FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Matochik, JA London, ED Eldreth, DA Cadet, JL Bolla, KI AF Matochik, JA London, ED Eldreth, DA Cadet, JL Bolla, KI TI Frontal cortical tissue composition in abstinent cocaine abusers: a magnetic resonance imaging study SO NEUROIMAGE LA English DT Article DE magnetic resonance imaging; gray matters; white matter; frontal cortex; anterior cingulate gyrus; orbitofrontal cortex; cocaine abuse ID VOXEL-BASED MORPHOMETRY; CRACK-COCAINE; DEPENDENCE; MORPHOLOGY; ALCOHOL; VOLUME; LOBE; MRI; PERFORMANCE; INSTITUTE AB Cocaine abusers exhibit impairment of executive cognitive functions that are mediated by the frontal cortex. This work tested for structural (i.e.. tissue composition) abnormalities that may underlie such performance deficits. Research participants were cocaine abusers (n = 14) abstinent for 20 days and a non-drug-using comparison group (n = 11), who underwent magnetic resonance imaging (T1-weighted scans of the brain). Gray matter and white matter tissue densities were determined using voxel-based morphometry with small volume correction based on a priori hypotheses derived from functional imaging of the same subjects. Cocaine abusers had significantly lower gray matter tissue density than did the non drub users in 10 of 13 small volumes analyzed in the frontal cortex [bilateral anterior cingulate gyrus (infragenual and perigenual regions) and medial orbitofrontal cortex and the lateral orbitofrontal cortex and middle/dorsal cingulate gyrus in the right hemisphere]. No group differences were found in white matter density of the frontal cortex. These results extend our previous findings of defective frontal cortical activation (indexed by cerebral blood flow) in cocaine abusers to include abnormalities in gray matter tissue density in the same frontal cortical regions. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NIDA, Neuroimaging Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. NIDA, Mol Neuropsychiat Branch, Intramural Res Program, Baltimore, MD 21224 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Biobehav Sci, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90024 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21224 USA. RP Matochik, JA (reprint author), NIDA, Neuroimaging Res Branch, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. FU NCRR NIH HHS [M01 RR02719]; NIDA NIH HHS [DA 11426] NR 32 TC 154 Z9 157 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUL PY 2003 VL 19 IS 3 BP 1095 EP 1102 DI 10.1016/S1053-8119(03)00244-1 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 706ZR UT WOS:000184485400055 PM 12880835 ER PT J AU Elvevag, B Kerbs, KM Malley, JD Seeley, E Goldberg, TE AF Elvevag, B Kerbs, KM Malley, JD Seeley, E Goldberg, TE TI Autobiographical memory in schizophrenia: An examination of the distribution of memories SO NEUROPSYCHOLOGY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; NEUROPSYCHOLOGICAL FUNCTION; MATCHED TASKS; IMPAIRMENT; RECALL; RECOGNITION; RETENTION; RETRIEVAL; DISORDER; REMOTE AB Patients with schizophrenia display numerous memory impairments. Examination of autobiographical memory distribution across the life span can constrain theories of how schizophrenia affects memory. Previously, schizophrenic patients were shown to produce fewer memories from early adulthood than from childhood or the recent past (A. Feinstein, T. E. Goldberg, B. Nowlin, & D. R. Weinberger, 1998), this temporal paucity corresponding with illness onset. The current study examined this issue further using a different (noncued) method. Age-matched schizophrenic patients (n = 21) and controls (n = 21) were to freely generate 50 episodes, after which they dated these memories. Patients generated fewer memories than did controls, especially from the recent decade. When the overall lower production of memories was controlled for, the groups displayed equivalent recency effects. It was concluded that patients' paucity of memories generated from the recent decade reflects encoding or acquisition problems, which may be associated with the illness period. C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. NIMH, Ctr Informat Technol, NIH, Bethesda, MD 20892 USA. RP Elvevag, B (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Bldg 10,Room 4S235, Bethesda, MD 20892 USA. EM elvevaab@intra.nimh.nih.gov NR 55 TC 25 Z9 25 U1 0 U2 1 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0894-4105 J9 NEUROPSYCHOLOGY JI Neuropsychology PD JUL PY 2003 VL 17 IS 3 BP 402 EP 409 DI 10.1037/0894-4105.17.3.402 PG 8 WC Psychology, Clinical; Neurosciences; Psychology SC Psychology; Neurosciences & Neurology GA 713BY UT WOS:000184836600007 PM 12959506 ER PT J AU Qu, Y Chang, L Klaff, J Seemann, R Rapoport, SI AF Qu, Y Chang, L Klaff, J Seemann, R Rapoport, SI TI Imaging brain phospholipase A(2)-mediated signal transduction in response to acute fluoxetine administration in unanesthetized rats SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE serotonin; phospholipase A(2); arachidonic acid; fluoxetine; signal transduction; reuptake; imaging ID FATTY-ACID INCORPORATION; POSITRON-EMISSION-TOMOGRAPHY; CEREBRAL GLUCOSE-UTILIZATION; SEROTONIN 5-HT2C RECEPTOR; H-3 ARACHIDONIC-ACID; AWAKE RATS; NUCLEUS-ACCUMBENS; EXTRACELLULAR SEROTONIN; UPTAKE INHIBITION; FRONTAL-CORTEX AB Fluoxetine, selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor, is used widely to treat depression and related disorders. By inhibiting presynaptic 5-HT reuptake, fluoxetine is thought to act by increasing 5-HT in the synaptic cleft, thus 5-HT binding to postsynaptic 5-HT2A/2C receptors. These receptors can be coupled via a G-protein to phospholipase A(2) (PLA(2)), which when activated releases the second messenger arachidonic acid from synaptic membrane phospholipids. To image this activation, fluoxetine (10 mg/kg) or saline vehicle was administered i.p. to unanesthetized rats, and regional brain incorporation coefficients k* of intravenously injected radiolabeled arachidonic acid were measured after 30 min. Compared with vehicle, fluoxetine significantly increased k* in prefrontal, motor, somatosensory, and olfactory cortex, as well as in the basal ganglia, hippocampus, and thalamus, Many of these regions demonstrate high densities of the serotonin reuptake transporter and of 5-HT2A/2C receptors. Brain stem, spinal cord, and cerebellum, which showed no significant response to fluoxetine, have low densities of the transporters and receptors. The results show that it is possible to image quantitatively PLA(2)-mediated signal transduction in vivo in response to fluoxetine. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Qu, Y (reprint author), Neurosci Johnson & Johnson Pharmaceut Res & Dev, 3210 Merryfield Row, San Diego, CA 92121 USA. NR 77 TC 20 Z9 21 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUL PY 2003 VL 28 IS 7 BP 1219 EP 1226 DI 10.1038/sj.npp.1300177 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 694KD UT WOS:000183773000001 PM 12784122 ER PT J AU Karcz-Kubicha, M Antoniou, K Terasmaa, A Quarta, D Solinas, M Justinova, Z Pezzola, A Reggio, R Muller, CE Fuxe, K Goldberg, SR Popoli, P Ferre, S AF Karcz-Kubicha, M Antoniou, K Terasmaa, A Quarta, D Solinas, M Justinova, Z Pezzola, A Reggio, R Muller, CE Fuxe, K Goldberg, SR Popoli, P Ferre, S TI Involvement of adenosine A1 and A(2A) receptors in the motor effects of caffeine after its acute and chronic administration SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE caffeine; adenosine A; receptor; adenosine A(2A) receptor; tolerance; motor activity; striatum ID LOCOMOTOR-ACTIVITY; NUCLEUS-ACCUMBENS; IN-VIVO; 6-HYDROXYDOPAMINE-LESIONED RATS; EXTRACELLULAR DOPAMINE; GLUTAMATE RELEASE; CEREBRAL-CORTEX; A(1) RECEPTORS; IP CAFFEINE; MOUSE-BRAIN AB The involvement of adenosine A(1) and A(2A) receptors in the motor effects of caffeine is still a matter of debate. In the present study, counteraction of the motor-depressant effects of the selective A(1) receptor agonist CPA and the A(2A) receptor agonist CGS 2 1680 by caffeine, the selective A, receptor antagonist CPT, and the A(2A) receptor antagonist MSX-3 was compared. CPT and MSX-3 produced motor activation at the same doses that selectively counteracted motor depression induced by CPA and CGS 2 1680, respectively. Caffeine also counteracted motor depression induced by CPA and CGS 21680 at doses that produced motor activation, However, caffeine was less effective than CPT at counteracting CPA and even less effective than MSX-3 at counteracting CGS 2 1680. On the other hand, when administered alone in habituated animals, caffeine produced stronger motor activation than CPT or MSX-3. An additive effect on motor activation was obtained when CPT and MSX-3 were coadministered. Altogether, these results suggest that the motor activating effects of acutely administered caffeine in rats involve the central blockade of both A(1) and A(2A) receptors, Chronic exposure to caffeine in the. drinking water (1,0 mg/ml) resulted in tolerance to the motor effects of an acute administration of caffeine, lack of tolerance to amphetamine, apparent tolerance to MSX-3 (shift to the left of its 'bell-shaped' dose-response curve), and true cross-tolerance to CPT. The present results suggest that development of tolerance to the effects of A(1) receptor blockade might be mostly responsible for the tolerance to the motor-activating effects of caffeine and that the residual motor-activating effects of caffeine in tolerant individuals might be mostly because of A(2A) receptor blockade. C1 NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, NIH,IRP,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. Karolinska Inst, Dept Neurosci, Stockholm, Sweden. Ist Super Sanita, Dept Pharmacol, I-00161 Rome, Italy. Univ Bonn, Inst Pharmaceut, D-5300 Bonn, Germany. RP Ferre, S (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, NIH,IRP,Dept Hlth & Human Serv, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Popoli, Patrizia/B-5397-2008; Justinova, Zuzana/A-9109-2011; Ferre, Sergi/K-6115-2014; Terasmaa, Anton/I-3312-2015; Solinas, Marcello/M-3500-2016; Muller, Christa/C-7748-2014 OI Justinova, Zuzana/0000-0001-5793-7484; Ferre, Sergi/0000-0002-1747-1779; Terasmaa, Anton/0000-0002-5139-1764; Solinas, Marcello/0000-0002-0664-5964; Muller, Christa/0000-0002-0013-6624 NR 59 TC 115 Z9 115 U1 3 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUL PY 2003 VL 28 IS 7 BP 1281 EP 1291 DI 10.1038/sj.npp.1300167 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 694KD UT WOS:000183773000008 PM 12700682 ER PT J AU Heekeren, HR Wartenburger, I Schmidt, H Schwintowski, HP Villringer, A AF Heekeren, HR Wartenburger, I Schmidt, H Schwintowski, HP Villringer, A TI An fMRI study of simple ethical decision-making SO NEUROREPORT LA English DT Article DE brain mapping; decision-making; moral judgement; neuroethics; social behavior ID PREFRONTAL CORTEX; MORAL JUDGMENT/; MIND; ACTIVATION; NETWORKS; MEMORY; BRAIN; TASK AB Recent functional neuroimaging studies suggest that ventromedial prefrontal cortex (vmPFC), left posterior superior temporal sulcus (pSTS) and posterior cingulate cortex are engaged during moral decision-making on complex dilemmatic or salient emotional stimuli. In this fMRI study we investigated which of these brain regions are activated during simple ethical decision-making about unambiguous scenarios not containing direct bodily harm or violence. Simple moral decisions compared to semantic decisions resulted in activation of left pSTS and middle temporal gyrus, bilateral temporal poles, left lateral PFC and bilateral vmPFC. These results suggest that pSTS and vmPFC are a common neuronal substrate of decision-making about complex ethical dilemmas, processing material evocative of moral emotions and simple ethical decision-making about scenarios devoid of violence and direct bodily harm. C1 NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Charite, Dept Neurol, Berlin, Germany. Univ Magdeburg, Dept Neurol 2, Magdeburg, Germany. Univ Potsdam, Dept Patholinguist, Potsdam, Germany. Humboldt Univ, Dept Law, Berlin, Germany. RP Heekeren, HR (reprint author), NIMH, Lab Brain & Cognit, NIH, Bldg 10,Rm 1D80, Bethesda, MD 20892 USA. RI Heekeren, Hauke/B-7739-2008; Wartenburger, Isabell/A-2820-2013 OI Heekeren, Hauke/0000-0001-7912-6826; NR 25 TC 143 Z9 145 U1 7 U2 36 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JUL 1 PY 2003 VL 14 IS 9 BP 1215 EP 1219 DI 10.1097/01.wnr.0000081878.45938.a7 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 707AC UT WOS:000184486400005 PM 12824762 ER PT J AU Ferguson, SA Delclos, KB Newbold, RR Flynn, KM AF Ferguson, SA Delclos, KB Newbold, RR Flynn, KM TI Dietary ethinyl estradiol exposure during development causes increased voluntary sodium intake and mild maternal and offspring toxicity in rats SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE ethinyl estradiol; endocrine disrupter; sodium intake; locomotor activity; play behavior; saccharin intake ID SEXUALLY DIMORPHIC BEHAVIOR; ESTROGEN-RECEPTORS-ALPHA; DOSE ORAL-CONTRACEPTIVES; FEMALE GUINEA-PIG; PRENATAL EXPOSURE; DIETHYLSTILBESTROL DES; SEX-DIFFERENCES; AGGRESSIVE-BEHAVIOR; GONADAL-HORMONES; ENDOCRINE DISRUPTORS AB Exogenous estrogen exposure during development often results in behavioral masculinization and/or defeminization of genetic females. Genetic males may be defeminized, hypermasculinized or even demasculinized after similar treatment. Here, pregnant Sprague-Dawley rats consumed phytoestrogen-free diets containing 0, 1, 5 or 200 ppb EE2 beginning on gestational day (GD) 7. Offspring were weaned to the same maternal diet and maintained gonadally intact. There were mild effects on body weight and food consumption in dams of the 200 ppb group and their offspring weighed less at birth than those of the control group; however, gross assessments of nursing behavior were normal in all dietary groups. Postweaning, offspring of the 200 ppb group weighed less and consumed less food than controls. There were no EE2-related effects on open-field activity (tested at postnatal days (PND) 22-24, 43-45 and 64-66), play behavior (tested at PND 35), running wheel activity (PND 63-77) or intake of a 0.3% saccharin-flavored solution (PND 69-71). Intake of a 3.0% sodium chloride-flavored solution on PND 73-75 was increased in both male and female offspring of the 200 ppb group relative to same-sex controls, an effect that is reportedly estrogen mediated. Sodium chloride-flavored solution intake is a sexually dimorphic behavior for which female rats consume more than males. Here, while EE2 exposure had few effects on the conventional tests of sexually dimorphic behaviors, exposure to 200 ppb in the diet appeared to feminize genetic males and hyperfeminize genetic females with regard to sodium intake. (C) 2003 Elsevier Science Inc. All rights reserved. C1 US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, Jefferson, AR 72079 USA. US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. NIEHS, Environm Toxicol Program, Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Ferguson, SA (reprint author), US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, 3900 NCTR Rd,HFT-132, Jefferson, AR 72079 USA. NR 71 TC 17 Z9 17 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD JUL-AUG PY 2003 VL 25 IS 4 BP 491 EP 501 DI 10.1016/S0892-0362(03)00015-1 PG 11 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 693AU UT WOS:000183693100008 PM 12798966 ER PT J AU Schwartz, S Elnitski, L Li, M Weirauch, M Riemer, C Smit, A Program, NCS Green, ED Hardison, RC Miller, W AF Schwartz, S Elnitski, L Li, M Weirauch, M Riemer, C Smit, A Program, NCS Green, ED Hardison, RC Miller, W TI MultiPipMaker and supporting tools: alignments and analysis of multiple genomic DNA sequences SO NUCLEIC ACIDS RESEARCH LA English DT Article ID LOCUS-CONTROL REGION; MOUSE GENOME; REGULATORY ELEMENTS; EVOLUTION; CIS; IDENTIFICATION; SUBSTITUTION; STRATEGIES; ENHANCER; PROGRAMS AB Analysis of multiple sequence alignments can generate important, testable hypotheses about the phylogenetic history and cellular function of genomic sequences. We describe the MultiPipMaker server, which aligns multiple, long genomic DNA sequences quickly and with good sensitivity (available at >http://bio.cse.psu.edu/ since May 2001). Alignments are computed between a contiguous reference sequence and one or more secondary sequences, which can be finished or draft sequence. The outputs include a stacked set of percent identity plots, called a MultiPip, comparing the reference sequence with subsequent sequences, and a nucleotide-level multiple alignment. New tools are provided to search MultiPipMaker output for conserved matches to a user-specified pattern and for conserved matches to position weight matrices that describe transcription factor binding sites (singly and in clusters). We illustrate the use of MultiPipMaker to identify candidate regulatory regions in WNT2 and then demonstrate by transfection assays that they are functional. Analysis of the alignments also confirms the phylogenetic inference that horses are more closely related to cats than to cows. C1 Penn State Univ, Dept Comp Sci & Engn, Pond Lab, University Pk, PA 16802 USA. Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. Penn State Univ, Dept Biol, University Pk, PA 16802 USA. Inst Syst Biol, Seattle, WA USA. NHGRI, Bethesda, MD 20892 USA. RP Miller, W (reprint author), Penn State Univ, Dept Comp Sci & Engn, Pond Lab, University Pk, PA 16802 USA. RI Hardison, Ross/G-1142-2010 OI Hardison, Ross/0000-0003-4084-7516 FU NHGRI NIH HHS [F32 HG002325, HG02325, R01 HG002238, HG02238]; NIDDK NIH HHS [DK27635] NR 45 TC 158 Z9 166 U1 0 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 JUL 1 PY 2003 VL 31 IS 13 BP 3518 EP 3524 DI 10.1093/nar/gkg579 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 695LT UT WOS:000183832900049 PM 12824357 ER PT J AU Liu, CY Bonner, TI Nguyen, T Lyons, JL Christian, SL Gershon, ES AF Liu, CY Bonner, TI Nguyen, T Lyons, JL Christian, SL Gershon, ES TI DNannotator: annotation software tool kit for regional genomic sequences SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DISORDER SUSCEPTIBILITY LOCUS; 13Q32; WORKBENCH; LINKAGE; SCHIZOPHRENIA; VISUALIZATION; PROGRAM; DNA AB Sequence annotation is essential for genomics-based research. Investigators of a specific genomic region who have developed abundant local discoveries such as genes and genetic markers, or have collected annotations from multiple resources, can be overwhelmed by the difficulty in creating local annotation and the complexity of integrating all the annotations. Presenting such integrated data in a form suitable for data mining and high-throughput experimental design is even more daunting. DNannotator, a web application, was designed to perform batch annotation on a sizeable genomic region. It takes annotation source data, such as SNPs, genes, primers, and so on, prepared by the end-user and/or a specified target of genomic DNA, and performs de novo annotation. DNannotator can also robustly migrate existing annotations in GenBank format from one sequence to another. Annotation results are provided in GenBank format and in tab-delimited text, which can be imported and managed in a database or spreadsheet and combined with existing annotation as desired. Graphic viewers, such as Genome Browser or Artemis, can display the annotation results. Reference data (reports on the process) facilitating the user's evaluation of annotation quality are optionally provided. DNannotator can be accessed at http://sky.bsd.uchicago.edu/DNannotator.htm. C1 Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. Cent S Univ, Natl Lab Med Genet China, Changsha, Hunan, Peoples R China. NIMH, Genet Lab, Bethesda, MD 20892 USA. Univ Illinois, Inst Psychiat, Chicago, IL USA. RP Liu, CY (reprint author), BSLC, R022,924 E 57th St, Chicago, IL 60637 USA. FU NIMH NIH HHS [R01 MH065560, R01 MH65560-01, R01 MH059535, R01MH59535] NR 23 TC 4 Z9 4 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 JUL 1 PY 2003 VL 31 IS 13 BP 3729 EP 3735 DI 10.1093/nar/gkg542 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 695LT UT WOS:000183832900097 PM 12824405 ER PT J AU Jarvholm, B Silverman, D AF Jarvholm, B Silverman, D TI Lung cancer in heavy equipment operators and truck drivers with diesel exhaust exposure in the construction industry SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID PROSTATE-CANCER; MORTALITY; RISK; ASSOCIATION; EMISSIONS AB Background: Several studies indicate that truck drivers have an increased risk of lung cancer, but few studies have examined lung cancer risk in heavy equipment operators. Workers in both occupations are exposed to diesel exhaust. Aims: To examine the incidence and mortality from lung cancer among truck drivers and among drivers of heavy vehicles. Methods: A computerised register of Swedish construction workers participating in health examinations between 1971 and 1992 was used. Male truck drivers (n = 6364) and drivers of heavy construction vehicles (n = 14 364) were selected as index groups; carpenters/electricians constituted the reference group (n = 119 984). Results: Operators of heavy construction equipment experienced no increased risk of lung cancer compared to risk among the carpenter/electrician referents (61 cases v 70.1 expected). However, a significant inverse trend risk with increasing use of cabins was apparent. Truck drivers had increased risks of cancer of the lung (61 cases v 47.3 expected) and prostate (124 cases v 99.7 expected), although only mortality for lung cancer was significantly increased. Comparisons with the general population showed similar results. Conclusion: Results are consistent with those of previous studies suggesting that heavy equipment operators with potential exposure to diesel exhaust may have little or no increased risk of lung cancer, although the use of cabins seemed to decrease the risk of lung cancer. The results for truck drivers are also consistent with previous reports of increased lung cancer risk among truck drivers exposed to diesel exhaust, as well as recent reports linking diesel exhaust exposure to prostate cancer. C1 Umea Univ, NUS, Dept Publ Hlth & Clin Med, S-90185 Umea, Sweden. NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Jarvholm, B (reprint author), Umea Univ, NUS, Dept Publ Hlth & Clin Med, S-90185 Umea, Sweden. NR 19 TC 34 Z9 36 U1 1 U2 8 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 JUL PY 2003 VL 60 IS 7 BP 516 EP 520 DI 10.1136/oem.60.7.516 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 692CC UT WOS:000183641900010 PM 12819286 ER PT J AU Lobdell, DT Buck, GM Weiner, JM Mendola, P AF Lobdell, DT Buck, GM Weiner, JM Mendola, P TI Using commercial telephone directories to obtain a population-based sample for mail survey of women of reproductive age SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article ID RESPONSE RATES; INCENTIVES; QUESTIONNAIRES; METAANALYSIS; PREVALENCE; IMPACT AB In the United States, sampling women of reproductive age from the general population for research purposes is a challenge. Even more difficult is conducting a population-based study of couples attempting pregnancy to assess fecundity and fertility or related impairments. To address the problem of obtaining representative samples from the population in order to study such health-related issues, a commercially and readily available CD-ROM telephone directory was used and tested as a sampling framework for studies aimed at enrolling gravid women aged 18-44 years. A