from a single local population, has almost certainly been involved in formation of several species flocks(1-4), and may be fairly common in nature(5). The most straightforward scenario for sympatric speciation requires disruptive selection favouring two substantially different phenotypes, and consists of the evolution of reproductive isolation between them followed by the elimination of all intermediate phenotypes(6). Here we use the hypergeometric phenotypic model(7-10) to show that sympatric speciation is possible even when fitness and mate choice depend on different quantitative traits, so that speciation must involve formation of covariance between these traits. The increase in the number of variable loci affecting fitness facilitates sympatric speciation, whereas the increase in the number of variable loci affecting mate choice has the opposite effect. These predictions may enable more cases of sympatric speciation to be identified. C1 Simons Rock Coll, Great Barrington, MA 01230 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Kondrashov, FA (reprint author), Simons Rock Coll, 84 Alford Rd, Great Barrington, MA 01230 USA. RI Kondrashov, Fyodor Alexeevich/H-6331-2015 OI Kondrashov, Fyodor Alexeevich/0000-0001-8243-4694 NR 27 TC 374 Z9 384 U1 1 U2 64 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 22 PY 1999 VL 400 IS 6742 BP 351 EP 354 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219CH UT WOS:000081590000046 PM 10432111 ER PT J AU Koshiya, N Smith, JC AF Koshiya, N Smith, JC TI Neuronal pacemaker for breathing visualized in vitro SO NATURE LA English DT Article ID RESPIRATORY RHYTHM GENERATION; PRE-BOTZINGER COMPLEX; SPINAL-CORD; MEDULLARY SLICES; MAMMALIAN BRAIN; MECHANISMS; CIRCUITRY; NETWORK; MOTOR; RAT AB Breathing movements in mammals arise from a rhythmic pattern of neural activity, thought to originate in the pre-Botzinger complex(1) in the lower brainstem. The mechanisms generating the neural rhythm in this region are unknown(2-5). The central question is whether the rhythm is generated by a network of bursting pacemaker neurons coupled by excitatory synapses that synchronize pacemaker activity. Here we visualized the activity of inspiratory pacemaker neurons at single-cell and population levels with calcium-sensitive dye. We developed methods to label these neurons retrogradely with the dye in neonatal rodent brainstem slices that retain the rhythmically active respiratory network We simultaneously used infrared structural imaging to allow patch-damp recording from the identified neurons, After we pharmacologically blocked glutamatergic synaptic transmission, a subpopulation of inspiratory neurons continued to burst rhythmically but asynchronously. The intrinsic bursting frequency of these pacemaker neurons depended on the baseline membrane potential, providing a cellular mechanism for respiratory frequency control. These results provide evidence that the neuronal kernel for rhythm generation consists of a network of synaptically-coupled pacemaker neurons. C1 NINDS, Cellular & Syst Neurobiol Sect, Neural Control Lab, NIH, Bethesda, MD 20892 USA. RP Koshiya, N (reprint author), NINDS, Cellular & Syst Neurobiol Sect, Neural Control Lab, NIH, Bethesda, MD 20892 USA. EM koshiya@nih.gov NR 30 TC 323 Z9 328 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 22 PY 1999 VL 400 IS 6742 BP 360 EP 363 DI 10.1038/22540 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219CH UT WOS:000081590000049 PM 10432113 ER PT J AU Grigoletto, F Zappala, G Anderson, DW Lebowitz, BD AF Grigoletto, F Zappala, G Anderson, DW Lebowitz, BD TI Norms for the Mini-Mental State Examination in a healthy population SO NEUROLOGY LA English DT Article ID ALZHEIMERS-DISEASE; REFERENCE VALUES; RANDOM SAMPLE; AGE; EDUCATION; DIAGNOSIS; COMMUNITY; DEMENTIA; ADULTS; TESTS AB Background: Although the Mini-Mental State Examination (MMSE) is widely used in clinical practice, few norms exist for healthy populations covering a broad range of ages. Objective: To obtain MMSE norms specific for age, gender, and education in healthy adults. Methods: From the population registers of seven communities across Italy, we selected a proportionate random sample of residents age 20 to 79 years to evaluate their health status with respect to conditions affecting cognitive performance. This sample yielded 908 persons who were deemed to be without cognitive impairment and who were then given the MMSE. We calculated fifth percentile norms and presented them as step functions. We then validated the norms as a screening tool for dementia in persons age 65 to 79 years. The validation was based on unpublished data from a separate study and involved estimates of sensitivity and specificity. Results: The norms declined with advancing age, especially for less educated women. Given any age and sex, the norms were higher for individuals with higher educational levels. In screening for dementia, the norms had a sensitivity of 85% and a specificity of 89%. Conclusions: When using MMSE scores, it is important to account for age, gender, and education, especially in populations where the educational level is low. Expressing MMSE norms as step functions provides an easy-to-use tool for neurologists and other clinicians. C1 Univ Padua, Inst Hyg, I-35131 Padua, Italy. Garibaldi Hosp, Div Neurol, Catania, Italy. Natl Inst Neurol Disorders & Stroke, Biometry & Field Studies Branch, Bethesda, MD USA. NIMH, Natl Inst Hlth, Intervent Res Branch, Bethesda, MD USA. RP Grigoletto, F (reprint author), Univ Padua, Inst Hyg, Via Loredan 18, I-35131 Padua, Italy. NR 36 TC 140 Z9 145 U1 6 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL 22 PY 1999 VL 53 IS 2 BP 315 EP 320 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 219BE UT WOS:000081587300013 PM 10430420 ER PT J AU Ross, GW Petrovitch, H White, LR Masaki, KH Li, CY Curb, JD Yano, K Rodriguez, BL Foley, DJ Blanchette, PL Havlik, R AF Ross, GW Petrovitch, H White, LR Masaki, KH Li, CY Curb, JD Yano, K Rodriguez, BL Foley, DJ Blanchette, PL Havlik, R TI Characterization of risk factors for vascular dementia - The Honolulu-Asia Aging Study SO NEUROLOGY LA English DT Article ID CORONARY HEART-DISEASE; ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E; JAPANESE MEN; ALPHA-TOCOPHEROL; STROKE; INFARCTS; HAWAII; AGE; CALIFORNIA AB Background: The Honolulu Heart Program (HHP) is a prospective study of heart disease and stroke that has accumulated risk factor data on a cohort of 8,006 Japanese American men since the study began in 1965. A recent examination of the cohort identified all patients with vascular dementia (VaD) using the criteria of the California Alzheimer's Disease Diagnostic and Treatment Center. Objective: To characterize patients with VaD by stroke subtype and to investigate risk factors for VaD in a cohort of Japanese American men, aged 71 to 93, living in Hawaii and participating in the HHP. Methods: Sixty-eight men with VaD were compared with 3,335 men without dementia or stroke (NSND). Men with VaD were also compared with 106 men with stroke who were not demented (SND). Candidate risk factors were measured prospectively. Results: Of the 68 men with VaD there were 34 (50%) whose VaD was attributed to small vessel infarcts, 16 (23%) whose VaD was related to large vessel infarcts, and 11 (16%) with both large and small vessel infarcts. The remainder could not be classified. In a multivariate logistic regression model for VaD compared with NSND containing variables found to be associated with VaD in a univariate analysis, age (odds ratio [OR] 1.19, 95% confidence interval [CI] 1.13 to 1.27), coronary heart disease (OR 2.50, 95% CI 1.35 to 4.62), and 1-hour postprandial glucose (OR 1.41, 95% CI 1.06 to 1.88) remained significantly predictive of VaD, whereas preference for a Western diet (OR 0.54, 95% CI 0.30 to 0.98) as opposed to an Oriental or mixed diet and use of supplementary vitamin E (OR 0.32, 95% CI 0.12 to 0.82) were protective. A similar model for the comparison of men with VaD and SND revealed age (OR 1.24, 95% CI 1.14 to 1.35) was predictive of VaD, whereas preference for a Western diet (OR 0.43, 95% CI 0.22 to 0.86) was protective. Conclusions: The most common stroke subtype associated with VaD was lacunar stroke. Age and traditional vascular risk factors are important contributors to the development of VaD in late life. The antioxidant vitamin E and presently unknown factors related to a Western diet as opposed to an Oriental diet may be protective against developing VaD. C1 Dept Vet Affairs, Honolulu, HI USA. Univ Hawaii, John A Burns Sch Med, Dept Med, Honolulu, HI 96822 USA. NIA, NIH, Bethesda, MD USA. Kuakini Med Ctr, Honolulu Asia Aging Study, Honolulu, HI USA. RP Ross, GW (reprint author), Vet Affairs Med & Reg Off Ctr, 151,PO Box 50188, Honolulu, HI 96850 USA. FU NHLBI NIH HHS [1V01 HL56274-O1A1, N01-HC-05102]; NIA NIH HHS [N01-AG-4-2149] NR 45 TC 98 Z9 100 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 JUL 22 PY 1999 VL 53 IS 2 BP 337 EP 343 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 219BE UT WOS:000081587300016 PM 10430423 ER PT J AU Seder, RA Gurunathan, S AF Seder, RA Gurunathan, S TI DNA vaccines - Designer vaccines for the 21st Century SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID LYMPHOCYTES C1 NIAID, Bethesda, MD 20892 USA. RP Seder, RA (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 5 TC 40 Z9 43 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 JUL 22 PY 1999 VL 341 IS 4 BP 277 EP 278 DI 10.1056/NEJM199907223410410 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 217ZL UT WOS:000081528800010 PM 10413742 ER PT J AU Dries, DL Exner, DV Domanski, MJ AF Dries, DL Exner, DV Domanski, MJ TI Racial differences in the outcome of left ventricular dysfunction - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID HYPERTENSION C1 NHLBI, Bethesda, MD 20892 USA. RP Dries, DL (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 22 PY 1999 VL 341 IS 4 BP 288 EP 288 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 217ZL UT WOS:000081528800019 ER PT J AU Mohiddin, SA Begley, D Fananapazir, L AF Mohiddin, SA Begley, D Fananapazir, L TI Myocardial bridging in children with hypertrophic cardiomyopathy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID SUDDEN-DEATH; RISK C1 NHLBI, Bethesda, MD 20892 USA. RP Mohiddin, SA (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. NR 4 TC 5 Z9 5 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 22 PY 1999 VL 341 IS 4 BP 288 EP 289 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 217ZL UT WOS:000081528800020 PM 10419391 ER PT J AU De Valck, D Jin, DY Heyninck, K Van de Craen, M Contreras, R Fiers, W Jeang, KT Beyaert, R AF De Valck, D Jin, DY Heyninck, K Van de Craen, M Contreras, R Fiers, W Jeang, KT Beyaert, R TI The zinc finger protein A20 interacts with a novel anti-apoptotic protein which is cleaved by specific caspases SO ONCOGENE LA English DT Article DE A20; TNF; tax; apoptosis; caspases ID TUMOR-NECROSIS-FACTOR; KAPPA-B ACTIVATION; HUMAN ENDOTHELIAL-CELLS; HTLV-I TAX; FACTOR-ALPHA; ICE/CED-3 PROTEASE; SIGNALING PROTEINS; COMMON MEDIATOR; EXPRESSION; INDUCTION AB A20 is a Cys(2)/Cys(2) zinc finger protein which is induced by a variety of inflammatory stimuli and which has been characterized as an inhibitor of cell death by a yet unknown mechanism. In order to clarify its molecular mechanism of action, we used the yeast two-hybrid system to screen for proteins that interact with A20. A cDNA fragment was isolated which encoded a portion of a novel protein (TXBP151), which was recently found to be a human T-cell leukemia virus type-I (HTLV-I) Tax-binding protein. The full-length 2386bp TXBP151 mRNA encodes a protein of 86kDa, Like A20, overexpression of TXBP151 could inhibit apoptosis induced by tumour necrosis factor (TNF) in NIH3T3 cells, Moreover, transfection of antisense TXBP151 partially abolished the anti-apoptotic effect of A20, Furthermore, apoptosis induced by TNF or CD95 (Fas/ APO-1) was associated with proteolysis of TXBP151. This degradation could be inhibited by the broad-spectrum caspase inhibitor zVAD-fmk or by expression of the cowpox virus-derived inhibitor CrmA, suggesting that TXBP151 is a novel substrate for caspase family members. TXBP151 was indeed found to be specifically cleaved in vitro by members of the caspase-3-like subfamily, viz, caspase-3, caspase-6 and caspase-7, Thus TXBP151 appears to be a novel A20-binding protein which might mediate the anti-apoptotic activity of A20, and which can be processed by specific caspases. C1 Flanders Interuniv Inst Biotechnol, Dept Biol Mol, B-9000 Ghent, Belgium. State Univ Ghent, B-9000 Ghent, Belgium. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Beyaert, R (reprint author), Flanders Interuniv Inst Biotechnol, Dept Biol Mol, Ledeganckstr 35, B-9000 Ghent, Belgium. RI Jeang, Kuan-Teh/A-2424-2008; Beyaert, Rudi/B-2589-2009; OI Beyaert, Rudi/0000-0002-5704-582X NR 46 TC 97 Z9 101 U1 1 U2 2 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUL 22 PY 1999 VL 18 IS 29 BP 4182 EP 4190 DI 10.1038/sj.onc.1202787 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 218FK UT WOS:000081542400002 PM 10435631 ER PT J AU Krieger, JN Nyberg, L Nickel, JC AF Krieger, JN Nyberg, L Nickel, JC TI NIH consensus definition and classification of prostatitis SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 Univ Washington, Seattle, WA 98195 USA. Queens Univ, Kingston, ON, Canada. NIDDKD, Bethesda, MD 20892 USA. RP Krieger, JN (reprint author), Univ Washington, Seattle, WA 98195 USA. NR 0 TC 512 Z9 609 U1 2 U2 12 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 JUL 21 PY 1999 VL 282 IS 3 BP 236 EP 237 DI 10.1001/jama.282.3.236 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 217MW UT WOS:000081504400026 PM 10422990 ER PT J AU Young, NS AF Young, NS TI Acquired aplastic anemia SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID BONE-MARROW TRANSPLANTATION; COLONY-STIMULATING FACTOR; ANTITHYMOCYTE GLOBULIN; MALIGNANT-TUMORS; GRAFT; CYCLOSPORINE; ADULTS; CYCLOPHOSPHAMIDE; SUSCEPTIBILITY; TRANSFUSION C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Young, NS (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Room 7C103,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 57 TC 40 Z9 44 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 JUL 21 PY 1999 VL 282 IS 3 BP 271 EP 278 DI 10.1001/jama.282.3.271 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 217MW UT WOS:000081504400034 PM 10422997 ER PT J AU Beerheide, W Bernard, HU Tan, YJ Ganesan, A Rice, WG Ting, AE AF Beerheide, W Bernard, HU Tan, YJ Ganesan, A Rice, WG Ting, AE TI Potential drugs against cervical cancer: Zinc-ejecting inhibitors of the human papillomavirus type 16 E6 oncoprotein SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID NUCLEOCAPSID PROTEIN; MUTATIONAL ANALYSIS; IN-VITRO; HYBRID-CELLS; P53; BINDING; IDENTIFICATION; KERATINOCYTES; DEGRADATION; EXPRESSION AB Background: The principal agent in the etiology of cervical cancer, i.e., human papillomavirus (HPV) type 16, encodes three oncoproteins, E5, E6, and E7, Structural and mutational studies have identified two potential zinc-finger domains as critical for E6 protein function. We investigated several assays to identify and characterize compounds that interfere with the binding of zinc to E6, Methods: Thirty-six compounds were selected on the basis of their structure, which would facilitate their participation in sulfhydryl residue-specific redox reactions, and were tested for their ability to release zinc from E6 protein. The zinc-ejecting compounds were then tested for their ability to inhibit E6 binding to E6-associated protein (E6AP) and E6-binding protein (E6BP), two coactivators of E6-mediated cellular transformation, The binding of E6 to E6BP and E6AP was measured by use of surface plasmon resonance (a technique that monitors molecular interactions by measuring changes in refractive index) and by use of in vitro translation assays. The compounds were also tested for their effects on the viability of HPV-containing cell lines. Results: Nine of the 36 tested compounds ejected zinc from E6, Two of the nine compounds inhibited the interaction of E6 with E6AP and E6BP, and one of these two, 4,4'-dithiodimorpholine, selectively inhibited cell viability and induced higher levels of p53 protein (associated with the induction of apoptosis [programmed cell death]) in tumorigenic HPV-containing cells. Conclusion: We have described assay systems to identify compounds, such as 4,4'-dithiodimorpholine, that can potentially interfere with the biology and pathology of HPV, These assay systems may be useful in the development of drugs against cervical cancer, genital warts, and asymptomatic infections by genital HPVs. C1 Natl Univ Singapore, Inst Mol & Cell Biol, Screening Novel Inhibitors Lab, Singapore 117609, Singapore. Natl Univ Singapore, Inst Mol & Cell Biol, Papillomavirus Biol Lab, Singapore 117609, Singapore. Natl Univ Singapore, Inst Mol & Cell Biol, Med & Combinatorial Chem Lab, Singapore 117609, Singapore. NCI, Lab Antiviral Drug Mechanisms, Sci Applicat Int Corp, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. RP Bernard, HU (reprint author), Natl Univ Singapore, Inst Mol & Cell Biol, Screening Novel Inhibitors Lab, 30 Med Dr, Singapore 117609, Singapore. RI Ganesan, A/F-6698-2011; ASTAR, IMCB/E-2320-2012 NR 52 TC 51 Z9 54 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 JUL 21 PY 1999 VL 91 IS 14 BP 1211 EP 1220 DI 10.1093/jnci/91.14.1211 PG 10 WC Oncology SC Oncology GA 225FA UT WOS:000081946700011 PM 10413422 ER PT J AU Kaufman, DJ Struewing, J AF Kaufman, DJ Struewing, J TI Re: Effect of BRCA1 and BRCA2 on the association between breast cancer risk and family history SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 NCI, Lab Populat Genet, Bethesda, MD 20892 USA. RP Struewing, J (reprint author), NIH, 41 Lib Dr,Bldg 41-D702, Bethesda, MD 20892 USA. RI Struewing, Jeffery/C-3221-2008; Struewing, Jeffery/I-7502-2013 OI Struewing, Jeffery/0000-0002-4848-3334 NR 5 TC 5 Z9 5 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 JUL 21 PY 1999 VL 91 IS 14 BP 1250 EP 1251 DI 10.1093/jnci/91.14.1250 PG 2 WC Oncology SC Oncology GA 225FA UT WOS:000081946700016 PM 10413427 ER PT J AU Malling, HV Newbold, RR Lewis, S Barnett, L Weaver, RP AF Malling, HV Newbold, RR Lewis, S Barnett, L Weaver, RP TI Mutagenesis of a single AT basepair in mice transgenic for PhiX174 am3, cs70 II. Brain SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE PhiX174; transgenic; mice; ENU; brain ID ETHYL-N-NITROSOUREA; ETHYLNITROSOUREA; MOUSE; DNA; MUTATIONS; SPECTRUM; PHI-X174; STRAIN; TUMORS; CELLS AB Most cell divisions in the mouse brain have ceased by 14 days after birth. Therefore, spontaneous mutations that occur in brain cells can be assumed to be fixed by replication during brain development. Spontaneous and ethylnitrosourea (ENU)-induced reverse mutations at a single AT base pair were measured in brain tissue by using mice transgenic for PhiX174 am3, cs70. The line (am54) has 50 PhiX genomes per haploid genome integrated in a tandem array and is maintained by random breeding on a C57BL/6 background. For mutagenesis studies, homozygous am54 males were mated to non-transgenic C57BL6/J females. Four-day old offspring from this cross were treated with 50 mg/kg ENU and were euthanized at 68-80 days of age. The ENU-treated animals had a significantly higher frequency of am3 revertants in brain than did concurrent controls. In a second experiment, hemizygous male offspring (85 to 94 days old) were treated with 150 mg/kg ENU and euthanized at various post-injection intervals (3, 10 and 110 days). The revertant frequencies 3 and 10 days after treatment were not significantly different from control values. At the 110 days post-injection interval, however, the average revertant frequency in the treated group was significantly lower than controls. In a second study animals were euthanized 3, 10 and 74 days after treatment. Two groups (3 and 74 days post-injection) also showed a significant decrease in the revertant frequency as compared to controls. Additional sets of adult animals were treated with 50 and 150 mg/kg ENU and were euthanized 195 to 201 days after treatment. The average revertant frequency of the animals that were treated with 50 or 150 mg/kg ENU was not significantly different from the control value. Thus, although an increase in mutant frequency is detected in the PhiX174 system when neonatal mice are treated with ENU, treatment of mature mice with ENU did not result in an increase in the mutant frequency. Moreover, under certain conditions, ENU-produced a significantly lower mutant frequency than was observed in the control animals. This decrease in the revertant frequency among the treated animals was Likely due to selective killing of cells with a higher spontaneous revertant frequency than cells with lower frequency. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIEHS, Mammalian Mutagenesis Grp, Toxicol Lab, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. NIEHS, Dev Endocrinol Sect, Reprod Toxicol Grp, Toxicol Lab,Environm Technol Program, Res Triangle Pk, NC 27709 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Res Triangle Inst, Ctr Life Sci & Toxicol, Res Triangle Pk, NC 27709 USA. RP Malling, HV (reprint author), NIEHS, Mammalian Mutagenesis Grp, Toxicol Lab, Environm Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. NR 19 TC 6 Z9 6 U1 0 U2 0 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 JUL 21 PY 1999 VL 444 IS 1 BP 85 EP 95 DI 10.1016/S1383-5718(99)00088-1 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 224PQ UT WOS:000081907800009 PM 10477342 ER PT J AU Donohue, PJ Sainz, E Akeson, M Kroog, GS Mantey, SA Battey, JF Jensen, RT Northup, JK AF Donohue, PJ Sainz, E Akeson, M Kroog, GS Mantey, SA Battey, JF Jensen, RT Northup, JK TI An aspartate residue at the extracellular boundary of TMII and an arginine residue in TMVII of the gastrin-releasing peptide receptor interact to facilitate heterotrimeric G protein coupling SO BIOCHEMISTRY LA English DT Article ID NEUROMEDIN-B RECEPTOR; BOMBESIN RECEPTOR; HIGH-AFFINITY; ALPHA(1B)-ADRENERGIC RECEPTOR; SIGNAL-TRANSDUCTION; MOLECULAR-CLONING; HORMONE RECEPTOR; AMINO-ACIDS; KINASE-C; ACTIVATION AB The mammalian bombesin receptor subfamily of G protein-coupled receptors currently consists of the gastrin-releasing peptide receptor (GRP-R), neuromedin B receptor, and bombesin receptor subtype 3. All three receptors contain a conserved aspartate residue (D98) at the extracellular boundary of transmembrane domain II and a conserved arginine residue (R309) near the extracellular boundary of transmembrane domain VII. To evaluate the functional role of these residues, site-directed GRP-R mutants were expressed in fibroblasts and assayed for their ability to both bind agonist and catalyze exchange of guanine nucleotides. Alanine substitution at GRP-R position 98 or 309 reduced agonist binding affinity by 24- and 56-fold, respectively, compared to wild-type GRP-R. Single swap GRP-R mutations either resulted in no receptor expression in the membrane (D98R) or the protein was not able to bind agonist (R309D). In contrast, the double swap mutation (D98R/R309D) had high-affinity agonist binding, reduced from wild-type GRP-R by only 6-fold. In situ reconstitution of urea-extracted membranes expressing either wild-type or mutant (D98A or R309A) GRP-R with G(q) indicated that alanine substitution greatly reduced G protein catalytic exchange compared to wild-type GRP-R. The D98R/R309D GRP-R had both a higher intrinsic basal activity and a higher overall catalytic exchange activity compared to wild-type; however, the wild-type GRP-R produced a larger agonist stimulated response relative to the double swap mutant. Taken together, these data show that GRP-R residues D98 and R309 are critical for efficient coupling of GRP-R to G(q). Furthermore, our findings are consistent with a salt bridge interaction between these two polar and oppositely charged amino acids that maintains the proper receptor conformation necessary to interact with G proteins. C1 NIDODS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NIDODS, Lab Cellular Biol, NIH, Bethesda, MD 20892 USA. NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Battey, JF (reprint author), NIDODS, Mol Biol Lab, NIH, Bldg 31,Room 3C02,9000 Rockville Pike, Bethesda, MD 20892 USA. FU NIDCD NIH HHS [IRP ZO1-DC-00028-02] NR 37 TC 13 Z9 13 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 JUL 20 PY 1999 VL 38 IS 29 BP 9366 EP 9372 DI 10.1021/bi990544h PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 219PQ UT WOS:000081616000020 PM 10413511 ER PT J AU Rivas, G Fernandez, JA Minton, AP AF Rivas, G Fernandez, JA Minton, AP TI Direct observation of the self-association of dilute proteins in the presence of inert macromolecules at high concentration via tracer sedimentation equilibrium: Theory, experiment, and biological significance SO BIOCHEMISTRY LA English DT Article ID BOVINE SERUM-ALBUMIN; ARBITRARY CONCENTRATION; VOLUME-EXCLUSION; TUBULIN; FIBRINOGEN; BINDING; THERMODYNAMICS; CONSEQUENCES; ANTAGONISTS; NONIDEALITY AB The technique of tracer sedimentation equilibrium [Rivas, G., et al. (1994) Biochemistry, 2341-2348 (1); Rivas, G., et al. (1996) J. Mol. Recognit. 9, 31-38 (2)] is utilized, together with an extension of the theory of sedimentation equilibrium of highly nonideal solutions [Chatelier and Minton, (1987) Biopolymers 26, 1097-1113 (3)], to characterize the thermodynamic activity and/or the state of association of a dilute, labeled macromolecular solute in the presence of an arbitary concentration of a second, unlabeled macromolecular solute. Experiments are performed on solutions of labeled fibrinogen (0.25-1 g/L) in bovine serum albumin (0-100 g/L) in the presence and absence of divalent cations (Ca2+, Mg2+), and on solutions of labeled tubulin (0.2-0.6 g/L) in dextran (0-100 g/L). It is found that in the absence of the divalent cations, the large dependence of the thermodynamic activity of fibrinogen on BSA concentration is well accounted for by a simple model for steric repulsion. In the presence of the cations and sufficiently large concentrations of BSA (>30 g/L), fibrinogen appears to self-associate to a weight-average molar mass approximately twice that of monomeric fibrinogen. Tubulin appears to self-associate to an extent that increases monotonically with increasing dextran concentration, reaching a weight average molar mass almost 3 times that of the alpha beta dimer in the presence of 100 g/L dextran. Possible biological ramifications are discussed. C1 CSIC, Ctr Invest Biol, E-28006 Madrid, Spain. NIDDKD, NIH, Bethesda, MD 20892 USA. RP CSIC, Ctr Invest Biol, Velazquez 144, E-28006 Madrid, Spain. OI Rivas, German/0000-0003-3450-7478 NR 56 TC 116 Z9 120 U1 1 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 20 PY 1999 VL 38 IS 29 BP 9379 EP 9388 DI 10.1021/bi990355z PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 219PQ UT WOS:000081616000022 PM 10413513 ER PT J AU Huhn, RD Tisdale, JF Agricola, B Metzger, ME Donahue, RE Dunbar, CE AF Huhn, RD Tisdale, JF Agricola, B Metzger, ME Donahue, RE Dunbar, CE TI Retroviral marking and transplantation of rhesus hematopoietic cells by nonmyeloablative conditioning SO HUMAN GENE THERAPY LA English DT Article ID COLONY-STIMULATING FACTOR; IMMUNE-DEFICIENT MICE; BLOOD CD34(+) CELLS; CHRONIC GRANULOMATOUS-DISEASE; LONG-TERM HEMATOPOIESIS; EX-VIVO EXPANSION; PERIPHERAL-BLOOD; STEM-CELLS; GENE-TRANSFER; BONE-MARROW AB The ability to engraft significant numbers of genetically modified hematopoietic stem and progenitor cells without the requirement for fully myeloablative conditioning therapy is a highly desirable goal for the treatment of many nonmalignant hematologic disorders. The aims of this study were to examine, in nonhuman primates (rhesus), (I) the effects of pretreatment of host animals; with cytokines (G-CSF and SCF), i.e., before nonmyeloablative irradiation, on the degree and duration of neo gene marking of circulating leukocytes after autologous cell reinfusion and (2) to compare transduction of primitive hematopoietic target cells in the presence of our standard transduction cytokine combination of IL-3, IL-6, and stem cell factor (SCF) and in the presence of an alternative combination containing SCF, G-CSF, and the thrombopoietin analog MGDF. Cytokine-mobilized rhesus peripheral blood progenitor/stem cells (PBSCs) were enriched for CD34(+) cells and transduced with neo vectors (either G1Na or LNLB) for 96 hr in cultures containing rhIL-3, rhIL-6, and rhSCF or MGDF, rhSCF, and rhG-CSF and cryopreserved. Four animals underwent minimal myeloablative conditioning with 500 cGy irradiation with or without pretreatment with SCF and G-CSF, followed by reinfusion of the cryopreserved cells on the subsequent day. Neutrophil nadirs (less than or equal to 500/mm(3)) were 0-3 days in duration; there were no significant periods of severe thrombocytopenia. Marking of circulating granulocytes and mononuclear cells was extensive and durable in all animals (exceeding 12% in the mononuclear cells of one animal) and persisted beyond the final sampling time in all animals (up to 33 weeks). No difference in extent or duration of marking was attributable to either cytokine presensitization of recipients prior to irradiation, or to the substitution of MDGF and G-CSF for IL-3 and IL-6 during transduction. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Dunbar, CE (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Room 7C103,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 41 TC 62 Z9 64 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD JUL 20 PY 1999 VL 10 IS 11 BP 1783 EP 1790 DI 10.1089/10430349950017464 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 221XZ UT WOS:000081754100006 PM 10446918 ER PT J AU Takeuchi, Y Liu, ZP Suzuki, E Shibata, N Kirk, KL AF Takeuchi, Y Liu, ZP Suzuki, E Shibata, N Kirk, KL TI N-fluoro-3-ethyl-3-methyl-1,1-dioxo-2,3-dihydro-1H-1 lambda(6)-benzo[e]1,2-thiazin-4-one, a new and efficient agent for electrophilic fluorination of carbanions SO JOURNAL OF FLUORINE CHEMISTRY LA English DT Article DE N-fluorosultams; electrophilic fluorination; alpha-fluoroketones ID ENANTIOSELECTIVE FLUORINATION; ASYMMETRIC FLUORINATION; ELEMENTAL FLUORINE; REAGENTS; F-TEDA-BF4; SALTS AB N-Fluoro-3-ethyl-3-methyl-1,1-dioxo-2,3-dihydro-1H-1 lambda(6)-benzo[e]1,2-thiazin-4-one (1) was prepared in good yield by fluorination of the corresponding sultam (3) with FClO3. The sultam (3) was prepared from saccharin (2) in 3 steps. The N-fluorosultam (1), a very stable crystalline solid, was found to fluorinate carbanions readily in good to excellent yields. (C) 1999 Elsevier Science S.A. All rights reserved. C1 Toyama Med & Pharmaceut Univ, Fac Pharmaceut Sci, Toyama 9300194, Japan. NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Takeuchi, Y (reprint author), Toyama Med & Pharmaceut Univ, Fac Pharmaceut Sci, Sugitani 2630, Toyama 9300194, Japan. NR 26 TC 19 Z9 19 U1 0 U2 1 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 0022-1139 J9 J FLUORINE CHEM JI J. Fluor. Chem. PD JUL 20 PY 1999 VL 97 IS 1-2 BP 65 EP 67 DI 10.1016/S0022-1139(99)00028-7 PG 3 WC Chemistry, Inorganic & Nuclear; Chemistry, Organic SC Chemistry GA 216AH UT WOS:000081417900008 ER PT J AU Hayakawa, Y Singh, M Shibata, N Takeuchi, Y Kirk, KL AF Hayakawa, Y Singh, M Shibata, N Takeuchi, Y Kirk, KL TI Regioselective electrophilic fluorination of indoles: syntheses of 4-fluoroserotonin and 4-fluoromelatonin SO JOURNAL OF FLUORINE CHEMISTRY LA English DT Article DE serotonin; melatonin; electrophilic fluorination ID HUMAN-PLATELETS; 1-TRIISOPROPYLSILYLGRAMINE AB Reaction of N-triisopropylsilyl-5-methoxygramine with t-butyllithium produces the 4-lithio derivative. Electrophilic fluorination with N-fluorobenzenesulfonimide (NFSi) followed by deprotection and side-chain elaboration provide convenient syntheses of 4-fluoroserotonin and 4-fluoromelatonin, new analogs of these important neurochemicals. (C) 1999 Elsevier Science S.A. All rights reserved. C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Toyama Med & Pharmaceut Univ, Fac Pharmaceut Sci, Toyama 9300194, Japan. RP Kirk, KL (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NR 12 TC 10 Z9 10 U1 0 U2 2 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 0022-1139 J9 J FLUORINE CHEM JI J. Fluor. Chem. PD JUL 20 PY 1999 VL 97 IS 1-2 BP 161 EP 164 DI 10.1016/S0022-1139(99)00044-5 PG 4 WC Chemistry, Inorganic & Nuclear; Chemistry, Organic SC Chemistry GA 216AH UT WOS:000081417900023 ER PT J AU Richter, F Huang, HFS Li, MT Danielpour, D Wang, SL Irwin, RJ AF Richter, F Huang, HFS Li, MT Danielpour, D Wang, SL Irwin, RJ TI Retinoid and androgen regulation of cell growth, epidermal growth factor and retinoic acid receptors in normal and carcinoma rat prostate cells SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE androgens; EGF-R; prostate cancer; retinoic acid receptor ID EPITHELIAL-CELLS; CANCER CELLS; EXPRESSION; PROLIFERATION; DIFFERENTIATION; LINES; ALPHA; GAMMA; RNA; D-3 AB Recent in vivo and in vitro studies suggest that retinoic acid receptor (RAR)-mediated processes may be involved in androgen regulation of prostate cells in a manner that may be altered during prostatic carcinogenesis. We tested this hypothesis in the newly established carcinoma and non-carcinoma rat prostate epithelial cell lines, NRP-154 and NRP-152, respectively. In DMEM/F-12 medium supplemented with 10% charcoal stripped fetal calf serum (cFCS), the number of both NRP-152 and NRP-154 cells were stimulated by testosterone (T), with a 4-fold greater effect in NRP-152 than in NRP-154 cells. Retinoic acid (RA) alone also stimulated the growth of NRP-152 cells, but failed to induce cell growth of NRP-154 cells. Importantly, the level of RAR alpha mRNA was elevated whereas the levels of RAR gamma and androgen receptor (AR) mRNA were lower in NRP-154 cells compared to those in NRP-152 cells. Treatment of NRP-152 cells with increasing doses of T resulted in a dose-dependent decrease and rebound of the level of RAR alpha and gamma mRNA in NRP-152 cells, these effects were not apparent, if not reversed, in NRP-154 cells. Both ligand binding and Western blot analyses revealed that epidermal,growth factor receptor (EGF-R) was stimulated by 20 nM T but was suppressed by 0.1 mu M RA, which also attenuated the stimulating effects of T on EGF-R in NRP-152 and to a lesser extent in NRP-154 cells. The differences in the level and androgen regulation of RAR mRNAs and reciprocal regulation of EGF-R expression by T and RA between NRP-154 and NRP-152 cells suggest that variations in the EGF-R and RAR signal events may contribute to differences in growth rate between these two cell lines. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Urol Sect, Newark, NJ 07103 USA. Univ Med & Dent New Jersey, New Jersey Dent Sch, Newark, NJ 07103 USA. VA Med Ctr, E Orange, NJ 07019 USA. NCI, Chemoprevent Lab, Bethesda, MD 20892 USA. RP Huang, HFS (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Urol Sect, 185 S Orange Ave,MSB G-506, Newark, NJ 07103 USA. NR 39 TC 19 Z9 19 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JUL 20 PY 1999 VL 153 IS 1-2 BP 29 EP 38 DI 10.1016/S0303-7207(99)00095-7 PG 10 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 217HX UT WOS:000081494900004 PM 10459851 ER PT J AU Wickner, S Maurizi, MR AF Wickner, S Maurizi, MR TI Here's the hook: Similar substrate binding sites in the chaperone domains of Clp and Lon SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID HEAT-SHOCK PROTEIN; N-END RULE; ESCHERICHIA-COLI; DEPENDENT PROTEASES; MOLECULAR CHAPERONE; TAGGING SYSTEM; MU-TRANSPOSASE; DEGRADATION; PDZ; PROTEOLYSIS C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wickner, S (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37,Room 2D19,37 Convent DR,MSC37-4255, Bethesda, MD 20892 USA. NR 32 TC 23 Z9 23 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 JUL 20 PY 1999 VL 96 IS 15 BP 8318 EP 8320 DI 10.1073/pnas.96.15.8318 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219CB UT WOS:000081589400004 PM 10411867 ER PT J AU Anfinrud, P de Vivie-Riedle, R Engel, V AF Anfinrud, P de Vivie-Riedle, R Engel, V TI Ultrafast detection and control of molecular dynamics SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article; Proceedings Paper CT 4th Annual German-American Frontiers of Science Symposium CY JUN 04-06, 1998 CL IRVINE, CALIFORNIA ID ELECTRON-DIFFRACTION; DOCKING SITE; HEME POCKET; MYOGLOBIN; CO AB Many elementary chemical and physical processes such as the breaking of a chemical bond or the vibrational motion of atoms within a molecule take place on a femtosecond (fs = 10(-15) s) or picosecond (ps = 10(-12) s) time scale. It is now possible to monitor these events as a function of time with temporal resolution well below 100 fs. This capability is based on the pump-probe technique where one optical pulse triggers a reaction and a second delayed optical pulse probes the changes that ensue. To illustrate this capability, the dynamics of ligand motion within a protein are presented. Moving beyond casual observation of a reaction to active control of its outcome requires additional experimental and theoretical effort. To illustrate the concept of control, the effect of optical pulse duration on the vibrational dynamics of a tri-atomic molecule are discussed. The experimental and theoretical resources currently available are poised to make the dream of reaction control a reality for certain molecular systems. C1 NIDDKD, NIH, Chem Phys Lab, Bethesda, MD 20892 USA. Max Planck Inst Quantenopt, D-85740 Garching, Germany. Univ Wurzburg, Inst Phys Chem, D-97074 Wurzburg, Germany. RP Anfinrud, P (reprint author), NIDDKD, NIH, Chem Phys Lab, Bldg 5,Room 134, Bethesda, MD 20892 USA. NR 18 TC 21 Z9 21 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 JUL 20 PY 1999 VL 96 IS 15 BP 8328 EP 8329 DI 10.1073/pnas.96.15.8328 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219CB UT WOS:000081589400008 PM 10411871 ER PT J AU Chen, X Court, DL Ji, XH AF Chen, X Court, DL Ji, XH TI Crystal structure of ERA: A GTPase-dependent cell cycle regulator containing an RNA binding motif SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SIGNAL-RECOGNITION PARTICLE; ESCHERICHIA-COLI GTPASE; FRAGILE-X-SYNDROME; KH-DOMAIN; PROTEIN-BIOSYNTHESIS; DIFFRACTION DATA; GROWTH-RATE; GENE; MUTANT; MACROMOLECULES AB ERA forms a unique family of GTPase. It is widely conserved and essential in bacteria. ERI functions in cell cycle control by coupling cell division with growth rate, ERA homologues also are found in eukaryotes. Here we report the crystal structure of ERA from Escherichia coli. The structure has been determined at 2.4-Angstrom resolution. It reveals a tno domain arrangement of the molecule: an N-terminal domain that resembles p21 Ras and a C-terminal domain that is unique. Structure-based topological search of the C domain fails to reveal any meaningful match, although sequence analysis suggests that it contains a KH domain. KH domains are RNA binding motifs that usually occur in tandem repeats and exhibit low sequence similarity except for the well-conserved segment VIGxxGxxIK. We have identified a beta alpha alpha beta fold that contains the VIGxxGxxIK sequence and is shared by the C domain of ERA and the ECH domain. We propose that this beta alpha alpha beta fold is the RNA binding motif, the minimum structural requirement for RNA binding, ERA dimerizes in crystal. The dimer formation involves a significantly distorted switch II region, which may shed light on how ERA protein regulates downstream events. C1 NCI, Biomol Struct Grp, Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA. NCI, Mol Control & Genet Sect, Adv BioSci Labs,Basic Res Program, Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA. RP Ji, XH (reprint author), NCI, Biomol Struct Grp, Frederick Canc Res & Dev Ctr, POB B, Ft Detrick, MD 21702 USA. RI Ji, Xinhua/C-9664-2012 OI Ji, Xinhua/0000-0001-6942-1514 NR 49 TC 77 Z9 89 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 JUL 20 PY 1999 VL 96 IS 15 BP 8396 EP 8401 DI 10.1073/pnas.96.15.8396 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219CB UT WOS:000081589400023 PM 10411886 ER PT J AU Nemes, Z Marekov, LN Fesus, L Steinert, PM AF Nemes, Z Marekov, LN Fesus, L Steinert, PM TI A novel function for transglutaminase 1: Attachment of long-chain omega-hydroxyceramides to involucrin by ester bond formation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CORNIFIED CELL-ENVELOPE; CROSS-LINKED ENVELOPE; KERATINOCYTE TRANSGLUTAMINASE; PERMEABILITY BARRIER; LAMELLAR ICHTHYOSIS; EPIDERMAL-CELLS; STRATUM-CORNEUM; GENE; MUTATIONS; LINKING AB Transglutaminases (TGases) are defined as enzymes capable of forming isopeptide bonds by transfer of an amine onto glutaminyl residues of a protein. Here we show that the membrane-bound form of the TGase 1 enzyme can also form ester bonds between specific glutaminyl 1 residues of human involucrin and a synthetic analog of epidermal specific omega-hydroxyceramides. The formation of a approximate to 5-nm-thick lipid envelope on the surface of epidermal keratinocytes is an important component of normal barrier function. The lipid envelope consists of omega-hydroxyceramides covalently linked by ester bonds to cornified envelope proteins, most abundantly to involucrin, We synthesized an analog of natural omega-hydroxyceramides, N-[16-(16-hydroxyhexadecyl)oxypalmitoyl]-sphingosine (lipid Z). When recombinant human TGase 1 and involucrin were reacted on the surface of synthetic lipid vesicles containing lipid Z, lipid Z was attached to involucrin and formed saponifiable protein-lipid adducts. By mass spectroscopy and sequencing of tryptic lipopeptides, the ester linkage formation used involucrin glutamine residues 107, 118, 122, 133, and 496 by converting the gamma-carboxamido groups to lipid esters, Several of these residues have been found previously to be attached to ceramides in vivo. Mass spectrometric analysis after acetonide derivatization also revealed that ester formation involved primarily the omega-hydroxyl group of lipid Z. Our data reveal a dual role for TGase 1 in epidermal barrier formation and provide insights into the pathophysiology of lamellar ichthyosis resulting from defects of TGase 1 enzyme. C1 NIAMSD, Lab Skin Biol, NIH, Bethesda, MD 20892 USA. Univ Med Sch Debrecen, Dept Biochem & Mol Biol, H-4012 Debrecen, Hungary. RP Steinert, PM (reprint author), NIAMSD, Lab Skin Biol, NIH, Bldg 6,Room 425, Bethesda, MD 20892 USA. NR 45 TC 146 Z9 153 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 JUL 20 PY 1999 VL 96 IS 15 BP 8402 EP 8407 DI 10.1073/pnas.96.15.8402 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219CB UT WOS:000081589400024 PM 10411887 ER PT J AU Goldin, E Cooney, A Kaneski, CR Brady, RO Schiffmann, R AF Goldin, E Cooney, A Kaneski, CR Brady, RO Schiffmann, R TI Mucolipidosis IV consists of one complementation group SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID FIBROBLASTS; CHLOROQUINE; INHIBITION; MECHANISM AB Mucolipidosis IV (MLIV) is an autosomal recessive disorder of unknown etiology characterized by severe visual impairment and psychomotor retardation. Recently, there has been considerable interest in positional cloning of the MLIV gene. It is unknown whether MLIV is a genetically homogenous disorder. In this paper, we present experiments that determined