self-administered questionnaire (SAQ) was mailed to a stratified random sample of 10 005 (3%) households in Erie County, NY, USA. Overall, 17% of the questionnaires were undeliverable despite updating all addresses with residential software before mailing. Thirteen per cent (n = 1089) of the households returned completed questionnaires, of which 35% (n = 377) were completed by women aged 18-44 years. Using 1990 census information for zip code, respondents were more likely to be white and to have higher median household incomes than non-respondents. Of the 377 women who completed the questionnaire, 79% had been pregnant at least once, 5% reported being unable to become pregnant, and 16% reporting never trying to become pregnant. Despite the overall low response to the SAQ, the sampling framework captured a diverse group of women of reproductive age who reported various fecundity and fertility outcomes. The use of low-cost commercially available software linked to census data for selecting samples of women or couples for reproductive and perinatal research may be possible; however, oversampling of households, use of incentives and follow-up of non-respondents is needed to ensure adequate sample sizes. C1 US EPA, Off Res & Dev, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. NICHHD, Epidemiol Branch, Div Epidemiol Stat & Prevent, Bethesda, MD 20892 USA. SUNY Buffalo, Sch Med & Biomed Sci, Dept Social & Prevent Med, Buffalo, NY 14260 USA. RP Lobdell, DT (reprint author), US EPA, Off Res & Dev, Natl Hlth & Environm Effects Res Lab, MD58A, Res Triangle Pk, NC 27711 USA. OI Mendola, Pauline/0000-0001-5330-2844; Buck Louis, Germaine/0000-0002-1774-4490 NR 27 TC 1 Z9 1 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD JUL PY 2003 VL 17 IS 3 BP 294 EP 301 DI 10.1046/j.1365-3016.2003.00502.x PG 8 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 701GB UT WOS:000184158900011 PM 12839542 ER PT J AU Neubert, JK Karai, L Jun, JH Kim, HS Olah, Z Iadarola, MJ AF Neubert, JK Karai, L Jun, JH Kim, HS Olah, Z Iadarola, MJ TI Peripherally induced resiniferatoxin analgesia SO PAIN LA English DT Article DE resiniferatoxin; vanilloid-1 receptor; analgesia; pain; rat ID VANILLOID CAPSAICIN RECEPTOR; RAT SENSORY GANGLIA; SPINAL-CORD; CONGENITAL INSENSITIVITY; TRIGEMINAL NEURALGIA; TOPICAL CAPSAICIN; PAIN SENSATION; NEURONS; HYPERALGESIA; VR1 AB Selective blockade of nociceptive pathways represents a mechanism-based approach that has attracted a large variety of pharmacological and molecular investigations. A potential site for selective intervention is the primary afferent nociceptive nerve terminal. Binding of resiniferatoxin (RTX) to the vanilloid-1 receptor (VR1) stimulates and then inactivates heat and vanilloid-responsive nerve endings involved in heat and inflammatory pain signaling which can progress to localized degeneration of the peripheral ending followed by regeneration. Application of RTX directly to peripheral nerve endings produces a long term, reversible attenuation of nociceptive transmission. Heat hyperalgesia and mechanical allodynia were assessed prior to injection of RTX into the hindpaw (baseline) and at acute (minutes-hours) and more chronic (days-weeks) times after injection. Acutely, an inverse dose-to-pain response (guarding, licking) for RTX (0.0625-2.0 mug) occurs, followed by selective attenuation of peripheral pain transmission. Thermal nociception was decreased in a concentration-dependent fashion and lasted up to 21 days, without impairing motor function. Administration of RTX blocked both inflammation-induced hyperalgesia and spinal c-Fos induction. The results demonstrate the efficacy and therapeutic potential of reversible, peripheral C-fiber 'inactivation' for intermediate duration pain control. (C) 2003 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. C1 Natl Inst Dent & Craniofacial Res, Pain Neurosensory Mech Branch, NIH, Bethesda, MD 20892 USA. Columbia Univ, Sch Dent & Oral Surg, New York, NY 10032 USA. RP Neubert, JK (reprint author), Natl Inst Dent & Craniofacial Res, Pain Neurosensory Mech Branch, NIH, Bethesda, MD 20892 USA. NR 39 TC 49 Z9 49 U1 4 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD JUL PY 2003 VL 104 IS 1-2 BP 219 EP 228 DI 10.1016/S0304-3959(03)00009-5 PG 10 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 703CP UT WOS:000184262700024 PM 12855332 ER PT J AU Nachman, S Kim, S King, J Abrams, EJ Margolis, D Petru, A Shearer, W Smith, E Moye, J Blanchard, S Hawkins, E Bouquin, P Vink, P Benson, M Estep, S Malinoski, F AF Nachman, S Kim, S King, J Abrams, EJ Margolis, D Petru, A Shearer, W Smith, E Moye, J Blanchard, S Hawkins, E Bouquin, P Vink, P Benson, M Estep, S Malinoski, F CA Pediat AIDS Clin Trials Grp Study TI Safety and immunogenicity of a heptavalent pneumococcal conjugate vaccine in infants with human immunodeficiency virus type 1 infection SO PEDIATRICS LA English DT Article DE heptavalent pneumococcal conjugate vaccine; Prevnar; safety; immunogenicity; HIV; pneumococcal polysaccharide vaccine ID CHILDREN; DISEASE AB Objective. Heptavalent pneumococcal conjugate vaccine (PCV) has been shown to be safe and effective in healthy infants and children. However, little is known about its use in children who have human immunodeficiency virus (HIV) infection and are known to be at increased risk of developing pneumococcal infections. This study was conducted to evaluate the safety and immunogenicity of heptavalent PCV in infants with HIV infection. Methods. The Pediatric AIDS Clinical Trials Group Study 292 Team randomized infants with HIV infection 2: 1 to receive heptavalent PCV or placebo in a double-blinded manner. Infants were vaccinated with 3 doses at 2-month intervals, starting at ages 56 to 180 days. A booster dose was given at 15 months of age. Immunogenicity was evaluated after the third dose of vaccine, before and after the booster dose, and at 24 months of age. Results. Thirty infants with HIV infection received PCV, and 15 received placebo. No differences in baseline characteristics were found across arms. Five severe acute reactions were experienced by 4 subjects: 3 in the PCV arm and 1 in the placebo arm; all occurred among subjects with symptomatic disease at study entry. No differences were found in the 2 arms with respect to the number or timing of new diagnoses through 24 months of age, including diagnoses of otitis media. However, when symptomatic subjects were examined separately, the first new diagnosis occurred more rapidly among PCV recipients. Three deaths, all judged to be unrelated to study vaccine, occurred during follow-up: 2 in the PCV arm and 1 in the placebo arm. The primary immunogenicity measures were based on composites of 4-fold changes in serotype-specific immunoglobulin G titers from preimmunization levels. We found a highly significant difference between the vaccine and placebo arms, with the PCV arm showing higher rates of response. Asymptomatic and symptomatic subjects who received PCV had similar immunologic responses for all serotypes. Conclusions. This study demonstrates that heptavalent PCV was well tolerated and not associated with vaccine-associated adverse reactions. Most important, this vaccine was immunogenic in the infant with HIV infection. However, additional studies of this vaccine (or others) must pay special attention to patients with symptomatic HIV disease, as they seem to be at higher risk for adverse events to any antigen. C1 SUNY Stony Brook, Hlth Sci Ctr, Dept Pediat, Stony Brook, NY 11794 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. Columbia Univ, Harlem Hosp Ctr, Dept Pediat, New York, NY USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Childrens Hosp Oakland, Dept Infect Dis, Oakland, CA USA. Texas Childrens Hosp, Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. NIAID, Pediat Med Branch, Div AIDS, NIH, Bethesda, MD 20892 USA. NICHHD, Pediat Adolescent & Mat AIDS Branch, NIH, Rockville, MD USA. Frontier Sci & Technol Res Fdn Inc, Stat & Data Anal Ctr, Chestnut Hill, MA USA. Pediat ACTG Operat Ctr, Rockville, MD USA. Frontier Sci & Technol Res Ctr, Stat & Data Management Ctr, Amherst, NY USA. San Francisco Gen Hosp, San Francisco, CA 94110 USA. NIAID, Pharmaceut & Regulatory Affairs Branch, Div AIDS, NIH, Bethesda, MD 20892 USA. Lederle Praxis Biol, W Henrietta, NY USA. RP Nachman, S (reprint author), SUNY Stony Brook, Hlth Sci Ctr, Dept Pediat, Stony Brook, NY 11794 USA. OI moye, john/0000-0001-9976-8586; Margolis, David/0000-0001-5714-0002 FU NIAID NIH HHS [AI-41110] NR 17 TC 53 Z9 58 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUL PY 2003 VL 112 IS 1 BP 66 EP 73 DI 10.1542/peds.112.1.66 PG 8 WC Pediatrics SC Pediatrics GA 696WR UT WOS:000183911000026 PM 12837869 ER PT J AU Blackmon, L Batton, DG Bell, EF Engle, WA Kanto, WP Martin, GI Rosenfeld, W Stark, AR Miller, CA Barrington, KJ Raju, T Riley, LE Tomashek, KM Couto, J AF Blackmon, L Batton, DG Bell, EF Engle, WA Kanto, WP Martin, GI Rosenfeld, W Stark, AR Miller, CA Barrington, KJ Raju, T Riley, LE Tomashek, KM Couto, J CA Comm Fetus Newborn TI Controversies concerning vitamin K and the newborn SO PEDIATRICS LA English DT Article ID CHILDHOOD-CANCER; PROPHYLAXIS; DEFICIENCY AB Prevention of early vitamin K deficiency bleeding (VKDB) of the newborn, with onset at birth to 2 weeks of age (formerly known as classic hemorrhagic disease of the newborn), by oral or parenteral administration of vitamin K is accepted practice. In contrast, late VKDB, with onset from 2 to 12 weeks of age, is most effectively prevented by parenteral administration of vitamin K. Earlier concern regarding a possible causal association between parenteral vitamin K and childhood cancer has not been substantiated. This revised statement presents updated recommendations for the use of vitamin K in the prevention of early and late VKDB. C1 NIH, Bethesda, MD 20892 USA. Amer Coll Obstetricians & Gynecologists, Washington, DC 20090 USA. Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. Natl Assoc Neonatal Nurses, Glenview, IL 60025 USA. NR 16 TC 51 Z9 53 U1 1 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 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD JUL PY 2003 VL 112 IS 1 BP 191 EP 192 PG 2 WC Pediatrics SC Pediatrics GA 696WR UT WOS:000183911000045 ER PT J AU Saari, TN AF Saari, TN CA Comm Infect Dis TI Immunization of preterm and low birth weight infants SO PEDIATRICS LA English DT Article ID HEPATITIS-B VACCINE; INACTIVATED POLIOVIRUS VACCINE; PNEUMOCOCCAL CONJUGATE VACCINE; EXTREMELY PREMATURE-INFANTS; HAEMOPHILUS-INFLUENZAE; ANTIBODY-RESPONSE; ACELLULAR PERTUSSIS; COMBINED DIPHTHERIA; IMMUNE-RESPONSES; FOLLOW-UP AB Preterm (PT) infants are at increased risk of experiencing complications of vaccine-preventable diseases but are less likely to receive immunizations on time. Medically stable PT and low birth weight (LBW) infants should receive full doses of diphtheria, tetanus, acellular pertussis, Haemophilus influenzae type b, hepatitis B, poliovirus, and pneumococcal conjugate vaccines at a chronologic age consistent with the schedule recommended for full-term infants. Infants with birth weight less than 2000 g may require modification of the timing of hepatitis B immunoprophylaxis depending on maternal hepatitis B surface antigen status. All PT and LBW infants benefit from receiving influenza vaccine beginning at 6 months of age before the beginning of and during the influenza season. All vaccines routinely recommended during infancy are safe for use in PT and LBW infants. The occurrence of mild vaccine-attributable adverse events are similar in both full-term and PT vaccine recipients. Although the immunogenicity of some childhood vaccines may be decreased in the smallest PT infants, antibody concentrations achieved usually are protective. C1 AAP, Practice Action Grp, Elk Grove Village, IL 60007 USA. Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. Amer Acad Family Physicians, Leawood, KS 66211 USA. NIH, Bethesda, MD 20892 USA. Natl Vaccine Program Off, Atlanta, GA USA. Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. US FDA, Rockville, MD 20857 USA. Amer Thorac Soc, New York, NY 10019 USA. RP Saari, TN (reprint author), AAP, Practice Action Grp, Elk Grove Village, IL 60007 USA. NR 44 TC 80 Z9 86 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUL PY 2003 VL 112 IS 1 BP 193 EP 198 DI 10.1542/peds.112.1.193 PG 6 WC Pediatrics SC Pediatrics GA 696WR UT WOS:000183911000046 PM 12837889 ER PT J AU Linet, MS Wacholder, S Zahm, SH AF Linet, MS Wacholder, S Zahm, SH TI Interpreting epidemiologic research: Lessons from studies of childhood cancer SO PEDIATRICS LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; NON-HODGKINS-LYMPHOMA; FREQUENCY MAGNETIC-FIELDS; PEDIATRIC BRAIN-TUMORS; ATOMIC-BOMB SURVIVORS; RESIDENTIAL RADON EXPOSURE; VOLTAGE POWER-LINES; X-RAY-EXPOSURE; TOXICITY ONCOGENICITY EVALUATION; NEONATAL RISK-FACTORS C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Linet, MS (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS Rm 7054, Bethesda, MD 20892 USA. RI Zahm, Shelia/B-5025-2015 NR 198 TC 61 Z9 61 U1 0 U2 5 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUL PY 2003 VL 112 IS 1 SU S BP 218 EP 232 PG 15 WC Pediatrics SC Pediatrics GA 698KQ UT WOS:000183999100003 PM 12837914 ER PT J AU Rogan, WJ Ragan, NB AF Rogan, WJ Ragan, NB TI Evidence of effects of environmental chemicals on the endocrine system in children SO PEDIATRICS LA English DT Article DE endocrine disruptors; puberty; lactation; thyroid; child ID DICHLORODIPHENYL DICHLOROETHENE DDE; POLYCHLORINATED-BIPHENYLS PCBS; SEX-RATIO; HUMAN-MILK; EXPOSURE; INFANTS; LACTATION; DIOXIN; ESTROGENS; DURATION AB Pollutant chemicals that are widespread in the environment can affect endocrine signaling, as evidenced in laboratory experiments and in wildlife with relatively high exposures. Although humans are commonly exposed to such pollutant chemicals, the exposures are generally low, and clear effects on endocrine function from such exposures have been difficult to demonstrate. Several instances in which there are data from humans on exposure to the chemical agent and the endocrine outcome are reviewed, including age at weaning, age at puberty, and sex ratio at birth, and the strength of the evidence is discussed. Although endocrine disruption in humans by pollutant chemicals remains largely undemonstrated, the underlying science is sound and the potential for such effects is real. C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Rogan, WJ (reprint author), NIEHS, Epidemiol Branch, Mail Drop A3-04,Box 12233, Res Triangle Pk, NC 27709 USA. RI Rogan, Walter/I-6034-2012 OI Rogan, Walter/0000-0002-9302-0160 NR 38 TC 44 Z9 46 U1 0 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUL PY 2003 VL 112 IS 1 SU S BP 247 EP 252 PG 6 WC Pediatrics SC Pediatrics GA 698KQ UT WOS:000183999100006 PM 12837917 ER PT J AU Ibia, EO Imoisili, M Pikis, A AF Ibia, EO Imoisili, M Pikis, A TI Group A beta-hemolytic streptococcal osteomyelitis in children SO PEDIATRICS LA English DT Article; Proceedings Paper CT Annual Meeting of the Pediatric-Academic-Societies CY APR 29-MAY 13, 2001 CL BALTIMORE, MARYLAND SP Pediatr Acad Soc DE acute hematogenous osteomyelitis; group A beta-hemolytic streptococcus; varicella ID ACUTE HEMATOGENOUS OSTEOMYELITIS; ERYTHROCYTE SEDIMENTATION-RATE; C-REACTIVE PROTEIN; INFLUENZAE TYPE-B; BLOOD-CELL COUNT; SEPTIC ARTHRITIS; JOINT INFECTIONS; VARICELLA; EPIDEMIOLOGY; INFANTS AB Objective Little attention has been given to acute hematogenous osteomyelitis (AHO) caused by group A beta-hemolytic Streptococcus (GABHS), although up to 10% of cases are caused by this microorganism. The objective of this study was to define the clinical and laboratory characteristics of AHO caused by GABHS. Methods. Between January 1983 and June 1999, 29 patients were treated at Children's National Medical Center with AHO caused by GABHS. The characteristics of these patients were compared with those of 28 patients with AHO caused by Streptococcus pneumoniae and those of a matched sample of 45 patients with AHO caused by Staphylococcus aureus. Results. Median ages of children with GABHS, S pneumoniae, and S aureus AHO were 36.0, 13.7, and 96.0 months, respectively. On admission, patients with GABHS AHO had a mean temperature of 38.9 +/- 1.3degreesC and a mean white blood cell count of 17 000 +/- 7800/mm(3), findings similar to those from patients with S pneumoniae AHO. Patients with S aureus AHO had significantly lower admission temperature (38.1 +/- 1.1degreesC) and white blood cell count (10 600 +/- 4900/mm(3)). Varicella infection was the risk factor in 5 cases (17%) of GABHS AHO, whereas none of the cases of AHO caused by S pneumoniae and S aureus was associated with varicella infection. Adjacent septic arthritis occurred in 22%, 28%, and 61% of children with GABHS, S aureus, and S pneumoniae AHO, respectively. Admission erythrocyte sedimentation rate and frequency of bacteremia were similar in all groups. However, time to normalization of erythrocyte sedimentation rate was longer for GABHS and S aureus than for S pneumoniae AHO. GABHS, like S pneumoniae, affected fewer nonextremity bones compared with S aureus. Conclusions. GABHS should be considered in pre-school- and early school-aged children who are suspected of having AHO and whose clinical and laboratory features are characterized by high fever and marked leukocytosis. It should also be highly considered in any child with AHO associated with varicella infection. C1 US FDA, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. Childrens Natl Med Ctr, Dept Infect Dis, Washington, DC 20010 USA. Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, NIH, Bethesda, MD USA. RP Pikis, A (reprint author), US FDA, Ctr Drug Evaluat & Res, 5600 Fishers Lane,HFD-530, Rockville, MD 20857 USA. NR 22 TC 30 Z9 31 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUL PY 2003 VL 112 IS 1 BP E22 EP E26 DI 10.1542/peds.112.1.e22 PG 5 WC Pediatrics SC Pediatrics GA 696WR UT WOS:000183911000005 PM 12837901 ER PT J AU Kim, SK Kim, SS Bang, YJ Kim, SJ Lee, BJ AF Kim, SK Kim, SS Bang, YJ Kim, SJ Lee, BJ TI In vitro activities of native and designed peptide antibiotics against drug sensitive and resistant tumor cell lines SO PEPTIDES LA English DT Article DE MDR; antimicrobial peptide; gaegurin 6; derivative; antitumor activity; MCF-7/DOX ID ANTIMICROBIAL PEPTIDES; INNATE IMMUNITY; P-GLYCOPROTEIN; MULTIDRUG TRANSPORTER; ANTICANCER ACTIVITY; CYTOLYTIC ACTIVITY; MEMBRANE; ANALOGS; DEATH; FROG AB In order to develop peptide agents with reduced length and enhanced tumoricidal activity, we have designed gaegurin 6 (GGN6) derivatives through deletions and/or substitutions of amino acids. The deletion of hydrophobic amino terminal region completely abolished antitumor activity whereas the deletion of carboxy terminal region had little influence on antitumor activity. Antitumor activity of the PTP peptides did not correlate with antibacterial activity. PTP7, the most potent derivative, was found to have comparable antitumor activity to GGN6 in spite of reduced number of amino acids which is about half the size of gaegurin 6; furthermore, it showed little cytotoxicity on PBMCs and RBCs. GGN6 and PTP7 also showed equivalent cytotoxicity against drug sensitive (MCF-7) and multidrug-resistant cell lines (MCF-7/DOX). Plasma membrane blebbing and DNA fragmentation of peptide-treated tumor cells indicated that the peptides could induce apoptosis in tumor cells. These results suggest that GGN6 and its derivatives can be developed as new anticancer agents and may provide a new strategy for overcoming MDR which is a major problem in cancer therapy. (C) 2003 Elsevier Inc. All rights reserved. C1 Seoul Natl Univ, Sch Biol Sci, Genet Mol Lab, Peptpharm Co Ltd, Seoul 151742, South Korea. Seoul Natl Univ, Coll Med, Dept Internal Med, Canc Res Inst, Seoul 110799, South Korea. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Lee, BJ (reprint author), Seoul Natl Univ, Sch Biol Sci, Genet Mol Lab, Peptpharm Co Ltd, Seoul 151742, South Korea. RI Bang, Yung Jue/J-2759-2012 NR 29 TC 64 Z9 67 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD JUL PY 2003 VL 24 IS 7 BP 945 EP 953 DI 10.1016/S0196-9781(03)00194-3 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 727QB UT WOS:000185668800001 PM 14499271 ER PT J AU Polianova, MT Ruscetti, FW Pert, CB Tractenberg, RE Leoung, G Strang, S Ruff, MR AF Polianova, MT Ruscetti, FW Pert, CB Tractenberg, RE Leoung, G Strang, S Ruff, MR TI Antiviral and immunological benefits in HIV patients receiving intranasal peptide T (DAPTA) SO PEPTIDES LA English DT Article DE peptide T; AIDS; entry inhibitor; CCR5; antiviral; clinical trial; chemokine receptor; viral reservoir; cytotoxic T-cells ID ACTIVE ANTIRETROVIRAL THERAPY; VIRUS-INFECTED PATIENTS; PROTEASE INHIBITORS; CONTROLLED-TRIAL; AIDS DEMENTIA; MONOCYTES AB D-Ala-Peptide T-amide (DAPTA), the first viral entry inhibitor, blocks chemokine (CCR5) receptors, not CD4. Early investigators could not "replicate" DAPTAs potent in vitro antiviral effect using the lab-adapted, X4, peptide T-insensitive strain, 11113, delaying clinical virological studies. We now report that DAPTA, administered to eleven long-term infected (mean = 17 years) patients with stable persistent plasma "virus" for up to 32 weeks did not change this level. Infectious virus could not be isolated from their plasma suggesting HIV RNA was devoid of replicative capacity. Progressively less actual virus (P < 0.01) could be isolated from white blood cells (PBMCs). DAPTA flushed the monocyte reservoir to undetectable viral levels in most patients. Five of eleven had a mean CD4 increase of 33%. Immune benefits also included a four-fold increase in gamma-interferon-secreting T-cells (antiviral cytotoxic T-cells) in the absence of drug-related toxicity. All five CD4 responders had increases in antiviral T cells and decreases in infected monocytes, an argument for initiating further studies promptly. (C) 2003 Elsevier Inc. All rights reserved. C1 Georgetown Univ, Sch Med, Dept Physiol & Biophys, Washington, DC 20057 USA. NCI, Leukocyte Biol Sect, Ctr Canc Res, FCRDC, Frederick, MD 21702 USA. Georgetown Univ, Sch Med, Dept Biostat & Biomath, Washington, DC 20057 USA. Univ Calif San Francisco, St Francis Mem Hosp, San Francisco, CA 94143 USA. RP Pert, CB (reprint author), Georgetown Univ, Sch Med, Dept Physiol & Biophys, Basic Sci Bldg,Room 203,Box 571460, Washington, DC 20057 USA. NR 19 TC 10 Z9 10 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD JUL PY 2003 VL 24 IS 7 BP 1093 EP 1098 DI 10.1016/S0196-9781(03)00176-1 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 727QB UT WOS:000185668800019 PM 14499289 ER PT J AU Schnermann, J AF Schnermann, J TI The expanding role of aldosterone in the regulation of body Na content SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Article ID EPITHELIAL SODIUM-CHANNEL C1 NIDDKD, NIH, Bethesda, MD 20892 USA. RP Schnermann, J (reprint author), NIDDKD, NIH, Bldg 10,Room 4 D51,10 Ctr Dr MSC 1370, Bethesda, MD 20892 USA. NR 6 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0031-6768 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PD JUL PY 2003 VL 446 IS 4 BP 410 EP 411 DI 10.1007/s00424-003-1046-7 PG 2 WC Physiology SC Physiology GA 699UR UT WOS:000184074800002 PM 12851818 ER PT J AU Gould, TD Gray, NA Manji, HK AF Gould, TD Gray, NA Manji, HK TI Effects of a glycogen synthase kinase-3 inhibitor, lithium, in adenomatous polyposis coli mutant mice SO PHARMACOLOGICAL RESEARCH LA English DT Article DE glycogen synthase kinase-3; cancer; lithium; adenomatous polyposis coli; Wnt-signaling pathway ID SMALL-MOLECULE INHIBITORS; WNT SIGNALING PATHWAY; ALZHEIMERS-DISEASE; COLORECTAL-CANCER; BIPOLAR DISORDER; MOOD STABILIZER; VALPROIC ACID; APC(MIN) MOUSE; APC GENE; CARBONATE AB Glycogen synthase kinase-3 (GSK-3) is an intermediary enzyme in various cellular pathways, and has been implicated in the pathophysiology and treatment of numerous diseases, including Alzheimer's disease, diabetes, and bipolar disorder. There is therefore in developing potent, selective GSK-3 inhibitors for the treatment of these devastating illnesses. A concern, however, is that the Wnt-signaling pathway-of which GSK-3 is an important intermediary molecule-has been implicated in many human cancers. It is thus of considerable importance to determine if GSK-3 inhibitors have tumorigenic potential in systems predisposed to developing tumors by virtue of mutations of the Wnt-signaling pathway. We therefore investigated the effects of a GSK-3 inhibitor, lithium, in a murine model predisposed to the formation of tumors due to activation of the Wnt pathway-the adenomatous polyposis coli (APC) multiple intestinal neoplasia (min) mouse. We found that 60 days of lithium treatment did not produce a significant increase in the number of tumors in these genetically predisposed mice. Lithium treatment resulted in a modest overall increase in the tumor size. The APC (min) mouse has previously been shown to be a robust indicator of tumorigenesis, with large increases in tumor number observed in response to a variety of agents; thus, our results suggest that lithium-and perhaps other inhibitors of GSK-3-pose a low risk for the development of cancers of the Wnt pathway. These results are consistent with the available epidemiological evidence that long-term lithium therapy does not increase cancer morbidity or mortality, but rather is associated with reduced overall mortality in bipolar disorder. Published by Elsevier Science Ltd. C1 NIMH, Mol Pathophysiol Lab, Bethesda, MD 20892 USA. RP Manji, HK (reprint author), NIMH, Mol Pathophysiol Lab, 49 Convent Dr,Room B1EE16, Bethesda, MD 20892 USA. NR 71 TC 51 Z9 58 U1 0 U2 1 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-6618 J9 PHARMACOL RES JI Pharmacol. Res. PD JUL PY 2003 VL 48 IS 1 BP 49 EP 53 DI 10.1016/S0143-6618(03)00096-3 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 692YF UT WOS:000183687300007 PM 12770514 ER PT J AU Patel, NM Rosenblatt, C Yu, YK AF Patel, NM Rosenblatt, C Yu, YK TI Reentrant synclinic phase in an electric-field-temperature-phase diagram for enantiomeric mixtures of an antiferroelectric liquid crystal SO PHYSICAL REVIEW E LA English DT Article ID DEPENDENT THERMAL-BEHAVIOR; MODEL; FILMS AB The threshold electric field E(th) for a transition from the anticlinic to the synclinic phase of enantiomeric mixtures of the liquid crystal TFMHPOBC was measured as a function of temperature T and enantiomeric excess X. For small X the phase boundary curve on a temperature-electric-field phase diagram exhibits the phase sequence synclinic-anticlinic-reentrant synclinic on decreasing the temperature. At one point along the curve the quantity dT/dE-->infinity. For large values of enantiomeric excess a reentrant phase is not observed. The results are discussed using a simple phenomenological theory that accounts for layer-layer interactions, such that the electric-field-induced transition to the synclinic phase, although completed by solitary-wave propagation, is facilitated by a percolation mechanism. C1 Case Western Reserve Univ, Dept Phys, Cleveland, OH 44106 USA. Florida Atlantic Univ, Dept Phys, Boca Raton, FL 33431 USA. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Patel, NM (reprint author), Case Western Reserve Univ, Dept Phys, Cleveland, OH 44106 USA. EM rosenblatt@cwru.edu NR 14 TC 8 Z9 8 U1 0 U2 1 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 J9 PHYS REV E JI Phys. Rev. E PD JUL PY 2003 VL 68 IS 1 AR 011703 DI 10.1103/PhysRevE.68.011703 PN 1 PG 5 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 708RJ UT WOS:000184582400042 PM 12935158 ER PT J AU Pandeya, SN Kohli, S Siddique, N Stables, JP AF Pandeya, SN Kohli, S Siddique, N Stables, JP TI Synthesis and anticonvulsant activities of 4-N-substituted arylsemicarbazones SO POLISH JOURNAL OF PHARMACOLOGY LA English DT Article DE anticonvulsant; 4-N-substituted arylsemicarbarones; sedative-hypnotic; synthesis ID SEMICARBAZONES; AGENTS; POTENT AB A series of 4-N-substituted arylsemicarbazones with increased lipophilicity were synthesized and evaluated for anticonvulsant activity. The compounds provided significant protection against maximal electroshock induced seizures (MES) and seizures indicated by sc pentetrazole administration (sc PTZ) at 300 mg/kg after 0.5 h. The compounds 8 and 4 were active in MES and sc PTZ indicated seizure. The study has shown that introduction of alkyl (ethyl) at the terminal amino group and alkoxy (methoxy) moiety at the distal aryl ring led to increased activity and decreased toxicity. C1 Banaras Hindu Univ, Inst Technol, Dept Pharmaceut, Varanasi 221005, Uttar Pradesh, India. Dept Pharmaceut Chem, New Delhi 110062, India. NIH, ADD Programme, Epilepsy Branch, Rockville, MD USA. RP Pandeya, SN (reprint author), Banaras Hindu Univ, Inst Technol, Dept Pharmaceut, Varanasi 221005, Uttar Pradesh, India. NR 16 TC 10 Z9 10 U1 0 U2 0 PU POLISH ACAD SCIENCES INST PHARMACOLOGY PI KRAKOW PA SMETNA 12, 31-343 KRAKOW, POLAND SN 1230-6002 J9 POL J PHARMACOL JI Pol. J. Pharmacol. PD JUL-AUG PY 2003 VL 55 IS 4 BP 565 EP 571 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 729AD UT WOS:000185747800006 PM 14581715 ER PT J AU Zanuy, D Zazueta, DA Aleman, C AF Zanuy, D Zazueta, DA Aleman, C TI Motion and sorption of gas molecules in poly(octadecyl acrylate) SO POLYMER LA English DT Article DE comb-like polymers; gas sorption; Monte Carlo simulations ID ALKYL SIDE-CHAINS; COMB-LIKE POLY(BETA-PEPTIDE)S; MONTE-CARLO; HELICAL POLY(BETA-L-ASPARTATE)S; NUCLEIC-ACIDS; FORCE-FIELD; SIMULATION; POLYMERS; CRYSTALLINE; POLYETHYLENE AB Monte Carlo simulations are reported on the sorption and motion of small gas molecules (CH4 and CO2) in poly(octadecyl acrylate), a typical comb-like polymer with biphasic structure. Calculations were performed using a computational procedure recently developed by us, which is suitable to simulate the motion and sorption of small molecules in dense comb-like polymers. To our knowledge, the problem of gas transport in comb-like polymers using explicit penetrant molecules is for the first time studied by computational techniques. The study involves more than 12 million Monte Carlo steps of systems constituted by more than 1470 explicit atoms/pseudoatoms. Solubility coefficients are discussed by comparison with recently reported experimental data. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 Univ Politecn Cataluna, ETS Engn Ind Barcelona, Dept Engn Quim, E-08028 Barcelona, Spain. NCI Frederick, Lab Expt & Computat Biol, Frederick, MD 21702 USA. RP Aleman, C (reprint author), Univ Politecn Cataluna, ETS Engn Ind Barcelona, Dept Engn Quim, Diagonal 647, E-08028 Barcelona, Spain. EM carlos.aleman@upc.es RI Zanuy, David/G-3930-2014 OI Zanuy, David/0000-0001-7704-2178 NR 40 TC 6 Z9 6 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0032-3861 J9 POLYMER JI Polymer PD JUL PY 2003 VL 44 IS 16 BP 4735 EP 4745 DI 10.1016/S0032-3861(03)00403-8 PG 11 WC Polymer Science SC Polymer Science GA 701LJ UT WOS:000184168800041 ER PT J AU Talbot, LA Fleg, JL Metter, EJ AF Talbot, LA Fleg, JL Metter, EJ TI Secular trends in leisure-time physical activity in men and women across four decades SO PREVENTIVE MEDICINE LA English DT Article DE leisure-time physical activity; public recommendations ID UNITED-STATES; OBESITY; HEALTH; ADULTS; PREVALENCE; OVERWEIGHT; EXERCISE; PATTERNS; FITNESS; DISEASE AB Background. We examined secular trends in leisure-time physical activities (LTPA) in health-conscious men (n = 1359) from 1958 to 1998 and in women (n = 839) from 1978 to 1998, who were participants of the Baltimore Longitudinal Study of Aging (BLSA). Methods. LTPA was the self-reported time spent performing 97 activities, and was converted to metabolic equivalent of oxygen uptake (MET) minutes per day. Evaluations of LTPA were averaged for each decade. The prevalence of a sedentary lifestyle in each decade was assessed based on compliance with widely publicized recommendations for participation in physical activity. All analyses were adjusted for age, education, and race differences across decades. Results. Median high-intensity LTPA, defined as activities greater than or equal to6 METs, increased from 30 to 80 MET min/day from the 1960s to the 1990s for men (P < 0.01) but did not change between the 1970s and the 1990s in women. Moderate-intensity LTPA, defined as 4-5.9 METs, did not change significantly over these periods in either sex. The percentage of sedentary men, defined as those performing <40 MET min/day of high-intensity LTPA, declined across the four decades, whereas for women it did not change significantly. Conclusions. In a health-conscious sample across a broad age range, national recommendations appear to have made modest progress in decreasing the proportion of sedentary adults. (C) 2003 American Health Foundation and Elsevier Science (USA). All rights reserved. C1 Johns Hopkins Univ, Sch Nursing, Baltimore, MD 21205 USA. NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. NIA, Gerontol Res Ctr, Clin Invest Lab, Baltimore, MD 21224 USA. RP Talbot, LA (reprint author), Johns Hopkins Univ, Sch Nursing, 525 N Wolfe St,Rm 445, Baltimore, MD 21205 USA. NR 34 TC 28 Z9 28 U1 2 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD JUL PY 2003 VL 37 IS 1 BP 52 EP 60 DI 10.1016/S0091-7435(03)00058-6 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 691VA UT WOS:000183625500007 PM 12799129 ER PT J AU Watterson, K Sankala, H Milstien, S Spiegel, S AF Watterson, K Sankala, H Milstien, S Spiegel, S TI Pleiotropic actions of sphingosine-1-phosphate SO PROGRESS IN LIPID RESEARCH LA English DT Review ID PROTEIN-COUPLED RECEPTOR; SPHINGOSINE 1-PHOSPHATE RECEPTOR; HUMAN ENDOTHELIAL-CELLS; FOCAL ADHESION KINASE; MULTIPLE SIGNALING PATHWAYS; NITRIC-OXIDE PRODUCTION; AIRWAY SMOOTH-MUSCLE; LYSOPHOSPHATIDIC ACID; PHOSPHOLIPASE-C; FUNCTIONAL-CHARACTERIZATION AB Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates diverse cellular responses including, growth, survival, cytoskeleton rearrangements and movement. S1P plays an important role during development, particularly in vascular maturation and has been implicated in pathophysiology of cancer, wound healing, and atherosclerosis. This review summarizes the evidence showing that signaling induced by S1P is complex and involves both intracellular and extracellular actions. The intracellular effects of S1P remain speculative awaiting the identification of specific targets whereas the extracellular effects of S1P are clearly mediated through the activation of five specific G protein coupled receptors, called SIP1-5. Recent studies demonstrate that intracellular generated S1P can act in a paracrine or autocrine manner to activate its cell surface receptors. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 Virginia Commonwealth Univ, Dept Biochem, Richmond, VA 23298 USA. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Virginia Commonwealth Univ, Dept Biochem, Med Coll Virginia Campus,1101 E Marshall St, Richmond, VA 23298 USA. FU NCI NIH HHS [CA61774]; NICHD NIH HHS [HD50094]; NIGMS NIH HHS [GM43880] NR 85 TC 71 Z9 76 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7827 J9 PROG LIPID RES JI Prog. Lipid Res. PD JUL PY 2003 VL 42 IS 4 BP 344 EP 357 DI 10.1016/S0163-7827(03)00015-8 PG 14 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 672MV UT WOS:000182525400004 PM 12790117 ER PT J AU Olsson, P Motegi, A Bera, TK Lee, B Pastan, I AF Olsson, P Motegi, A Bera, TK Lee, B Pastan, I TI PRAC2: A new gene expressed in human prostate and prostate cancer SO PROSTATE LA English DT Article DE EST; LNCaP; Hoxb-13; CLL ID NUCLEAR-PROTEIN; EVOLUTION; HOXB-13; TESTIS; REGION; CELLS AB BACKGROUND. The database of human Expressed Sequence Tags was previously used to identify PRAC (Prostate 47:125-131, 2001), a novel gene specifically expressed in human prostate, prostate cancer, rectum, and distal colon. In this report, we have identified PRAC2, another gene with a similar expression pattern that is located adjacent to the original PRAC gene on chromosome 17q21.3. METHODS. Using a computer-based analysis, a cluster of sequence homologous ESTs was identified that is mainly derived from human prostate cDNA libraries. The tissue specificity was examined by multiple tissue RNA dot blots and RT-PCR. The PRAC2 transcript and protein were identified using Northern blot analysis, RACE-PCR, primer extension, and Western blots. RESULTS. PRAC2 encodes a 564 nucleotide RNA found in prostate, rectum, distal colon, and testis. Weak expression was also found in placenta, peripheral blood leukocytes, skin, and in two prostate cancer cell lines: LNCaP and PC-3. The transcript seems to encode a 10.5-kDa nuclear protein. The PRAC2 gene is located on chromosome 17 at position 17q21, between the Hoxb-13 gene and the recently discovered PRAC gene. CONCLUSIONS. Because of the higher expression of PRAC2 in prostate and its proximity to Hoxb-13, PRAC2 may have a function in prostate growth and development. (C) 2003 Wiley-Liss, Inc. C1 NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 5106,MSC 4264, Bethesda, MD 20892 USA. NR 17 TC 9 Z9 10 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 0270-4137 J9 PROSTATE JI Prostate PD JUL 1 PY 2003 VL 56 IS 2 BP 123 EP 130 DI 10.1002/pros.10185 PG 8 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 693TC UT WOS:000183733600006 PM 12746837 ER PT J AU Wang, T Evdokimov, E Yiadom, K Yan, ZY Chock, PB Yang, DCH AF Wang, T Evdokimov, E Yiadom, K Yan, ZY Chock, PB Yang, DCH TI Biotin-ubiquitin tagging of mammalian proteins in Escherichia coli SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article ID CHICK SKELETAL-MUSCLE; HIGH-LEVEL EXPRESSION; FUSION-PROTEIN; FUNCTIONAL-ANALYSIS; NUCLEAR-BODIES/; TRANSFER-RNA; CLONING; SYSTEM; SUMO; BIOTINYLATION AB Ubiquitin has been used in protein expression for enhancing yields and biological activities of recombinant proteins. Biotin binds tightly and specifically to avidin and has been widely utilized as a tag for protein purification and monitoring. Here, we report a versatile system that takes the advantages of both biotin and ubiquitin for protein expression, purification, and monitoring. The tripartite system contained coding sequences for a leader biotinylation peptide, ubiquitin, and biotin holoenzyme synthetase in two reading frames under the control of T7 promoter. The expression and purification of several large mammalian enzymes as biotin-ubiquitin fusions were accomplished including human ubiquitin activating enzyme, SUMO activating enzymes, and aspartyl-tRNA synthetase. Expressed proteins were purified by one-step affinity column chromatography on monomeric avidin columns and purified proteins exhibited active function. Additionally, the ubiquitin protein hydrolase UBP41, expressed and purified as biotin-UBP41, efficiently and specifically cleaved off the biotin-ubiquitin tag from biotin-ubiquitin fusions to produce unmodified proteins. The present expression system should be useful for the expression, purification, and functional characterization of mammalian proteins and the construction of protein microarrays. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Georgetown Univ, Dept Chem, Washington, DC 20057 USA. RW Johnson Pharmaceut Res Inst, Spring House, PA 19477 USA. NHLBI, Biochem Lab, Bethesda, MD 20892 USA. RP Yang, DCH (reprint author), Georgetown Univ, Dept Chem, Washington, DC 20057 USA. RI Yang, David/A-7294-2009 NR 45 TC 19 Z9 19 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD JUL PY 2003 VL 30 IS 1 BP 140 EP 149 DI 10.1016/S1046-5928(03)00098-6 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 697BE UT WOS:000183921700018 PM 12821332 ER PT J AU Halperin, I Wolfson, H Nussinov, R AF Halperin, I Wolfson, H Nussinov, R TI SiteLight: Binding-site prediction using phage display libraries SO PROTEIN SCIENCE LA English DT Article DE binding-site; phage display library; artificial evolution; active site prediction; graph algorithms ID PROTEIN-PROTEIN INTERACTION; RANDOM PEPTIDE LIBRARIES; RECEPTOR-ALPHA-CHAIN; HOT-SPOTS; STRUCTURAL STABILITY; HIV-1 PROTEASE; IN-VITRO; INTERFACES; SEQUENCES; SURFACES AB Phage display enables the presentation of a large number of peptides on the surface of phage particles. Such libraries can be tested for binding to target molecules of interest by means of affinity selection. Here we present SiteLight, a novel computational tool for binding site prediction using phage display libraries. SiteLight is an algorithm that maps the 1D peptide library onto a three-dimensional (3D) protein surface. It is applicable to complexes made up of a protein Template and any type of molecule termed Target. Given the three-dimensional structure of a Template and a collection of sequences derived from biopanning against the Target, the Template interaction site with the Target is predicted. We have created a large diverse data set for assessing the ability of SiteLight to correctly predict,binding sites. SiteLight predictive mapping enables discrimination between the binding and nonbinding parts of the surface. This prediction can be used to effectively reduce the surface by 75% without excluding the binding site. In 63% of the cases we have tested, there is at least one binding site prediction that overlaps the interface by at least 50%. These results suggest the applicability of phage display libraries for automated binding site prediction on three-dimensional structures. For most effective binding site prediction we propose using a random phage display library twice, to scan both binding partners of a given complex. The derived peptides are mapped to the other binding partner (now used as a Template). Here, the surface of each partner is reduced by 75%, focusing their relative positions with respect to each other significantly. Such information can be utilized to improve docking algorithms and scoring functions. C1 NCI Frederick, Lab Expt & Computat Biol, Intramural Res Support Program, SAIC Inc, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Genet, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Sch Comp Sci, Fac Exact Sci, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI Frederick, Lab Expt & Computat Biol, Intramural Res Support Program, SAIC Inc, Bldg 469,Room 151, Frederick, MD 21702 USA. RI Wolfson, Haim/A-1837-2011 FU NCI NIH HHS [N01CO12400, N01 CO 12400] NR 63 TC 41 Z9 47 U1 1 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD JUL PY 2003 VL 12 IS 7 BP 1344 EP 1359 DI 10.1110/ps.0237103 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 694CR UT WOS:000183756700004 PM 12824481 ER PT J AU Katoh, E Louis, JM Yamazaki, T Gronenborn, AM Torchia, DA Ishima, R AF Katoh, E Louis, JM Yamazaki, T Gronenborn, AM Torchia, DA Ishima, R TI A solution NMR study of the binding kinetics and the internal dynamics of an HIV-1 protease-substrate complex SO PROTEIN SCIENCE LA English DT Article DE aspartic protease; enzyme; protein; AIDS; relaxation; slow exchange ID DRUG-RESISTANCE; 3-DIMENSIONAL STRUCTURES; CRYSTAL-STRUCTURES; INHIBITOR BINDING; FLAP REGION; FLEXIBILITY; FLUCTUATIONS; MECHANISM; MUTANTS AB NMR studies of the binding of a substrate to an inactive HIV-1 protease construct, containing an active site mutation PRD25N, are reported. Substrate titration measurements monitored by HSQC spectra and a N-15-edited NOESY experiment show that the chromogenic substrate analog of the capsid/p2 cleavage site binds to PRD25N with an equilibrium dissociation constant, K-D, of 0.27 +/- 0.05 mM, and upper limits of the association and dissociation rate constants, 2 x 10(4) M-1 s(-1) and 10 s(-1), respectively, at 20degreesC, pH 5.8. This association rate constant is not in the diffusion limit, suggesting that association is controlled by a rare event, such as opening of the protease flaps. Analysis of N-15 relaxation experiments reveals a slight reduction of S-2 values in the flap region, indicating a small increase in the amplitude of internal motion on the sub-nsec timescale. In addition, several residues in the flap region are mobile on the conformational exchange timescale, msec-musec. Flap dynamics of the protease-substrate complex are compared with those of protease-inhibitor complexes, and the implications of these results for substrate-binding models are discussed. C1 Natl Inst Dent & Craniofacial Res, Struct Mol Biol Unit, NIH, Bethesda, MD 20892 USA. Natl Inst Agrobiol Sci, Dept Biochem, Tsukuba, Ibaraki 3058602, Japan. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Ishima, R (reprint author), Natl Inst Dent & Craniofacial Res, Struct Mol Biol Unit, NIH, Bethesda, MD 20892 USA. EM rishima@dir.nidcr.nih.gov OI Gronenborn, Angela M/0000-0001-9072-3525 NR 32 TC 63 Z9 63 U1 1 U2 9 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 JUL PY 2003 VL 12 IS 7 BP 1376 EP 1385 DI 10.1110/ps.0300703 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 694CR UT WOS:000183756700007 PM 12824484 ER PT J AU Schneidman-Duhovny, D Inbar, Y Polak, V Shatsky, M Halperin, I Benyamini, H Barzilai, A Dror, O Haspel, N Nussinov, R Wolfson, HJ AF Schneidman-Duhovny, D Inbar, Y Polak, V Shatsky, M Halperin, I Benyamini, H Barzilai, A Dror, O Haspel, N Nussinov, R Wolfson, HJ TI Taking geometry to its edge: Fast unbound rigid (and hinge-bent) docking SO PROTEINS-STRUCTURE FUNCTION AND GENETICS LA English DT Article DE CAPRI; unbound docking; flexible docking; PatchDock; binding site focusing ID PROTEIN INTERFACES; SHAPE COMPLEMENTARITY; HOT-SPOTS; REGIONS; BINDING AB We present a very efficient rigid "unbound" soft docking methodology, which is based on detection of geometric shape complementarity, allowing liberal steric clash at the interface. The method is based on local shape feature matching, avoiding the exhaustive search of the 6D transformation space. Our experiments at CAPRI rounds 1 and 2 show that although the method does not perform an exhaustive search of the 6D transformation space, the "correct" solution is never lost. However, such a solution might rank low for large proteins, because there are alternatives with significantly larger geometrically compatible interfaces. In many cases this problem can be resolved by successful a priori focusing on the vicinity of potential binding sites as well as the extension of the technique to flexible (hinge-bent) docking. This is demonstrated in the experiments performed as a lesson from our CAPRI experience. (C) 2003 Wiley-Liss, Inc. C1 Tel Aviv Univ, Sch Comp Sci, Raymond & Beverly Sackler Fac Exact Sci, IL-69978 Tel Aviv, Israel. NCI, Basic Res Program, SAIC Frederick Inc, Lab Expt & Computat Biol, Frederick, MD 21701 USA. Tel Aviv Univ, Sackler Fac Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Wolfson, HJ (reprint author), Tel Aviv Univ, Sch Comp Sci, Raymond & Beverly Sackler Fac Exact Sci, IL-69978 Tel Aviv, Israel. RI Wolfson, Haim/A-1837-2011; Haspel, Nurit/D-1961-2017 FU NCI NIH HHS [N01-CO-12400] NR 20 TC 135 Z9 139 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-3585 J9 PROTEINS JI Proteins PD JUL 1 PY 2003 VL 52 IS 1 BP 107 EP 112 DI 10.1002/prot.10397 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 687NN UT WOS:000183383500018 PM 12784375 ER PT J AU Steinberg, ML Hall, SM Rustin, T AF Steinberg, ML Hall, SM Rustin, T TI Psychosocial therapies for tobacco dependence in mental health and other substance use populations SO PSYCHIATRIC ANNALS LA English DT Article ID COGNITIVE-BEHAVIORAL THERAPY; INCREASES ABSTINENCE RATES; SMOKING-CESSATION; MAJOR DEPRESSION; NICOTINE DEPENDENCE; ALCOHOL DEPENDENCE; CIGARETTE-SMOKING; MOOD MANAGEMENT; SMOKERS; TRIAL C1 Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Div Addict Psychiat, Newark, NJ 07103 USA. Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. Natl Inst Drug Abuse, Habit Abatement Clin, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, Houston, TX USA. RP Steinberg, ML (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Div Addict Psychiat, Newark, NJ 07103 USA. NR 48 TC 2 Z9 2 U1 3 U2 5 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD JUL PY 2003 VL 33 IS 7 BP 469 EP 478 PG 10 WC Psychiatry SC Psychiatry GA 699NZ UT WOS:000184064000006 ER PT J AU Bluman, LG Rimer, BK Sterba, KR Lancaster, J Clark, S Borstelmann, N Iglehart, JD Winer, EP AF Bluman, LG Rimer, BK Sterba, KR Lancaster, J Clark, S Borstelmann, N Iglehart, JD Winer, EP TI Attitudes, knowledge, risk perceptions and decision-making among women with breast and/or ovarian cancer considering testing for BRCA1 and BRCA2 and their spouses SO PSYCHO-ONCOLOGY LA English DT Article ID HUNTINGTON-DISEASE; HEREDITARY BREAST; SUSCEPTIBILITY; IMPACT; FAMILY; PATIENT; TRIAL AB A limited number of studies have examined the involvement of spouses in the decision-making process for genetic testing as well as impact of the actual testing. This report presents data from 40 women with a personal history of breast and/or ovarian cancer who were considering genetic testing for BRCA1 and BRCA2 and their spouses. We examined knowledge and attitudes regarding genetic testing for breast cancer susceptibility, perceptions of the likelihood that their wives (the women) had a BRCA1 or BRCA2 mutation, pros and cons of genetic testing, spouses' satisfaction with their involvement in the decision-making process and additional resources they would find helpful. Knowledge about cancer genetics and genetic testing for BRCA1 and BCA2 was limited among both women and their spouses. Up to one-third of spouses indicated that they would like to avail themselves of additional sources of information about BRCA1 and BRCA2 testing. Most spouses indicated that they thought their wives had a mutation in BRCA1 or BRCA2 and that their wives' breast cancers would recur. Pros of genetic testing were emphasized more than cons among both parties. Overall, spouses were satisfied with their role in the decision-making process. Future interventions to improve the decision-making process regarding genetic testing for breast cancer susceptibility should be undertaken. Copyright (C) 2003 John Wiley Sons, Ltd. C1 Dana Farber Canc Inst, Breast Oncol Ctr, Boston, MA 02115 USA. NCI, NIH, Div Canc Control & Populat, Bethesda, MD USA. Univ N Carolina, Chapel Hill, NC USA. Duke Univ, Ctr Med, Durham, NC USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Winer, EP (reprint author), Dana Farber Canc Inst, Breast Oncol Ctr, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA668438] NR 35 TC 18 Z9 19 U1 3 U2 5 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD JUL-AUG PY 2003 VL 12 IS 5 BP 410 EP 427 DI 10.1002/pon.653 PG 18 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 701VL UT WOS:000184189600002 PM 12833555 ER PT J AU Johansson, C Willeit, M Levitan, R Partonen, T Smedh, C del Favero, J Kacem, SB Rieder, NPS Neumeister, A Masellis, M Basile, V Zill, P Bondy, B Paunio, T Kasper, S Van Broeckhoven, C Nilsson, LG Lam, R Schalling, M Adolfsson, R AF Johansson, C Willeit, M Levitan, R Partonen, T Smedh, C del Favero, J Kacem, SB Rieder, NPS Neumeister, A Masellis, M Basile, V Zill, P Bondy, B Paunio, T Kasper, S Van Broeckhoven, C Nilsson, LG Lam, R Schalling, M Adolfsson, R TI The serotonin transporter promoter repeat length polymorphism, seasonal affective disorder and seasonality SO PSYCHOLOGICAL MEDICINE LA English DT Article ID FUNCTIONAL POLYMORPHISM; REGULATORY REGION; GENETIC-FACTORS; ASSOCIATION; AVAILABILITY; 5-HTTLPR; LINKAGE; TRAITS; MOOD AB Background. Conflicting results have been reported in previous association studies of the serotonin transporter promoter repeat length polymorphism (5-HTTLPR), seasonal affective disorder (SAD) and seasonality (seasonal variations in mood and behaviour). The aim of this study was to test for association in new case-control and population-based materials, and to perform a combined analysis of all published studies of 5-HTTLPR and SAD. Method. One hundred and forty-seven new SAD cases and 115 controls were genotyped for 5-HTTLPR and in total 464 patients and 414 controls were included in the pooled analysis. In addition, 226 individuals selected for unusually high or low seasonality scores from a population based material and 46 patients with non-seasonal depression were analysed. Different genetic models were tested and seasonality was analysed both as a qualitative (high v. low) and as a quantitative trait in the different sample sets. Results. No association between 5-HTTLPR and SAD was found in the new case-control material, in the combined analysis of all samples, or when only including 316 patients with controls (N=298) selected for low seasonality. A difference was detected between the population based high and low seasonality groups, when assuming a recessive effect of the short allele (20% and 10% short allele homozygotes, respectively, OR (95% CI): 2.24 (1.03-4.91)). Quantitative analysis of seasonality revealed no association with 5-HTTLPR in any sample set. Conclusions. These results do not suggest a major role of the short variant of 5-HTTLPR in susceptibility to SAD, but provide modest evidence for an effect on seasonality. C1 Karolinska Hosp, Neurogenet Unit, S-17176 Stockholm, Sweden. Karolinska Inst, Dept Mol Med, Stockholm, Sweden. Stockholm Univ, Dept Psychol, S-10691 Stockholm, Sweden. Umea Univ, Div Psychiat, Dept Clin Sci, Umea, Sweden. Univ Vienna, Dept Gen Psychiat, Vienna, Austria. Univ Toronto, Dept Psychiat, Toronto, ON M5S 1A8, Canada. Univ British Columbia, Dept Psychiat, Vancouver, BC V6T 2A1, Canada. Natl Publ Hlth Inst, Dept Mental Hlth & Alcohol Res, Helsinki, Finland. Natl Publ Hlth Inst, Dept Human Mol Genet, Helsinki, Finland. Univ Antwerp VIB, B-2020 Antwerp, Belgium. NIMH, Mood & Anxiety Disorders Preogram, Bethesda, MD 20892 USA. Univ Munich, Dept Neurochem, Munich, Germany. RP Johansson, C (reprint author), Karolinska Hosp, Neurogenet Unit, CMM L8-00, S-17176 Stockholm, Sweden. RI Partonen, Timo/G-1105-2012; Hertzman Johansson, Carolina/D-6570-2013; Lam, Raymond/D-2529-2013; OI Partonen, Timo/0000-0003-1951-2455; Lam, Raymond/0000-0001-7142-4669; Del Favero, jurgen/0000-0002-7427-7489; Hertzman Johansson, Carolina/0000-0002-7787-0608; Adolfsson, Rolf/0000-0001-9785-8473 NR 24 TC 21 Z9 22 U1 2 U2 4 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 EI 1469-8978 J9 PSYCHOL MED JI Psychol. Med. PD JUL PY 2003 VL 33 IS 5 BP 785 EP 792 DI 10.1017/S0033291703007372 PG 8 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 704VZ UT WOS:000184362600004 PM 12877393 ER PT J AU Low, A Bentin, S Rockstroh, B Silberman, Y Gomolla, A Cohen, R Elbert, T AF Low, A Bentin, S Rockstroh, B Silberman, Y Gomolla, A Cohen, R Elbert, T TI Semantic categorization in the human brain: Spatiotemporal dynamics revealed by magnetoencephalography SO PSYCHOLOGICAL SCIENCE LA English DT Article ID HUMAN OBJECT AREAS; TEMPORAL CORTEX; FACE PERCEPTION; RECOGNITION; REPRESENTATION; STIMULI AB We examined the cortical representation of semantic categorization using magnetic source imaging in a task that revealed both dissociations among superordinate categories and associations among different base-level concepts within these categories. Around 200 ms after stimulus onset, the spatiotemporal correlation of brain activity elicited by base-level concepts was greater within than across superordinate categories in the right temporal lobe. Unsupervised clustering of data showed similar categorization between 210 and 450 ms mainly in the left hemisphere. This pattern suggests that well-defined semantic categories are represented in spatially distinct, macroscopically separable neural networks, independent of physical stimulus properties. In contrast, a broader, task-required categorization (natural/man-made) was not evident in our data. The perceptual dynamics of the categorization process is initially evident in the extrastriate areas of the right hemisphere: this activation is followed by higher-level activin: along the ventral processing stream, implicating primarily the left temporal lobe. C1 Univ Konstanz, D-7750 Constance, Germany. Hebrew Univ Jerusalem, Jerusalem, Israel. RP Low, A (reprint author), Univ Florida, NIMH, Ctr Study Emot & Attent, Dept Clin & Hlth Psychol, POB 100165, Gainesville, FL 32610 USA. EM loew@ufl.edu RI Elbert, Thomas/C-8556-2009 NR 31 TC 19 Z9 19 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0956-7976 J9 PSYCHOL SCI JI Psychol. Sci. PD JUL PY 2003 VL 14 IS 4 BP 367 EP 372 DI 10.1111/1467-9280.24451 PG 6 WC Psychology, Multidisciplinary SC Psychology GA 698CY UT WOS:000183981100014 PM 12807412 ER PT J AU Shaham, Y Miczek, KA AF Shaham, Y Miczek, KA TI Reinstatement - toward a model of relapse SO PSYCHOPHARMACOLOGY LA English DT Editorial Material ID COCAINE; ADDICTION; ABUSE; PHARMACOTHERAPIES; NEUROBIOLOGY; INITIATION; BEHAVIOR; SEEKING; STRESS; HEROIN C1 NIDA, Behav Neurosci Branch, Intramural Res Program, DHHS,NIH, Baltimore, MD 21224 USA. Tufts Univ, Dept Psychol, Medford, MA 02155 USA. Tufts Univ, Dept Pharmacol, Medford, MA 02155 USA. Tufts Univ, Dept Neurosci, Medford, MA 02155 USA. Tufts Univ, Dept Psychiat, Medford, MA 02155 USA. RP Shaham, Y (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, DHHS,NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI shaham, yavin/G-1306-2014 NR 18 TC 31 Z9 32 U1 0 U2 6 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2003 VL 168 IS 1-2 BP 1 EP 2 DI 10.1007/s00213-003-1469-z PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 698YT UT WOS:000184028600001 ER PT J AU Shaham, Y Shalev, U Lu, L de Wit, H Stewart, J AF Shaham, Y Shalev, U Lu, L de Wit, H Stewart, J TI The reinstatement model of drug relapse: history, methodology and major findings SO PSYCHOPHARMACOLOGY LA English DT Review DE alcohol; cocaine; conditioned drug cues; extinction; heroin; reinstatement; relapse; review; reward; stress ID COCAINE-SEEKING BEHAVIOR; CORTICOTROPIN-RELEASING-FACTOR; STRESS-INDUCED RELAPSE; CONDITIONED PLACE PREFERENCE; SELF-ADMINISTRATION BEHAVIOR; VENTRAL TEGMENTAL AREA; EXTRACELLULAR DOPAMINE LEVELS; DEPENDENT PROTEIN-KINASE; NUCLEUS-ACCUMBENS; HEROIN-SEEKING AB Rational and objectives.. The reinstatement model is currently used in many laboratories to investigate mechanisms underlying relapse to drug seeking. Here, we review briefly the history of the model and describe the different procedures that have been used to study the phenomenon of reinstatement of drug seeking. The results from studies using pharmacological and neuroanatomical techniques to determine the neuronal events that mediate reinstatement of heroin, cocaine and alcohol seeking by acute priming injections of drugs, drug-associated cues and environmental stressors are summarized. In addition, several issues are discussed, including (1) the concordance between the neuronal mechanisms involved in drug-induced reinstatement and those involved in drug reward and discrimination, (2) the role of drug withdrawal states and periods in reinstatement of drug seeking, (3) the role of neuronal adaptations induced by exposure to drugs in relapse, and (4) the degree to which the rat reinstatement model provides a suitable preclinical model of relapse to drug taking. Conclusions.. The data derived from studies using the reinstatement model suggest that the neuronal events that mediate drug-, cue- and stress-induced reinstatement of drug seeking are not identical, that the mechanisms underlying drug-induced reinstatement are to some degree different from those mediating drug discrimination or reward, and that the duration of the withdrawal period following cocaine and heroin self-administration has a profound effect on reinstatement induced by drug cues and stress. Finally, there appears to be a good correspondence between the events that induce reinstatement in laboratory animals and those that provoke relapse in humans. C1 NIDA, Behav Neurosci Branch, IRP, Baltimore, MD 21224 USA. Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. Concordia Univ, Dept Psychol, Ctr Studies Behav Neurobiol, Montreal, PQ H3G 1M8, Canada. RP Shaham, Y (reprint author), NIDA, Behav Neurosci Branch, IRP, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM yshaham@intra.nida.nih.gov RI shaham, yavin/G-1306-2014; OI de Wit, Harriet/0000-0002-7211-8994 NR 190 TC 865 Z9 890 U1 8 U2 51 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2003 VL 168 IS 1-2 BP 3 EP 20 DI 10.1007/s00213-002-1224-x PG 18 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 698YT UT WOS:000184028600002 PM 12402102 ER PT J AU Katz, JL Higgins, ST AF Katz, JL Higgins, ST TI The validity of the reinstatement model of craving and relapse to drug use SO PSYCHOPHARMACOLOGY LA English DT Editorial Material DE reinstatement; animal models; drug craving; relapse to drug abuse; odel validation ID COCAINE-SEEKING BEHAVIOR; HEROIN-SEEKING; WITHDRAWAL; DEPENDENCE; ABSTINENCE; STRESS; NICOTINE; AGONISTS; RATS; CONSUMPTION AB Rationale. The reinstatement procedure has been used increasingly as a laboratory model of craving and relapse to drug abuse. With the number of reports involving this procedure growing, its validity as a model of relapse merits discussion. Objectives. The present commentary addresses the validity of the reinstatement procedure in relation to the following three types of models: 1) formal equivalence models, which are assessed on the basis of how well they resemble some phenomenon outside the laboratory (i.e. face validity); 2) correlational models, which are assessed on the basis of how well they predict outcomes of various interventions (such as drug administration or environmental change) when effected outside the laboratory (i.e. predictive validity); and 3) functional equivalence models, which are assessed on the basis of whether the laboratory phenomenon is mechanistically identical or reasonably similar to the phenomenon outside the laboratory (i.e. content validity). Methods. In order to evaluate the reinstatement model, we briefly examined its various forms and uses, and compared preclinical outcomes to what is known about relapse from the clinical literature. Results. In its most general form, the reinstatement model has reasonable face validity; that is, there is a general agreement in appearance or form of the behavior in the model and the clinical target, relapse. This face validity is generally absent for the procedure when it is used as a model of craving. The predictive validity of the model has not been established. Evidence from studies of treatments for drug relapse have not supported the validity of the model, however from studies of the effects of the presentation of various types of stimuli (e.g. drug 'priming') there is mixed evidence supporting predictive validity. With regard to functional equivalence, there is reasonable evidence supporting functional commonalities between drug self-administration in laboratory animals and human drug abusers, which lends support to the validity of the reinstatement model. However, there are several specific areas of departure between the methods and results using the model and clinical practices and observations about relapse, suggesting a lack of functional equivalence. Conclusions. There is reasonable evidence to support the face validity of the model, but at this time, neither its predictive validity nor functional equivalence has been fully established, which underscores the need for caution in generalizing results from the model to the clinical condition. C1 NIDA, Psychobiol Sect, Addict Res Ctr, DHHS,NIH, Baltimore, MD 21224 USA. Univ Vermont, Dept Psychiat, Burlington, VT 05401 USA. Univ Vermont, Dept Psychol, Burlington, VT 05401 USA. RP Katz, JL (reprint author), NIDA, Psychobiol Sect, Addict Res Ctr, DHHS,NIH, Baltimore, MD 21224 USA. OI Katz, Jonathan/0000-0002-1068-1159 FU NIDA NIH HHS [R01DA09378, R01DA08076] NR 66 TC 162 Z9 167 U1 3 U2 12 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2003 VL 168 IS 1-2 BP 21 EP 30 DI 10.1007/s00213-003-1441-y PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 698YT UT WOS:000184028600003 PM 12695875 ER PT J AU Epstein, DH Preston, KL AF Epstein, DH Preston, KL TI The reinstatement model and relapse prevention: a clinical perspective SO PSYCHOPHARMACOLOGY LA English DT Editorial Material ID COCAINE-SEEKING BEHAVIOR; CORTICOTROPIN-RELEASING-FACTOR; STRESS-INDUCED REINSTATEMENT; INTENSIVE OUTPATIENT TREATMENT; DOPAMINE-RECEPTOR ANTAGONISTS; METHADONE-MAINTAINED PATIENTS; RANDOMIZED CONTROLLED TRIAL; ALCOHOL DEPENDENCE; HEROIN-SEEKING; DRUG-SEEKING AB Objectives. This commentary assesses the degree to which the reinstatement model is homologous to the human experience of relapse. Results. A review of the literature suggests that the relationship is less clear than is often assumed, largely due to a lack of prospective data on the precipitants and process of relapse (especially relapse to heroin or cocaine abuse). However, reinstatement does not need to resemble relapse to have immediate clinical value; predictive validity as a medication screen would be sufficient. Whether the model has predictive validity is unknown, because, to date, very few clinical trials have tested medications that are effective in the reinstatement model, and even fewer have used designs comparable to those of reinstatement experiments. A clinical trial comparable to a reinstatement experiment would enroll participants who are already abstinent, and its main outcome measure would be propensity to undergo a specific type of relapse (e.g., relapse induced by stress or cues). Conclusions. Until clinical and preclinical work are more comparable, criticisms of the reinstatement model's presumed shortcomings are premature. C1 NIDA, IRP, Treatment Sect, Intramural Res Program, Baltimore, MD 21224 USA. RP Epstein, DH (reprint author), NIDA, IRP, Treatment Sect, Intramural Res Program, 5500 Nathn Shock Dr, Baltimore, MD 21224 USA. EM depstein@intra.nida.nih.gov RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 FU NIDA NIH HHS [Z01 DA000234-13] NR 96 TC 79 Z9 81 U1 1 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2003 VL 168 IS 1-2 BP 31 EP 41 DI 10.1007/s00213-003-1470-6 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 698YT UT WOS:000184028600004 PM 12721778 ER PT J AU Hayes, RJ Vorel, SR Spector, J Liu, X Gardner, EL AF Hayes, RJ Vorel, SR Spector, J Liu, X Gardner, EL TI Electrical and chemical stimulation of the basolateral complex of the amygdala reinstates cocaine-seeking behavior in the rat SO PSYCHOPHARMACOLOGY LA English DT Article DE addiction; amygdala; cocaine; craving; excitatory amino acid; relapse; reinstatement; self-administration; stimulation ID CONDITIONED PLACE PREFERENCE; VENTRAL TEGMENTAL AREA; EXTRACELLULAR DOPAMINE LEVELS; SELF-ADMINISTRATION BEHAVIOR; NUCLEUS-ACCUMBENS DOPAMINE; STRESS-INDUCED RELAPSE; DRUG-SEEKING; PREFRONTAL CORTEX; REWARD; GLUTAMATE AB Rationale. The basolateral complex of the amygdala (BLC) is part of a neural circuit that is activated in humans during cocaine craving elicited by exposure to drug-related environmental cues. In animals, the BLC is necessary for cocaine-seeking behavior elicited by cocaine-associated cues. It has not been determined whether BLC activation is sufficient to reinstate cocaine seeking. Objectives. To determine whether electrical or excitatory amino-acid stimulation of the BLC is sufficient to induce reinstatement of cocaine seeking in rats. Methods. Rats were catheterized and trained to lever-press for intravenous cocaine infusions on a fixed ratio (FR)-1 schedule of reinforcement. Once baseline cocaine-taking criteria were met, lever-pressing behavior was extinguished by substitution of saline for cocaine. After meeting criteria for extinction, animals were subjected to brief electrical (20 Hz, 400 muA or 2 Hz, 400 muA; 200 pulses per stimulation) or N-methyl-D-aspartate (NMDA; 250 ng/0.5 mul) BLC stimulation and lever pressing behavior was monitored. Results. Electrical BLC stimulation with 20-Hz produced reinstatement of lever pressing previously associated with cocaine self-administration, while 2-Hz stimulation did not. Electrical stimulation of cerebellar and medial forebrain bundle loci did not reinstate cocaine seeking. Hence, the reinstatement was frequency dependent and anatomically selective. NMDA microinjections into the BLC also reinstated cocaine-seeking behavior. Conclusions. BLC stimulation is sufficient to reinstate cocaine-seeking behavior in the rat. These results are congruent with the hypothesis that the basolateral complex of the amygdala is part of a neural system mediating drug-seeking behavior. C1 NIDA, Intramural Res Program, Dept Hlth & Human Serv, NIH, Baltimore, MD 21224 USA. Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10461 USA. Albert Einstein Coll Med, Dept Psychiat, Bronx, NY 10461 USA. RP Gardner, EL (reprint author), NIDA, Intramural Res Program, Dept Hlth & Human Serv, NIH, POB 5180, Baltimore, MD 21224 USA. NR 75 TC 45 Z9 45 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2003 VL 168 IS 1-2 BP 75 EP 83 DI 10.1007/s00213-002-1328-3 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 698YT UT WOS:000184028600009 PM 12545331 ER PT J AU Shalev, U Marinelli, M Baumann, MH Piazza, PV Shaham, Y AF Shalev, U Marinelli, M Baumann, MH Piazza, PV Shaham, Y TI The role of corticosterone in food deprivation-induced reinstatement of cocaine seeking in the rat SO PSYCHOPHARMACOLOGY LA English DT Article DE adrenalectomy; cocaine; corticosterone; extinction; food deprivation; reinstatement; relapse; stress ID CORTICOTROPIN-RELEASING-FACTOR; STRESS-INDUCED RELAPSE; INDUCED SENSITIZATION; DRUG-ABUSE; BEHAVIORAL SENSITIZATION; GLUCOCORTICOID RECEPTOR; LOCOMOTOR RESPONSE; HEROIN-SEEKING; REWARD; RESTRICTION AB Rational and objectives.. Acute 1-day food deprivation stress reinstates heroin seeking in rats, but the generality of this effect to other drugs, and its underlying mechanisms, are largely unknown. Here we studied whether food deprivation would reinstate cocaine seeking and whether the stress hormone, corticosterone, is involved in this effect. Methods.. Rats were trained to press a lever for cocaine for 10-12 days (0.5-1.0 mg/kg per infusion, IV, 4 h/day) and were then divided into four groups that underwent different manipulations of plasma corticosterone levels: (1) bilateral adrenalectomy (ADX) surgery, (2) ADX surgery+50-mg corticosterone pellets (ADX+P), (3) ADX surgery+50-mg corticosterone pellets+4-h access (0800-1200 hours) to corticosterone (50 mug/ml) dissolved in a drinking solution (ADX+P/W), or (4) sham surgery. Next, rats were given 7-12 days of extinction training (during which lever presses were not reinforced with cocaine), and after reaching an extinction criterion they were tested for reinstatement of cocaine seeking following exposure to 21 h of food deprivation. Results.. Food deprivation was found to reinstate cocaine seeking in sham-operated rats, but not in rats in which circulating corticosterone was removed (ADX group). In addition, the effect of food deprivation on reinstatement of cocaine seeking was significantly attenuated in rats maintained on basal diurnal levels of corticosterone (ADX+P group). However, food deprivation reinstated cocaine seeking in rats with limited daily access to additional corticosterone in the drinking water (ADX+P/W group). In this group, corticosterone levels were twice as high as the ADX+P group but were significantly lower than those of sham rats. Conclusions.. The present data, together with previous work on footshock-induced reinstatement of drug seeking, suggest that corticosterone plays a permissive role in stress-induced reinstatement of cocaine seeking, yet its effects are not associated with the stressor-induced increases in plasma corticosterone levels. C1 NIDA, Behav Neurosci Branch, IRP, NIH, Baltimore, MD 21224 USA. INSERM, U259, Lab Psychobiol Comportements Adaptat, Bordeaux, France. NIDA, Medicat Discovery Res Branch, IRP, NIH, Baltimore, MD USA. RP Shalev, U (reprint author), NIDA, Behav Neurosci Branch, IRP, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM ushalev@intra.nida.nih.gov RI shaham, yavin/G-1306-2014 NR 49 TC 77 Z9 78 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2003 VL 168 IS 1-2 BP 170 EP 176 DI 10.1007/s00213-002-1200-5 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 698YT UT WOS:000184028600020 PM 12845419 ER PT J AU Le, AD Wang, A Harding, S Juzytsch, W Shaham, Y AF Le, AD Wang, A Harding, S Juzytsch, W Shaham, Y TI Nicotine increases alcohol self-administration and reinstates alcohol seeking in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE alcohol; extinction; nicotine; reinstatement; relapse; self-administration ID STRESS-INDUCED RELAPSE; CORTICOTROPIN-RELEASING FACTOR; LOCOMOTOR STIMULANT ACTION; MALE WISTAR RATS; NUCLEUS-ACCUMBENS; ETHANOL INTAKE; PRIMING INJECTIONS; RECEPTOR BLOCKADE; DOPAMINE RELEASE; COCAINE SEEKING AB Rationale and objective. Alcohol and tobacco are often co-abused in humans and previous studies found that nicotine increases alcohol consumption in rats. Here, we studied whether nicotine would reinstate alcohol-taking behavior in drug-free rats and whether this effect would be enhanced by prior exposure to nicotine during alcohol self-administration training. Methods. Rats were trained to press a lever for alcohol (12% w/v, 1 h/day), and following stable alcohol intake groups of rats (n=11-12) were given daily vehicle or nicotine (0.2, 0.4 or 0.8 mg/kg, SC) injections just prior to the self-administration sessions for 10 days. Rats were then given 6 days of alcohol self-administration in the absence of nicotine and an additional 5-10 drug-free days during which lever presses were not reinforced (extinction). Subsequently, rats were tested for reinstatement of alcohol seeking following exposure to priming injections of vehicle or nicotine (0.4 mg/kg, SC). Results. Nicotine increased alcohol self-administration in a dose- and time-dependent manner over the 10-day period. Nicotine also reinstated alcohol seeking after extinction of the alcohol-reinforced behavior, and this effect was strongly enhanced by prior nicotine exposure. Conclusions. The present data extend previous studies on the effect of nicotine on alcohol self-administration, and further indicate that nicotine is an effective stimulus for reinstatement of alcohol seeking during drug-free periods. C1 Ctr Addict & Mental Hlth, Toronto, ON M5S 2S1, Canada. Univ Toronto, Dept Pharmacol, Toronto, ON, Canada. Univ Toronto, Dept Psychiat, Toronto, ON, Canada. NIDA, Behav Neurosci Branch, IRP, NIH,DHHS, Baltimore, MD USA. RP Le, AD (reprint author), Ctr Addict & Mental Hlth, 33 Russell St, Toronto, ON M5S 2S1, Canada. RI shaham, yavin/G-1306-2014 NR 59 TC 98 Z9 99 U1 2 U2 8 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2003 VL 168 IS 1-2 BP 216 EP 221 DI 10.1007/s00213-002-1330-9 PG 6 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 698YT UT WOS:000184028600026 PM 12536264 ER PT J AU Panlilio, LV Thorndike, EB Schindler, CW AF Panlilio, LV Thorndike, EB Schindler, CW TI Reinstatement of punishment-suppressed opioid self-administration in rats: an alternative model of relapse to drug abuse SO PSYCHOPHARMACOLOGY LA English DT Article DE priming; remifentanil; food; rat ID STRESS-INDUCED RELAPSE; COCAINE-SEEKING; SUBSTANCE-ABUSE; ELECTRIC-SHOCK; BEHAVIOR; HEROIN; EXTINCTION; NEUROBIOLOGY; MAINTENANCE; INJECTIONS AB Rationale.. Animal models of relapse to drug abuse typically assess the ability of various manipulations to reinstate responding that has ceased due to non-reinforcement (extinction). However, there is a lack of information concerning the reinstatement of responding that has ceased for reasons other than extinction. Objectives.. This study examined the ability of response-independent reinforcer delivery (priming) to reinstate food- or drug-reinforced responding that had been suppressed by response-contingent footshock (punishment). Methods.. Nose-poke responding by separate groups of rats was reinforced with food (45 mg/delivery) or intravenous remifentanil (4 mug/kg per infusion), a short-acting mu-opioid agonist. After either 3 or 27 days of training (with 100 reinforcers/day), a punishment contingency was introduced that rapidly suppressed responding. Then, the punishment contingency was discontinued, and half the rats received priming. Results.. Priming by non-contingent delivery of food or remifentanil significantly reduced the number of sessions required for responding to resume. There were no significant differences in this effect between short-term and long-term training or between food- and drug-trained groups. Conclusions.. Self-administration responding that has been suppressed by punishment can be reinstated by priming, and it can eventually resume even without priming. Under the conditions studied here, priming after punishment had effects qualitatively similar to those typically seen after extinction. This punishment/reinstatement procedure may be useful for comparing the effects of other manipulations known to affect behavior in the extinction/reinstatement model of relapse. C1 NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Panlilio, LV (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM lpanlili@intra.nida.nih.gov NR 35 TC 25 Z9 25 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2003 VL 168 IS 1-2 BP 229 EP 235 DI 10.1007/s00213-002-1193-0 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 698YT UT WOS:000184028600028 PM 12845420 ER PT J AU Carey, MA Swanson, J AF Carey, MA Swanson, J TI Funding for qualitative research SO QUALITATIVE HEALTH RESEARCH LA English DT Article DE qualitative research; funding AB Obtaining funding for qualitative research remains a challenge for many researchers, more so than for most quantitative research. In this article, the authors describe useful approaches to planning qualitative research and writing an application. Included is information on exploring funding sources that are likely to be receptive, developing a research plan and a team, and suggestions on the language to be used in the application. C1 NIMH, Div Extramural Act, Bethesda, MD 20892 USA. Educ & Res Associates, Bodega Bay, CA USA. RP Carey, MA (reprint author), NIMH, Div Extramural Act, Bethesda, MD 20892 USA. NR 3 TC 5 Z9 5 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1049-7323 J9 QUAL HEALTH RES JI Qual. Health Res. PD JUL PY 2003 VL 13 IS 6 BP 852 EP 856 DI 10.1177/1049732303255512 PG 5 WC Information Science & Library Science; Social Sciences, Interdisciplinary; Social Sciences, Biomedical SC Information Science & Library Science; Social Sciences - Other Topics; Biomedical Social Sciences GA 693VT UT WOS:000183739600006 PM 12891718 ER PT J AU Vannier, MW Summers, RM AF Vannier, MW Summers, RM TI Sharing images SO RADIOLOGY LA English DT Editorial Material ID DATABASES; NEUROSCIENCE; RESOURCE; UPDATE C1 NCI, Biomed Imaging Program, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Vannier, MW (reprint author), Univ Iowa Hosp & Clin, Dept Radiol, 200 Hawkins Dr,3966A JPP, Iowa City, IA 52242 USA. OI Vannier, Michael/0000-0001-9898-384X NR 27 TC 19 Z9 19 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUL PY 2003 VL 228 IS 1 BP 23 EP 25 DI 10.1148/radiol.2281021654 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 692ZG UT WOS:000183689700005 PM 12832571 ER PT J AU Coleman, CN AF Coleman, CN TI Linking radiation oncology and imaging through molecular biology (or now that therapy and diagnosis have separated, it's time to get together again!) SO RADIOLOGY LA English DT Article DE neoplasms, therapeutic radiology; radiations, protective and therapeutic agents and devices; radiobiology, cell and tissue studies; radiology and radiologists, research; therapeutic radiology ID POSITRON-EMISSION-TOMOGRAPHY; DOUBLE-STRAND BREAKS; NF-KAPPA-B; IONIZING-RADIATION; INDUCED APOPTOSIS; GENE-EXPRESSION; TUMOR HYPOXIA; CANCER CELLS; DNA-DAMAGE; GAMMA-RAYS AB Among the areas defined by the National Cancer Institute as "Extraordinary Opportunities for Research Investment" that are highly relevant to the technology-oriented disciplines within the broad field of radiology are cancer imaging, defining the signatures (ie, underlying molecular features) of cancer cells, and molecular targets of prevention and treatment. In molecular target credentialing, a specific molecular target is imaged, the molecular signature is defined, a treatment is given; and the effect of the intervention on the image findings and the signature is then evaluated. Such an approach is used to validate the proposed target as a legitimate one for cancer therapy or prevention and to provide the opportunity to ultimately individualize therapy on the basis of both the initial characteristics of the tumor and the tumor's response to an intervention. Therapeutic radiation is focused biology (ie, radiation produces molecular events in the irradiated tissue). Radiation can (a) kill cancer cells by itself, (b) be combined with cytotoxic or cytostatic drugs, and (C) serve to initiate radiation-inducible molecular targets that are amenable to treatment with drugs and/or biologic therapies. Focused biology can be anatomically confined with various types of external beams and with brachytherapy, and it can be used systemically with targeted radioisotopes. These new paradigms link diagnostic imaging, radiation therapy; and nuclear medicine in unique ways by way of basic biology. It is timely to develop new collaborative research, training, and education agendas by building on one another's expertise and adopting new fields of microtechnology, nanotechnology, and mathematical analysis and optimization. C1 NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Coleman, CN (reprint author), NCI, Radiat Oncol Branch, NIH, Bldg 10,B3-B69, Bethesda, MD 20892 USA. NR 75 TC 27 Z9 28 U1 2 U2 4 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUL PY 2003 VL 228 IS 1 BP 29 EP 35 DI 10.1148/radiol.2281021567 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 692ZG UT WOS:000183689700007 PM 12832573 ER PT J AU Wess, J Duttaroy, A Zhang, W Gomeza, J Cui, Y Miyakawa, T Bymaster, FP McKinzie, L Felder, CC Lamping, KG Faraci, FM Deng, C Yamada, M AF Wess, J Duttaroy, A Zhang, W Gomeza, J Cui, Y Miyakawa, T Bymaster, FP McKinzie, L Felder, CC Lamping, KG Faraci, FM Deng, C Yamada, M TI M-1-M-5 muscarinic receptor knockout mice as novel tools to study the physiological roles of the muscarinic cholinergic system SO RECEPTORS & CHANNELS LA English DT Review DE acetylcholine; gene targeting; knockout mice; muscarinic agonists; muscarinic receptors; oxotremorine ID MELANIN-CONCENTRATING HORMONE; NITRIC-OXIDE SYNTHASE; CEREBRAL BLOOD-FLOW; HIPPOCAMPAL PYRAMIDAL CELLS; SUBTYPE-SPECIFIC ANTIBODIES; LATERAL HYPOTHALAMIC AREA; ACETYLCHOLINE-RECEPTOR; RAT-BRAIN; SMOOTH-MUSCLE; MESSENGER-RNA AB A large body of evidence indicates that muscarinic acetylcholine receptors (mAChRs) play critical roles in regulating the activity of many important functions of the central and peripheral nervous systems. However, identification of the physiological and pathophysiological roles of the individual mAChR subtypes (M-1-M-5) has proven a difficult task, primarily due to the lack of ligands endowed with a high degree of receptor subtype selectivity and the fact that most tissues and organs express multiple mAChRs. To circumvent these difficulties, we used gene targeting technology to generate mutant mouse lines containing inactivating mutations of the M-1-M-5 mAChR genes. The different mAChR mutant mice and the corresponding wild-type control animals were subjected to a battery of physiological, pharmacological, behavioral, biochemical, and neurochemical tests. The M-1-M-5 mAChR mutant mice were viable and reproduced normally. However, each mutant line displayed specific functional deficits, suggesting that each mAChR subtype mediates distinct physiological functions. These results should offer new perspectives for the rational development of novel muscarinic drugs. C1 NIDDKD, Bioorgan Chem Lab, Bethesda, MD 20892 USA. Mitre Corp, Ctr Learning & Memory, Cambridge, MA USA. Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. Vet Adm Med Ctr, Iowa City, IA USA. Univ Iowa, Ctr Cardiovasc, Dept Internal Med, Iowa City, IA 52242 USA. Univ Iowa, Ctr Cardiovasc, Dept Pharmacol, Iowa City, IA 52242 USA. NIDDKD, Biochem & Metab Lab, Bethesda, MD 20892 USA. RP Wess, J (reprint author), NIDDKD, Bioorgan Chem Lab, Bldg 8A,room B1A-05,8 Ctr Dr, Bethesda, MD 20892 USA. RI Miyakawa, Tsuyoshi/A-7741-2008; deng, chuxia/N-6713-2016 OI Miyakawa, Tsuyoshi/0000-0003-0137-8200; FU NHLBI NIH HHS [HL-38901, HL-39050, HL-62984]; NINDS NIH HHS [NS-24621] NR 124 TC 55 Z9 59 U1 3 U2 7 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1060-6823 J9 RECEPTOR CHANNEL JI Recept. Channels PD JUL-AUG PY 2003 VL 9 IS 4 BP 279 EP 290 DI 10.1080/10606820390217401 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 739KU UT WOS:000186344300006 PM 12893539 ER PT J AU Idler, EL Musick, MA Ellison, CG George, LK Krause, N Ory, MG Pargament, KI Powell, LH Underwood, LG Williams, DR AF Idler, EL Musick, MA Ellison, CG George, LK Krause, N Ory, MG Pargament, KI Powell, LH Underwood, LG Williams, DR TI Measuring multiple dimensions of religion and spirituality or health research - Conceptual background and findings from the 1998 General Social Survey SO RESEARCH ON AGING LA English DT Article; Proceedings Paper CT 52nd Annual Meeting of the Gerontological-Society-of-America CY NOV 19-23, 1999 CL SAN FRANCISCO, CALIFORNIA SP Gerontol Soc Amer DE religiousness; spirituality; health; medicine; aging ID NONDISABLED PERSONS; CARDIAC-SURGERY; OLDER ADULTS; MORTALITY; INVOLVEMENT; PATTERNS; STRESS; FORGIVENESS; ATTENDANCE; DEPRESSION AB Progress in studying the relationship between religion and health has been hampered by the absence of an adequate measure of religiousness and spirituality. This article reports on the conceptual and empirical development of an instrument to measure religiousness and spirituality, intended explicitly for studies of health. It is multidimensional to allow investigation of multiple possible mechanisms of effect, brief enough to be included in clinical or epidemiological surveys, inclusive of both traditional religiousness and noninstitutionally based spirituality, and appropriate for diverse Judeo-Christian populations. The measure may be particularly useful for studies of health in elderly populations in which religious involvement is higher. The measure was tested in the nationally representative 1998 General Social Survey (N = 1,445). Nine dimensions have indices with moderate-to-good internal consistency, and there are three single-item domains. Analysis by age and sex shows that elderly respondents report higher levels of religiousness in virtually every domain of the measure. C1 Rutgers State Univ, Piscataway, NJ 08855 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Univ Texas, Austin, TX 78712 USA. Duke Univ, Durham, NC 27706 USA. NIA, Bethesda, MD 20892 USA. Bowling Green State Univ, Bowling Green, OH 43403 USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. RP Idler, EL (reprint author), Rutgers State Univ, Piscataway, NJ 08855 USA. NR 98 TC 247 Z9 249 U1 5 U2 33 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0164-0275 J9 RES AGING JI Res. Aging PD JUL PY 2003 VL 25 IS 4 BP 327 EP 365 DI 10.1177/0164027503252749 PG 39 WC Gerontology SC Geriatrics & Gerontology GA 689PW UT WOS:000183503000001 ER PT J AU Keller, A Jeffries, NO Blumenthal, J Clasen, LS Liu, H Giedd, JN Rapoport, JL AF Keller, A Jeffries, NO Blumenthal, J Clasen, LS Liu, H Giedd, JN Rapoport, JL TI Corpus callosum development in childhood-onset schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE corpus callosum; childhood-onset schizophrenia; MRI ID AFFECTIVE-DISORDERS; BRAIN-DEVELOPMENT; LONGITUDINAL MRI; K-SADS; SIZE; MORPHOLOGY; CHILDREN; ADOLESCENCE; ABNORMALITIES; RELIABILITY AB Objective: Corpus callosum (CC) size and interhemispheric communication differences have been reported between patients with schizophrenia and normal controls. Childhood-onset schizophrenia (COS) is a severe form of the disorder that is continuous with later-onset disorder. Corpus callosal area was examined for COS at initial scan and prospectively through adolescence, and related to other developmental abnormalities for this group. Method: A total of 113 anatomic brain MRI scans were obtained from 55 COS (22 female) and 110 scans from 56 age- and gender-matched healthy volunteers (22 female), across ages 8-24. Baseline and prospective rescans were obtained at approximately 2-year intervals. The midsagittal areas for total corpus callosum and seven subregions were calculated using an automated system. Cross-sectional and longitudinal data were combined using mixed model regression analysis to compare developmental changes for the two groups. Results: No diagnostic differences were seen at time of initial scan. Longitudinally, and in contrast to healthy volunteers, patients with schizophrenia showed a significant difference in developmental trajectory for the area of the splenium, both before (p=0.012) and after (p=0.05) adjustment for total cerebral volume. The area of the splenium becomes significantly smaller in COS, starting at about age 22. Conclusion: Patients with schizophrenia showed a significant difference in developmental trajectory for the splenial area, which seems to decline for COS. If replicated, this may reflect anticipated late occipital and extrastriate changes in brain regions. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Rapoport, JL (reprint author), NIMH, Child Psychiat Branch, Bldg 10,Room 3N 202,10 Ctr Dr MSC 1600, Bethesda, MD 20892 USA. RI Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 NR 75 TC 34 Z9 34 U1 2 U2 3 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 1 PY 2003 VL 62 IS 1-2 BP 105 EP 114 DI 10.1016/S0920-9964(02)00354-7 PG 10 WC Psychiatry SC Psychiatry GA 689CF UT WOS:000183473500014 PM 12765750 ER PT J AU Jaffe, ES Krenacs, L Raffeld, M AF Jaffe, ES Krenacs, L Raffeld, M TI Classification of cytotoxic T-Cell and natural killer cell lymphomas SO SEMINARS IN HEMATOLOGY LA English DT Review ID EPSTEIN-BARR-VIRUS; NON-HODGKINS-LYMPHOMA; ANGIOCENTRIC IMMUNOPROLIFERATIVE LESIONS; DISTINCT CLINICOPATHOLOGICAL ENTITY; CELIAC-DISEASE PATIENTS; IN-SITU HYBRIDIZATION; GAMMA-DELTA; ALPHA-BETA; NK-CELL; MALIGNANT HISTIOCYTOSIS C1 NCI, Pathol Lab, Ctr Canc Res, Hematopathol Sect, Bethesda, MD 20892 USA. Bay Zoltan Fdn Appl Res, Inst Biotechnol, Lab Tumor Pathol & Mol Diagnost, Szeged, Hungary. RP Jaffe, ES (reprint author), NCI, Pathol Lab, Ctr Canc Res, Hematopathol Sect, Bldg 10,Room 2N202,10 Ctr Dr,MSC-1500, Bethesda, MD 20892 USA. RI Krenacs, Laszlo/L-8063-2014 OI Krenacs, Laszlo/0000-0001-6541-3031 NR 109 TC 69 Z9 79 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD JUL PY 2003 VL 40 IS 3 BP 175 EP 184 DI 10.1016/S0037-163(03)00132-X PG 10 WC Hematology SC Hematology GA 701KM UT WOS:000184166800002 PM 12876666 ER PT J AU Balow, JE Austin, HA AF Balow, JE Austin, HA TI Therapy of membranous nephropathy in systemic lupus erythematosus SO SEMINARS IN NEPHROLOGY LA English DT Review ID NEPHROTIC SYNDROME; RISK-FACTOR; NEPHRITIS; PROGNOSIS; DISEASE; GLOMERULONEPHRITIS; CLASSIFICATION; COMPLICATIONS; CYCLOSPORINE; RAPAMYCIN C1 NIDDKD, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. RP Balow, JE (reprint author), NIDDKD, Kidney Dis Sect, NIH, Bldg 10,Room 9N-222, Bethesda, MD 20892 USA. NR 41 TC 17 Z9 21 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9295 J9 SEMIN NEPHROL JI Semin. Nephrol. PD JUL PY 2003 VL 23 IS 4 BP 386 EP 391 DI 10.1016/S0270-9295(03)00056-1 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 712JR UT WOS:000184795000009 PM 12923727 ER PT J AU Trotti, A Colevas, AD Setser, A Rusch, V Jaques, D Budach, V Langer, C Murphy, B Cumberlin, R Coleman, CN Rubin, P AF Trotti, A Colevas, AD Setser, A Rusch, V Jaques, D Budach, V Langer, C Murphy, B Cumberlin, R Coleman, CN Rubin, P TI CTCAE v3.0: Development of a comprehensive grading system for the adverse effects of cancer treatment SO SEMINARS IN RADIATION ONCOLOGY LA English DT Article ID TOXICITY CRITERIA; RADIOTHERAPY; RTOG C1 Univ S Florida, H Lee Moffitt Canc Ctr, Radiat Oncol Program, Tampa, FL 33612 USA. NCI, Investigat Drug Branch, CTEP, NIH, Rockville, MD USA. Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. Charite Univ Hosp, Berlin, Germany. Fox Chase Canc Ctr, Dept Med Oncol, Philadelphia, PA 19111 USA. Vanderbilt Univ, Dept Med Oncol, Nashville, TN USA. NCI, Radiat Oncol Sci Program, DCTD, Bethesda, MD 20892 USA. Univ Rochester, Med Ctr, Dept Radiat Oncol, Rochester, NY 14642 USA. RP Trotti, A (reprint author), Univ S Florida, H Lee Moffitt Canc Ctr, Radiat Oncol Program, 12902 Magnolia Dr, Tampa, FL 33612 USA. FU NCI NIH HHS [R13 CA 93030-01] NR 10 TC 1251 Z9 1358 U1 2 U2 41 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 1053-4296 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD JUL PY 2003 VL 13 IS 3 BP 176 EP 181 DI 10.1016/S01053-4296(03)00031-6 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 710FN UT WOS:000184670300002 PM 12903007 ER PT J AU Davis, AM Dische, S Gerber, L Saunders, M Leung, SF O'Sullivan, B AF Davis, AM Dische, S Gerber, L Saunders, M Leung, SF O'Sullivan, B TI Measuring postirradiation subcutaneous soft-tissue fibrosis: State-of-the-art and future directions SO SEMINARS IN RADIATION ONCOLOGY LA English DT Article ID BREAST-CANCER PATIENTS; POST-MASTECTOMY RADIOTHERAPY; TREATMENT-RELATED MORBIDITY; RADIATION-INDUCED FIBROSIS; POSTMASTECTOMY RADIOTHERAPY; CONVENTIONAL RADIOTHERAPY; ACCELERATED FRACTIONATION; RANDOMIZED TRIAL; LIMB FUNCTION; NECK-CANCER C1 Univ Toronto, Toronto Rehabil Inst, Toronto, ON M5G 2A2, Canada. Mt Vernon Hosp, Ctr Canc Treatment, Northwood HA6 2RN, Middx, England. NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. Prince Wales Hosp, Dept Clin Oncol, Hong Kong, Hong Kong, Peoples R China. Princess Margaret Hosp, Dept Radiat Oncol, Toronto, ON M4X 1K9, Canada. Univ Toronto, Toronto, ON, Canada. RP Davis, AM (reprint author), Univ Toronto, Toronto Rehabil Inst, Room 1119,550 Univ Ave, Toronto, ON M5G 2A2, Canada. NR 61 TC 21 Z9 21 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 1053-4296 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD JUL PY 2003 VL 13 IS 3 BP 203 EP 213 DI 10.1016/S1053-4296(03)00022-5 PG 11 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 710FN UT WOS:000184670300005 PM 12903010 ER PT J AU Cheville, AL McGarvey, CL Petrek, JA Russo, SA Thiadens, SRJ Taylor, ME AF Cheville, AL McGarvey, CL Petrek, JA Russo, SA Thiadens, SRJ Taylor, ME TI The grading of lymphedema in oncology clinical trials SO SEMINARS IN RADIATION ONCOLOGY LA English DT Article ID BREAST-CANCER PATIENTS; AXILLARY DISSECTION; MAGNETIC-RESONANCE; ARM EDEMA; BIOELECTRICAL-IMPEDANCE; PSYCHOLOGICAL DISTRESS; EXTREMITY LYMPHEDEMA; NODE DISSECTION; SOMA SCALE; DIAGNOSIS C1 Univ Penn, Hlth Syst, Dept Rehabil Med, Philadelphia, PA 19104 USA. NIH, Dept Rehabil Med, Warren Magnuson Clin Ctr, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Evelyn H Lauder Breast Ctr, New York, NY 10021 USA. Columbia Presbyterian Med Ctr, Dept Radiat Oncol, New York, NY 10032 USA. Washington Univ, Sch Med, Dept Radiat Oncol, St Louis, MO USA. Natl Lymphedema Network, Oakland, CA USA. RP Cheville, AL (reprint author), Univ Penn, Hlth Syst, Dept Rehabil Med, 5 West Gates,3400 Spruce St, Philadelphia, PA 19104 USA. NR 49 TC 73 Z9 77 U1 0 U2 4 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 1053-4296 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD JUL PY 2003 VL 13 IS 3 BP 214 EP 225 DI 10.1016/S1053-4296(03)00038-9 PG 12 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 710FN UT WOS:000184670300006 PM 12903011 ER PT J AU Aziz, NM Rowland, JH AF Aziz, NM Rowland, JH TI Trends and advances in cancer survivorship research: Challenge and opportunity SO SEMINARS IN RADIATION ONCOLOGY LA English DT Article ID LONG-TERM SURVIVORS; ACUTE LYMPHOBLASTIC-LEUKEMIA; QUALITY-OF-LIFE; BREAST-CANCER; CHILDHOOD-CANCER; CRANIAL IRRADIATION; HODGKINS-DISEASE; MALIGNANT NEOPLASMS; COGNITIVE FUNCTION; ADJUVANT TREATMENT C1 NCI, Div Canc Prevent & Control, Off Canc Survivorship, DHHS,NIH, Bethesda, MD 20892 USA. RP Aziz, NM (reprint author), NCI, Div Canc Prevent & Control, Off Canc Survivorship, DHHS,NIH, 6130 Execut Blvd, Bethesda, MD 20892 USA. NR 97 TC 150 Z9 150 U1 0 U2 7 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 1053-4296 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD JUL PY 2003 VL 13 IS 3 BP 248 EP 266 DI 10.1016/S1053-4296(03)00024-9 PG 19 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 710FN UT WOS:000184670300009 PM 12903014 ER PT J AU Cheville, AL McGarvey, CL Petrek, JA Russo, SA Taylor, ME Thiadens, SRJ AF Cheville, AL McGarvey, CL Petrek, JA Russo, SA Taylor, ME Thiadens, SRJ TI Lymphedema management SO SEMINARS IN RADIATION ONCOLOGY LA English DT Review ID INTERMITTENT PNEUMATIC COMPRESSION; LYMPHOCYTE INJECTION THERAPY; MANUAL LYMPHATIC DRAINAGE; BREAST-CANCER; AXILLARY DISSECTION; ARM LYMPHEDEMA; OMENTAL TRANSPOSITION; RANDOMIZED-TRIAL; NODE BIOPSY; LYMPHOEDEMA C1 Univ Penn, Hlth Syst, Dept Rehabil Med, Philadelphia, PA 19104 USA. NIH, Dept Rehabil Med, Warren Magnuson Clin Ctr, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Evelyn H Lauder Breast Ctr, New York, NY 10021 USA. Columbia Presbyterian Med Ctr, Dept Radiat Oncol, New York, NY 10032 USA. Washington Univ, Sch Med, Dept Radiat Oncol, St Louis, MO USA. Natl Lymphedema Network, Oakland, CA USA. RP Univ Penn, Hlth Syst, Dept Rehabil Med, 5 West Gates,3400 Spruce St, Philadelphia, PA 19104 USA. NR 106 TC 66 Z9 66 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1053-4296 EI 1532-9461 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD JUL PY 2003 VL 13 IS 3 BP 290 EP 301 DI 10.1016/S1053-4296(03)00035-3 PG 12 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 710FN UT WOS:000184670300012 PM 12903017 ER PT J AU Gaydos, CA Howell, MR Quinn, TC Mckee, KT Gaydos, JC AF Gaydos, CA Howell, MR Quinn, TC Mckee, KT Gaydos, JC TI Sustained high prevalence of Chlamydia trachomatis infections in female army recruits SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID LIGASE CHAIN-REACTION; PELVIC INFLAMMATORY DISEASE; DNA AMPLIFICATION ASSAYS; FAMILY-PLANNING CLINICS; FIRST-VOID URINE; COST-EFFECTIVENESS; UNITED-STATES; MILITARY RECRUITS; WOMEN; DIAGNOSIS AB Background: Chlamydia trachomatis infections are prevalent among young sexually active females, have serious sequelae, and are mostly asymptomatic. Screening and treatment of infected females has been demonstrated to prevent sequelae such as pelvic inflammatory disease. Goal: To assess prevalence and risk factors for chlamydia infection in US Army female recruits, whether these changed over time, and to examine variables contributing to any observed patterns. Study Design: Prevalence study of 23,010 non-healthcare-seeking female Army recruits enrolled in a chlamydia screening program at Fort Jackson, SC, from January 1996 through June 1999. Each of the 4-year cohorts was examined separately for prevalence and risk factors. Main Outcome Measures: Urine-based testing for C trachomatis by ligase chain reaction was used to determine prevalence, and questionnaires were used to collect demographic and risk information. State home of record for each recruit was transformed into Public Health reporting region: West, Midwest, South, Northeast, and Territories. Results: Prevalence for all years was 9.51%, but a progressive increase from 8.51% to 9.92% occurred over the course of study (P = 0.018). The proportion of individuals reporting specific risk factors during the 90 days preceding the study generally decreased over time. In a regression model, significant risk factors for infection included black race, age 25 years or younger, home-of-record from the South, being screened during years 3 and 4 of the study, more than one sex partner, a new sex partner, and history of any sexually transmitted disease. Condom use was protective. In another model controlling for age and home-of-record from the South, being screened in years 2, 3, and 4 of the study were significantly predictive for being chlamydia positive. Conclusion: A high and slightly increasing prevalence of C trachomatis infection was observed among young females entering the military over 4 consecutive years. Young age, black race, home-of-record from the South, more than one sex partner, a new sex partner, condom use, and a history of having a sexually transmitted disease were correlates of chlamydia infection. Sustained high rates of C trachomatis infection in this population provide clear justification for a chlamydia control program for young women entering the Army consisting of screening at entry on the basis of age and possibly home-of-record together with continued periodic rescreening. Summary: A study of 23,010 female Army recruits demonstrated that a high prevalence of C trachomatis was sustained during 4 years of observation. Year of study, young age, and being from the South were significant predictors of infection. C1 Johns Hopkins Univ, Div Infect Dis, Baltimore, MD 21205 USA. NIAID, NIH, Bethesda, MD USA. Womack Army Med Ctr, Ft Bragg, NC USA. Dept Def Global Emerging Infect Surveillance & Re, Silver Spring, MD USA. RP Gaydos, CA (reprint author), Johns Hopkins Univ, Div Infect Dis, 1159 Ross Res Bldg,720 Rutland Ave, Baltimore, MD 21205 USA. RI Gaydos, Charlotte/E-9937-2010 NR 37 TC 42 Z9 44 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD JUL PY 2003 VL 30 IS 7 BP 539 EP 544 DI 10.1097/00007435-200307000-00002 PG 6 WC Infectious Diseases SC Infectious Diseases GA 699CE UT WOS:000184037700002 PM 12838080 ER PT J AU Castle, PE Escoffery, C Schachter, J Rattray, C Schiffman, M Moncada, J Sugai, K Brown, C Cranston, B Hanchard, B Palefsky, JM Burk, RD Hutchinson, ML Strickler, HD AF Castle, PE Escoffery, C Schachter, J Rattray, C Schiffman, M Moncada, J Sugai, K Brown, C Cranston, B Hanchard, B Palefsky, JM Burk, RD Hutchinson, ML Strickler, HD TI Chlamydia trachomatis, herpes simplex virus 2, and human T-cell lymphotrophic virus type 1 are not associated with grade of cervical neoplasia in Jamaican colposcopy patients SO SEXUALLY TRANSMITTED DISEASES LA English DT Article; Proceedings Paper CT 20th International Papillomavirus Conference CY OCT 04-09, 2002 CL PARIS, FRANCE ID HUMAN-PAPILLOMAVIRUS INFECTION; HTLV-I; RISK FACTOR; CANCER; CARCINOMA; ANTIBODY; HYPERSENSITIVITY; PREVALENCE; POPULATION; WORLDWIDE AB Background: A few recent studies have suggested that other sexually transmitted infections may increase the likelihood of a human papillomavirus (HPV) infection progressing to high-grade cervical neoplasia and cancer. Goal. The goal was to assess whether exposures to Chlamydia trachomatis, human T-cell lymphotrophic virus type 1 (HTLV-I), and/or human simplex virus type 2 (HSV-2) are greater in colposcopy patients with cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) than in patients with low-grade cervical neoplasia (CIN1). Study Design: Sequential patients (n = 447) attending a colposcopy clinic in Kingston, Jamaica, a country with high cervical cancer rates and high HTLV-I prevalence, were tested for (1) HPV DNA by L1 consensus primer (MY09/11) pollymerase chain reaction assays, (2) C trachomatis DNA by ligase chain reaction, (3) C trachomatis antibodies by both microimmunofluorescence and a peptide (VS4) enzyme linked immunosorbent assay (ELISA), (4) HTLV-I antibodies by ELISA confirmed by western blotting, and (5) HSV-2 antibodies by a recombinant HSV-2-specific ELISA. Odds ratios and 95% confidence intervals were estimated with use of multinormal logistic regression models. Results: HPV DNA detection was associated with grade of cervical neoplasia but other evaluated sexually transmitted infections were not. Conclusions: HTLV-I, C trachomatis, and/or HSV-2 were not associated with severity of cervical neoplasia in Jamaican women. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ W Indies, Kingston, Jamaica. Univ Calif San Francisco, Chlamydia Res Lab, Dept Lab Med, San Francisco, CA USA. Univ Calif San Francisco, Dept Lab Med & Stomatol, San Francisco, CA USA. Albert Einstein Coll Med, Dept Epidemiol & Social Med, Bronx, NY USA. Women & Infants Hosp Rhode Isl, Providence, RI USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,MSC 7234, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA13330] NR 27 TC 24 Z9 25 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD JUL PY 2003 VL 30 IS 7 BP 575 EP 580 DI 10.1097/00007435-200307000-00009 PG 6 WC Infectious Diseases SC Infectious Diseases GA 699CE UT WOS:000184037700009 PM 12838087 ER PT J AU Ranjan, A Tarigopula, L Srivastava, RK Obasanjo, OO Obah, E AF Ranjan, A Tarigopula, L Srivastava, RK Obasanjo, OO Obah, E TI Effectiveness of the clinical pathway in the management of congestive heart failure SO SOUTHERN MEDICAL JOURNAL LA English DT Review DE clinical pathway; congestive heart failure; cost control; quality of care AB Background: The prevalence of congestive heart failure (CHF) in the United States is approximately 4 million, with associated annual health care expenditures exceeding $8 billion. Clinical pathways for CHF have been developed, but they have not been rigorously evaluated regarding efficacy and improvement in the quality of care. We sought to evaluate the effect of a CHF clinical pathway on hospital charges, length of stay, and use of angiotensin-converting enzyme (ACE) inhibitors in patients with CHF in a retrospective cohort study. Methods: We studied 371 patients (age range, 44-92 yr) with discharge diagnoses of CHF in a 376-bed community hospital between July 1996 and December 1997. We conducted chart reviews to determine length of stay, hospital charges, and use of ACE inhibitors. Results: Of the 371 patients, 174 were assigned to the clinical pathway and 197 were not. Baseline characteristics of the two groups were similar. The benchmark of less than 4 days' in-hospital stay was achieved in 65% of patients on the pathway and 42% who were not on the pathway (odds ratio, 2.6; 95% confidence interval, 1.67-4.05; P < 0.001). The median hospital charges were lower in the group on the clinical pathway ($3,000 versus $5,500, P < 0.001). In addition, 81% of the patients on the clinical pathway were administered ACE inhibitors, compared with 48% of equally eligible patients from the nonpathway group (odds ratio, 4.68; 95% confidence interval, 2.85-7.72; P < 0.001). Conclusion: The clinical pathway for CHF was associated with increased use of ACE inhibitors as well as reduced length of stay and hospital charges. C1 Greater Baltimore Med Ctr, Baltimore, MD 21204 USA. NIA, NIH, Bethesda, MD 20892 USA. RP Obah, E (reprint author), Greater Baltimore Med Ctr, Phys Pavill E,Suite 203, Baltimore, MD 21204 USA. NR 11 TC 14 Z9 15 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0038-4348 J9 SOUTH MED J JI South.Med.J. PD JUL PY 2003 VL 96 IS 7 BP 661 EP 663 DI 10.1097/01.SMJ.0000060581.77206.ED PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 831CE UT WOS:000222169700007 PM 12940315 ER PT J AU Warach, S AF Warach, S TI Is there a perihematomal ischemic penumbra? More questions and an overlooked clue SO STROKE LA English DT Editorial Material ID INTRACEREBRAL HEMORRHAGE; BRAIN INJURY C1 NINDS, NIH, Bethesda, MD 20892 USA. RP Warach, S (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 4 TC 12 Z9 17 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 JUL PY 2003 VL 34 IS 7 BP 1680 EP 1680 DI 10.1161/01.STR.0000077013.83817.12 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 697NH UT WOS:000183949200034 PM 12805501 ER PT J AU Becker, K Kindrick, D McCarron, R Hallenbeck, J Winn, R AF Becker, K Kindrick, D McCarron, R Hallenbeck, J Winn, R TI Adoptive transfer of myelin basic protein-tolerized splenocytes to naive animals reduces infarct size - A role for lymphocytes in ischemic brain injury? SO STROKE LA English DT Article DE cytokines; immune tolerance; inflammation; stroke; T-lymphocytes ID GROWTH-FACTOR-BETA; CEREBRAL-ARTERY OCCLUSION; MULTIPLE-SCLEROSIS; IMMUNE-RESPONSE; T-CELLS; AUTOIMMUNE ENCEPHALOMYELITIS; ORAL TOLERANCE; STROKE; RELEASE; ANTIGEN AB Background and Purpose - Breakdown of the blood-brain barrier during stroke allows central nervous system antigens to leak into the systemic circulation and allows circulating leukocytes access to the brain. Encounter of central nervous system antigens by the peripheral immune system can be capitalized on to modulate the postischemic inflammatory response and potentially improve outcome from stroke. Methods - Male Lewis rats were tolerized to myelin basic protein (MBP) or ovalbumin ( OVA) and subjected to 3 hours of middle cerebral artery occlusion (MCAO) or used as splenocyte donors for immunologically naive animals undergoing MCAO. Infarct size was determined at 24 hours by 2,3,5-triphenyltetrazolium chloride staining. In separate studies, mononuclear cells were removed from the brains of animals after MCAO for enzyme-linked immunospot (ELISPOT) assay and flow cytometry. Results - Median infarct volume in animals tolerized to MBP and those receiving splenocytes from MBP-tolerized donors was less than in animals tolerized to OVA and those receiving splenocytes from OVA-tolerized donors (87.7 +/- 54.9 versus 148 +/- 61.6 mm(3) [P = 0.01] and 89.2 +/- 77.5 versus 153 +/- 77.1 mm(3) [P = 0.05], respectively). There was an increase in the number of transforming growth factor-beta1-secreting mononuclear cells in MBP-tolerized animals undergoing sham surgery ( P = 0.001) as well as in ischemic animals 48 hours ( P = 0.02) and 336 hours ( P = 0.04) after stroke. A distinct subset of gammadelta T cells was present in the brains of MBP-tolerized but not control animals after stroke. Conclusions - Immunologic tolerance and its neuroprotective effects can be transferred to naive animals and appear to be related to antigen-specific induction of transforming growth factor-beta1. C1 Univ Washington, Sch Med, Harborview Med Ctr, Dept Neurol, Seattle, WA 98104 USA. Univ Washington, Sch Med, Harborview Med Ctr, Dept Surg, Seattle, WA 98104 USA. Naval Med Res Ctr, Resuscitat Med Dept, Silver Spring, MD USA. Natl Inst Neurol Disorders & Stroke, Stroke Branch, NIH, Bethesda, MD USA. RP Becker, K (reprint author), Univ Washington, Sch Med, Harborview Med Ctr, Dept Neurol, Box 359775,325 9th Ave, Seattle, WA 98104 USA. FU NINDS NIH HHS [K02 NS02160-01 NST] NR 39 TC 57 Z9 60 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 JUL PY 2003 VL 34 IS 7 BP 1809 EP 1815 DI 10.1161/01.STR.0000078308.77727.EA PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 697NH UT WOS:000183949200059 PM 12791945 ER PT J AU Spivak, CE Beglan, CL Zollner, C Surratt, CK AF Spivak, CE Beglan, CL Zollner, C Surratt, CK TI beta-funaltrexamine, a gauge for the recognition site of wildtype and mutant H297Q mu-opioid receptors SO SYNAPSE LA English DT Article DE Xenopus oocyte; voltage clamp; GIRK potassium channel; G-protein-coupled receptor; partial agonist ID OPIATE RECEPTOR; BINDING; EXPRESSION; CLONING; ANTAGONISM; NALTREXONE; ACTIVATION; MEMBRANES; KINETICS; AGONISTS AB The antagonist beta-funaltrexamine (beta-FNA), known to bind covalently to L-opioid receptors by a two-step, doubly discriminating sequence, was used as a sensitive gauge to compare wildtype to mutant H297Q mu-opioid receptors. We addressed whether this mutation, which enhances the intrinsic activities of alkaloid mu-receptor agents, affects both the reversible and covalent phases of beta-FNA binding. Such altered binding serves as a reporter for the dimensions and topography of the receptor's recognition site. Using the voltage-clamped Xenopus oocyte expression system with coexpressed GIRK potassium channels, we found that beta-FNA blocked the wildtype and mutant H297Q receptors both reversibly and irreversibly, indicating overall conserved tertiary structure in the mutant. The mutant H297Q receptor, however, was more resistant to both phases of blockade, indicating some disturbance of the mutant H297Q receptor recognition site. beta-FNA acted as a partial agonist at the mutant H297Q receptor expressed in both oocytes, as measured by the activation of GIRK channels, and in COS-7 cells assayed by GTPgamma(35)S binding. beta-FNA showed no activity at the wildtype receptor expressed in oocytes, but surprisingly induced binding of GTPgamma(35)S in transfected COS-7 cells. Thus, the topography of the mutant H297Q receptor recognition site is sufficiently conserved to allow the selective binding of beta-FNA, but the decrease in binding affinity and increase in efficacy in oocytes demonstrates clear differences from the wildtype receptor. (C) 2003 Wiley-Liss, Inc. C1 NIDA, Intramural Res Program, Cellular Neurobiol Branch, DHHS,NIH, Baltimore, MD 21224 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10461 USA. Duquesne Univ, Div Pharmaceut Sci, Pittsburgh, PA 15282 USA. RP Spivak, CE (reprint author), NIDA, Intramural Res Program, Cellular Neurobiol Branch, DHHS,NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 16 TC 4 Z9 4 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD JUL PY 2003 VL 49 IS 1 BP 55 EP 60 DI 10.1002/syn.10205 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 682KB UT WOS:000183089800006 PM 12710015 ER PT J AU Bae, DS Handa, RJ Yang, RSH Campain, JA AF Bae, DS Handa, RJ Yang, RSH Campain, JA TI Gene expression patterns as potential molecular biomarkers for malignant transformation in human keratinocytes treated with MNNG, arsenic, or a metal mixture SO TOXICOLOGICAL SCIENCES LA English DT Article DE arsenic; metal mixture; gene expression; cDNA microarray; real-time RT-PCR; human keratinocytes; RHEK-1 cells ID GROWTH-FACTORS; CHRONIC STIMULATION; TUMOR PROGRESSION; EPITHELIAL-CELLS; CARCINOMA-CELLS; SKIN NEOPLASIA; HUMAN-MELANOMA; ENDEMIC AREA; PROTEIN; PROFILES AB In previous studies, treatment with 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) enhanced malignant transformation of immortal human epidermal (RHEK-1) keratinocytes. In contrast, arsenic (As) alone or in a mixture of As, cadmium (Cd), chromium (Cr), and lead (Pb) inhibited this process. Microarray analysis showed unique gene expression patterns in RHEK-1 exposed to MNNG, As, or the metal mixture. From this analysis, we have selected 16 genes potentially involved in the enhancement or inhibition of transformation. These 16 genes, nine (IFN inducible protein 9-27, MAA A32, CCLB protein, integrin beta4, XRCC1, K8, K18, MT3, MAPKK6) of which were altered in a chemical-specific manner and seven (MIC1, bikunin, MTS1, BMP4, RAD23A, DOC2, vimentin) of which were commonly affected by the MNNG and As or mixture treatments, were examined for expression in detail by real-time RT-PCR. Qualitatively, both microarray and real-time RT-PCR analyses gave comparable results for 15 of 16 genes, i.e., genes were consistently induced or suppressed under the different treatment regimens when measured by either technique. Of the seven genes altered in their expression by multiple chemical treatments, five showed patterns consistent with a role in the transformation process, i.e., they were oppositely regulated in MNNG-transformed RHEK-1 cells (designated as OM3) as compared to the nonmalignant As- and mixture-exposed cells. Through time-course studies, we also identified markers whose expression correlates with acquisition of transformation-associated characteristics in OM3. Identification of a battery of genes altered during progressive transformation of RHEK-1 should aid in developing a mechanistic understanding of this process, as well as strengthening the utility of these genes as biomarkers. C1 Colorado State Univ, Dept Environm & Radiol Sci, Ctr Environm Toxicol & Technol, Quantitat & Computat Toxicol Grp, Ft Collins, CO 80523 USA. NIH, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. Colorado State Univ, Dept Biomed Sci, Ft Collins, CO 80523 USA. RP Campain, JA (reprint author), Colorado State Univ, Dept Environm & Radiol Sci, Ctr Environm Toxicol & Technol, Quantitat & Computat Toxicol Grp, Ft Collins, CO 80523 USA. FU NIEHS NIH HHS [P42 ES05949] NR 39 TC 15 Z9 15 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JUL PY 2003 VL 74 IS 1 BP 32 EP 42 DI 10.1093/toxsci/kfg124 PG 11 WC Toxicology SC Toxicology GA 692NG UT WOS:000183666700005 PM 12773770 ER PT J AU Ashby, J Tinwell, H Lefevre, PA Joiner, R Haseman, J AF Ashby, J Tinwell, H Lefevre, PA Joiner, R Haseman, J TI The effect on sperm production in adult Sprague-Dawley rats exposed by gavage to bisphenol a between postnatal days 91-97 SO TOXICOLOGICAL SCIENCES LA English DT Article DE bisphenol A; sperm production; testis ID NORMAL SEXUAL DEVELOPMENT; REPRODUCTIVE TOXICITY; IN-UTERO; LACTATIONAL EXPOSURE; MATERNAL EXPOSURE; PROSTATE-GLAND; 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN; DIETHYLSTILBESTROL; TRANSIT; MICE AB M. Sakaue et al. (2001,J. Occup. Health vol. 43, pp. 185-190) have described how oral exposure of sexually mature male rats to bisphenol A (BPA) between postnatal days (PND) 91-97 led to a reduction in daily sperm production (DSP) 5 weeks later (18 weeks of age). Activity was observed over the dose range 20 mug/kg-200 mg/kg BPA, with an absence of activity over the dose range 2 ng/kg-2 mug/kg BPA. There was no evidence of a dose response relationship over the active dose range (five orders of magnitude range). The observation of endocrine disruption (ED) effects for BPA at such low doses, and in sexually mature animals, was unexpected. It was therefore decided to mount an independent repeat of their study. A total of four independent studies were conducted according to the protocol used by Sakaue et al. Doses of 20 mug/kg, 2 mg/kg, or 200 mg/kg BPA were administered to adult