whether the MLIV phenotype in fibroblasts could be corrected by fusing normal cells to MLIV cells and fusing fibroblasts from pairs of patients. All of our MLIV patients fulfilled several diagnostic criteria that He developed. In addition, we found high sensitivity to chloroquine in cultured fibroblasts from MLIV patients. We found that normal cells corrected the MLIV phenotype. Fusion products of normal and MLIV fibroblasts, but not MLIV fibroblasts themselves, were relatively protected against chloroquine selection. In addition, 74% of the normal-to-patient fusion products had reduced levels or total loss of MLIV characteristic autofluorescence. However, there,vas no complementation of the phenotype in fibroblast cultures from any of our MLIV patients, including those of non-Jewish ancestry, In fusion products of MLIV cultures from 24 patients, 90-100% of the cells remained autofluorescent, These results indicate that all of our known MLIV patients, regardless of ancestry or severity of the developmental defect, have a single mutated gene. C1 Natl Inst Neurol Disorders & Stroke, NIH, Dev Metab Neurol Branch, Bethesda, MD 20892 USA. RP Natl Inst Neurol Disorders & Stroke, NIH, Dev Metab Neurol Branch, Bldg 10,Room 3D04,10 Hlth Ctr Dr MSC1260, Bethesda, MD 20892 USA. EM goldin@codon.nih.gov OI Kaneski, Christine/0000-0003-1453-2502 NR 19 TC 22 Z9 23 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 JUL 20 PY 1999 VL 96 IS 15 BP 8562 EP 8566 DI 10.1073/pnas.96.15.8562 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219CB UT WOS:000081589400052 PM 10411915 ER PT J AU Wofsy, C Vonakis, BM Metzger, H Goldstein, B AF Wofsy, C Vonakis, BM Metzger, H Goldstein, B TI One Lyn molecule is sufficient to initiate phosphorylation of aggregated high-affinity IgE receptors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PROTEIN-TYROSINE KINASE; BASOPHILIC LEUKEMIA-CELLS; MEDIATED SIGNAL-TRANSDUCTION; IMMUNOGLOBULIN-E RECEPTOR; EPIDERMAL GROWTH-FACTOR; ACTIVATION MOTIFS; MEMBRANE DOMAINS; ANTIGEN RECEPTOR; LIVING CELLS; SYK AB In response to antigenic stimuli, the multi-subunit immune recognition receptors become aggregated and then phosphorylated on their cytoplasmic tyrosines, For the clonotypic receptors of B and T cells and for Fc receptors such as the high-affinity receptor for IgE (Fc epsilon RI), a Src family kinase initiates this phosphorylation. We ask whether aggregation of the initiating kinase itself is required for signal transduction or whether, alternatively, a single associated kinase molecule can phosphorylate the receptors in an aggregate. We formulate the alternative molecular mechanisms mathematically and compare predictions with experimental findings on Fc epsilon RI-bearing cells expressing varying amounts of the transfected Src family kinase Lyn. The data are consistent with the requirement of only a single Lyn molecule per Fc epsilon RI aggregate to initiate signaling and are inconsistent with a mechanism requiring more than one Lyn molecule. C1 NIAMSD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. Univ Calif Los Alamos Natl Lab, Theoret Biol & Biophys Grp, Div Theoret, Los Alamos, NM 87545 USA. Univ New Mexico, Dept Math & Stat, Albuquerque, NM 87131 USA. RP Metzger, H (reprint author), NIAMSD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. FU NIGMS NIH HHS [GM35556, R37 GM035556, R01 GM035556] NR 42 TC 28 Z9 28 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 JUL 20 PY 1999 VL 96 IS 15 BP 8615 EP 8620 DI 10.1073/pnas.96.15.8615 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219CB UT WOS:000081589400061 PM 10411924 ER PT J AU Yoshimura, K Kato, R Yusa, K Kavlick, MF Maroun, V Nguyen, A Mimoto, T Ueno, T Shintani, M Falloon, J Masur, H Hayashi, H Erickson, J Mitsuya, H AF Yoshimura, K Kato, R Yusa, K Kavlick, MF Maroun, V Nguyen, A Mimoto, T Ueno, T Shintani, M Falloon, J Masur, H Hayashi, H Erickson, J Mitsuya, H TI JE-2147: A dipeptide protease inhibitor (PI) that potently inhibits multi-PI-resistant HIV-1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; VARIANTS RESISTANT; THERAPY; SELECTION; MUTATIONS; GENE; ALLOPHENYLNORSTATINE; SENSITIVITY; EMERGENCE; PATTERNS AB We designed, synthesized, and identified JE-2147, an allophenylnorstatine-containing dipeptide HIV protease inhibitor (PI), which is potent against a wide spectrum of HIV-1, HIV-2, simian immunodeficiency virus, and various clinical HIV-1 strains in vitro. Drug-resistant clinical HIV-1 strains, isolated from seven patients who had failed 9-11 different anti-HIV therapeutics after 32-83 months, had a variety of drug-resistance-related amino acid substitutions and were highly and invariably resistant to all of the currently available anti-HIV agents. JE-2147 was, however, extremely potent against all such drug-resistant strains, with IC50 values ranging from 13-41 nM (<2-fold changes in IC50 compared with that of wild-type HIV-1). The emergence of JE-2147-resistant HIV-1 variants in vitro was substantially delayed compared with that of HIV-1 resistant to another allophenylnorstatine-containing compound, KNI-272, and other related PIs. Structural analysis revealed that the presence of a flexible P2' moiety is important for the potency of JE-2147 toward wild-type and mutant viruses. These data suggest that the use of flexible components may open a new avenue for designing PIs that resist the emergence of PI-resistant HIV-1. Further development of JE-2147 for treating patients harboring multi-PI-resistant HIV-1 is warranted. C1 NCI, Expt Retrovirol Sect, Med Branch, Div Clin Sci,NIH, Bethesda, MD 20892 USA. NIH, Crit Care Med Dept, Ctr Clin, Bethesda, MD 20892 USA. NCI, Struct Biochem Program, Sci Applicat Int Corp, Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA. NCI, HIV Clin Interface Lab,Dev Therapeut Program, Sci Applicat Int Corp, Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA. Japan Energy Corp, Pharmaceut & Biotechnol Lab, Toda, Saitama 335, Japan. Kumamoto Univ, Sch Med, Dept Internal Med 2, Kumamoto 860, Japan. RP Mitsuya, H (reprint author), NCI, Expt Retrovirol Sect, Med Branch, Div Clin Sci,NIH, Bldg 10,Room 5A11, Bethesda, MD 20892 USA. RI Ueno, Takamasa/F-5788-2013 OI Ueno, Takamasa/0000-0003-4852-4236 NR 24 TC 89 Z9 91 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 JUL 20 PY 1999 VL 96 IS 15 BP 8675 EP 8680 DI 10.1073/pnas.96.15.8675 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219CB UT WOS:000081589400071 PM 10411934 ER PT J AU Nunoi, H Yamazaki, T Tsuchiya, H Kato, S Malech, HL Matsuda, I Kanegasaki, S AF Nunoi, H Yamazaki, T Tsuchiya, H Kato, S Malech, HL Matsuda, I Kanegasaki, S TI A heterozygous mutation of beta-actin associated with neutrophil dysfunction and recurrent infection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; OXIDASE COMPONENTS; PROFILIN; PROTEINS; GENE; ELECTROPHORESIS; CYTOSKELETAL; DEFICIENCY; ATP AB A human disorder caused by mutation in nonmuscle actin has not been reported. We report here a variant of nonmuscle actin in a female patient with recurrent infections, photosensitivity, and mental retardation. She also had abnormalities in neutrophil chemotaxis, superoxide production, and membrane potential response. Two-dimensional PAGE analysis of proteins from neutrophils and other cell types from this patient demonstrated a unique protein spot migrating at 42 kDa with pI shifted slightly to neutral relative to normal beta- and gamma-actin. Digestion peptide mapping and Western blotting showed this spot to be an abnormal actin. A full-length cDNA library was constructed by using mRNA from patient's cells and cDNA encoding the mutant beta-actin molecule was identified by an in vitro translation method. Sequencing of the clones demonstrated a G-1174 to A substitution, predicting a glutamic acid-364 to lysine substitution in beta-actin and eliminating a HinfI DNase restriction site found in normal beta-actin sequence. By HinfI digestion and by sequencing, the mutation in one allele of patient's genomic DNA was confirmed. Though no defect in cell-free polymerization of actin was detected, this defect lies in a domain important for binding to profilin and other actin-regulatory molecules. In fact, the mutant actin bound to profilin less efficiently than normal actin did. Heterozygous expression of mutant beta-actin in neutrophils and other cells of this patient may act in a dominant-negative fashion to adversely affect cellular activities dependent on the function of nonmuscle actin. C1 Univ Tokyo, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan. Kumamoto Univ, Sch Med, Dept Pediat, Kumamoto 8608556, Japan. Sagami Chem Res Ctr, Sagamihara, Kanagawa 2290012, Japan. NIAID, NIH, Bethesda, MD 20892 USA. RP Nunoi, H (reprint author), Kumamoto Univ, Sch Med, Dept Pediat, 1-1-1 Honjo, Kumamoto 8608556, Japan. NR 32 TC 46 Z9 49 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 JUL 20 PY 1999 VL 96 IS 15 BP 8693 EP 8698 DI 10.1073/pnas.96.15.8693 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219CB UT WOS:000081589400074 PM 10411937 ER PT J AU Chalecka-Franaszek, E Chuang, DM AF Chalecka-Franaszek, E Chuang, DM TI Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GLYCOGEN-SYNTHASE KINASE-3; METHYL-D-ASPARTATE; CEREBELLAR GRANULE NEURONS; PHOSPHATIDYLINOSITOL 3-KINASE; GROWTH-FACTOR; INSULIN; PHOSPHORYLATION; APOPTOSIS; SURVIVAL; DEATH AB This report describes a modulatory action of lithium and glutamate on the activity of serine/threonine kinase Akt-1, Lithium is most commonly used to treat bipolar disorder, but the mechanism of its therapeutic action remains unknown, We have recently demonstrated that lithium protects against glutamate-induced excitotoxicity in cultured brain neurons and in an animal model of cerebral ischemia, This study was undertaken to investigate the role of Akt-1, activated by the phosphatidylinositol 3-kinase (PI 3-K) signaling pathway, in mediating glutamate excitotoxicity and lithium protection in cerebellar granule cells. High levels of phosphorylation and activity of Akt-1 were detected in cerebellar neurons;cultured in the presence of serum. Protracted treatment with selective PI 3-K inhibitors, wortmannin and LY294002, abolished Akt-1 activity and induced neuronal death that could be reduced by long-term lithium pretreatment, Exposure of cells to glutamate induced a rapid and reversible loss of Akt-1 phosphorylation and kinase activity, These effects were closely correlated with excitotoxicity and caspase 3 activation and were prevented by phosphatase inhibitors, okadaic acid and caliculin A, Long-term lithium pretreatment suppressed glutamate-induced loss of Akt-1 activity and accelerated its recovery toward the control levels. Lithium treatment alone induced rapid increase in PI 3-K activity, and Akt-1 phosphorylation with accompanying kinase activation, which was blocked by PI 3-K inhibitors. Lithium also increased the phosphorylation of glycogen synthase kinase-3 (GSK-3), a downstream physiological target of Akt, Thus, modulation of Akt-1 activity appears to play a key role in the mechanism of glutamate excitotoxicity and lithium neuroprotection. C1 NIMH, NIH, Biol Psychiat Branch, Mol Neurobiol Sect, Bethesda, MD 20892 USA. RP Chuang, DM (reprint author), NIMH, NIH, Biol Psychiat Branch, Mol Neurobiol Sect, Bethesda, MD 20892 USA. NR 36 TC 333 Z9 339 U1 1 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 20 PY 1999 VL 96 IS 15 BP 8745 EP 8750 DI 10.1073/pnas.96.15.8745 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219CB UT WOS:000081589400083 ER PT J AU Skiadopoulos, MH Surman, SR St Claire, M Elkins, WR Collins, PL Murphy, BR AF Skiadopoulos, MH Surman, SR St Claire, M Elkins, WR Collins, PL Murphy, BR TI Attenuation of the recombinant human parainfluenza virus type 3 cp45 candidate vaccine virus is augmented by importation of the respiratory syncytial virus cpts530 L polymerase mutation SO VIROLOGY LA English DT Article ID TEMPERATURE-SENSITIVE MUTANTS; STRAND RNA VIRUSES; SENDAI-VIRUS; L-PROTEIN; HEMAGGLUTININ-NEURAMINIDASE; SERONEGATIVE CHIMPANZEES; GENE-EXPRESSION; CELL-CULTURE; C-PROTEINS; V-PROTEIN AB A phenylalanine to leucine mutation at position 521 in the L polymerase of cpts530, a live-attenuated respiratory syncytial virus (RSV) cold-passaged (cp), temperature-sensitive (ts) candidate vaccine, specifies the ts and attenuation (att) phenotypes. Sequence alignment of this region in the L proteins of several distantly related paramyxoviruses revealed that this phenylalanine is conserved. Using reverse genetics, the analogous phenylalanine at position 456 in the L protein of wild-type PIV3 was mutagenized to leucine (F456L). The resulting virus, designated r456(L), was ts (40 degrees C shut-off temperature of plaque formation), and its replication in the upper, but not the lower, respiratory tract of hamsters was 10-Told reduced compared with that of the recombinant wild-type PIV3 (Mrt). Thus the phenylalanine to leucine mutation specified a similar level of temperature sensitivity and attenuation in two distantly related paramyxoviruses. We next sought to determine whether the addition of this mutation to the L protein of two rPIV3 candidate vaccine viruses, one bearing the three cp45 ts missense mutations in the L protein (rcp45(L)) and the other bearing all 15 cp45 mutations (rcp45), would further attenuate the viruses in viva. Each rcp45 derivative to which the F456L mutation was added exhibited an increased level of temperature sensitivity. Furthermore rcp45(L)-456 and rcp45-456 were 100- to 1000-fold more restricted in replication in hamsters than their rcp45, and rcp45 parents. Despite the high level of restriction of replication in hamsters, immunization with rcp45-456 induced a moderate level of resistance to replication of PIV3 challenge virus. In contrast to the highly restricted replication observed in hamsters, rcp45-456 was only fivefold more restricted in the respiratory tract of chimpanzees than rcp45 and induced a comparable, moderate to high level of PIV3-specific serum antibodies, rcp45 and rcp45-456 viruses isolated from chimpanzees throughout the 2-week course of replication maintained the level of temperature sensitivity of their respective input viruses, illustrating their phenotypic stability. Thus the acquisition of the F456L mutation by the cp45 virus resulted in a small, incremental increase in its level of attenuation, indicating its possible usefulness in the fine tuning of the level of attenuation of the cp45 vaccine candidate. The ability to transfer mutations identified in heterologous paramyxoviruses, which in this case represent different subfamilies, greatly enhances our ability to rapidly develop novel parainfluenza virus candidate vaccines. (C) 1999 Academic Press. C1 NIAID, Resp Viruses Sect, NIH, Bethesda, MD 20892 USA. NIAID, Expt Primate Virol Sect, Infect Dis Lab, Bethesda, MD 20892 USA. BIOQUAL Inc, Rockville, MD 20850 USA. RP Skiadopoulos, MH (reprint author), NIAID, Resp Viruses Sect, NIH, Bldg 7,Rm 100,7 Ctr Dr,MSC 0720, Bethesda, MD 20892 USA. NR 42 TC 28 Z9 28 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 JUL 20 PY 1999 VL 260 IS 1 BP 125 EP 135 DI 10.1006/viro.1999.9802 PG 11 WC Virology SC Virology GA 220XK UT WOS:000081693600015 PM 10405364 ER PT J AU Fernandes, AM Hamburger, AW Gerwin, BI AF Fernandes, AM Hamburger, AW Gerwin, BI TI Production of epidermal growth factor related ligands in tumorigenic and benign human lung epithelial cells SO CANCER LETTERS LA English DT Article DE epidermal growth factor; human lung epithelial cells; transforming growth factor alpha ID FACTOR-RELATED PEPTIDES; FACTOR RECEPTOR; SIGNAL-TRANSDUCTION; BETACELLULIN; EXPRESSION; OVEREXPRESSION; HEREGULIN; DISTINCT; ERBB2 AB We recently demonstrated that human lung epithelial cells, overexpressing ErbB-2, formed tumors in nude mice only when high levels of transforming growth factor alpha (TGF alpha) were produced. Cells transfected with a TGF alpha antisense vector failed to form tumors in nude mice. In order to further evaluate the importance, for tumorigenicity, of TGF alpha and its stimulation of ErbB family signalling, the production of other EGF family growth factors by these human lung epithelial cells was studied. We demonstrate for the first time that both tumorigenic and non-tumorigenic human lung epithelial cells produced, in addition to TGF alpha, amphiregulin, betacellulin, heparin-binding EGF and heregulin. These data suggest that human lung epithelial cells have the potential for multifactorial modulation of ErbB receptor family signalling through control of Ligand as well as receptor production. In this system, the probable importance of TGF alpha-stimulated signaling for tumorigenicity is supported by its 13-fold higher production in tumorigenic as compared with non-tumorigenic cells and the 2-fold or lower differences observed in production of the other epidermal growth factor (EGF) family ligands. (C) 1999 Published by Elsevier Science Ireland Ltd. All rights reserved. C1 NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. RP Gerwin, BI (reprint author), NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. FU NCI NIH HHS [F33CA63763] NR 25 TC 18 Z9 18 U1 1 U2 1 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 JUL 19 PY 1999 VL 142 IS 1 BP 55 EP 63 DI 10.1016/S0304-3835(99)00166-4 PG 9 WC Oncology SC Oncology GA 211UR UT WOS:000081180700008 PM 10424781 ER PT J AU Hodes, RJ AF Hodes, RJ TI Telomere length, aging, and somatic cell turnover SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Editorial Material ID HUMAN FIBROBLASTS; HUMAN-LYMPHOCYTES; ACTIVATION; LIFE; AGE; DNA C1 NIA, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. RP Hodes, RJ (reprint author), NIA, NIH, Bldg 10,Rm 4B17,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 30 TC 72 Z9 73 U1 0 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 19 PY 1999 VL 190 IS 2 BP 153 EP 156 DI 10.1084/jem.190.2.153 PG 4 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 219PJ UT WOS:000081615400001 PM 10432278 ER PT J AU Wang, ZG Marincola, FM Rivoltini, L Parmiani, G Ferrone, S AF Wang, ZG Marincola, FM Rivoltini, L Parmiani, G Ferrone, S TI Selective histocompatibility leukocyte antigen (HLA)-A2 loss caused by aberrant pre-mRNA splicing in 624MEL28 melanoma cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE histocompatibility leukocyte antigen class I splicing defect; truncated heavy chain; melanoma ID HLA CLASS-I; POLYMERASE CHAIN-REACTION; CYTOLYTIC T-CELLS; MONOCLONAL-ANTIBODIES; MESSENGER-RNA; TUMOR-ANTIGENS; MONOMORPHIC DETERMINANTS; RESTRICTION ELEMENT; DOWN-REGULATION; B2M GENE AB Histocompatibility leukocyte antigen (HLA)-A2 is used as a restricting element to present several melanoma-associated antigen (MAA)-derived peptides to cytotoxic T lymphocytes (CTLs). HLA-A2 antigen is selectively lost in primary melanoma lesions and more frequently in metastases. Only scanty information is available about the molecular mechanisms underlying this abnormality, in spite of its potentially negative impact on the clinical course of the disease and on the outcome of T cell-based immunotherapy. Therefore, in this study we have shown that the selective HLA-A2 antigen loss in melanoma cells 624MEL28 is caused by a splicing defect of HLA-A2 pre-mRNA because of a base substitution at the 5' splice donor site of intron 2 of the HLA-A2 gene. As a result, HLA-A2 transcripts are spliced to two aberrant forms, one with exon 2 skipping and the other with intron 2 retention. The latter is not translated because of an early premature stop codon in the retained intron. In contrast, the transcript with exon 2 skipping is translated to a truncated HLA-A2 heavy chain without the cr, domain. Such a polypeptide is synthesized in vitro but is not detectable in cells, probably because of the low steady state level of the corresponding mRNA and the low translation efficiency. These results indicate that a single mutational event in an HLA class I gene is sufficient for loss of the corresponding allele. This may account, at least in part, for the high frequency of selective HLA class I allele loss in melanoma cells. Our conclusion emphasizes the need to implement active specific immunotherapy with a combination of peptides presented by various HLA class I alleles. This strategy may counteract the ability of melanoma cells with selective HLA class I allele loss to escape from immune recognition. C1 Roswell Pk Canc Inst, Dept Immunol, Buffalo, NY 14263 USA. NCI, Surg Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. NIH, HLA Lab, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. Ist Nazl Tumori, Div Expt Oncol D, I-20133 Milan, Italy. RP Ferrone, S (reprint author), Roswell Pk Canc Inst, Dept Immunol, Elm & Carlton St, Buffalo, NY 14263 USA. OI Rivoltini, Licia/0000-0002-2409-6225 FU NCI NIH HHS [CA67108, R01 CA067108] NR 57 TC 75 Z9 75 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 19 PY 1999 VL 190 IS 2 BP 205 EP 215 DI 10.1084/jem.190.2.205 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 219PJ UT WOS:000081615400007 PM 10432284 ER PT J AU Iwasaki, A Kelsall, BL AF Iwasaki, A Kelsall, BL TI Freshly isolated Peyer's patch, but not spleen, dendritic cells produce interleukin 10 and induce the differentiation of T helper type 2 cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE antigen presentation; cytokine; mucosal immunity ID TRANSFORMING GROWTH-FACTOR; ANTIGEN-PRESENTING CELLS; ORAL TOLERANCE; FACTOR-BETA; IN-VITRO; CYTOKINE EXPRESSION; LYMPHOID-TISSUE; TRANSGENIC MICE; MACROPHAGES; INFECTION AB Orally administered antigens often generate immune responses that are distinct from those injected systemically. The role of antigen-presenting cells in determining the type of T helper cell response induced at mucosal versus systemic sites is unclear. Here we examine the phenotypic and functional differences between dendritic cells (DCs) freshly isolated from Peyer's patches (PP) and spleen (SP). Surface phenotypic analysis of CD 11c(+) DC populations revealed that PP DCs expressed higher levels of major histocompatibility complex class TI molecules, but similar levels of costimulatory molecules and adhesion molecules compared with SP DCs. Freshly isolated, now cytometrically sorted 98-100% pure CD11c(+) DC populations from PP and SP were compared for their ability to stimulate naive T cells. First, PP DCs were found to be much more potent in stimulating allogeneic T cell proliferation compared with SP DCs. Second, by using naive T cells from ovalbumin peptide-specific T cell receptor transgenic mice, these ex vivo DCs derived from PP, but not from SP, were found to prime for the production of interleukin (IL)-4 and IL-10 (Th2 cytokines). In addition, PP DCs were found to prime T cells for the production of much lower levels of interferon (IFN)-gamma (Th1) compared with SP DCs. The presence of neutralizing antibody against IL-10 in the priming culture dramatically enhanced IFN-gamma production by T cells stimulated with PP DCs. Furthermore, stimulation of freshly isolated PP DCs via the CD40 molecule resulted in secretion of high levels of IL-10, whereas the same stimulus induced no IL-10 secretion from SP DCs. These results suggest that DCs residing in different tissues are capable of inducing distinct immune responses and that this may be related to the distinct cytokines produced by the DCs from these tissues. C1 NIAID, Mucosal Immun Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Kelsall, BL (reprint author), NIAID, Mucosal Immun Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. NR 43 TC 481 Z9 497 U1 0 U2 5 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 JUL 19 PY 1999 VL 190 IS 2 BP 229 EP 239 DI 10.1084/jem.190.2.229 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 219PJ UT WOS:000081615400009 PM 10432286 ER PT J AU Srivastava, RK Sasaki, CY Hardwick, JM Longo, DL AF Srivastava, RK Sasaki, CY Hardwick, JM Longo, DL TI Bcl-2-mediated drug resistance: Inhibition of apoptosis by blocking nuclear factor of activated T lymphocytes (NFAT)-induced Fas ligand transcription SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE Fas ligand; apoptosis; NFAT; Bcl-2; paclitaxel ID CD95 APO-1/FAS SYSTEM; INDUCED CELL-DEATH; CYCLOSPORINE-A; CANCER-CELLS; NF-AT; MEDIATED TRANSCRIPTION; BCL2 PHOSPHORYLATION; ENDOTHELIAL-CELLS; DEFICIENT MICE; IMMUNE EVASION AB Bcl-2 inhibits apoptosis induced by a variety of stimuli, including chemotherapy drugs and glucocorticoids. It is generally accepted that Bcl-2 exerts its antiapoptotic effects mainly by dimerizing with proapoptotic members of the Bcl-2 family such as Bar and Bad. However, the mechanism of the antiapoptotic effects is unclear. Paclitaxel and other drugs that disturb microtubule dynamics kill cells in a Fas/Fas ligand (FasL)-dependent manner; antibody to Fast. inhibits paclitaxel-induced apoptosis. We have found that Bcl-2 overexpression leads to the prevention of chemotherapy (paclitaxel)-induced expression of Fast and blocks paclitaxel-induced apoptosis. The mechanism of this effect is that Bcl-2 prevents the nuclear translocation of NFAT (nuclear factor of activated T lymphocytes, a transcription factor activated by microtubule damage) by binding and sequestering calcineurin, a calcium-dependent phosphatase that must dephosphorylate NFAT to move to the nucleus. Without NFAT nuclear translocation, the Fast gene is not transcribed. Thus, it appears that paclitaxel and other drugs that disturb microtubule function kill cells at least in part through the induction of FasL. Furthermore, Bcl-2 antagonizes drug-induced apoptosis by inhibiting calcineurin activation, blocking NFAT nuclear translocation, and preventing Fast expression. The effects of Bcl-2 can be overcome, at least partially, through phosphorylation of Bcl-2. Phosphorylated Bcl-2 cannot bind calcineurin, and NFAT activation, Fast expression, and apoptosis can occur after Bcl-2 phosphorylation. C1 NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Publ Hlth, Dept Mol Biol & Immunol, Baltimore, MD 21205 USA. RP Srivastava, RK (reprint author), NIA, Immunol Lab, NIH, 5600 Nathan Shock Dr,Box 9, Baltimore, MD 21224 USA. NR 77 TC 109 Z9 115 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 19 PY 1999 VL 190 IS 2 BP 253 EP 265 DI 10.1084/jem.190.2.253 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 219PJ UT WOS:000081615400011 PM 10432288 ER PT J AU Crawley, JN AF Crawley, JN TI Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests SO BRAIN RESEARCH LA English DT Article; Proceedings Paper CT 1st Brain Research Interactive Symposium CY NOV 04-06, 1998 CL SAN DIEGO, CALIFORNIA ID INBRED MOUSE STRAINS; CORTICOTROPIN-RELEASING FACTOR; NEURODEGENERATIVE DISEASES; TARGETED DISRUPTION; INDUCED ANALGESIA; STARTLE RESPONSE; GENETIC-ANALYSIS; RECEPTOR GENE; LACKING; MEMORY AB Rigorous experimental design can minimize the high risk of false positives and false negatives in the behavioral phenotyping of a new transgenic or knockout mouse. Use of well established, quantitative, reproducible behavioral tasks, appropriate Ns, correct statistical methods, consideration of background genes contributed by the parental strains, and attention to litter and gender issues, will maximize meaningful comparisons of -/-, +/-, and +/+ genotypes. Strategies developed and used by our laboratory are described in this review. Preliminary observations evaluate general health and neurological reflexes. Sensory abilities and motor functions are extensively quantitated. Specific tests include observations of home cage behaviors, body weight, body temperature, appearance of the fur and whiskers, righting reflex, acoustic startle, eye blink, pupil constriction, vibrissae reflex, pinna reflex, Digiscan open field locomotion, rotarod motor coordination, hanging wire, footprint pathway, visual cliff, auditory threshold, pain threshold, and olfactory acuity. Hypothesis testing then focuses on at least three well-validated tasks within each relevant behavioral domain. Specific tests for mice are described herein for the domains of learning and memory, feeding, nociception, and behaviors relevant to discrete symptoms of human anxiety, depression, schizophrenia, and drug addiction. An example of our approach is illustrated in the behavioral phenotyping of C/EBP delta knockout mice, which appear to be normal on general health, neurological reflexes, sensory and motor tasks, and the Morris water task, but show remarkably enhanced performance on contextual fear conditioning. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIMH, Sect Behav Neuropharmacol, Expt Therapeut Branch, Bethesda, MD 20892 USA. RP Crawley, JN (reprint author), NIMH, Sect Behav Neuropharmacol, Expt Therapeut Branch, Bldg 10,Room 4D11, Bethesda, MD 20892 USA. NR 77 TC 468 Z9 478 U1 1 U2 35 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUL 17 PY 1999 VL 835 IS 1 SI SI BP 18 EP 26 DI 10.1016/S0006-8993(98)01258-X PG 9 WC Neurosciences SC Neurosciences & Neurology GA 219VH UT WOS:000081627500003 PM 10448192 ER PT J AU Wilkin, DJ Artz, AS South, S Lachman, RS Rimoin, DL Wilcox, WR McKusick, VA Stratakis, CA Francomano, CA Cohn, DH AF Wilkin, DJ Artz, AS South, S Lachman, RS Rimoin, DL Wilcox, WR McKusick, VA Stratakis, CA Francomano, CA Cohn, DH TI Small deletions in the type II collagen triple helix produce Kniest dysplasia SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE Kniest dysplasia; type II collagen; COL2A1; mutation ID SUBSTITUTION; CARTILAGE; COL2A1; EXPRESSION; MUTATION; PATIENT; DEFECT AB Kniest dysplasia is a moderately severe type II collagenopathy, characterized by short trunk and limbs, kyphoscoliosis, midface hypoplasia, severe myopia, and hearing loss. Mutations in the gene that encodes type II collagen (COL2A1), the predominant protein of cartilage, have been identified in a number of individuals with Kniest dysplasia, All but two of these previously described mutations cause in-frame deletions in type II collagen, either by small deletions in the gene or splice site alterations, Furthermore, all but one of these mutations is located between exons 12 and 24 in the COL2A1 gene, We used heteroduplex analysis to identify sequence anomalies in five individuals with Kniest dysplasia, Sequencing of the index patients' genomic DNA identified four new dominant mutations in COL2A1 that result in Kniest dysplasia: a 21-bp deletion in exon 16, an 18-bp deletion in exon 19, and 4-bp deletions in the splice donor sites of introns 14 and 20, A previously described 28-bp deletion at the COL2A1 exon 12-intron 12 junction, deleting the splice donor site, was identified in the fifth case. The latter three mutations are predicted to result in exon skipping in the mRNA encoded from the mutant allele, These data suggest that Kniest dysplasia results from shorter type II collagen monomers, and support the hypothesis that alteration of a specific COL2A1 domain, which may span from exons 12 to 24, leads to the Kniest dysplasia phenotype, Am. J Med, Genet, 85:105-112, 1999, Published 1999 Wiley-Liss, Inc.dagger C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Sch Med, Ahmanson Pediat Ctr, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Steven Spielberg Pediat Res Ctr, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Cedars Sinai Med Ctr, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Dept Pediat, Los Angeles, CA 90024 USA. Johns Hopkins Univ, Sch Med, Ctr Med Genet, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. NICHHD, Unit Genet & Endocrinol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Wilkin, DJ (reprint author), NHGRI, Med Genet Branch, NIH, 10 Ctr Dr MSC 1267,Bldg 10,Room 3D45, Bethesda, MD 20892 USA. FU NICHD NIH HHS [HD22657]; NIGMS NIH HHS [GM16219] NR 24 TC 28 Z9 29 U1 0 U2 4 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 JUL 16 PY 1999 VL 85 IS 2 BP 105 EP 112 DI 10.1002/(SICI)1096-8628(19990716)85:2<105::AID-AJMG2>3.0.CO;2-Z PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 208UK UT WOS:000081010100002 PM 10406661 ER PT J AU Ramanathan, VK Hall, ZW AF Ramanathan, VK Hall, ZW TI Altered glycosylation sites of the delta subunit of the acetylcholine receptor (AChR) reduce alpha delta association and receptor assembly SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GATED ION CHANNELS; MAMMALIAN MUSCLE; COS CELLS; ENDOPLASMIC-RETICULUM; HETERODIMER FORMATION; TORPEDO-CALIFORNICA; EPSILON SUBUNIT; LIGAND-BINDING; BETA-SUBUNIT; MOUSE AB We have used mutagenesis to investigate the potential N-glycosylation sites in the delta subunit of the mouse muscle acetylcholine receptor (AChR). Of the three sites, Asn(76), Asn(143), and Asn(169), only the first two were glycosylated when the delta subunit was expressed in COS cells. Because the heterologously expressed delta subunit was similar in its properties to that expressed in C2 muscle cells, the sites of glycosylation are likely to be the same in both cases. In COS cells, mutations of the delta subunit that prevented glycosylation at either of the sites did not change its metabolic stability nor its steady-state level. These results are in contrast to those found previously for the alpha subunit, in which glycosylation at a single site metabolically stabilized the polypeptide (Blount, P., and Merlie, J, P. (1990) J. Cell Biol. 111, 2613-2622). Mutations of the delta subunit that prevented glycosylation, however, decreased its ability to form an alpha delta heterodimer when the alpha and delta subunit were expressed together. When all four subunits of the AChR (alpha, beta, delta, and epsilon) were coexpressed, mutation of the delta subunit to prevent glycosylation resulted in a reduced amount of fully assembled AChR and reduced surface AChR levels, consistent with the role of the heterodimer in the assembly reaction. These results suggest that glycosylation of the delta subunit at both Asn(76) and Asn(143) is needed for its efficient folding and/or its subsequent interaction with the alpha subunit. C1 NIMH, Sect Synapt Mechanisms, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. RP Ramanathan, VK (reprint author), SmithKline Beecham Pharmaceut, POB 1539, King Of Prussia, PA 19406 USA. NR 46 TC 21 Z9 21 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 JUL 16 PY 1999 VL 274 IS 29 BP 20513 EP 20520 DI 10.1074/jbc.274.29.20513 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 216JE UT WOS:000081438300073 PM 10400680 ER PT J AU Bird, GS Takahashi, M Tanzawa, K Putney, JW AF Bird, GS Takahashi, M Tanzawa, K Putney, JW TI Adenophostin A induces spatially restricted calcium signaling in Xenopus laevis oocytes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; TRISPHOSPHATE; ENTRY; DISSOCIATION; BINDING; RELEASE; INFLUX; STORES AB The activation of intracellular calcium release and calcium entry across the plasmalemma in response to intracellular application of inositol 2,4,5-trisphosphate and adenophostin A, two metabolically stable agonists for inositol 1,4,5-trisphosphate receptors, was investigated using Xenopus laevis oocytes and confocal imaging. Intracellular injection of inositol 2,4,5-trisphosphate induced a rapidly spreading calcium signal associated with regenerative calcium waves; the calcium signal filled the peripheral regions of the cell in 1-5 min. Injection of high concentrations of adenophostin A (250 nM) similarly induced rapidly spreading calcium signals. Injection of low concentrations of adenophostin A resulted in calcium signals that spread slowly (>1 h). With extremely low concentrations of adenophostin A (similar to 10 pM), stable regions of Ca2+ release were observed that did not expand to peripheral regions. When the adenophostin A-induced calcium signal was restricted to central regions, compartmentalized calcium oscillations were sometimes observed. Restoration of extracellular calcium caused a rise in cytoplasmic calcium restricted to the region of adenophostin A-induced calcium mobilization, The limited diffusion of adenophostin A provides an opportunity to examine calcium signaling processes under spatially restricted conditions and provides insights into mechanisms of intracellular calcium oscillations and capacitative calcium entry. C1 NIEHS, Calcium Regulat Sect, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. Sankyo Co Ltd, Biol Res Labs, Tokyo 140, Japan. RP Putney, JW (reprint author), NIEHS, Calcium Regulat Sect, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. NR 20 TC 22 Z9 22 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 JUL 16 PY 1999 VL 274 IS 29 BP 20643 EP 20649 DI 10.1074/jbc.274.29.20643 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 216JE UT WOS:000081438300089 PM 10400696 ER PT J AU Tamura, M Gu, JG Danen, EHJ Takino, T Miyamoto, S Yamada, KM AF Tamura, M Gu, JG Danen, EHJ Takino, T Miyamoto, S Yamada, KM TI PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-TYROSINE KINASE; TUMOR-SUPPRESSOR; SIGNALING PATHWAYS; GLIOMA-CELLS; PHOSPHATASE-ACTIVITY; GLIOBLASTOMA CELLS; GERMLINE MUTATIONS; PROSTATE-CANCER; MMAC1/PTEN GENE; MAP KINASE AB The tumor suppressor PTEN is a phosphatase with sequence homology to tensin. PTEN dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PIP3) and focal adhesion kinase (FAK), and it can inhibit cell growth, invasion, migration, and focal adhesions. We investigated molecular interactions of PTEN and FAK in glioblastoma and breast cancer cells lacking PTEN. The PTEN trapping mutant D92A bound wild-type FAK, requiring FAK autophosphorylation site Tyr(397). In PTEN-mutated cancer cells, PAK phosphorylation was retained even in suspension after detachment from extracellular matrix, accompanied by enhanced PI 3-K association with FAK and sustained PIS-K activity, PIP3 levels, and Akt phosphorylation; expression of exogenous PTEN suppressed all five properties. PTEN-mutated cells were resistant to apoptosis in suspension, but most of the cells entered apoptosis after expression of exogenous PTEN or wortmannin treatment. Moreover, overexpression of FAK in PTEN-transfected cells reversed the decreased FAK phosphorylation and PI 3-K activity, and it partially rescued PIP3 levels, Akt phosphorylation, and PTEN-induced apoptosis. Our results show that FAK Tyr(397) is important in PTEN interactions with FAK, that PTEN regulates FAK phosphorylation and molecular associations after detachment from matrix, and that PTEN negatively regulates the extracellular matrix-dependent PI 3-K/Akt cell survival pathway in a process that can include FAK. C1 NIDCR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. RP Yamada, KM (reprint author), NIDCR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bldg 30,Rm 421,30 Convent Dr MSC 4370, Bethesda, MD 20892 USA. RI TAKINO, Takahisa/D-8460-2015; OI Yamada, Kenneth/0000-0003-1512-6805 NR 82 TC 272 Z9 287 U1 0 U2 6 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 JUL 16 PY 1999 VL 274 IS 29 BP 20693 EP 20703 DI 10.1074/jbc.274.29.20693 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 216JE UT WOS:000081438300096 PM 10400703 ER PT J AU Dhamija, S Liu, Y Yamada, Y Snead, ML Krebsbach, PH AF Dhamija, S Liu, Y Yamada, Y Snead, ML Krebsbach, PH TI Cloning and characterization of the murine ameloblastin promoter SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DENTIN PHOSPHOPROTEIN; PROTEIN INTERACTIONS; TOOTH DEVELOPMENT; CULTURED-CELLS; RAT INCISORS; EXPRESSION; GENES; DIFFERENTIATION; AMELOGENIN; MATRIX AB The molecular mechanisms directing the highly restricted expression pattern of murine ameloblastin were characterized by cloning and functional analysis of the ameloblastin promoter. The transcription start site, mapped by primer extension, was located 19 base pairs (bp) 5' of the published cDNA. The promoter was analyzed in a mouse ameloblast-like cell line (LS8) and was compared with promoter activity in primary gingival fibroblasts and pulp fibroblasts. Sequential 5'-deletion mutants encompassing DNA sequences from -1616 to -781 bp exhibited high promoter activity in LS8 cells, whereas the promoter activity decreased to 50% of the full-length construct in the -781- and -477-bp regions. The -217-bp promoter region regained promoter activity that approached the activity of the full-length promoter construct, suggesting that both positive and negative cis-acting regions may be involved in ameloblastin transcriptional regulation. Activity of the ameloblastin promoter in gingival and pulp fibroblasts was minimal and ranged from 8 to 30% of the activity in ameloblast-like cells. Several DNA-protein complexes were formed between functionally important promoter fragments and nuclear extracts from LS8 cells. The inactivity of promoter constructs in pulp and gingival fibroblasts as well as the absence of similar DNA-protein complexes from these cells suggest that regulatory regions of the murine ameloblastin promoter may function in a cell-specific manner. C1 Univ Michigan, Sch Dent, Dept Oral Med Pathol & Oncol, Ann Arbor, MI 48109 USA. NIDCR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. Univ So Calif, Sch Dent, Ctr Craniofacial Mol Biol, Los Angeles, CA 90033 USA. RP Krebsbach, PH (reprint author), Univ Michigan, Sch Dent, Dept Oral Med Pathol & Oncol, Rm 4207, Ann Arbor, MI 48109 USA. FU NIDCR NIH HHS [K02 DE00426, R29 DE12502] NR 26 TC 25 Z9 27 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 JUL 16 PY 1999 VL 274 IS 29 BP 20738 EP 20743 DI 10.1074/jbc.274.29.20738 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 216JE UT WOS:000081438300102 PM 10400709 ER PT J AU Reiter, Y Schuck, P Boyd, LF Plaksin, D AF Reiter, Y Schuck, P Boyd, LF Plaksin, D TI An antibody single-domain phage display library of a native heavy chain variable region: Isolation of functional single-domain VH molecules with a unique interface SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE antibody; phage-display; single-domain; VH; inclusion bodies ID ANTIGEN-BINDING; ESCHERICHIA-COLI; FV-FRAGMENTS; H DOMAIN; AFFINITY; IMMUNOTOXINS; RECEPTOR; PEPTIDE; SPECIFICITY; ASSOCIATION AB To develop very small antibody-derived recognition units for experimental, medical, and drug design purposes, a heavy chain variable region (VH) single-domain phage-display library was designed and constructed. The scaffold that was used for library construction was a native sequence of a monoclonal antibody with a unique VH/VL interface. There was no need to modify any residues in the VL interface to avoid non-specific binding of VH domain. The library repertoire, consisting of 4 x 10(8) independent clones, was generated by the randomization of nine amino acid residues in complementary determining region 3. The library was screened by binding to protein antigens, and individual clones were isolated. The VH genes encoding for specific binding clones were rescued and large amounts of soluble and stable single-domain VH protein were made from insoluble inclusion bodies by in vitro refolding and purification. Biochemical and biophysical characterization of the VH protein revealed a highly specific, correctly folded, and stable monomeric molecule. Binding studies demonstrated an affinity of 20 nM. The properties of these molecules make them attractive for clinical, industrial, and research applications, as well as a step toward improvement in the design of small molecules that are based on the hypervariable loops of antibodies. (C) 1999 Academic Press. C1 Peptor Ltd, Mol Biol Grp, IL-76326 Rehovot, Israel. Technion Israel Inst Technol, Fac Biol, IL-32000 Haifa, Israel. NIH, ORS, Mol Interact Resource, Bioengn & Phys Sci Program, Bethesda, MD 20892 USA. NIAID, Mol Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Plaksin, D (reprint author), Peptor Ltd, Mol Biol Grp, IL-76326 Rehovot, Israel. OI Schuck, Peter/0000-0002-8859-6966 NR 48 TC 64 Z9 66 U1 1 U2 5 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 JUL 16 PY 1999 VL 290 IS 3 BP 685 EP 698 DI 10.1006/jmbi.1999.2923 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 217PM UT WOS:000081508200007 PM 10395823 ER PT J AU Hussain, SP Harris, CC AF Hussain, SP Harris, CC TI p53 mutation spectrum and load: the generation of hypotheses linking the exposure of endogenous or exogenous carcinogens to human cancer SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article; Proceedings Paper CT 3rd International Conference on Environmental Mutagens in Human Populations CY NOV 28-DEC 04, 1998 CL BANGKOK, THAILAND DE p53; nitric oxide; mutation; lung cancer ID NITRIC-OXIDE SYNTHASE; TUMOR-SUPPRESSOR GENE; WILD-TYPE P53; TATA-BINDING PROTEIN; BRONCHIAL EPITHELIAL-CELLS; NECROSIS-FACTOR-ALPHA; HEPATITIS-B VIRUS; SKIN-CANCER; TRANSCRIPTIONAL ACTIVATION; HEPATOCELLULAR-CARCINOMA AB The activation of protooncogenes and inactivation of tumor suppressor genes in affected cells an considered as the core events that provide a selective growth advantage and clonal expansion during the multistep process of carcinogenesis. Somatic mutations, induced by exogenous or endogenous mechanisms, were found to alter the normal functions of the p53 tumor suppressor gene. p53 is the most prominent example of tumor suppressor genes because it is mutated in about half of all human cancer. In contrast to other tumor suppressor genes (like APC and RE), about 80% of p53 mutations are missense mutations that lead to amino acid substitutions in proteins and can alter the protein conformation and increase the stability of p53. These changes can also alter the sequence-specific DNA binding and transcription factor activity of p53. These abnormalities can abrogate p53 dependent pathways involved in important cellular functions like cell-cycle control, DNA repair, differentiation, genomic plasticity and programmed cell death. A number of different carcinogens have been found to cause different characteristic mutations in the p53 gene. For example, exposure to ultraviolet light is correlated with transition mutations at dipyrimidine sites; aflatoxin B-1 exposure is correlated with a G:C to T:A transversion that leads to a serine substitution at residue 249 of p53 in hepatocellular carcinoma; and exposure to cigarette smoke is correlated with G:C to T:A transversions in lung carcinoma. Therefore, measuring the characteristic p53 mutation load or frequency of mutated alleles in nontumorous tissue (before the clonal expansion of mutated cells), can generate hypotheses, e.g., providing a molecular linkage between exposure to a particular carcinogen and cancer, and identifying individuals at increased cancer risk. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, NIH, Bldg 37,Rm 2C05, Bethesda, MD 20892 USA. NR 119 TC 118 Z9 126 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JUL 16 PY 1999 VL 428 IS 1-2 BP 23 EP 32 DI 10.1016/S1383-5742(99)00028-9 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 234RU UT WOS:000082498800005 PM 10517975 ER PT J AU Olivero, OA Parikka, R Poirier, MC Vahakangas, K AF Olivero, OA Parikka, R Poirier, MC Vahakangas, K TI 3 '-azido-3 '-deoxythymidine (AZT) transplacental perfusion kinetics and DNA incorporation in normal human placentas perfused with AZT SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article; Proceedings Paper CT 3rd International Conference on Environmental Mutagens in Human Populations CY NOV 28-DEC 04, 1998 CL BANGKOK, THAILAND DE AIDS; transplacental carcinogenesis; zidovudine; placental perfusion ID ZIDOVUDINE TREATMENT; IN-UTERO; 3'-AZIDO-2',3'-DIDEOXYTHYMIDINE; TRANSMISSION; MICE; TYPE-1; DAMAGE AB Vertical transmission of the human immunodeficiency virus 1 (HIV-1) is reduced from similar to 25% to similar to 7% as a result of 3'-azido-3'-deoxythymidine (AZT) therapy given during pregnancy; however, the consequences of transplacental AZT exposure to the fetus remain unknown. To address the extent and kinetics of AZT transfer across the human placenta, perfusion studies have been performed with fresh uninfected human placentas perfused with 0.5, 1.0 and 5.0 mg AZT/ml for 2 h using a dual recirculating single cotyledon perfusion apparatus [T.I. Ala-Kokko, P. Pienimaki, R. Herva, A.I. Hollmen, O. Pelkonen, K. Vahakangas, Transfer of lidocaine and bupivacaine across the isolated perfused human placenta, Pharmacol. Toxicol, 77 (1995) 142-148]. For two placentas, samples of perfusion effluent were taken every 15 min from the maternal and fetal sides of the apparatus and AZT levels were determined by AZT radioimmunoassay (RIA). At the end of the perfusion, AZT-DNA incorporation into placental DNA was determined by AZT-RIA. The concentration of AZT in the fetal perfusate increased with time, along with a concomitant slow decrease in the concentration of AZT in the maternal perfusates. For three different placentas, at 2 h after the start of perfusion, AZT-DNA incorporation values (molecules of AZT/10(6) nucleotides) were 11.8 for the 0.5 mg AZT/ml perfusate, 13.7 for the 1.0 mg AZT/ml perfusion, and 42.0 for the 5 mg AZT/ml perfusion. An additional placenta perfused with 1 mg AZT/ml did not have detectable values of AZT incorporated into DNA (data not shown). The data show that AZT crosses the human placenta and becomes rapidly incorporated into DNA of placental tissue in a dose-dependent fashion, suggesting that even short exposures to this drug might induce fetal genotoxicity and might also inhibit maternal-fetal viral transmission. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. Univ Oulu, Dept Pharmacol & Toxicol, Oulu, Finland. RP Olivero, OA (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. NR 16 TC 28 Z9 28 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JUL 16 PY 1999 VL 428 IS 1-2 BP 41 EP 47 DI 10.1016/S1383-5742(99)00030-7 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 234RU UT WOS:000082498800007 PM 10517977 ER PT J AU Fenech, M Holland, N Chang, WP Zeiger, E Bonassi, S AF Fenech, M Holland, N Chang, WP Zeiger, E Bonassi, S TI The HUman MicroNucleus Project - An international collaborative study on the use of the micronucleus technique for measuring DNA damage in humans SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article; Proceedings Paper CT 3rd International Conference on Environmental Mutagens in Human Populations CY NOV 28-DEC 04, 1998 CL BANGKOK, THAILAND DE human biomonitoring; epidemiology; micronucleus; human lymphocytes; exfoliated cells; cytochalasin B; cytokinesis-block ID IN-SITU HYBRIDIZATION; BLOCKED HUMAN-LYMPHOCYTES; EXFOLIATED UROTHELIAL CELLS; SISTER-CHROMATID EXCHANGES; CHROMOSOMAL-ABERRATIONS; X-CHROMOSOME; ORAL-MUCOSA; CANCER RISK; CIRCULATING LYMPHOCYTES; HOMOCYSTEINE STATUS AB The International Collaborative Project on Micronucleus Frequency in Human Populations (HUMN) was organized to collect data on micronucleus (MN) frequencies in different human populations and different cell types. The test procedures considered by this project are assays using human lymphocytes (cytokinesis-block method), exfoliated epithelial cells, and other cell types. Data (including descriptions of the populations monitored, detailed test protocols, and test results) are being obtained from a large number of laboratories throughout the world and are being entered into a unified database. The information will be used to: (1) determine the extent of variation of 'normal' values for different laboratories and the influence of other factors potentially affecting baseline MN frequency, e.g., age, gender and Life-style; (2) provide information on the effect of experimental protocol variations on MN frequency measurements; (3) design and test optimal protocols for the different cell types; and (4) determine the extent to which MN frequency is a valid biomarker of ageing and risk for diseases such as cancer. (C) 1999 Elsevier Science B.V. All rights reserved. C1 CSIRO, Adelaide, SA 5000, Australia. Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. Natl Yang Ming Univ, Sch Med, Inst Publ Hlth, Taipei 112, Taiwan. NIEHS, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. Ist Nazl Ric Canc, Dept Environm Epidemiol, I-16132 Genoa, Italy. RP Fenech, M (reprint author), CSIRO, Gouger St,POB 10041, Adelaide, SA 5000, Australia. OI bonassi, stefano/0000-0003-3833-6717 NR 73 TC 332 Z9 350 U1 1 U2 20 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JUL 16 PY 1999 VL 428 IS 1-2 BP 271 EP 283 DI 10.1016/S1383-5742(99)00053-8 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 234RU UT WOS:000082498800029 PM 10517999 ER PT J AU Litvan, I AF Litvan, I TI Recent advances in Parkinson's disease SO REVISTA DE NEUROLOGIA LA Spanish DT Article DE catechol-O-methyltransferase enzyme inhibitors; diagnosis; dopaminergic agonists; drug treatment; levodopa; Parkinson's disease ID DOUBLE-BLIND; MOTOR FLUCTUATIONS; CLINICAL-DIAGNOSIS; PRAMIPEXOLE; BROMOCRIPTINE; LEVODOPA; PLACEBO; CABERGOLINE; ROPINIROLE; MULTICENTER AB Objective. To evaluate the latest advances in the diagnosis and symptomatic pharmacological treatment of patients with Parkinson's disease at different stages. Development. In this article we summarize the criteria for clinical diagnosis of Parkinson's disease based on recent clinico-pathological studies. We evaluate the different therapeutic options at early and late stages of the illness in view of the results of recent, controlled double-blind studies in which the efficacy of new dopaminergic agonists (carbergolin, pramipexol and ropinirol) and catechol-O-methyl-transferase enzyme inhibitors (COMT; entacapone and tolcapone) are compared with placebo and with established treatments (e.g. levodopa and bromocryptin). Conclusions. Levodopa is still the most important advance yet made in the treatment of Parkinson's disease, but new dopaminergic agonists and COMT inhibitors are useful additions to the possibilities available for the treatment of early and late stages of the illness and may be included in modern guidelines for treatment. C1 NINCDS, Unit Neuropharmacol, Def & Vet Head Injury Program, Henry M Jackson Fdn,NIH, Bethesda, MD 20892 USA. NINCDS, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. OI Litvan, Irene/0000-0002-3485-3445 NR 35 TC 0 Z9 0 U1 0 U2 0 PU REVISTA DE NEUROLOGIA PI BARCELONA PA C/O CESAR VIGUERA, EDITOR, APDO 94121, 08080 BARCELONA, SPAIN SN 0210-0010 J9 REV NEUROLOGIA JI Rev. Neurologia PD JUL 16 PY 1999 VL 29 IS 2 BP 139 EP 145 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 233YM UT WOS:000082454800012 PM 10528328 ER PT J AU Plotkin, SA Aubin, F Robbins, J AF Plotkin, SA Aubin, F Robbins, J TI Vaccines SO VACCINE LA English DT Letter ID METAANALYSIS C1 Pasteru Merieux, Doylestown, PA USA. Pasteur Merieux, Dept Biometry, Marnes La Coquette, France. NICHHD, Dev & Mol Immun Lab, NIH, Bethesda, MD 20892 USA. RP Plotkin, SA (reprint author), Pasteru Merieux, Doylestown, PA USA. NR 5 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUL 16 PY 1999 VL 17 IS 22 BP 2763 EP 2763 PG 1 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 214FJ UT WOS:000081317700001 PM 10438044 ER PT J AU Holubkov, R Detre, KM Sopko, G Sutton-Tyrrell, K Kelsey, SF Frye, RL AF Holubkov, R Detre, KM Sopko, G Sutton-Tyrrell, K Kelsey, SF Frye, RL CA BARI Investigators TI Trends in coronary revascularization 1989 to 1997: The Bypass Angioplasty Revascularization Investigation (BARI) survey of procedures SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article AB Use of catheter-based and surgical coronary revascularization has steadily increased in North America. Introduction of catheter-based "new devices," including intracoronary stents, has expanded the range of patients who can be treated with percutaneous approaches. We sought to address trends in the practice of catheter-based and surgical coronary revascularization during 1989 to 1997, The 17 North American institutions participating in the NHLBI Bypass Angioplasty Revascularization Investigation (BARI) periodically completed a 5-working day survey of all surgical and catheter-based coronary revascularizations. Data collected included patient demographics, vessel disease, prior interventions, and use of new devices or minimally invasive surgical techniques, The proportion of all procedures that were catheter based (vs surgical) increased from 52.1% in 1989/1990 to 62.0% in 1997 (p <0.001), Among surgically treated patients, prevalence of prior bypass surgery decreased from 13.4% in 1989/1990 to 7.5% in 1997 (p <0.001). In 1997, 3% of surgical procedures used minimal incisions or were performed without cardiopulmonary bypass, Among patients undergoing catheter-based intervention, prevalence of left main disease increased from 2.2% to 5.7% (p <0.001), myocardial infarction within 24 hours increased from 2.4% to 9.7% (p <0.001), and prior bypass surgery increased from 16.2% to 20.8% (p = 0.056), Use of new devices increased from 11.6% of catheter-based procedures in 1990 to 67.0% in 1997 (p <0.001), Compared with the early 1990s, catheter-based revascularization is currently more commonly used for patients with acute myocardial infarction, prior bypass surgery, or severe left main narrowing. These trends are likely due to the proliferation of new devices, especially intracoronary stents,since the mid 1990s. (C) 1999 by Excerpta Medica, Inc. C1 Univ Pittsburgh, Epidemiol Data Coordinating Ctr, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. NHLBI, Div Heart & Vasc Dis, NIH, Bethesda, MD 20892 USA. Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. RP Holubkov, R (reprint author), Univ Pittsburgh, Epidemiol Data Coordinating Ctr, Grad Sch Publ Hlth, Dept Epidemiol, 127 Parran Hall,130 Desoto St, Pittsburgh, PA 15261 USA. FU NHLBI NIH HHS [HL38493, HL38504, HL38509] NR 10 TC 6 Z9 6 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 245 WEST 17TH STREET, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 15 PY 1999 VL 84 IS 2 BP 157 EP 161 DI 10.1016/S0002-9149(99)00226-X PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 214WY UT WOS:000081351600008 PM 10426332 ER PT J AU Nieto, FJ Folsom, AR Sorlie, PD Grayston, JT Wang, SP Chambless, LE AF Nieto, FJ Folsom, AR Sorlie, PD Grayston, JT Wang, SP Chambless, LE CA ARIC Study Investigators TI Chlamydia pneumoniae infection and incident coronary heart disease - The Atherosclerosis Risk in Communities Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE atherosclerosis; Chlamydia pneumoniae; cohort studies; coronary disease; smoking ID ACUTE MYOCARDIAL-INFARCTION; ARTERY DISEASE; STRAIN TWAR; CAROTID-ARTERY; IN-VITRO; ASSOCIATION; SMOKING; LESIONS; SEROPOSITIVITY; AZITHROMYCIN AB Pathologic findings and cross-sectional epidemiologic studies suggest that past infection with Chlamydia pneumoniae is associated with clinical and subclinical atherosclerotic disease, although evidence from prospective studies is still scarce. The association between chronic infection by C. pneumoniae and incident coronary heart disease (CHD) was investigated in a case-cohort study conducted among participants in the Atherosclerosis Risk in Communities Study who were free of CHD at the baseline examination (1986-1989). Levels of C. pneumoniae immunoglobulin G (IgG) antibodies in serum collected at baseline from 246 incident cases of CHD identified during follow-up (median, 3.3 years; maximum, 5 years) were compared with those from a stratified sample of the baseline cohort (n = 550). Among incident CHD cases, 65% had IgG antibody titers greater than or equal to 1:64, compared with 55% of noncases (compared with negative IgG titers, the relative hazard of CHD was 1.6 (p < 0.01)). In multivariate analyses controlling for other risk factors (age, gender, smoking, serum cholesterol, hypertension, diabetes mellitus, and educational level), the above estimates were substantially reduced and became statistically nonsignificant (relative hazard = 1.2). A significantly increased CHD hazard associated with IgG antibody titers greater than or equal to 1:64 was observed among nonsmokers, even after adjustment for other risk factors. Overall, these results do not provide strong support for the hypothesis that C. pneumoniae infection is a risk factor for clinical CHD. Studies with longer follow-up periods will be necessary to determine whether C. pneumoniae infection is involved as an etiologic factor in earlier phases of atherogenesis. C1 Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. NHLBI, Bethesda, MD 20892 USA. Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. Univ Washington, Sch Publ Hlth & Community Med, Dept Pathobiol, Seattle, WA 98195 USA. Univ N Carolina, Sch Publ Hlth, Dept Biostat, Chapel Hill, NC USA. RP Nieto, FJ (reprint author), Johns Hopkins Sch Hyg & Publ Hlth, Dept Epidemiol, 615 N Wolfe St, Baltimore, MD 21205 USA. FU NHLBI NIH HHS [N01-HC-55018, N01-HC-55016, N01-HC-55015] NR 53 TC 61 Z9 64 U1 0 U2 2 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 15 PY 1999 VL 150 IS 2 BP 149 EP 156 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 216KN UT WOS:000081441400006 PM 10412959 ER PT J AU Hirvonen, T Pietinen, P Virtanen, M Albanes, D Virtamo, J AF Hirvonen, T Pietinen, P Virtanen, M Albanes, D Virtamo, J TI Nutrient intake and use of beverages and the risk of kidney stones among male smokers SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE beer; beverages; diet; dietary fiber; drinking; kidney calculi; magnesium; smoking ID DIETARY CALCIUM; MAGNESIUM-OXIDE; BRAN; UROLITHIASIS; RECURRENCE; PREVENTION; DISEASE; WOMEN; URINE; TRIAL AB High intakes of calcium, potassium, and fluids have been shown to be associated with lowered risk of kidney stones. The authors studied the associations between diet and risk of kidney stones in a cohort of 27,001 Finnish male smokers aged 50-69 years who were initially free of kidney stones. All men participated in the Alpha-Tocopherol, Beta-Carotene Lung Cancer Prevention Study and completed a validated dietary questionnaire at baseline. After 5 years of follow-up (1985-1988), 329 men had been diagnosed with kidney stones. After data were controlled for possible confounders, the relative risk of kidney stones for men in the highest quartile of magnesium intake was 0.52 (95% confidence interval (CI) 0.32-0.85) as compared with men in the lowest quartile. Intake of fiber was directly associated with risk (relative risk (RR) = 2.06, 95% CI 1.39-3.03). Calcium intake was not associated with the risk of kidney stones. Beer consumption was inversely associated with risk of kidney stones; each bottle of beer consumed per day was estimated to reduce risk by 40% (RR = 0.60, 95% CI 0.47-0.76). In conclusion, the authors observed that magnesium intake and beer consumption were inversely associated and fiber intake was directly associated with risk of kidney stones. C1 Natl Publ Hlth Inst, Dept Nutr, FIN-00300 Helsinki, Finland. NCI, Div Clin Sci, Bethesda, MD 20892 USA. RP Hirvonen, T (reprint author), Natl Publ Hlth Inst, Dept Nutr, Mannerheimintie 166, FIN-00300 Helsinki, Finland. RI Albanes, Demetrius/B-9749-2015 FU NCI NIH HHS [N01-CN-45165] NR 24 TC 27 Z9 27 U1 1 U2 3 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 15 PY 1999 VL 150 IS 2 BP 187 EP 194 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 216KN UT WOS:000081441400011 PM 10412964 ER PT J AU Weed, DL Hursting, SD AF Weed, DL Hursting, SD TI "Biologic plausibility in causal inference: Current method and practice" - Reply SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Weed, DL (reprint author), NCI, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 15 PY 1999 VL 150 IS 2 BP 218 EP 219 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 216KN UT WOS:000081441400017 ER PT J AU Ripp, SL Itagaki, K Philpot, RM Elfarra, AA AF Ripp, SL Itagaki, K Philpot, RM Elfarra, AA TI Methionine S-oxidation in human and rabbit liver microsomes: Evidence for a high-affinity methionine S-oxidase activity that is distinct from flavin-containing monooxygenase 3 SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE flavin-containing monooxygenases; FMO3; FMO4; methionine; S-allyl-cysteine ID BENZYL-L-CYSTEINE; KIDNEY MICROSOMES; RAT-LIVER; CATALYTIC PROPERTIES; ESCHERICHIA-COLI; EXPRESSION; METABOLISM; SULFOXIDE; CLONING; LUNG AB Methionine has previously been shown to be S-oxidized by flavin-containing monooxygenase (FMO) forms 1, 2, and 3. The most efficient catalyst was FMO3, which has a K-m value for methionine S-oxidation of approximately 4 mM, and exhibits high selectivity for formation of the D-diastereoisomer of methionine sulfoxide. The current studies provide evidence for an additional methionine S-oxidase activity in liver microsomes. Human and rabbit Liver microsomes exhibited a biphasic response to methionine at concentrations ranging from 0.05 to 10 mM, as indicated by both Eadie-Hofstee plots and nonlinear regression. The low-affinity component of the biphasic response had II, values of approximately 3 and 5 nM for humans and rabbits, respectively, as web as high diastereoselectivity for methionine sulfoxide formation. The low-affinity activity in rabbit Liver microsomes was inhibited by methimazole, S-allyl-L-cysteine, and by mild heat treatment, suggesting the activity is FMO3. The high-affinity component of the biphasic response had K-m values of approximately 0.07 and 0.01 mM for humans and rabbits, respectively, as well as lower diastereoselectivity for methionine sulfoxide formation. Further characterization of the high-affinity activity in rabbit liver microsomes indicated lack of involvement of cytochrome P450s or reactive oxygen species. The high-affinity activity was inhibited 25% by potassium cyanide and greater than 50% by methimazole and S-allyl-L-cysteine. Mild heat treatment produced 85% inhibition of the low-affinity activity, but only 30% inhibition of the high-affinity activity. Both high- and low-affinity activities were decreased by 85% in flavin-depleted microsomes. Because these results suggested the additional S-oxidase activity has characteristics of an FMO, recombinant human FMO4 was evaluated as a potential catalyst of this activity. Recombinant FMO4 catalyzed S-oxidation of both methionine and S-allyl-L-cysteine, with similar diastereoselectivity to the high-affinity microsomal S-oxidase; however, the K(m)values for both reactions appeared to be greater than 10 mM. In summary, these studies provide evidence for two microsomal methionine S-oxidase activities. FMO3 is the predominant catalyst at millimolar concentrations of methionine. However, at micromolar methionine concentrations, there is an additional S-oxidase activity that is distinct from FMO3. (C) 1999 Academic Press. C1 Univ Wisconsin, Sch Vet Med, Ctr Environm Toxicol, Madison, WI 53706 USA. Univ Wisconsin, Dept Comparat Biosci, Madison, WI 53706 USA. NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. RP Elfarra, AA (reprint author), Univ Wisconsin, Sch Vet Med, Ctr Environm Toxicol, 2015 Linden Dr W, Madison, WI 53706 USA. FU NIDDK NIH HHS [DK44295] NR 38 TC 32 Z9 32 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JUL 15 PY 1999 VL 367 IS 2 BP 322 EP 332 DI 10.1006/abbi.1999.1247 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 219RM UT WOS:000081620900022 PM 10395751 ER PT J AU Nelson, TJ Zhao, WQ Yuan, SN Favit, A Pozzo-Miller, L Alkon, DL AF Nelson, TJ Zhao, WQ Yuan, SN Favit, A Pozzo-Miller, L Alkon, DL TI Calexcitin interaction with neuronal ryanodine receptors SO BIOCHEMICAL JOURNAL LA English DT Article DE calcium-binding proteins; calcium channels; liposomes; memory; squid ID CA2+ RELEASE CHANNELS; CYCLIC ADP-RIBOSE; SKELETAL-MUSCLE; SARCOPLASMIC-RETICULUM; CALCIUM-RELEASE; CALMODULIN; PROTEIN; BINDING; GTP; MEMORY AB Calexcitin (CE), a Ca2+- and GTP-binding protein, which is phosphorylated during memory consolidation, is shown here to co-purify with ryanodine receptors (RyRs) and bind to RyRs in a calcium-dependent manner. Nanomolar concentrations of CE released up to 46% of the Ca-45 label from microsomes preloaded with (CaCl2)-Ca-45. This release was Ca2+-dependent and was blocked by antibodies against the RyR or CE, by the RyR inhibitor dantrolene, and by a seven-amino-acid peptide fragment corresponding to positions 4689-4697 of the RyR, but not by heparin, an Ins(1,4,5)P-3-receptor antagonist. Anti-CE antibodies, in the absence of added CE, also blocked Ca2+ release elicited by ryanodine, suggesting that the CE and ryanodine binding sites were in relative proximity. Calcium imaging with bis-fura-2 after loading CE into hippocampal CA1 pyramidal cells in hippocampal slices revealed slow, local calcium transients independent of membrane depolarization. Calexcitin also released Ca2+ from liposomes into which purified RyR had been incorporated, indicating that CE binding can be a proximate cause of Ca2+ release. These results indicated that CE bound to RyRs and suggest that CE may be an endogenous modulator of the neuronal RyR. C1 NIH, Lab Adapt Syst, Bethesda, MD 20892 USA. NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Nelson, TJ (reprint author), NIH, Lab Adapt Syst, Bladg 36,Room 4A-23, Bethesda, MD 20892 USA. NR 40 TC 31 Z9 31 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 JUL 15 PY 1999 VL 341 BP 423 EP 433 DI 10.1042/0264-6021:3410423 PN 2 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 219FQ UT WOS:000081597600025 PM 10393102 ER PT J AU Barnes, DM Sykes, B Miller, DS AF Barnes, DM Sykes, B Miller, DS TI Multiple effects of mercuric chloride on hexose transport in Xenopus oocytes SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Article DE mercury; insulin; hexose transport; cell volume regulation; Xenopus ID RAT ADIPOCYTES; GLUCOSE-TRANSPORT; CELL-VOLUME; INSULIN; MECHANISM; STIMULATION; VANADATE AB HgCl2 had both stimulatory and inhibitory effects on [H-3]2-deoxyglucose (DG) uptake in Xenopus laevis oocytes. The Hg dose response was complex, with 0.1-10 mu M Hg increasing total DG uptake, 30-50 mu M Hg inhibiting, and concentrations > 100 mu M increasing uptake. Analyses of the effects of Hg on DG transport kinetics and cell membrane permeability indicated that low concentrations of Hg stimulated mediated uptake, intermediate concentrations inhibited mediated uptake, but high Hg concentrations increased non-mediated uptake. 10 mu M Hg increased the apparent V-max for DG uptake, but caused little or no change in apparent K-m. Phenylarsine oxide prevented the increase in DG uptake by 10 mu M Hg, suggesting that the increase was due to transporter recruitment. Microinjecting low doses of HgCl2 into the cell increased mediated DG uptake. Higher intracellular doses of Hg increased both mediated and non-mediated DG uptake. Both insulin and Hg cause cell swelling in isotonic media and, for insulin, this swelling has been linked to the mechanism of hormone action. Osmotically swelling Xenopus oocytes stimulated DG transport 2-5-fold and this increase was due to an increased apparent V-max. Exposing cells to 10 mu M Hg or 140 nM insulin both increased cellular water content by 18% and increased hexose transport 2-4-fold. These data indicate that low concentrations of Hg and insulin affect hexose transport in a similar manner and that for both an increase cellular water content could be an early event in signaling the increase in hexose transport. (C) 1999 Published by Elsevier Science B.V. All rights reserved. C1 Univ Arkansas, Ctr Excellence Poultry Sci, Fayetteville, AR 72701 USA. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Barnes, DM (reprint author), Univ Arkansas, Ctr Excellence Poultry Sci, Fayetteville, AR 72701 USA. NR 21 TC 8 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD JUL 15 PY 1999 VL 1419 IS 2 BP 289 EP 298 DI 10.1016/S0005-2736(99)00077-2 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 219QZ UT WOS:000081619400016 PM 10407079 ER PT J AU Dukoff, R Wilkinson, CW Lasser, P Friz, J Conway, A Bahro, M Peskind, ER Sunderland, T AF Dukoff, R Wilkinson, CW Lasser, P Friz, J Conway, A Bahro, M Peskind, ER Sunderland, T TI Physostigmine challenge before and after chronic cholinergic blockade in elderly volunteers SO BIOLOGICAL PSYCHIATRY LA English DT Article DE aging; Alzheimer's; neuroendocrine; cortisol; physostigmine; scopolamine; plasticity ID ADRENOCORTICAL AXIS RESPONSES; ALZHEIMERS-DISEASE; RECEPTOR PLASTICITY; NEUROENDOCRINE RESPONSES; ANTERIOR-PITUITARY; FRONTAL-CORTEX; SCOPOLAMINE; BRAIN; RATS; AGE AB Background: As a test of possible muscarinic up-regulation, the cortisol response to intravenous (IV) physostigmine (an anticholinesterase) was measured in 9 elderly volunteers before and after chronic cholinergic blockade with the muscarinic cholinergic antagonist scopolamine, Methods: Each of the 9 elderly control subjects was given two physostigmine (0.5 mg IV) infusions separated by 21 doses of nightly scopolamine (1.2 mg p.o,). No scopolamine tr as administered the night before infusions, and glycopyrrolate (0.2 mg IV) was administered prior to physostigmine to block its peripheral effects, Vital signs were monitored and blood samples were collected at six time points surrounding the physostigmine infusion (-10, +10, +20 +30, +50, and +70 min). Behavioral measures and cognitive tests were administered prior to and 30 min after the physostigmine. Results: The cortisol response to physostigmine was greater after the second (post-chronic scopolamine) infusion study compared to the first (p < .05) as measured by an area under the curve analysis of all time points. When individual time points were compared, the mean cortisol response was significantly increased after the second physostigmine infusion at the +50- and +70-min rime points (p < .05). There were no significant changes in behavioral rating scales, cognitive tests, or vital signs between the Mlo physostigmine infusion study days. Conclusions: This study demonstrates increased hypothalamic-pituitary-adrenocortical axis responsivity to a central nervous system cholinergic stimulus after chronic muscarinic blockade in 9 elderly control subjects. it also gives further evidence to support previous suggestions of muscarinic plasticity, specifically postsynaptic up-regulation, in the aging brain following exposure to chronic anticholinergic treatment. (C) 1999 Society of Biological Psychiatry. C1 NIMH, Geriatr Psychiat Branch, NIH, Ctr Clin, Bethesda, MD 20892 USA. Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. Vet Affairs Puget Sound Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Seattle, WA USA. Vet Affairs Puget Sound Hlth Care Syst, Mental Hlth Serv, Seattle, WA USA. Vet Affairs Puget Sound Hlth Care Syst, Mental Res Educ & Clin Ctr, Seattle, WA USA. RP Sunderland, T (reprint author), NIMH, Geriatr Psychiat Branch, NIH, Ctr Clin, Bldg 10,Rm 3N228,10 Ctr Dr,MSC 1264, Bethesda, MD 20892 USA. NR 53 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUL 15 PY 1999 VL 46 IS 2 BP 189 EP 195 DI 10.1016/S0006-3223(98)00286-8 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 217BL UT WOS:000081479400005 PM 10418693 ER PT J AU Hough, C Lu, SJ Davis, CL Chuang, DM Post, RM AF Hough, C Lu, SJ Davis, CL Chuang, DM Post, RM TI Elevated basal and thapsigargin-stimulated intracellular calcium of platelets and lymphocytes from bipolar affective disorder patients measured by a fluorometric microassay SO BIOLOGICAL PSYCHIATRY LA English DT Article DE calcium; bipolar; unipolar; platelets; lymphocytes; thapsigargin ID SINGLE T-LYMPHOCYTES; DEPRESSED-PATIENTS; HEALTHY CONTROLS; MOBILIZATION; SEROTONIN; CARBAMAZEPINE; LITHIUM; STORES; CA2+ AB Background: A number of investigators have reported finding elevated basal and stimulated intracellular calcium levels in the platelets or lymphocytes of bipolar disorder patients. Methods: Intracellular calcium was measured by a micro fura-2 fluorometric method in the platelets and lymphocytes of 30 affective disorder patients and 14 control subjects. Results: We observed significantly elevated basal calcium concentrations in bipolar patient platelets and lymphocytes compared to control subjects. Bipolar patient platelet calcium responses to thrombin, serotonin, and thapsigargin were also significantly greater than control subjects, The peak calcium levels of lymphocytes of bipolar patients were greater than control subjects only when stimulated by thapsigargin, There were significant differences between bipolar and unipolar patients in basal and thapsigargin-stimulated calcium measures but not between bipolar I and bipolar II patients. Unmedicated versus medicated calcium measures were not significantly different. We also found little correlation between calcium measures and the severity of mood rating, Conclusions: Using this method, we were able to confirm and extend the work of others, indicating altered intracellular calcium homeostasis in the blood cells of bipolar disorder patients. In addition, our data suggest that storage operated calcium channels may be the source of the elevated intracellular calcium in platelets and lymphocytes of bipolar patients. (C) 1999 Society of Biological Psychiatry. C1 Uniformed Serv Univ Hlth Sci, Dept Psychiat, Bethesda, MD 20814 USA. NIMH, Behav Endocrinol Branch, Bethesda, MD 20892 USA. NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. RP Hough, C (reprint author), Uniformed Serv Univ Hlth Sci, Dept Psychiat, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. NR 24 TC 53 Z9 53 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUL 15 PY 1999 VL 46 IS 2 BP 247 EP 255 DI 10.1016/S0006-3223(98)00308-4 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 217BL UT WOS:000081479400012 PM 10418700 ER PT J AU Cossman, J Annunziata, CM Barash, S Staudt, L Dillon, P He, WW Ricciardi-Castagnoli, P Rosen, CA Carter, KC AF Cossman, J Annunziata, CM Barash, S Staudt, L Dillon, P He, WW Ricciardi-Castagnoli, P Rosen, CA Carter, KC TI Reed-Sternberg cell genome expression supports a B-cell lineage SO BLOOD LA English DT Article ID HODGKINS-DISEASE; GENE-EXPRESSION; DENDRITIC CELLS; CLONING; ACTIVATION; CHEMOKINE; PROTEIN; BIOLOGY; ANTIGEN; FAMILY AB The malignant Reed-Sternberg cell of Hodgkin's disease, first described a century ago, has resisted in-depth analysis due to its extreme rarity in lymphomatous tissue. To directly study its genome-wide gene expression, approximately 11,000,000 bases (27,518 cDNA sequences) of expressed gene sequence was determined from living single Reed-Sternberg cells, Hodgkin's tissue, and cell lines. This approach increased the number of genes known to be expressed in Hodgkin's disease by 20-fold to 2,666 named genes. The data here indicate that Reed-Sternberg cells from both nodular sclerosing and lymphocyte predominant Hodgkin's disease were derived from an unusual B-cell lineage based on a comparison of their gene expression to approximately 40,000,000 bases (10(5) sequences) of expressed gene sequence from germinal center B cells (GCB) and dendritic cells. The data set of expressed genes, reported here and on the World Wide Web, forms a basis to understand the genes responsible for Hodgkin's disease and develop novel diagnostic markers and therapies. This study of the rare Reed-Sternberg cell, concealed in its heterogenous cellular context, also provides a formidable test case to advance the limit of analysis of differential gene expression to the single disease cell. (C) 1999 by The American Society of Hematology. C1 Georgetown Univ, Med Ctr, Washington, DC 20007 USA. Human Genome Sci Inc, Rockville, MD USA. NCI, NIH, Bethesda, MD 20892 USA. Univ Milano Bicocca, Milan, Italy. RP Cossman, J (reprint author), Georgetown Univ, Med Ctr, NW 103 Med Dent Bldg,3900 Reservoir Rd NW, Washington, DC 20007 USA. RI Castagnoli, Paola/E-8288-2010; Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 NR 29 TC 88 Z9 89 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1200 19TH ST, NW, STE 300, WASHINGTON, DC 20036-2422 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 15 PY 1999 VL 94 IS 2 BP 411 EP 416 PG 6 WC Hematology SC Hematology GA 214RX UT WOS:000081342300005 PM 10397707 ER PT J AU Redner, RL Wang, JX Liu, JM AF Redner, RL Wang, JX Liu, JM TI Chromatin remodeling and leukemia: New therapeutic paradigms SO BLOOD LA English DT Review ID ACUTE PROMYELOCYTIC LEUKEMIA; ACUTE MYELOID-LEUKEMIA; TRANS-RETINOIC ACID; PML-RAR-ALPHA; TRANSCRIPTION FACTOR-BINDING; SWI-SNF COMPLEX; TRANSFORMED-CELL DIFFERENTIATION; MAMMALIAN HISTONE DEACETYLASE; NUCLEAR RECEPTOR COACTIVATOR; T(8-21) FUSION PROTEIN C1 Univ Pittsburgh, Med Ctr, Dept Med, Div Hematol Oncol, Pittsburgh, PA 15213 USA. NHLBI, Hematol Branch, Bethesda, MD 20892 USA. RP Redner, RL (reprint author), Univ Pittsburgh, Med Ctr, Dept Med, Div Hematol Oncol, E1058 Biomed Sci Tower,211 Lothrop St, Pittsburgh, PA 15213 USA. FU NCI NIH HHS [CA67346] NR 150 TC 147 Z9 160 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1200 19TH ST, NW, STE 300, WASHINGTON, DC 20036-2422 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 15 PY 1999 VL 94 IS 2 BP 417 EP 428 PG 12 WC Hematology SC Hematology GA 214RX UT WOS:000081342300006 PM 10397708 ER PT J AU Haddad, E Cramer, E Riviere, C Rameau, P Louache, F Guichard, J Nelson, DL Fischer, A Vainchenker, W Debili, N AF Haddad, E Cramer, E Riviere, C Rameau, P Louache, F Guichard, J Nelson, DL Fischer, A Vainchenker, W Debili, N TI The thrombocytopenia of Wiskott Aldrich syndrome is not related to a defect in proplatelet formation SO BLOOD LA English DT Article ID ACTIN-DEPOLYMERIZING PROTEIN; X-LINKED THROMBOCYTOPENIA; SRC HOMOLOGY-3 DOMAINS; WASP GENE-MUTATIONS; PLATELET FORMATION; TYROSINE KINASES; FACTOR-1 SDF-1; BLOOD-CELLS; MPL-LIGAND; N-WASP AB The Wiskott-Aldrich syndrome (WAS) is an X-linked hereditary disease characterized by thrombocytopenia with small platelet size, eczema, and increased susceptibility to infections. The gene responsible for WAS was recently cloned. Although the precise function of WAS protein (WASP) is unknown, it appears to play a critical role in the regulation of cytoskeletal organization. The platelet defect, resulting in thombocytopenia and small platelet size, is a consistent finding in patients with mutations in the WASP gene. However, its exact mechanism is unknown. Regarding WASP function in cytoskeletal organization, we investigated whether these platelet abnormalities could be due to a defect in proplatelet formation or in megakaryocyte (MK) migration. CD34(+) cells were isolated from blood and/or marrow of 14 WAS patients and five patients with hereditary X-linked thrombocytopenia (XLT) and cultured in serum-free liquid medium containing recombinant human Mpl-L (PEG-rHuMGDF) and stem-cell factor (SCF) to study in vitro megakaryocytopoiesis. In all cases, under an inverted microscope, normal MK differentiation and proplatelet formation were observed. At the ultrastructural level, there was also no abnormality in MK maturation, and normal filamentous MK were present. Moreover, the in vitro produced platelets had a normal size, while peripheral blood platelets of the same patients exhibited an abnormally small site. However, despite this normal platelet production, we observed that F-actin distribution was abnormal in MKs from WAS patients. Indeed, F-actin was regularly and linearly distributed under the cytoplasmic membrane in normal MKs, but it was found concentrated in the center of the WAS MKs. After adhesion, normal MKs extended very long filopodia in which WASP could be detected. In contrast, MKs from WAS patients showed shorter and less numerous filopodia. However, despite this abnormal filopodia formation, MKs from WAS patients normally migrated in response to stroma-derived factor-1 alpha (SDF-1 alpha), and actin normally polymerized after SDF-1 alpha or thrombin stimulation. These results suggest that the platelet defect in WAS patients is not due to abnormal platelet production, but instead to cytoskeletal changes occuring in platelets during circulation. (C) 1999 by The American Society of Hematology. C1 Inst Gustave Roussy, INSERM, U362, PRI, F-94805 Villejuif, France. Hop Henri Mondor, INSERM, U474, F-94010 Creteil, France. Hop Necker Enfants Malad, Serv Immunohematol Pediat, Paris, France. NCI, Metab Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Haddad, E (reprint author), Inst Gustave Roussy, INSERM, U362, PRI, F-94805 Villejuif, France. NR 47 TC 60 Z9 62 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1200 19TH ST, NW, STE 300, WASHINGTON, DC 20036-2422 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 15 PY 1999 VL 94 IS 2 BP 509 EP 518 PG 10 WC Hematology SC Hematology GA 214RX UT WOS:000081342300016 PM 10397718 ER PT J AU El Abdaimi, K Papavasiliou, V Rabbani, SA Rhim, JS Goltzman, D Kremer, R AF El Abdaimi, K Papavasiliou, V Rabbani, SA Rhim, JS Goltzman, D Kremer, R TI Reversal of hypercalcemia with the vitamin D analogue EB1089 in a human model of squamous cancer SO CANCER RESEARCH LA English DT Article ID NORMAL HUMAN KERATINOCYTES; HORMONE-RELATED PEPTIDE; GENE-EXPRESSION; CELL-PROLIFERATION; TUMOR PROGRESSION; GROWTH; 1,25-DIHYDROXYVITAMIN-D3; DIFFERENTIATION; INVIVO; INVITRO AB EB1089, an analogue of 1,25 dihydroxyvitamin D with low calcemic activity is a potent inhibitor of parathyroid hormone-related peptide (PTHRP) production in vitro. The purpose of the present study was to determine whether EB1089 could reverse established hypercalcemia in BALE C nude mice implanted s.c. with a human epithelial cancer previously shown to produce high levels of PTHRP in vitro. Total plasma calcium was monitored before and after tumor development and increased steadily when the tumor reached greater than or equal to 0.5 cm(3). When total calcium was greater than or equal to 2.85 mmol/liter, animals were treated with a constant infusion of EB1089 or vehicle alone for a period of 2 weeks. A significant and sustained reduction of plasma calcium from 3.2 +/- 0.1 to 2.7 +/- 0.08 (P < 0.01) mmol/liter was observed during infusion with EB1089. In contrast, calcium levels in vehicle-treated animals continued to rise during the infusion period, Tumor growth velocity also slowed significantly after the administration of EB1089 as compared with vehicle-treated animals. Plasma PTHRP levels measured at the end of the 2 weeks' infusion period were significantly lower in animals treated with EB1089 as compared with animals treated with vehicle alone (44 +/- 8 pg/ml versus 194 +/- 35 pg/ml, P < 0.001). These results, therefore, demonstrate that EB1089 can reverse established hypercalcemia in a human model of squamous cancer. C1 Royal Victoria Hosp, Calcium Res Lab, Dept Med, Montreal, PQ H3A 1A1, Canada. McGill Univ, Dept Med, Montreal, PQ H3A 1A1, Canada. NCI, Mol Oncol Lab, Frederick, MD 21702 USA. RP Kremer, R (reprint author), Royal Victoria Hosp, Calcium Res Lab, Dept Med, H4-67,687 Pine Ave W, Montreal, PQ H3A 1A1, Canada. NR 37 TC 23 Z9 23 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 JUL 15 PY 1999 VL 59 IS 14 BP 3325 EP 3328 PG 4 WC Oncology SC Oncology GA 218EH UT WOS:000081539900008 PM 10416587 ER PT J AU Reddy, BS Kawamori, T Lubet, RA Steele, VE Kelloff, GJ Rao, CV AF Reddy, BS Kawamori, T Lubet, RA Steele, VE Kelloff, GJ Rao, CV TI Chemopreventive efficacy of sulindac sulfone against colon cancer depends on time of administration during carcinogenic process SO CANCER RESEARCH LA English DT Article ID FAMILIAL ADENOMATOUS POLYPOSIS; ANTIINFLAMMATORY AGENT; N-METHYLNITROSOUREA; MURINE MODEL; CYCLOOXYGENASE-2; INHIBITION; APOPTOSIS; ASPIRIN; EXPRESSION; TUMORS AB Epidemiological and model studies with laboratory animals have provided evidence that nonsteroidal anti-inflammatory drugs reduce the risk of colon cancer. Sulindac, a nonsteroidal anti-inflammatory drug, has been shown to inhibit azoxymethane (AOM)-induced colon carcinogenesis in rats when administered continuously before, during, and after carcinogen treatment (initiation and postinitiation periods) or when given continuously beginning 14 weeks after carcinogen administration (promotion/progression stage). The present study was designed to investigate the chemopreventive efficacy of sulindac sulfone (exisulind), the sulfone metabolite of sulindac, when administered during the promotion/progression stage of colon carcinogenesis in comparison to the effect during the initiation and postinitiation periods. We have also studied the modulating effect of exisulind on colonic tumor apoptosis. At 5 weeks of age, groups of male F344 rats were fed diets containing 0%, 0.06%, and 0.12% exisulind. At 7 weeks of age, groups of animals were injected s.c. with AOM (15 mg/kg body weight, once weekly for 2 weeks). Animals intended for the promotion/progression study and receiving 0% exisulind were switched to an experimental diet containing 0.12% exisulind at 14 weeks after the second AOM treatment. All rats remained on their respective dietary regimens until the termination of the study, 50 weeks after the second AOM injection. Colon tumors were evaluated histopathologically for tumor type. Administration of 0.06% and 0.12% exisulind during the initiation and postinitiation periods significantly inhibited the incidence and multiplicity of invasive and/or noninvasive adenocarcinomas of the colon. The inhibition of colon tumorigenesis by exisulind was associated with a significant retardation of body weight gain shortly after sulfone administration and increased apoptosis in the colon tumors. In contrast, administration of the higher dose (0.12%) of exisulind during the promotion/progression stage had only minimal effects on colon tumorigenesis and apoptosis in the colon tumors, suggesting that early administration, but not late administration, may be required for chemopreventive efficacy of this drug. C1 Amer Hlth Fdn, Div Nutr Carcinogenesis, Valhalla, NY 10595 USA. NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. RP Reddy, BS (reprint author), Amer Hlth Fdn, Div Nutr Carcinogenesis, 1 Dana Rd, Valhalla, NY 10595 USA. RI Chinthalapally, Rao/B-3633-2010; Kawamori, Toshihiko/G-7636-2012 FU NCI NIH HHS [CA17613, N01-CN-55150] NR 32 TC 85 Z9 89 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 JUL 15 PY 1999 VL 59 IS 14 BP 3387 EP 3391 PG 5 WC Oncology SC Oncology GA 218EH UT WOS:000081539900020 PM 10416599 ER PT J AU Gnant, MFX Puhlmann, M Alexander, HR Bartlett, DL AF Gnant, MFX Puhlmann, M Alexander, HR Bartlett, DL TI Systemic administration of a recombinant vaccinia virus expressing the cytosine deaminase gene and subsequent treatment with 5-fluorocytosine leads to tumor-specific gene expression and prolongation of survival in mice SO CANCER RESEARCH LA English DT Article ID SUICIDE GENE; HEPATIC METASTASES; ANTITUMOR-ACTIVITY; MEDIATED TRANSFER; CARCINOMA-CELLS; COLON-CARCINOMA; GM-CSF; THERAPY; CANCER; VECTORS AB Suicide gene therapy using the cytosine deaminase (CD) gene and 5-fluorocytosine (5-FC) has shown promising results for the treatment of colon carcinoma cells ire vitro. Efficient viral infection and tumor-specific gene delivery is crucial for clinically measurable treatment effects. After proving efficient gene transfer in vitro, we demonstrate here that genes can be delivered to metastatic liver tumors in vivo in a highly selective manner using systemic delivery of a thymidine kinase-deleted (TK-) recombinant vaccinia virus (Western Reserve strain), When the vector was administered systemically in C57BL/6 mice or nude/athymic mice with established disseminated MC38 Liver metastases, transgene expression in tumors was usually 1,000- to 10,000-fold higher compared with other organs (n = 160; P < 0.00001). This tumor-specific gene transfer Leads to significant tumor responses and subsequent survival benefits after the transfer of the CD gene to liver metastases and subsequent systemic treatment with the prodrug 5-FC (P < 0.0001), We describe reporter gene and survival experiments both in immunocompetent and athymic nude mice, establishing a gene expression pattern over time and characterizing the treatment effects of the virus delivery/prodrug system. Cure rates of up to 30% in animals with established liver metastases show that suicide gem therapy using TK- vaccinia virus as a vector may be a promising system for the clinical application of tumor-directed gene therapy. C1 NCI, Surg Metab Sect, Surg Branch, NIH, Bethesda, MD 20892 USA. Univ Vienna, Dept Surg, A-1090 Vienna, Austria. Tech Univ Munich, Dept Surg, D-86175 Munich, Germany. RP Bartlett, DL (reprint author), NCI, Surg Metab Sect, Surg Branch, NIH, Bldg 10,Room 2B07,9000 Rockville Pike, Bethesda, MD 20892 USA. OI Gnant, Michael/0000-0003-1002-2118 NR 59 TC 59 Z9 61 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 JUL 15 PY 1999 VL 59 IS 14 BP 3396 EP 3403 PG 8 WC Oncology SC Oncology GA 218EH UT WOS:000081539900022 PM 10416601 ER PT J AU Duffey, DC Chen, Z Dong, G Ondrey, FG Wolf, JS Brown, K Siebenlist, U Van Waes, C AF Duffey, DC Chen, Z Dong, G Ondrey, FG Wolf, JS Brown, K Siebenlist, U Van Waes, C TI Expression of a dominant-negative mutant inhibitor-kappa B alpha of nuclear factor-kappa B in human head and neck squamous cell carcinoma inhibits survival, proinflammatory cytokine expression, and tumor growth in vivo SO CANCER RESEARCH LA English DT Article ID INDEPENDENT GROWTH; REGULATORY SYSTEM; INDUCED APOPTOSIS; SIGNAL RESPONSE; BREAST-CANCER; ACTIVATION; INTERLEUKIN-1-ALPHA; TRANSCRIPTION; PROLIFERATION; ANTIBODY AB We demonstrated recently that constitutive expression of proinflammatory cytokines interleukin (TL)-1 alpha; IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor in head and neck squamous cell carcinoma is correlated with activation of transcription factor nuclear factor (NF)-kappa B/Rel A (p50/p65), which binds the promoter region within each of the genes encoding this repertoire of cytokines. NF-kappa B can be activated after signal-dependent phosphorylation and degradation of inhibitor-kappa B alpha and has been reported to promote cell survival and growth. In the present study, we expressed a phosphorylation site mutant of inhibitor-kappa B alpha (I kappa B alpha M) In head and neck squamous cell carcinoma Lines UM-SCC-9, -11B, and -38 to determine the effect of inhibition of NF-kappa B on cytokine expression, cell survival in vitro, and growth in vivo. After transfection with I kappa B alpha M, only a few UM-SCC-9 clones were obtained that stably expressed the mutant I kappa B, suggesting that expression of a mutant I kappa B alpha may affect survival of the transfected UM-SCC cell lines. After cotransfection of I kappa B alpha M with a Lac-Z reporter, we Found that the number of surviving beta-galactosidase-positive cells in the three edl lines was reduced by 70-90% when compared with controls transfected with vector lacking the insert. In UM-SCC-9 cells that stably expressed I kappa B alpha M, inhibition of constitutive and tumor necrosis factor-alpha induced NF-kappa B activation, and production of all four cytokines was observed. Although UM-SCC-9 I kappa B alpha M-transfected cells proliferated at the same rate as vector-transfected cells in vitro, a significant reduction in growth of tumor xenografts was observed in SCID mice in vivo, The decreased growth of UM-SCC-9 I kappa B alpha M-transfected tumor cells accompanied decreased immunohistochemical detection of the activated form of NF-kappa B itt sits. These results provide evidence that NF-kappa B and I kappa B alpha play an important role in survival, constitutive and inducible expression of proinflammatory cytokines, and growth of squamous cell carcinoma. NF-kappa B could serve as a potential target for therapeutic intervention against cytokine and other immediate-early gene responses that contribute to the survival, growth, and pathogenesis of these cancers. C1 Natl Inst Deafness & Other Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, Bethesda, MD 20892 USA. Natl Inst Immunol Allergy & Infect Dis, Immunoregulat Lab, Bethesda, MD 20892 USA. RP Van Waes, C (reprint author), Natl Inst Deafness & Other Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, Bldg 10,Room 5D55,MSC-1419,10 Ctr Dr, Bethesda, MD 20892 USA. FU NIDCD NIH HHS [Z01-DC-00016] NR 56 TC 227 Z9 235 U1 0 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 JUL 15 PY 1999 VL 59 IS 14 BP 3468 EP 3474 PG 7 WC Oncology SC Oncology GA 218EH UT WOS:000081539900033 PM 10416612 ER PT J AU Mutoh, M Lung, FD Long, YQ Roller, PP Sikorski, RS O'Connor, PM AF Mutoh, M Lung, FD Long, YQ Roller, PP Sikorski, RS O'Connor, PM TI A p21(Waf1/Cip1) carboxyl-terminal peptide exhibited cyclin-dependent kinase-inhibitory activity and cytotoxicity when introduced into human cells SO CANCER RESEARCH LA English DT Article ID TUMOR-SUPPRESSOR GENE; ACTIVITY IN-VIVO; DNA-REPLICATION; NUCLEAR ANTIGEN; POTENTIAL MEDIATOR; LEUKEMIA-CELLS; CDK INHIBITOR; G(1) ARREST; P21; PCNA AB In the present study, we report the cyclin-dependent kinase (Cdk)inhibitory activity of a series of p21(Waf1/Cip1) (p21) peptide fragments spanning the whole protein against the cyclin D1/Cdk4 and cyclin E/Cdk2 enzymes. The most potent p21 peptide tested in our initial peptide series, designated Will, spanned amino acids 139 to 164, a region of p21 that has been found independently to bind to proliferating cell nuclear antigen and also to inhibit Cdk activity. We go on to report the importance of putative beta-strand and 3(10)-helix moths in Bile W10 peptide for cyclin-dependent kinase-inhibitory activity. We also describe the cellular activity of W10 and derivatives that were chemically linked to an antennapedia peptide, the latter segment acting as a cell membrane carrier. We found that the W10AP peptide exhibited growth inhibition that resulted from necrosis in human lymphoma CA46 cells. Furthermore, regions in the W10 peptide responsible for Cdk-inhibition were also important for the degree of this cellular activity. These studies provide insights that may eventually, through further design, yield agents for the therapy of cancer. C1 NCI, Med Chem Lab, NIH, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. NCI, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Roller, PP (reprint author), NCI, Med Chem Lab, NIH, Bldg 37,Room 5C-02, Bethesda, MD 20892 USA. NR 66 TC 63 Z9 63 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 1999 VL 59 IS 14 BP 3480 EP 3488 PG 9 WC Oncology SC Oncology GA 218EH UT WOS:000081539900035 PM 10416614 ER PT J AU Dong, G Chen, Z Kato, T Van Waes, C AF Dong, G Chen, Z Kato, T Van Waes, C TI The host environment promotes the constitutive activation of nuclear factor-kappa B and proinflammatory cytokine expression during metastatic tumor progression of murine squamous cell carcinoma SO CANCER RESEARCH LA English DT Article ID MELANOMA-CELLS; BREAST-CANCER; IN-VITRO; INDEPENDENT GROWTH; ALPHA DEGRADATION; INDUCED APOPTOSIS; EPITHELIAL-CELLS; NECROSIS-FACTOR; SERUM LEVELS; P65 SUBUNIT AB We reported previously that tumor cells isolated from metastases of the in vitro transformed squamous cell carcinoma Line Pam 212 exhibit an elevation in constitutive production of proinflammatory cytokines interleukin (IL)-1 alpha, IL-6, granulocyte-macrophage colony-stimulating factor, and KC (the murine homologue of chemokine Gro-alpha). The basis for constitutive expression of these cytokines after tumor progression in vivo is unknown. Regulation of the expression of these proinflammatory cytokines involves transcription factor nuclear factor kappa B (NF-kappa B), which can be activated by cytokines such as tumor necrosis factor (TNF)-alpha. In this study, we compared the constitutive and TNF-alpha-induced expression of proinflammatory cytokines in parental Pam 212 and metastatic LY-2 and LY-8 cell lines and determined the relationship of cytokine expression to activation of NF-kappa B, We found that the metastatic cell lines exhibited an increase in constitutive and TNF-alpha-inducible expression of proinflammatory cytokines when compared with parental Pam 212 cells, The increased cytokine expression was associated with an increase in constitutive and TNF-alpha-inducible activation of NF-kappa B as demonstrated by electrophoretic mobility shift assay and luciferase-reporter gene assay. Constitutive nuclear localization of NF-kappa B p65 was observed in LY-2 and LY-8 cells in culture and in tumor specimens but rarely in Pam 212 cells, consistent with the constitutive activation of NF-kappa B in tumor cells after selection in vivo. Induction of NF-kappa B by TNF-alpha was inhibited by the addition of protease inhibitors calpain inhibitor I and N-tosyl-phechloromethyl ketone and antioxidant 1-pyrrolidinecarbodithioic acid, whereas constitutive activation of NF-kappa B and cytokine KC mRNA expression was inhibited by N-tosyl-phechloromethyl ketone alone. Overexpression of a human I kappa B alpha dominant suppresser in Pam 212 cells inhibited TNF-alpha-induced NF-kappa B binding activity and KC expression. These data indicate that activation of NF-kappa B contributes to increased expression of proinflammatory cytokines during metastatic tumor progression of squamous cell carcinoma, and that distinct mechanisms may be involved in the regulation of constitutive and TNF-alpha-induced activation of NF-kappa B in squamous cell carcinoma. C1 Natl Inst Deafness & Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD 20892 USA. RP Van Waes, C (reprint author), Natl Inst Deafness & Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bldg 10,Room 5D55,MSC-1419, Bethesda, MD 20892 USA. FU NIDCD NIH HHS [Z01-DC-00016] NR 57 TC 124 Z9 129 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 1999 VL 59 IS 14 BP 3495 EP 3504 PG 10 WC Oncology SC Oncology GA 218EH UT WOS:000081539900037 PM 10416616 ER PT J AU Kervinen, J Tobin, GJ Costa, J Waugh, DS Wlodawer, A Zdanov, A AF Kervinen, J Tobin, GJ Costa, J Waugh, DS Wlodawer, A Zdanov, A TI Crystal structure of plant aspartic proteinase prophytepsin: inactivation and vacuolar targeting SO EMBO JOURNAL LA English DT Article DE aspartic proteinases; phytepsin; saposin-like domain; transport to vacuoles; zymogen structure ID CYNARA-CARDUNCULUS L; HYDROLYTIC SPECIFICITY; PORCINE PEPSINOGEN; BARLEY GRAINS; CATHEPSIN-D; NK-LYSIN; CELLS; RESOLUTION; LOCALIZATION; ACTIVATION AB We determined at 2.3 Angstrom resolution the crystal structure of prophytepsin, a zymogen of a barley vacuolar aspartic proteinase. In addition to the classical pepsin-like bilobal main body of phytepsin, we also traced most of the propeptide, as well as an independent plant-specific domain, never before described in structural terms. The structure revealed that, in addition to the propeptide, 13 N-terminal residues of the mature phytepsin are essential for inactivation of the enzyme. Comparison of the plant-specific domain with NK-lysin indicates that these two saposin-like structures are closely related, suggesting that all saposins and saposin-like domains share a common topology. Structural analysis of prophytepsin led to the identification of a putative membrane receptor-binding site involved in Golgi-mediated transport to vacuoles. C1 NCI, Prot Struct Sect, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, Prot Engn Grp,Macromol Struct Lab, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, Lab Cell & Mol Struct SAIC, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Univ Nova Lisboa, Inst Tecnol Quim & Biol, Inst Biol Expt & Tecnol, P-2780 Oeiras, Portugal. RP Zdanov, A (reprint author), NCI, Prot Struct Sect, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. EM zdanov@ncifcrf.gov RI Costa, Julia/B-7131-2008 OI Costa, Julia/0000-0001-7782-6319 NR 51 TC 110 Z9 112 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD JUL 15 PY 1999 VL 18 IS 14 BP 3947 EP 3955 DI 10.1093/emboj/18.14.3947 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 221QL UT WOS:000081737700007 PM 10406799 ER PT J AU Prioleau, MN Nony, P Simpson, M Felsenfeld, G AF Prioleau, MN Nony, P Simpson, M Felsenfeld, G TI An insulator element and condensed chromatin region separate the chicken beta-globin locus from an independently regulated erythroid-specific folate receptor gene SO EMBO JOURNAL LA English DT Article DE beta-globin locus; boundary; condensed chromatin; domain; methylation ID AUTOSOMAL SEX REVERSAL; I-SENSITIVE DOMAIN; SRY-RELATED GENE; BITHORAX COMPLEX; CAMPOMELIC DYSPLASIA; TRANSGENIC MICE; HYPERSENSITIVE SITES; MOLECULAR ANALYSIS; ACTIVATION REGION; BINDING PROTEIN AB We have identified a folate receptor gene upstream of the chicken beta-globin locus and separated from it by a 16 kbp region of silent chromatin, We find that this receptor is expressed only at a stage of erythroid differentiation (CFU-E) preceding the activation of beta-globin genes, consistent with the role of folate receptors in proliferation. This discovery raises the question of how these two loci are regulated during erythropoiesis. Our data suggest that the folate receptor gene and the beta-globin locus are regulated independently. We show that a 3.3 kbp DNA region upstream of the folate receptor gene is sufficient to induce strong expression of a transgene in CFU-E stage cells. We also find that the region between the beta-globin locus and the folate receptor gene is fully methylated and condensed at this stage of differentiation. Its 3' boundary coincides with the 5' beta-globin insulator. We speculate that the 5' beta-globin boundary element might be important for the proper regulation of two adjacent domains activated at two different stages during differentiation. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Felsenfeld, G (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RI Prioleau, Marie-Noelle/G-9824-2014 NR 57 TC 131 Z9 134 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD JUL 15 PY 1999 VL 18 IS 14 BP 4035 EP 4048 DI 10.1093/emboj/18.14.4035 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 221QL UT WOS:000081737700016 PM 10406808 ER PT J AU Gubin, AN Njoroge, JM Bouffard, GG Miller, JL AF Gubin, AN Njoroge, JM Bouffard, GG Miller, JL TI Gene expression in proliferating human erythroid cells SO GENOMICS LA English DT Article ID HUMAN-BONE-MARROW; TRANSFERRIN RECEPTORS; LIQUID CULTURE; ERYTHROPOIETIN RECEPTOR; SEQUENCE TAGS; PROGENITORS; DIFFERENTIATION; PROTEIN; CLONES; MICE AB A complete understanding of human erythropoiesis will require a robust description of transcriptional activity in hematopoietic cells that proliferate and differentiate in response to erythropoietin (EPO). For this purpose, we cultured peripheral blood mononuclear cells in the presence or in the absence of EPO and examined the transcriptional profile of those cells arising only in response to EPO, A distinct population of CD71(++++) cells that demonstrated an average of six additional doublings in suspension culture and erythroid colony formation in methylcellulose was isolated. Suppression subtractive hybridization of mRNA isolated from those cells permitted the identification of transcribed genes. A summary of 719 expressed sequence tags (ESTs) describing 505 independent transcripts is provided here with a full analysis of each EST available at http://hembase.niddk.nih.gov. Several transcripts that matched genes previously reported in the context of erythroid differentiation including 4 cell surface proteins were expressed at this developmental stage. Active chromatin remodeling was suggested by the identification of 4 histone proteins, 4 high-mobility group proteins, 13 transcription factors, and 6 genes involved in DNA recombination and repair. Numerous genes associated with leukemic translocations were also recognized including topoisomerases I and II, nucleophosmin, Translin, EGR1, dek, pim-1, TFG, and MLL. In addition to known transcripts, 44 novel EST were discovered. This transcriptional profile provides the first genomic-scale description of gene activity in erythroid progenitor cells. C1 NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. RP Miller, JL (reprint author), NIDDK, Biol Chem Lab, NIH, Bldg 10,Room 9N308,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 36 TC 63 Z9 63 U1 1 U2 3 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 JUL 15 PY 1999 VL 59 IS 2 BP 168 EP 177 DI 10.1006/geno.1999.5855 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 221YZ UT WOS:000081756600007 PM 10409428 ER PT J AU Song, JS Haleem-Smith, H Arudchandran, R Gomez, J Scott, PM Mill, JF Tan, TH Rivera, J AF Song, JS Haleem-Smith, H Arudchandran, R Gomez, J Scott, PM Mill, JF Tan, TH Rivera, J TI Tyrosine phosphorylation of Vav stimulates IL-6 production in mast cells by a Rac/c-Jun N-terminal kinase-dependent pathway SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FC-EPSILON-RI; ACTIVATED T-CELLS; MULTIPLE SIGNALING PATHWAYS; NECROSIS-FACTOR-ALPHA; PROTOONCOGENE PRODUCT; NUCLEAR FACTOR; RHO-FAMILY; CYTOSKELETAL REORGANIZATION; MEDIATED INDUCTION; HISTAMINE-RELEASE AB This study investigates whether the guanine nucleotide exchange activity of Vav is linked to cytokine production in mast cells, Overexpression of Vav in the RBL-2H3 mast cell line resulted in the constitutive tyrosine phosphorylation and activation of Vav, We analyzed the functional effect of Vav overexpression on cytokine production. IL-2 and IL-6 mRNA levels were dramatically increased in Vav-overexpressing cells and correlated with increased NF-AT activity. Little or no effect was observed on the mRNA levels of IL-3, IL-4, GM-CSF, TNF-alpha, and TGF-beta, Fc epsilon RI engagement did not further enhance IL-2 and IL-6 mRNA levels and only slightly enhanced NF-AT activity, but dramatically increased the mRNA levels of other tested cytokines. To understand the signal transduction required, we focused primarily on IL-6 induction by measuring mitogen-activated protein kinase activity and analyzing the effects of mutant or dominant negative forms of Vav, Rad, and c-Jun N-terminal kinase-1 (JNK1), Vav overexpression resulted in the constitutive activation of JNK1 with little or no effect on p38 mitogen-activated protein kinase and ERK2, This was dependent on Vav-mediated activation of Rad as a Dbl domain-mutated Vav, inactive Rac N17, and inactive JNK1 do,m-regulated the Vav-induced JNK1 or IL-6 responses. Vav expression, but not expression of domain-mutated Vav, increased IL-6 secretion from nonimmortalized bone marrow-derived mast cells upon FceRI engagement. We conclude that Vav phosphorylation contributes to IL-6 induction in mast cells. C1 NIAMSD, Sect Chem Immunol, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Sch Med, Dept Obstet & Gynecol PHC3, Perinatal Res Facil, Washington, DC 20012 USA. Baylor Coll Med, Dept Microbiol & Immunol, Houston, TX 77030 USA. RP Rivera, J (reprint author), NIAMSD, Sect Chem Immunol, NIH, Bldg 10,Room 9N228,10 Ctr Dr,MSC 1820, Bethesda, MD 20892 USA. RI Tan, Tse-Hua/E-3983-2010 OI Tan, Tse-Hua/0000-0003-4969-3170 NR 62 TC 51 Z9 52 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 1999 VL 163 IS 2 BP 802 EP 810 PG 9 WC Immunology SC Immunology GA 215AY UT WOS:000081360800035 PM 10395673 ER PT J AU Zhou, P Devadas, K Tewari, D Jegorow, A Notkins, AL AF Zhou, P Devadas, K Tewari, D Jegorow, A Notkins, AL TI Processing, secretion, and anti-HIV-1 activity of IL-16 with or without a signal peptide in CD4(+) T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LYMPHOCYTE CHEMOATTRACTANT FACTOR; ESCHERICHIA-COLI HEMOLYSIN; NUCLEOTIDE-SEQUENCE; PROTEIN GLYCOSYLATION; HUMAN LYMPHOKINES; MOLECULAR-BASIS; GROWTH-FACTOR; PDZ DOMAIN; INTERLEUKIN-16; EXPRESSION AB CD4(+) T cells transfected with the C-terminal 130 aa of human IL-16 are rendered resistant to HIV infection. Whether the constitutively expressed IL-16 acts intracellularly, extracellularly, or both is not clear, To address this question and to further study the processing of IL-16, new constructs containing either the C-terminal 130 aa or the C-terminal 100 as (PDZ-like motif) were constructed with and without a signal peptide. Pulse-chase experiments and treatment of cells with brefeldin A and/or tunicamycin showed that IL-16 is secreted despite the absence of a signal peptide, but with a signal peptide IL-16 is processed through the endoplasmic reticulum-golgi pathway and is glycosylated, Cells expressing IL-16 linked to a signal peptide secrete considerably more IL-16 into the supernatant than cells expressing IL-16 without a signal peptide and are considerably more resistant to HIV replication. Resistance extends to almost 25 days for cells expressing IL-16 with signal peptide as compared with only 15 days for cells without signal peptide. Cells expressing the C-terminal 100 as not linked to a signal peptide are poor secretors of IL-16 and show little if any resistance to HIV. In contrast, cells expressing the C-terminal 100 as linked to a signal peptide secrete IL-16 and are resistant to HIT:replication, It is concluded that the secretion of IL-16 is required for HIV inhibition. C1 NIDR, Expt Med Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Zhou, P (reprint author), SW Fdn Biomed Res, Dept Virol & Immunol, POB 760549, San Antonio, TX 78245 USA. NR 40 TC 18 Z9 19 U1 1 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 1999 VL 163 IS 2 BP 906 EP 912 PG 7 WC Immunology SC Immunology GA 215AY UT WOS:000081360800048 PM 10395686 ER PT J AU Hoffmann, KF James, SL Cheever, AW Wynn, TA AF Hoffmann, KF James, SL Cheever, AW Wynn, TA TI Studies with double cytokine-deficient mice reveal that highly polarized Th1-and Th2-type cytokine and antibody responses contribute equally to vaccine-induced immunity to Schistosoma mansoni SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PROTECTIVE IMMUNITY; IFN-GAMMA; IRRADIATED CERCARIAE; INDUCED RESISTANCE; LIVER PATHOLOGY; DOWN-REGULATION; NITRIC-OXIDE; LUNG-STAGE; TNF-ALPHA; T-CELLS AB A fundamental obstacle to vaccine development in schistosomiasis mansoni is a lack of understanding of what type of an immune response should be invoked. We have addressed this central issue by using the radiation-attenuated cercariae vaccine in mice genetically engineered to exhibit highly polarized type 1 (IL-10/IL-4-deficient) or type 2 (IL-10/IL-12-deficient) cytokine and Ab phenotypes, Our data show that while significant differences in immunity exist after a single vaccination with irradiated cercariae in double cytokine-deficient vs wild-type mice, these differences disappear after two vaccinations. The most important finding of these studies, however, was revealed in vaccinated IL-10-deficient mice. These mice developed a mixed and elevated type 1- and type 2-associated immune response and developed anti-schistosome immunity at levels equal to or better than those in wild-type mice. This immunity in IL-10-deficient mice correlated with higher parasite-specific Ab titers, greater proliferative capacity of lymphocytes, increased frequency of IFN-gamma- and IL-4-secreting cells, elevated perivascular/peribronchial inflammatory responses in the lung, and greater in vitro schistosomulacidal capacity of parasite Ag-elicited cells. These results suggest that optimal vaccine-induced immunity against schistosomes is linked not to the development of a highly polarized response, but, rather, to the induction of both type 1- and type 2-associated immune responses. C1 NIAID, Parasit Dis Lab, Immunobiol Sect, NIH, Bethesda, MD 20892 USA. Biomed Res Inst, Rockville, MD 20852 USA. RP Wynn, TA (reprint author), NIAID, Parasit Dis Lab, Immunobiol Sect, NIH, Bldg 4,Room 126,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Wynn, Thomas/C-2797-2011 NR 53 TC 107 Z9 116 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 1999 VL 163 IS 2 BP 927 EP 938 PG 12 WC Immunology SC Immunology GA 215AY UT WOS:000081360800051 PM 10395689 ER PT J AU Yang, RC Salazar-Onfray, F Charo, J Malmberg, KJ Evrin, K Maes, H Kono, K Hising, C Petersson, M Larsson, O Lan, L Appella, E Sette, A Celis, E Kiessling, R AF Yang, RC Salazar-Onfray, F Charo, J Malmberg, KJ Evrin, K Maes, H Kono, K Hising, C Petersson, M Larsson, O Lan, L Appella, E Sette, A Celis, E Kiessling, R TI Identification of new HER2/neu-derived peptide epitopes that can elicit specific CTL against autologous and allogeneic carcinomas and melanomas SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; TUMOR-INFILTRATING LYMPHOCYTES; OVARIAN-CANCER; DENDRITIC CELLS; HLA-A2 MELANOMAS; ANTIGEN; RECOGNIZE; EXPRESSION; INDUCTION; RECEPTOR AB Twenty-two new HLA-A2.1-binding peptides derived from the protooncogene HER2/neu were identified and analyzed for their capacity to elicit peptide and tumor-specific CTL responses. We used peptide-pulsed autologous DC from the ascites of patients with ovarian carcinomas to induce CTL. Of the 22 tested new HER2/neu-derived epitopes that could bind HLA-A2,vith high (IC50 < 50 nM) or intermediate (50 nM < IC50 < 500 nM) affinity, we report the recognition by CTL of at least four novel epitopes, including HER2(9(435)), HER2(9(665)), HER2(9(689)), and HER2(10(952)), and confirm that of the known HER2 (9(369)) epitope, These epitopes were able to elicit CTL that specifically killed peptide-sensitized target cells and, most importantly, a HER2/neu-transfected cell line and the autologous tumor cells. We also confirm that HER2/neu is overexpressed in several melanoma lines, and as a new finding, report that some of these lines are sensitive to CTL induced by the HER2 (9(369)), HER2(9(435)), and HER2(9(689)) epitopes. Finally, CTL clones specific for HER2 (9(369)), HER2(9(435)), and HER2(9(689)) epitopes were isolated from tumor-specific CTL lines, further demonstrating the immunodominance of these epitopes, These findings broaden the potential application of HER2/neu-based immunotherapy. C1 Karolinska Hosp, Radiumhemmet, Dept Pathol & Oncol, S-17176 Stockholm, Sweden. Karolinska Inst, Ctr Microbiol & Tumor Biol, Stockholm, Sweden. Yamanashi Med Univ, Dept Surg 1, Yamanashi, Japan. NCI, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Epiimmune, San Diego, CA 92121 USA. RP Kiessling, R (reprint author), Karolinska Hosp, Radiumhemmet, Dept Pathol & Oncol, S-17176 Stockholm, Sweden. RI Charo, Jehad/K-4433-2013; OI Charo, Jehad/0000-0002-5409-9160; Malmberg, Karl-Johan/0000-0002-8718-9373 NR 40 TC 0 Z9 0 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 1999 VL 163 IS 2 BP 1037 EP 1044 PG 8 WC Immunology SC Immunology GA 215AY UT WOS:000081360800064 ER PT J AU Fischer, B Yefidoff, R Major, DT Rutman-Halili, I Shneyvays, V Zinman, T Jacobson, KA Shainberg, A AF Fischer, B Yefidoff, R Major, DT Rutman-Halili, I Shneyvays, V Zinman, T Jacobson, KA Shainberg, A TI Characterization of "mini-nucleotides" as P2X receptor agonists in rat cardiomyocyte cultures. An integrated synthetic, biochemical, and theoretical study SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MOLECULAR-ORBITAL METHODS; VALENCE BASIS-SETS; EXTRACELLULAR ATP; ADENOSINE RECEPTORS; 2-THIOETHER DERIVATIVES; VENTRICULAR MYOCYTES; CARDIAC MYOCYTES; 2ND-ROW ELEMENTS; PURINOCEPTORS; SYSTEM AB The design and synthesis of "mini-nucleotides", based on a xanthine-alkyl phosphate scaffold, are described. The physiological effects of the new compounds were evaluated in rat cardiac cell culture regarding Ca2+ elevation and contractility. The results indicate biochemical and physiological profiles similar to those of ATP, although at, higher concentrations. The biological target molecules of these "mini-nucleotides" were identified by using selective P2-R and A(1)-R antagonists and P2-R subtype selective agonists. On the basis of these results and of experiments in Ca2+ free medium, in which [Ca2+](i) elevation was not observed, we concluded that interaction of the analogues is likely with P2X receptor subtypes, which causes Ca2+ influx. Theoretical calculations analyzing electronic effects within the series of xanthine-alkyl phosphates were performed on reduced models at quantum mechanical levels. Calculated dipole moment vectors, electrostatic potential maps, and volume parameters suggest an explanation for the activity or inactivity of the synthesized derivatives and predict a putative binding site environment for the active agonists. Xanthine-alkyl phosphate analogues proved to be selective agents for activation of PBX-R subtypes, whereas ATP activated all P2-R subtypes in cardiac cells. Therefore, these analogues may serve as prototypes of selective drugs aiming at cardiac disorders mediated through P2X receptors. C1 Bar Ilan Univ, Dept Chem, IL-52900 Ramat Gan, Israel. Bar Ilan Univ, Fac Life Sci, Gonda Goldschmied Med Res Ctr, IL-52900 Ramat Gan, Israel. NIDDK, LBC, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. RP Fischer, B (reprint author), Bar Ilan Univ, Dept Chem, IL-52900 Ramat Gan, Israel. RI Jacobson, Kenneth/A-1530-2009; Major, Dan/J-8761-2014 OI Jacobson, Kenneth/0000-0001-8104-1493; Major, Dan/0000-0002-9231-0676 NR 59 TC 21 Z9 22 U1 0 U2 3 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 JUL 15 PY 1999 VL 42 IS 14 BP 2685 EP 2696 DI 10.1021/jm990085i PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 218BB UT WOS:000081532500020 PM 10411489 ER PT J AU Farshori, P Kachar, B AF Farshori, P Kachar, B TI Redistribution and phosphorylation of occludin during opening and resealing of tight junctions in cultured epithelial cells SO JOURNAL OF MEMBRANE BIOLOGY LA English DT Article DE tight junction; occludin; ZO-1; transepithelial resistance ID PROTEIN-KINASE-C; PHORBOL ESTER; POSSIBLE INVOLVEMENT; MEMBRANE-PROTEIN; ZONULA-OCCLUDENS; CYCLIC-AMP; PERMEABILITY; LOCALIZATION; STRANDS; IDENTIFICATION AB We studied the expression, distribution, and phosphorylation of the tight junction (TJ) protein occludin in confluent MDCK cell monolayers following three procedures for opening and resealing of TJs. When Ca2+ is transiently removed from the culture medium, the TJs open and the cells separate from each other, but the occludin band around each cell is retained. When Ca2+ is reintroduced, the TJs reseal. When the monolayers are exposed to prolonged Ca2+ starvation the cells maintain contact, but occludin disappears from the cell borders and can be detected only in a cytoplasmic compartment. When Ca2+ is reintroduced, new TJs are assembled and the transepithelial electrical resistance (TER) is reestablished in about 20 hr. Monolayers treated with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) show a different pattern of TJ opening: the cell-cell contact is maintained but the TJ strand network, as seen in freeze-fracture replicas, becomes discontinuous. Occludin is still localized at the cell periphery, but in a pattern of distribution that matches the discontinuous TJ. These TJs do not reseal even 24 hr after removal of the TPA. Western blot analysis showed that the 62-65 kD double band of occludin did not change with these treatments. However, in vivo phosphorylation analysis showed that the TPA treatment reduced the phosphorylation levels of occludin, while the prolonged Ca2+ starvation completely dephosphorylated the two occludin bands. In addition, a highly phosphorylated 71 kD band that immunoprecipitates with occludin is not present when TJ is opened by the Ca2+ removal. Phosphoaminoacid analysis showed that the 62-65 kD occludin bands are phosphorylated on serine and threonine, while the 71 kD band was phosphorylated exclusively on serine. Our results provide further evidence that phosphorylation of occludin is an important step in regulating TJ formation and permeability. C1 Natl Inst Deafness & Other Commun Disorders, Sect Struct Cell Biol, NIH, Bethesda, MD 20892 USA. RP Kachar, B (reprint author), Natl Inst Deafness & Other Commun Disorders, Sect Struct Cell Biol, NIH, Bethesda, MD 20892 USA. NR 44 TC 117 Z9 118 U1 0 U2 6 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0022-2631 J9 J MEMBRANE BIOL JI J. Membr. Biol. PD JUL 15 PY 1999 VL 170 IS 2 BP 147 EP 156 DI 10.1007/s002329900544 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Physiology SC Biochemistry & Molecular Biology; Cell Biology; Physiology GA 220UW UT WOS:000081686700005 PM 10430658 ER PT J AU Ohshima, T Gilmore, EC Longenecker, G Jacobowitz, DM Brady, RO Herrup, K Kulkarni, AB AF Ohshima, T Gilmore, EC Longenecker, G Jacobowitz, DM Brady, RO Herrup, K Kulkarni, AB TI Migration defects of cdk5(-/-) neurons in the developing cerebellum is cell autonomous SO JOURNAL OF NEUROSCIENCE LA English DT Article DE neuronal migration; cdk5; cerebellar development; Purkinje cell; granule cell; cell autonomous ID CYCLIN-DEPENDENT KINASE-5; DIRECTED PROTEIN-KINASE; REELER-LIKE PHENOTYPE; WEAVER MOUSE CEREBELLUM; GRANULE CELL; CORTICAL DEVELOPMENT; MOLECULAR-CLONING; MUTANT MICE; REGULATORY SUBUNIT; CDC2-LIKE KINASE AB Cyclin-dependent kinase 5 (Cdk5) is a member of the family of cell cycle-related kinases. Previous neuropathological analysis of cdk5(-/-) mice showed significant changes in CNS development in regions from cerebral cortex to brainstem. Among the defects in these animals, a disruption of the normal pattern of cell migrations in cerebellum was particularly apparent, including a pronounced abnormality in the location of cerebellar Purkinje cells. Complete analysis of this brain region is hampered in the mutant because most of cerebellar morphogenesis occurs after birth and the cdk5(-/-) mice die in the perinatal period. To overcome this disadvantage, we have generated chimeric mice by injection of cdk5(-/-) embryonic stem cells into host blastocysts. Analysis of the cerebellum from the resulting cdk5(-/-) <-> cdk5(+/+) chimeric mice shows that the abnormal location of the mutant Purkinje cells is a cell-autonomous defect. In addition, significant numbers of granule cells remain located in the molecular layer, suggesting a failure to complete migration from the external to the internal granule cell layer. In contrast to the Purkinje and granule cell populations, all three of the deep cerebellar nuclear cell groupings form correctly and are composed of cells of both mutant and wild-type genotypes. Despite similarities of the cdk5(-/-) phenotype to that reported in reeler and mdab-1(-/-) (scrambler/yotari) mutant brains, reelin and disabled-1 mRNA were found to be normal in cdk5(-/-) brain. Together, the data further support the hypothesis that Cdk5 activity is required for specific components of neuronal migration that are differentially required by different neuronal cell types and by even a single neuronal cell type at different developmental stages. C1 NIDCR, Funct Genom Unit, Gene Targeting Facil, NIH, Bethesda, MD 20892 USA. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. Case Western Reserve Univ, Sch Med, Alzheimer Res Lab, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Neurosci, Cleveland, OH 44106 USA. RP Ohshima, T (reprint author), RIKEN, Inst Phys & Chem Res, Brain Sci Inst, Dev Neurobiol Lab, 2-1 Hirosawa, Wako, Saitama 3510198, Japan. FU NINDS NIH HHS [NS20591] NR 57 TC 104 Z9 109 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 15 PY 1999 VL 19 IS 14 BP 6017 EP 6026 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 215JB UT WOS:000081377600030 PM 10407039 ER PT J AU Merchan, M Serrano-Andres, L Slater, LS Roos, BO McDiarmid, R Xing, Y AF Merchan, M Serrano-Andres, L Slater, LS Roos, BO McDiarmid, R Xing, Y TI Electronic spectra of 1,4-cyclohexadiene and 1,3-cyclohexadiene: A combined experimental and theoretical investigation SO JOURNAL OF PHYSICAL CHEMISTRY A LA English DT Article ID MULTICONFIGURATIONAL PERTURBATION-THEORY; NORBORNADIENE; TRANSITIONS; STATE; CYCLOPENTADIENE; CYCLOHEXADIENE; SPECTROSCOPY; CYCLOHEXENE; IONIZATION AB The electronically excited states of the two isomers 1,3- and 1,4-cyclohexadiene are examined by means of multiconfigurational second-order perturbation (CASPT2) theory with extended ANO-type basis sets. The calculations comprise the lower valence excited states plus all singlet 3s, 3p, and 3d members of the Rydberg series converging to the first ionization limit for the 1,3 isomer and the two first limits for 1,4. Companion optical and resonantly enhanced multiphoton ionization spectroscopic measurements were made on the 1,3 isomer. The computed vertical excitation energies were found to be in agreement with the available experimental energies for both systems. New assignments are proposed on the basis of combined experimental and theoretical efforts. C1 Univ Valencia, Dept Quim Fis, E-46100 Valencia, Spain. Chem Ctr Lund, Dept Theoret Chem, S-22100 Lund, Sweden. Natl Inst Hlth, Chem Phys Lab, Natl Inst Diabetes & Digest & Kidney Dis, Bethesda, MD 20892 USA. RP Roos, BO (reprint author), Univ Valencia, Dept Quim Fis, Dr Moliner 50 Burjossot, E-46100 Valencia, Spain. NR 43 TC 28 Z9 28 U1 2 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1089-5639 J9 J PHYS CHEM A JI J. Phys. Chem. A PD JUL 15 PY 1999 VL 103 IS 28 BP 5468 EP 5476 DI 10.1021/jp991266z PG 9 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 219FX UT WOS:000081598200010 ER PT J AU Kim, S Ge, H Ohtaka-Maruyama, C Chepelinsky, AB AF Kim, S Ge, H Ohtaka-Maruyama, C Chepelinsky, AB TI The transcription factor Sp3 interacts with promoter elements of the lens specific MIP gene SO MOLECULAR VISION LA English DT Article ID MAJOR INTRINSIC PROTEIN; BOX-BINDING-PROTEINS; C-MYC; SP1-MEDIATED TRANSCRIPTION; SYNERGISTIC ACTIVATION; REGULATORY ELEMENTS; FUNCTIONAL ANALYSES; NEGATIVE REGULATOR; OCULAR LENS; RAT LENS AB PURPOSE: To characterize the cis regulatory elements and their interaction with transcription factors responsible for the lens specific expression of the MIP gene, which encodes the Major Intrinsic Protein of the lens fiber membranes. METHODS: Study interaction of factors present in newborn mouse lens nuclear extracts with DNA fragments corresponding to mouse MIP gene 5' flanking sequence by electrophoresis mobility shift assay (EMSA) and DNase I footprinting. RESULTS: We found a high degree of identity in the first 100 bp of 5' flanking sequence of mice and humans, however, a lower degree of conservation is observed further upstream. We have found by DNase I footprinting analysis that lens specific factors may interact with the first 100 bp of 5' flanking sequence. A domain containing an E box, conserved in mouse and human, may interact with a lens specific factor. However, general factors may interact with a NF-1 binding site. An overlapping GC and CT box is present in the mouse MIP gene. In the human MIP gene GC and CT boxes are found in different domains of the MIP gene promoter. Both CT boxes interact with factors present in lens nuclear extracts including Sp3. They are able to interact with purified Sp1but not with Sp1 present in mouse lens nuclear extracts. CONCLUSIONS: The transcription factor Sp3 may play an important role in regulating MIP gene expression in the lens. C1 NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Chepelinsky, AB (reprint author), NEI, Mol & Dev Biol Lab, NIH, Bldg 6,Rm 211,6 Ctr Dr,MSC 2730, Bethesda, MD 20892 USA. NR 83 TC 0 Z9 0 U1 0 U2 0 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD JUL 15 PY 1999 VL 5 IS 12 BP U1 EP U10 PG 10 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 240JZ UT WOS:000082824000001 ER EF