Sprague-Dawley (SD) rats over PND 91-97, and the studies were terminated when the rats reached the age of 18 weeks. Three different rodent diets were employed (RM3, Purina 5002, and CE2), the last of which had been used by Sakaue et al. BPA failed to give any evidence of ED activities, including the changes in DSP reported by Sakaue et al. 2001. During the course of these studies, the test protocol was adapted to coincide more precisely with that used by Sakaue et al.; this included restricting the number of animals per cage, removing bedding from the cages, and changing to the use of glass water bottles in the cages. The only thing of interest to emerge from our studies was the observation of a significant difference in DSP between the control groups of our first and second study. As the change in diet from RM3 to Purina 5002 was the major difference between those two studies, we conducted a repeat of the second study, but we were unable to confirm the differences seen between the first and second study. The probability that those differences arose either by chance, or as the result of intrinsic study-to-study variability, was strengthened by the absence of significant differences in the sperm parameters in a final (fifth) study where the sperm parameters for control animals maintained on the three different diets were compared under the conditions of the main experiments. No explanation for our failure to replicate the effects reported by Sakaue et al. is evident. A review of DSP values reported in the recent literature is provided and discussed, and it is concluded that use of the term DSP/g testis rather than DSP/testis could increase the sensitivity of DSP assessments. C1 Syngenta Cent Toxicol Lab, Alderley Pk SK10 4TJ, Cheshire, England. GE Co, Pittsfield, MA 01201 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Ashby, J (reprint author), Syngenta Cent Toxicol Lab, Alderley Pk SK10 4TJ, Cheshire, England. NR 37 TC 48 Z9 51 U1 2 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JUL PY 2003 VL 74 IS 1 BP 129 EP 138 DI 10.1093/toxsci/kfg093 PG 10 WC Toxicology SC Toxicology GA 692NG UT WOS:000183666700014 PM 12773777 ER PT J AU Liu, J Lei, DW Waalkes, MP Beliles, RP Morgan, DL AF Liu, J Lei, DW Waalkes, MP Beliles, RP Morgan, DL TI Genomic analysis of the rat lung following elemental mercury vapor exposure SO TOXICOLOGICAL SCIENCES LA English DT Article DE mercury vapor inhalation; lung; microarray; gene expression; adaptation ID METALLOTHIONEIN-NULL MICE; GENE-EXPRESSION; INORGANIC MERCURY; SUPEROXIDE-DISMUTASE; REAL-TIME; TOXICITY; INHALATION; TOXICOLOGY; PROTEIN; KIDNEY AB Elemental mercury (Hg-0) is a highly toxic chemical with increasing public health concern. Although the lung receives the highest exposure to Hg-0 vapor, it is resistant to Hg-0 toxicity relative to the kidney and brain. In an earlier study, exposure of rats to 4 mg Hg-0 vapor/m(3), 2 h per day for 10 days, did not produce pathological alterations in the lung but increased metallothionein and glutathione S-transferase in the kidney. This study was undertaken to examine pulmonary gene expression associated with Hg-0 vapor inhalation. Total RNA was extracted from lung tissues of rats, previously exposed to air or Hg-0 vapor, and subjected to microarray analysis. Hg-0 vapor exposure increased the expression of genes encoding inflammatory responses, such as chemokines, tumor necrosis factor-alpha (TNFalpha), TNF-receptor-1, interleukin-2 (IL-2), IL-7, prostaglandin E2 receptor, and heat-shock proteins. As adaptive responses, glutathione S-transferases (GST-pi, mGST1), metallothionein, and thioredoxin peroxidase were all increased in response to Hg exposure. Some transporters, such as multidrug resistance-associated protein (MRP), P-glycoprotein, and zinc transporter ZnT1, were also increased in an attempt to reduce pulmonary Hg load. The expression of transcription factor c-jun/AP-1 and PI3-kinases was suppressed, while the expression of protein kinase-C was increased. Expression of epidermal fatty acid-binding protein was also enhanced. Real-time RT-PCR and Western blot analyses confirmed the microarray results. In summary, genomic analysis revealed an array of gene alterations in response to Hg-0 vapor exposure, which could be important for the development of pulmonary adaptation to Hg during Hg-0 vapor inhalation. C1 NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Inorgan Carcinogenesis Sect, NCI, Res Triangle Pk, NC 27709 USA. US EPA, ORD, NCEA, Oakton, VA USA. Guiyang Med Coll, Guizhou 550004, Peoples R China. RP Morgan, DL (reprint author), NIEHS, Mol Toxicol Lab, MD IF-00, Res Triangle Pk, NC 27709 USA. NR 35 TC 26 Z9 31 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JUL PY 2003 VL 74 IS 1 BP 174 EP 181 DI 10.1093/toxsci/kfg091 PG 8 WC Toxicology SC Toxicology GA 692NG UT WOS:000183666700019 PM 12730625 ER PT J AU Kodavanti, UP Ledbetter, AD Schladweiler, MC Costa, DL Moyer, CF Hauser, R Christiani, DC Nyska, A AF Kodavanti, UP Ledbetter, AD Schladweiler, MC Costa, DL Moyer, CF Hauser, R Christiani, DC Nyska, A TI Untitled - Reply SO TOXICOLOGICAL SCIENCES LA English DT Letter ID ZINC METALLOTHIONEIN; INHIBITION; RAT C1 US EPA, Pulm Toxicol Branch, Expt Toxicol Div,Natl Hlth & Environm Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. Pathol Associates Inc, Raleigh, NC 27606 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. RP Kodavanti, UP (reprint author), US EPA, Pulm Toxicol Branch, Expt Toxicol Div,Natl Hlth & Environm Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. NR 15 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JUL PY 2003 VL 74 IS 1 BP 228 EP 230 DI 10.1093/toxsci/kfg127 PG 3 WC Toxicology SC Toxicology GA 692NG UT WOS:000183666700025 ER PT J AU Dimcheff, DE Portis, JL Caughey, B AF Dimcheff, DE Portis, JL Caughey, B TI Prion proteins meet protein quality control SO TRENDS IN CELL BIOLOGY LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; PRP; UBIQUITIN; NEUROTOXICITY; AGGREGATION; CONVERSION; CYTOSOL; PARKIN AB Recent work on transmissible spongiform encephalopathies (TSEs) suggests a role for protein quality-control mechanisms in both prion protein aggregation and pathogenesis. Cytosolic accumulation of prion protein seems to be neurotoxic and might occur when proteasome function is compromised and quality control is overwhelmed. These findings are discussed in the light of other studies linking proteasome inhibition and neurodegeneration. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. RP Dimcheff, DE (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. NR 17 TC 19 Z9 21 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 JUL PY 2003 VL 13 IS 7 BP 337 EP 340 DI 10.1016/S0962-8924(03)00125-9 PG 4 WC Cell Biology SC Cell Biology GA 700QX UT WOS:000184123600001 PM 12837603 ER PT J AU Rigden, DJ Jedrzejas, MJ Moroz, OV Galperin, MY AF Rigden, DJ Jedrzejas, MJ Moroz, OV Galperin, MY TI Structural diversity of calcium-binding proteins in bacteria: single-handed EF-hands? SO TRENDS IN MICROBIOLOGY LA English DT Letter ID CRYSTAL-STRUCTURE; DOMAIN; CA2+ C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Natl Ctr Genet Resources & Biotechnol, BR-70770900 Brasilia, DF, Brazil. Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA. Univ York, York Struct Biol Lab, Dept Chem, York YO10 5YW, N Yorkshire, England. RP Galperin, MY (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RI Galperin, Michael/B-5859-2013; OI Galperin, Michael/0000-0002-2265-5572; Rigden, Daniel/0000-0002-7565-8937 NR 10 TC 18 Z9 18 U1 0 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0966-842X J9 TRENDS MICROBIOL JI Trends Microbiol. PD JUL PY 2003 VL 11 IS 7 BP 295 EP 297 DI 10.1016/S0966-842X(03)00153-7 PG 3 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 707YU UT WOS:000184538200002 PM 12875810 ER PT J AU Hegde, RS Rane, NS AF Hegde, RS Rane, NS TI Prion protein trafficking and the development of neurodegeneration SO TRENDS IN NEUROSCIENCES LA English DT Article ID ENDOPLASMIC-RETICULUM; DISEASES; CYTOSOL; PRP; TRANSLOCATION; NEUROTOXICITY; TRANSMISSION; UBIQUITIN; RODENTS AB The prion protein (PrP) is involved in causing a group of diverse transmissible, heritable and sporadically occurring neurodegenerative diseases. Although the identity, nature and replication of the transmissible agent have been intensely studied for decades, the cellular events underlying neuronal dysfunction and death have received comparatively little attention. Recent studies examining the occurrence and consequences of inappropriate cytoplasmic expression of the normally cell-surface PrP underscore an emerging role for PrP trafficking in prion disease pathogenesis. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Hegde, RS (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. OI Hegde, Ramanujan/0000-0001-8338-852X NR 17 TC 28 Z9 29 U1 1 U2 5 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD JUL PY 2003 VL 26 IS 7 BP 337 EP 339 DI 10.1016/S0166-2236(03)00143-7 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 703AV UT WOS:000184258600002 PM 12850426 ER PT J AU Pevny, L Rao, MS AF Pevny, L Rao, MS TI The stem-cell menagerie SO TRENDS IN NEUROSCIENCES LA English DT Review ID CENTRAL-NERVOUS-SYSTEM; ADULT MAMMALIAN FOREBRAIN; FIBROBLAST-GROWTH-FACTOR; RADIAL GLIAL-CELLS; OLIGODENDROCYTE PRECURSOR CELLS; EMBRYONIC SPINAL-CORD; NEURAL STEM; PROGENITOR CELLS; CEREBRAL-CORTEX; ALDEHYDE DEHYDROGENASE AB The numbers, types and locations of stem cells in the nervous system have been the subject of much discussion. This review summarizes data on the types of stem cell present at different stages of development and in the adult brain, and the markers suggested to distinguish between the various possibilities that have been reported. We present evidence that more than one class of stem cell is present in the developing and adult nervous systems, and that it might be possible to distinguish between stem-cell populations and to localize the cell of origin of a particular neurosphere, based on markers that persist in culture and by using universal stem-cell markers prospectively to identify stem cells in vivo. C1 Univ N Carolina, Ctr Neurosci, Dept Genet, Chapel Hill, NC 27599 USA. NIA, Neurosci Lab, Baltimore, MD 21224 USA. RP Pevny, L (reprint author), Univ N Carolina, Ctr Neurosci, Dept Genet, Chapel Hill, NC 27599 USA. NR 92 TC 108 Z9 113 U1 1 U2 4 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD JUL PY 2003 VL 26 IS 7 BP 351 EP 359 DI 10.1016/S0166-2236(03)00169-3 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 703AV UT WOS:000184258600007 PM 12850431 ER PT J AU Garraud, O Perraut, R Riveau, G Nutman, TB AF Garraud, O Perraut, R Riveau, G Nutman, TB TI Class and subclass selection in parasite-specific antibody responses SO TRENDS IN PARASITOLOGY LA English DT Article ID RECOMBINANT FILARIAL PROTEINS; PLASMODIUM-FALCIPARUM MALARIA; IMMUNOGLOBULIN-G; TH2-CELL COMMITMENT; PROTECTIVE IMMUNITY; INFECTIOUS-DISEASE; FC RECEPTOR; HUMAN IGE; ANTIGEN; IGG4 AB Antibodies are characteristically induced in many parasitic infection processes. The class and subclass of the antibody response is instrumental because each isotype has a distinct biological function. It is thus crucially important for an infected individual to mount the most appropriate secondary antibody response - that is the response that has the best chance of clearing the infection and/or controlling disease. This represents a fundamental of vaccine strategies. Immuno-epidemiological surveys and in vitro models of antibody production have helped to understand some of the goals which should be achieved when designing antiparasitic vaccines. C1 Univ St Etienne, Fac Med, Grp Immun Muqueuses & Agents Pathogens EA3064, F-42023 St Etienne 02, France. Inst Pasteur, Immunol Lab, Dakar, Senegal. Inst Pasteur, Unite Inst Francais Sante & Rech Med, U547, F-59019 Lille, France. Inst Pasteur, Ctr Immunol & Biol Parasitaire, F-59019 Lille, France. NIAID, Helminth Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Garraud, O (reprint author), Univ St Etienne, Fac Med, Grp Immun Muqueuses & Agents Pathogens EA3064, 15 Rue Ambroise Pare, F-42023 St Etienne 02, France. NR 45 TC 53 Z9 57 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4922 J9 TRENDS PARASITOL JI Trends Parasitol. PD JUL PY 2003 VL 19 IS 7 BP 300 EP 304 DI 10.1016/S1471-4922(03)00139-9 PG 5 WC Parasitology SC Parasitology GA 707YV UT WOS:000184538300008 PM 12855380 ER PT J AU Perry, T Greig, NH AF Perry, T Greig, NH TI The glucagon-like peptides: a double-edged therapeutic sword? SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID DEPENDENT PROTEIN-KINASE; PANCREATIC BETA-CELLS; INSULIN-SECRETION; RAT-BRAIN; IN-VIVO; PEPTIDE-1-(7-36) AMIDE; GLUCOSE-INTOLERANCE; INHIBITS APOPTOSIS; DIABETIC-PATIENTS; GENE-EXPRESSION AB Glucagon-like peptide-1(7-36)-amide (GLP-1) is an endogenous peptide that is secreted from the gut in response to the presence of food. Recent studies have established that GLP-1 and its longer-acting analog exendin-4 have multiple synergistic effects on glucose-dependent, insulin secretion pathways of the pancreatic beta-cell and on plasticity in neuronal cells. Recent interest has focused on the development of these peptides as a novel therapeutic strategy for non-insulin-dependent (type 2) diabetes mellitus and associated neuropathy. This is with a view to developing lead compounds, based on neurotrophic action, for central and peripheral degenerative disorders such as stroke and Alzheimer's disease in addition to the peripheral neuropathy associated with type 2 diabetes mellitus. Here, we address recent advances in the biological action of GLP-1 and its related analogs. C1 NIA, Sect Drug Design & Dev, Neurosci Lab, Gerontol Res Ctr,NIH, Baltimore, MD 21224 USA. RP Perry, T (reprint author), NIA, Sect Drug Design & Dev, Neurosci Lab, Gerontol Res Ctr,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 65 TC 77 Z9 81 U1 3 U2 10 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD JUL PY 2003 VL 24 IS 7 BP 377 EP 383 DI 10.1016/S015-6147(03)00160-3 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 707XC UT WOS:000184534300011 PM 12871671 ER PT J AU Sosnovtsev, SV Prikhod'ko, EA Belliot, G Cohen, JI Green, KY AF Sosnovtsev, SV Prikhod'ko, EA Belliot, G Cohen, JI Green, KY TI Feline calicivirus replication induces apoptosis in cultured cells SO VIRUS RESEARCH LA English DT Article DE feline calicivirus; apoptosis; caspases ID RABBIT HEMORRHAGIC-DISEASE; HEPATITIS-A VIRUS; CASPASE ACTIVATION; LANGAT FLAVIVIRUS; INFECTED-CELLS; POLIOVIRUS; CLEAVAGE; GENOME; DEATH; RNA AB Infection of Crandell-Rees feline kidney (CRFK) cells by feline calicivirus (FCV) causes rapid cytopathic effects followed by cell death. In this study, we observed that FCV replication in cells results in the induction of changes characteristic of apoptosis, including translocation of phosphatidyl serine to the cell outer membrane, chromatin condensation, and oligonucleosomal DNA fragmentation. FCV infection was associated with increases in the activities of caspase-3, -8, and -9, with the level of activation of caspase-3 higher than those of caspases-8 and -9. Caspase activation in CRFK cells was not observed when cells were inoculated with UV-inactivated FCV or when cycloheximide was present during virus infection, indicating that FCV replication and de novo synthesis of virus proteins are critical for induction of apoptosis. Published by Elsevier Science B.V. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Sosnovtsev, SV (reprint author), NIAID, Infect Dis Lab, NIH, 50 S Dr MSC8007,Bldg 50,Room 6316, Bethesda, MD 20892 USA. NR 48 TC 28 Z9 28 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD JUL PY 2003 VL 94 IS 1 BP 1 EP 10 DI 10.1016/S0168-1702(03)00115-1 PG 10 WC Virology SC Virology GA 701VU UT WOS:000184190300001 PM 12837551 ER PT J AU Song, CZ Bai, ZL Song, CC Wang, QW AF Song, CZ Bai, ZL Song, CC Wang, QW TI Aggregate formation of hepatitis B virus X protein affects cell cycle and apoptosis SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article ID HBX PROTEIN; SYSTEM; HEPATOCARCINOGENESIS; EXPRESSION; PATHWAYS; MUTANTS; KINASE AB AIM: To investigate whether the formation of aggregated HBx has a potential linking with its cellular responses. METHODS: Recombinant HBx was expressed in Escherichia coli and purified by Ni-NTA metal-affinity chromatography. Anti-HBx monoclonal antibody was developed for immunocytochemical detection. Bicistronic expression vector harboring full-length DNA of HBx was employed for transfection of human HepG2 cells. Immunocytochemical staining was used to examine the intracellular HBx aggregates in cells. The effects of HBx aggregation on cell cycle and apoptosis were assessed by flow cytometry. RESULTS: Immunocytochemical staining revealed most of the HBx was formed intracellular aggregate in cytoplasm and frequently accumulated in large granules. Flow cytometry analysis showed that HepG2 cells transfected with vector harboring HBx significantly increased apoptosis and largely accumulated in the G0-G1 phase by maintenance in serum medium for 36 hours. Control cells without HBx aggregates in the presence of serum entered S phase and proliferated more rapidly at the same time. EGFP fluorescence in HBx expression cells was significantly decreased. CONCLUSION: Our observations show that cells with HBx aggregate undergo growth arrest and apoptosis, whereas control cells without HBx remain in growth and progression into S phase. Our data may provide helpful information to understand the biological effects of HBx aggregates on cells. C1 Shandong Acad Med Sci, Shandong Res Ctr Med Biotechnol, Project Viral Vaccine, Jinan 250062, Shandong, Peoples R China. Shandong Univ, Coll Life Sci, Immunobiol Lab, Jinan 250100, Shandong, Peoples R China. NCI, Basic Res Lab, Frederick, MD 21702 USA. Shandong Univ, Qilu Hosp, Ctr Canc Res, Jinan 250012, Shandong, Peoples R China. RP Song, CZ (reprint author), Shandong Acad Med Sci, Shandong Res Ctr Med Biotechnol, Project Viral Vaccine, Jinan 250062, Shandong, Peoples R China. NR 21 TC 11 Z9 14 U1 0 U2 1 PU W J G PRESS PI BEIJING PA PO BOX 2345, BEIJING 100023, PEOPLES R CHINA SN 1007-9327 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD JUL PY 2003 VL 9 IS 7 BP 1521 EP 1524 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 722MB UT WOS:000185377600030 PM 12854155 ER PT J AU Basrai, M Espinoza, L AF Basrai, M Espinoza, L TI A specific role for the evolutionarily conserved S-cerevisiae Spt4p in specialized chromatin at kinetochores and silenced heterochromatin regions. SO YEAST LA English DT Meeting Abstract CT 21st International Conference on Yeast Genetics and Molecular Biology CY JUL 07-12, 2003 CL GOTHENBURG, SWEDEN C1 NCI, Bethesda, MD 20889 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0749-503X J9 YEAST JI Yeast PD JUL PY 2003 VL 20 SU 1 BP S99 EP S99 PG 1 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology GA 701HH UT WOS:000184161800215 ER PT J AU Bonangelino, C Chavez, E Bonifacino, J AF Bonangelino, C Chavez, E Bonifacino, J TI Genomic Screen for new vacuole protein sorting mutants in Saccharomyces cerevisiae. SO YEAST LA English DT Meeting Abstract CT 21st International Conference on Yeast Genetics and Molecular Biology CY JUL 07-12, 2003 CL GOTHENBURG, SWEDEN C1 NICHD, CBMB, NIH, Bethesda, MD 20982 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0749-503X J9 YEAST JI Yeast PD JUL PY 2003 VL 20 SU 1 BP S271 EP S271 PG 1 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology GA 701HH UT WOS:000184161800645 ER PT J AU Kim, Y Yon, CW Moore, RE Philpott, CC AF Kim, Y Yon, CW Moore, RE Philpott, CC TI Ferrichrome induces endosome to plasma membrane cycling of the ferrichrome transporter, Arn1p, in Saccharomyces cerevisiae. SO YEAST LA English DT Meeting Abstract CT 21st International Conference on Yeast Genetics and Molecular Biology CY JUL 07-12, 2003 CL GOTHENBURG, SWEDEN C1 NIH, Liver Dis Sect, Bethesda, MD 20892 USA. Korea Res Inst Chem Technol, Taejon 305600, South Korea. Univ Wisconsin, Dept Chem, Oshkosh, WI USA. NIDDK, Liver Dis Sect, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0749-503X J9 YEAST JI Yeast PD JUL PY 2003 VL 20 SU 1 BP S235 EP S235 PG 1 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology GA 701HH UT WOS:000184161800558 ER PT J AU Nielsen, KH Szamecz, B Jivotovskaya, A Valasek, L Hinnebusch, AG AF Nielsen, KH Szamecz, B Jivotovskaya, A Valasek, L Hinnebusch, AG TI In vivo evidence that translation initiation factor 3 functions in ribosomal scanning and GCN4 translational control SO YEAST LA English DT Meeting Abstract CT 21st International Conference on Yeast Genetics and Molecular Biology CY JUL 07-12, 2003 CL GOTHENBURG, SWEDEN C1 NIH, LGRD, Bethesda, MD 20892 USA. RI Valasek, Leos/I-5743-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0749-503X J9 YEAST JI Yeast PD JUL PY 2003 VL 20 SU 1 BP S150 EP S150 PG 1 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology GA 701HH UT WOS:000184161800338 ER PT J AU Stepchenkova, E Alenin, V Pavlov, Y AF Stepchenkova, E Alenin, V Pavlov, Y TI Genome-wide screen for genes controlling sensitivity to mutagenic base analogs in yeast SO YEAST LA English DT Meeting Abstract CT 21st International Conference on Yeast Genetics and Molecular Biology CY JUL 07-12, 2003 CL GOTHENBURG, SWEDEN C1 St Petersburg State Univ, Dept Genet, St Petersburg 199034, Russia. NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RI Stepchenkova, Elena/F-9931-2014 OI Stepchenkova, Elena/0000-0002-5854-8701 NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0749-503X J9 YEAST JI Yeast PD JUL PY 2003 VL 20 SU 1 BP S90 EP S90 PG 1 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology GA 701HH UT WOS:000184161800189 ER PT J AU Wickner, R Edskes, H Baxa, U Steven, A Roberts, T Ross, E Pierce, M Brachmann, A AF Wickner, R Edskes, H Baxa, U Steven, A Roberts, T Ross, E Pierce, M Brachmann, A TI Yeast prions: biology and mechanisms SO YEAST LA English DT Meeting Abstract CT 21st International Conference on Yeast Genetics and Molecular Biology CY JUL 07-12, 2003 CL GOTHENBURG, SWEDEN C1 NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. NIAMS, Struct Biol Lab, NIH, Bethesda, MD USA. RI Brachmann, Andreas/I-2241-2013 OI Brachmann, Andreas/0000-0001-7980-8173 NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0749-503X J9 YEAST JI Yeast PD JUL PY 2003 VL 20 SU 1 BP S17 EP S17 PG 1 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology GA 701HH UT WOS:000184161800016 ER PT J AU Yu, R Yakar, S Liu, YL Lu, YR LeRoith, D Miao, DS Liu, JL AF Yu, R Yakar, S Liu, YL Lu, YR LeRoith, D Miao, DS Liu, JL TI Liver-specific IGF-I gene deficient mice exhibit accelerated diabetes in response to streptozotocin, associated with early onset of insulin resistance SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE Cre/loxP; insulin resistance; pancreatic islets; immunohistochemistry ID GROWTH-FACTOR-I; BETA-CELL MASS; TRANSGENIC MICE; SIGNAL-TRANSDUCTION; GLUCOSE; HORMONE; PROTEIN; EXPRESSION; RECEPTORS; LEADS AB Liver-specific IGF-I gene deficient (LID) mice exhibit pancreatic islet hyperplasia and insulin resistance. To clarify their causal relationship, we studied age-dependent changes in these two aspects and the response to beta-cell damage caused by streptozotocin in adult mice. As a result. the onset of insulin resistance in LID mice was detectable as early as I-month of age, while hyperinsulinemia was developed after a significant delay at 2.5-month. Upon streptozotocin administration, control mice exhibited significant hyperglycemia after 9 days, and glucose levels continued to rise at 12-15 days. LID mice developed diabetes much more rapidly, with hyperglycemia after 6 days and higher glucose levels up to 15 days. They also exhibited significant weight loss and 6/19 died. Serum insulin assay, insulin mRNA analysis and immunohistochemistry revealed that the more severe diabetes in LID mice was not due to more damage to their beta-cells. Thus LID mice are more sensitive to streptozotocin-induced beta-cell damage, due to a primary defect in insulin responsiveness. The pancreatic islet hyperplasia observed in these mice seems to represent a compensatory response to insulin resistance, therefore, offers no protection against beta-cell damage. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved. C1 McGill Univ, Dept Med, Fraser Labs, Ctr Hlth, Montreal, PQ H3A 1A1, Canada. NIDDK, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Liu, JL (reprint author), McGill Univ, Dept Med, Fraser Labs, Ctr Hlth, M3-15,687 Pine Ave W, Montreal, PQ H3A 1A1, Canada. NR 36 TC 23 Z9 25 U1 0 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JUN 30 PY 2003 VL 204 IS 1-2 BP 31 EP 42 DI 10.1016/S0303-7207(03)00145-X PG 12 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 703XA UT WOS:000184306400004 PM 12850279 ER PT J AU Follmann, DA AF Follmann, DA TI Comparing HLA antigen frequencies between two groups of patients SO STATISTICS IN MEDICINE LA English DT Article DE Bonferroni; binomial test; two-stage procedure ID ASSOCIATIONS; DISEASE; TESTS; ANEMIA AB For diseases that involve the immune system, the alleles of the human leukocyte antigen (HLA) complex can play a major role. For example, if responsiveness to therapy is immunologically mediated, one would think that responders and non-responders might tend to have different HLA alleles. However, comparing the frequencies between the two groups of patients at each allele can introduce a substantial multiple comparisons problem as the number of alleles is large. This paper proposes an efficient two-stage procedure for identifying alleles that may mediate response. In the first-stage, the distribution of all alleles for the patients are compared to a reference population and a few alleles are selected. These candidate alleles are then compared between the two groups of patients using a. modest Bonferroni correction. The two-stage procedure strongly controls the type I error rate as the first-stage selection is statistically independent of the second-stage tests. We analyse a cohort of patients with bone marrow failure who are classified as responders or non-responders to immunosuppressive therapy. Published in (C) 2003 by John Wiley Sons, Ltd. C1 NHLBI, Math Stat Off Biostat Res, Rockledge Ctr 2, Bethesda, MD 20892 USA. RP Follmann, DA (reprint author), NHLBI, Math Stat Off Biostat Res, Rockledge Ctr 2, Bethesda, MD 20892 USA. NR 13 TC 2 Z9 2 U1 1 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD JUN 30 PY 2003 VL 22 IS 12 BP 1999 EP 2013 DI 10.1002/sim.1426 PG 15 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 691MN UT WOS:000183610200005 PM 12802818 ER PT J AU Pastwa, E Lubner, EM Mezhevaya, K Neumann, RD Winters, TA AF Pastwa, E Lubner, EM Mezhevaya, K Neumann, RD Winters, TA TI DNA uptake and repair enzyme access to transfected DNA is under reported by gene expression SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE DNA uptake; transfection efficiency; double-strand break repair ID DOUBLE-STRAND BREAK; MAMMALIAN-CELLS; PROTEIN-KINASE; DELIVERY; VECTOR; SUBUNIT AB Gene expression is the typical biological end point of interest following transfection. However, transcription may not accurately assess DNA uptake, or the ability of transfected DNA to be acted on by other enzymatic pathways. We have compared DNA uptake to gene expression and the unrelated enzymatic process of DNA double strand break (DSB) repair. Transfection efficiency (at limiting DNA concentration) was assessed as a function of DNA uptake and gene expression in the DSB repair proficient WI38VA13 and MO59K cell lines and the DSB repair defective cell line MO59J, by comparing eGFP expression from the gEGFP expression vector with uptake of rhodamine labeled linear pSP189 plasmid (3:1). Repair proficient cells expressed eGFP most efficiently, but never approached DNA uptake levels ( greater than or equal to90%). Although transfected DNAs were stable in repair proficient cells and degraded in MO59J cells, most cells did not express eGFP, but in the repair proficient cells linear DNA did undergo DSB repair. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NIH, Warren Grant Magnuson Clin Ctr, Dept Nucl Med, Bethesda, MD 20892 USA. Med Univ Lodz, Inst Physiol & Biochem, Dept Gen Chem, Lodz, Poland. Carroll Coll, Waukesha, WI 53186 USA. Fidel Syst Inc, Gaithersburg, MD 20879 USA. RP Winters, TA (reprint author), NIH, Warren Grant Magnuson Clin Ctr, Dept Nucl Med, Bldg 10, Bethesda, MD 20892 USA. NR 16 TC 2 Z9 2 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 27 PY 2003 VL 306 IS 2 BP 421 EP 429 DI 10.1016/S0006-291X(03)00972-0 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 693TQ UT WOS:000183734800016 PM 12804580 ER PT J AU Peng, YB Kenshalo, DR Gracely, RH AF Peng, YB Kenshalo, DR Gracely, RH TI Periaqueductal gray-evoked dorsal root reflex is frequency dependent SO BRAIN RESEARCH LA English DT Article DE dorsal root ganglion; spinal cord; primary afferent; synapse ID CENTRAL-NERVOUS-SYSTEM; PRIMARY AFFERENT DEPOLARIZATION; RAT SPINAL-CORD; RECEPTOR ANTAGONISTS; INDUCED INHIBITION; 5-HT3 RECEPTORS; HORN NEURONS; AMINO-ACIDS; GABA; BICUCULLINE AB The dorsal root reflex (DRR) is an antidromic action potential originating in the spinal cord that propagates toward the periphery. Given that both GABA A and 5-HT3 receptors are involved in the generation of DRRs and stimulation of the periaqueductal gray (PAG) can induce the release of GABA and serotonin within the spinal cord, we investigated the modulation of DRRs by the PAG descending system. The central end of the cut left L5 dorsal root in adult Sprague-Dawley rats was tested with single fiber recording. Stimulating electrodes were placed in the PAG. sciatic nerve, or transcutaneously across hindpaws. Fifty-seven DRRs were recorded for the effect of PAG stimulation in 19 rats. and 51 DRRs from 26 rats and nine DRRs from seven rats were recorded for an effect of ipsilateral and contralateral peripheral stimulation, respectively. The results were expressed as a percentage of the number of DRRs over the number of stimuli. PAG stimulation at 0.2. 0.5, 5, 20, and 50 Hz produced ratio's of 113.16 +/- 9.84, 114.54 +/- 12.22, 24.6 +/- 3.23, 17.77 +/- 4.76, and 12.62 +/- 3.44 (%). respectively. Stimulation at ipsilateral peripheral nerve evoked DRRs of 103.26 +/- 8.93, 95.27 +/- 10.57, 37.66 +/- 7.55, 11.32 +/- 4.96, and 5.32 +/- 3.82 (%), respectively. Stimulation of the contralateral peripheral nerve evoked DRRs of 90.88 +/- 15.59, 44.30 +/- 10.77, 6.29 +/- 1.63. 0.45 +/- 0.19, and 0.29 +/- 0.15 (%), respectively. Transection at the thoracic spinal level completely eliminated PAG-incluced DRRs. In conclusion, both PAG and peripheral stimulation produced DRRs in a frequency dependent manner. Stimulus intensity has no significant effect on DRRs. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Univ Texas, Dept Psychol, Arlington, TX 76019 USA. Natl Inst Dent & Craniofacial Res, Pain & Neurosensory Mech Branch, NIH, Bethesda, MD 20892 USA. NIH, Ctr Sci Review, Bethesda, MD 20814 USA. Univ Michigan Hlth Syst, Dept Med Rheumatol & Neurol, Ann Arbor, MI 48105 USA. RP Peng, YB (reprint author), Univ Texas, Dept Psychol, 501 S Nedderman Dr,POB 19528, Arlington, TX 76019 USA. NR 50 TC 9 Z9 9 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 27 PY 2003 VL 976 IS 2 BP 217 EP 226 DI 10.1016/S0006-8993(03)02718-5 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 688QB UT WOS:000183445900009 PM 12763256 ER PT J AU Macpherson, GR Franks, M Tomoaia-Cotisel, A Ando, Y Price, DK Figg, WD AF Macpherson, GR Franks, M Tomoaia-Cotisel, A Ando, Y Price, DK Figg, WD TI Current status of thalidomide and its role in the treatment of metastatic prostate cancer SO CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY LA English DT Article; Proceedings Paper CT Conference on Targeted Therapies and the Treatment of Genitourinary Cancers CY APR 17-21, 2002 CL BARCELONA, SPAIN SP Abbott Labs, Celgene Corp, AstraZeneca Pharmaceut, Aventis Oncol, Eli Lilly & Co, Ortho Biotech Oncol, Pharmacia Corp, Genta Inc DE thalidomide; prostate; prostate cancer ID NECROSIS-FACTOR-ALPHA; PHASE-II TRIAL; MICROVESSEL DENSITY ANALYSIS; ENDOTHELIAL GROWTH-FACTOR; VERSUS-HOST DISEASE; TUMOR ANGIOGENESIS; PATHOLOGICAL STAGE; RADICAL PROSTATECTOMY; MULTIPLE-MYELOMA; TNF-ALPHA AB Following the discovery of its anti-angiogenic properties and despite its tragic history, thalidomide has re-surfaced in the field of oncology. Concurrent with its evaluation in various clinical trials for cancer, thalidomide's mechanism of action is sought and new analogues with improved efficacy and pharmacological profile are emerging. This review is a critical evaluation of thalidomide metabolism, molecular targets, anti-angiogenic activity and clinical efficacy with an emphasis on metastatic prostate cancer. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved. C1 NCI, Mol Pharmacol Sect, Div Clin Sci, Canc Therapeut Branch,Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, Div Clin Sci, Canc Therapeut Branch,Ctr Canc Res,NIH, Bldg 10,Room 5 A01,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Ain, Kenneth/A-5179-2012; Figg Sr, William/M-2411-2016 OI Ain, Kenneth/0000-0002-2668-934X; NR 86 TC 14 Z9 16 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1040-8428 J9 CRIT REV ONCOL HEMAT JI Crit. Rev. Oncol./Hematol. PD JUN 27 PY 2003 VL 46 SU S BP S49 EP S57 DI 10.1016/S1040-8428(03)00064-7 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 706VE UT WOS:000184475100007 PM 12850527 ER PT J AU Bevilacqua, A Ceriani, MC Canti, G Asnaghi, L Gherzi, R Brewer, G Papucci, L Schiavone, N Capaccioli, S Nicolin, A AF Bevilacqua, A Ceriani, MC Canti, G Asnaghi, L Gherzi, R Brewer, G Papucci, L Schiavone, N Capaccioli, S Nicolin, A TI Bcl-2 protein is required for the adenine/uridine-rich element (ARE)-dependent degradation of its own messenger SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID 3' UNTRANSLATED REGION; DOWN-REGULATES BCL-2; LYMPHOID-CELL LINES; RNA DEGRADATION; C-MYC; PROTOONCOGENE EXPRESSION; FOLLICULAR LYMPHOMA; BINDING-PROTEINS; APOPTOSIS; LEUKEMIA AB We have shown previously that the decay of human bcl-2 mRNA is mediated by an adenine/uridine-rich element (ARE) located in the 3'-untranslated region. Here, we have utilized a non-radioactive cell-free mRNA decay system to investigate the biochemical and functional mechanisms regulating the ARE-dependent degradation of bcl-2 mRNA. Using RNA substrates, mutants, and competitors, we found that decay is specific and ARE-dependent, although maximized by the ARE-flanking regions. In unfractionated extracts from different cell types and in whole cells, the relative enzymatic activity was related to the amount of Bcl-2 protein expressed by the cells at steady state. The degradation activity was lost upon Bcl-2 depletion and was reconstituted by adding recombinant Bcl-2. Ineffective extracts from cells that constitutively do not express Bcl-2 acquire full degradation activity by adding recombinant Bcl-2 protein. We conclude that Bcl-2 is necessary to activate the degradation complex on the relevant RNA target. C1 Univ Milan, Dept Pharmacol, I-20129 Milan, Italy. Natl Canc Inst, I-16132 Genoa, Italy. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Mol Genet & Microbiol, Piscataway, NJ 08854 USA. Univ Florence, Dept Expt Pathol & Oncol, I-50134 Florence, Italy. RP Nicolin, A (reprint author), Univ Milan, Dept Pharmacol, Via Vanvitelli 32, I-20129 Milan, Italy. RI Bevilacqua, Annamaria/C-6357-2008; OI Bevilacqua, Annamaria/0000-0002-3136-3424; Schiavone, Nicola/0000-0002-1592-4244; Papucci, Laura/0000-0002-8450-7428 NR 63 TC 11 Z9 12 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 27 PY 2003 VL 278 IS 26 BP 23451 EP 23459 DI 10.1074/jbc.M210620200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 692AR UT WOS:000183638600031 PM 12702730 ER PT J AU Sharma, S Sommers, JA Driscoll, HC Uzdilla, L Wilson, TM Brosh, RM AF Sharma, S Sommers, JA Driscoll, HC Uzdilla, L Wilson, TM Brosh, RM TI The exonucleolytic and endonucleolytic cleavage activities of human exonuclease 1 are stimulated by an interaction with the carboxyl-terminal region of the Werner syndrome protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SACCHAROMYCES-CEREVISIAE EXO1; SYNDROME GENE-PRODUCT; DNA MISMATCH REPAIR; SINGLE-STRANDED-DNA; SYNDROME CELL-LINES; FLAP ENDONUCLEASE-1; HOMOLOGOUS RECOMBINATION; MITOTIC RECOMBINATION; SYNDROME HELICASE; S-PHASE AB Exonuclease 1 ( EXO-1), a member of the RAD2 family of nucleases, has recently been proposed to function in the genetic pathways of DNA recombination, repair, and replication which are important for genome integrity. Although the role of EXO-1 is not well understood, its 5' to 3'-exonuclease and flap endonuclease activities may cleave intermediates that arise during DNA metabolism. In this study, we provide evidence that the Werner syndrome protein (WRN) physically interacts with human EXO-1 and dramatically stimulates both the exonucleolytic and endonucleolytic incision functions of EXO-1. The functional interaction between WRN and EXO-1 is mediated by a protein domain of WRN which interacts with flap endonuclease 1 ( FEN-1). Thus, the genomic instability observed in WRN-/- cells may be at least partially attributed to the lack of interactions between the WRN protein and human nucleases including EXO-1. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Univ Maryland, Radiat Oncol Res Lab, Dept Radiat Oncol, Baltimore, MD 21201 USA. Univ Hyderabad, Sch Life Sci, Dept Biochem, Hyderabad 500046, Andhra Pradesh, India. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Sharma, Sudha/0000-0003-2765-2482 NR 57 TC 44 Z9 47 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 27 PY 2003 VL 278 IS 26 BP 23487 EP 23496 DI 10.1074/jbc.M212798200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 692AR UT WOS:000183638600035 PM 12704184 ER PT J AU Lloyd-Evans, E Pelled, D Riebeling, C Bodennec, J de-Morgan, A Waller, H Schiffmann, R Futerman, AH AF Lloyd-Evans, E Pelled, D Riebeling, C Bodennec, J de-Morgan, A Waller, H Schiffmann, R Futerman, AH TI Glucosylceramide and glucosylsphingosine modulate calcium mobilization from brain microsomes via different mechanisms SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ISOLATED SARCOPLASMIC-RETICULUM; INDUCED CA-2+ RELEASE; QUANTAL CA2+ RELEASE; RYANODINE RECEPTOR; GAUCHER-DISEASE; SPHINGOSINE 1-PHOSPHATE; RAT-LIVER; INTRACELLULAR STORES; T-CELLS; CHANNEL AB We recently demonstrated that elevation of intracellular glucosylceramide (GlcCer) levels results in increased functional Ca2+ stores in cultured neurons, and suggested that this may be due to modulation of ryanodine receptors (RyaRs) by GlcCer (Korkotian, E., Schwarz, A., Pelled, D., Schwarzmann, G., Segal, M. and Futerman, A. H. (1999) J. Biol. Chem. 274, 21673-21678). We now systematically examine the effects of exogenously added GlcCer, other glycosphingolipids (GSLs) and their lyso-derivatives on Ca2+ release from rat brain microsomes. GlcCer had no direct effect on Ca2+ release, but rather augmented agonist-stimulated Ca2+ release via RyaRs, through a mechanism that may involve the redox sensor of the RyaR, but had no effect on Ca2+ release via inositol 1,4,5-trisphosphate receptors. Other GSLs and sphingolipids, including galactosylceramide, lactosylceramide, ceramide, sphingomyelin, sphingosine 1-phosphate, sphinganine 1-phosphate, and sphingosylphosphorylcholine had no effect on Ca2+ mobilization from rat brain microsomes, but both galactosylsphingosine ( psychosine) and glucosylsphingosine stimulated Ca2+ release, although only galactosylsphingosine mediated Ca2+ release via the RyaR. Finally, we demonstrated that GlcCer levels were similar to10-fold higher in microsomes prepared from the temporal lobe of a type 2 Gaucher disease patient compared with a control, and Ca2+ release via the RyaR was significantly elevated, which may be of relevance for explaining the pathophysiology of neuronopathic forms of Gaucher disease. C1 Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Futerman, AH (reprint author), Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. OI Riebeling, Christian/0000-0003-1991-0170; Futerman, Anthony/0000-0003-0013-0115 NR 65 TC 94 Z9 97 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 27 PY 2003 VL 278 IS 26 BP 23594 EP 23599 DI 10.1074/jbc.M300212200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 692AR UT WOS:000183638600049 PM 12709427 ER PT J AU Ahvazi, B Boeshans, KM Idler, W Baxa, U Steinert, PM AF Ahvazi, B Boeshans, KM Idler, W Baxa, U Steinert, PM TI Roles of calcium ions in the activation and activity of the transglutaminase 3 enzyme SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BINDING PROTEIN; CROSS-LINKING; GTP; CRYSTALLOGRAPHY; IDENTIFICATION; PARAMETERS; INVOLUCRIN; REFINEMENT; INHIBITOR; RECEPTOR AB The transglutaminase 3 enzyme is widely expressed in many tissues including epithelia. We have shown previously that it can bind three Ca2+ ions, which in site one is constitutively bound, while those in sites two and three are acquired during activation and are required for activity. In particular, binding at site three opens a channel through the enzyme and exposes two tryptophan residues near the active site that are thought to be important for enzyme reaction. In this study, we have solved the structures of three more forms of this enzyme by x-ray crystallography in the presence of Ca2+ and/or Mg2+, which provide new insights on the precise contribution of each Ca2+ ion to activation and activity. First, we found that Ca2+ ion in site one can be exchanged with difficulty, and it has a binding affinity of K-d = 0.3 muM (DeltaH = -6.70 +/- 0.52 kcal/mol), which suggests it is important for the stabilization of the enzyme. Site two can be occupied by some lanthanides but only Ca2+ of the Group 2 family of alkali earth metals, and its occupancy are required for activity. Site three can be occupied by some lanthanides, Ca2+, or Mg2+; however, when Mg2+ is present, the enzyme is inactive, and the channel is closed. Thus Ca2+ binding in both sites two and three cooperate in opening the channel. We speculate that manipulation of the channel opening could be controlled by intracellular cation levels. Together, these data have important implications for reaction mechanism of the enzyme: the opening of a channel perhaps controls access to and manipulation of substrates at the active site. C1 NIAMS, Lab Xray Crystallog, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. NIAMS, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. NIAMS, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. RP Ahvazi, B (reprint author), NIAMS, Lab Xray Crystallog, Off Sci & Technol, NIH, Bldg 50,Rm 1524,50 South Dr, Bethesda, MD 20892 USA. NR 34 TC 34 Z9 36 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 27 PY 2003 VL 278 IS 26 BP 23834 EP 23841 DI 10.1074/jbc.M301162200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 692AR UT WOS:000183638600079 PM 12679341 ER PT J AU Liang, JS Kim, T Fang, SY Yamaguchi, J Weissman, AM Fisher, EA Ginsberg, HN AF Liang, JS Kim, T Fang, SY Yamaguchi, J Weissman, AM Fisher, EA Ginsberg, HN TI Overexpression of the tumor autocrine motility factor receptor Gp78, a ubiquitin protein ligase, results in increased ubiquitinylation and decreased secretion of apolipoprotein B100 in HepG2 cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID B-CONTAINING LIPOPROTEINS; TRIGLYCERIDE TRANSFER PROTEIN; ENDOPLASMIC-RETICULUM; INTRACELLULAR DEGRADATION; PROTEASOME PATHWAY; APOPROTEIN B100; TRANSLOCATION; COMPLEX; HEAT-SHOCK-PROTEIN-70; MECHANISMS AB Apolipoprotein B100 (apoB) is a large (520-kDa) complex secretory protein; its secretion is regulated post-transcriptionally by several degradation pathways. The best described of these degradative processes is co-translational ubiquitinylation and proteasomal degradation of nascent apoB, involving the 70- and 90-kDa heat shock proteins and the multiple components of the proteasomal pathway. Ubiquitinylation involves several proteins, including ligases called E3s, that coordinate the covalent binding of ubiquitin to target proteins. The recent discovery that tumor autocrine motility factor receptor, also known as gp78, is an endoplasmic reticulum (ER)-associated E3, raised the possibility that this E3 might be involved in the ER-associated degradation of nascent apoB. In a series of experiments in HepG2 cells, we demonstrated that overexpression of gp78 was sufficient for increased ubiquitinylation and proteasomal degradation of apoB, with reduced secretion of apoB-lipoproteins. This action of gp78 was specific: overexpression of the protein did not affect secretion of either albumin or apolipoprotein AI. Furthermore, overexpression of a cytosolic E3, Itch, had no effect on apoB secretion. Finally, using an in vitro translation system, we demonstrated that gp78 led to increased ubiquitinylation and proteasomal degradation of apoB48. Together, these results indicate that an ER-associated protein, gp78, is a bona fide E3 ligase in the apoB ER-associated degradation pathway. C1 Columbia Univ Coll Phys & Surg, Dept Med, New York, NY 10032 USA. Mt Sinai Sch Med, Dept Med, New York, NY 10025 USA. Mt Sinai Sch Med, Dept Biochem, New York, NY 10025 USA. NCI, Regulat Cell Growth Lab, Frederick, MD 21702 USA. RP Ginsberg, HN (reprint author), Columbia Univ Coll Phys & Surg, Dept Med, 630 W 168th St, New York, NY 10032 USA. RI Fang, Shengyun/H-3802-2011; OI Fisher, Edward/0000-0001-9802-143X FU NHLBI NIH HHS [HL55368, HL58541] NR 34 TC 66 Z9 69 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 27 PY 2003 VL 278 IS 26 BP 23984 EP 23988 DI 10.1074/jbc.M302683200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 692AR UT WOS:000183638600098 PM 12670940 ER PT J AU Zheng, YL Li, BS Veeranna Pant, HC AF Zheng, YL Li, BS Veeranna Pant, HC TI Phosphorylation of the head domain of neurofilament protein (NF-M) - A factor regulating topographic phosphorylation of NF-M tail domain KSP sites in neurons SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CYCLIN-DEPENDENT KINASE-5; AMYOTROPHIC LATERAL SCLEROSIS; C-TERMINAL PHOSPHORYLATION; UNDERGO AXONAL-TRANSPORT; NERVE GROWTH-FACTOR; INTERMEDIATE-FILAMENTS; PKA PHOSPHORYLATION; CDC2-LIKE KINASE; SQUID AXOPLASM; SUBUNIT AB In neurons the phosphorylation of neurofilament (NF) proteins NF-M and NF-H is topographically regulated. Although kinases and NF subunits are synthesized in cell bodies, extensive phosphorylation of the KSP repeats in tail domains of NF-M and NF-H occurs primarily in axons. The nature of this regulation, however, is not understood. As obligate heteropolymers, NF assembly requires interactions between the core NF-L with NF-M or NF-H subunits, a process inhibited by NF head domain phosphorylation. Phosphorylation of head domains at protein kinase A (PKA)-specific sites seems to occur transiently in cell bodies after NF subunit synthesis. We have proposed that transient phosphorylation of head domains prevents NF assembly in the soma and inhibits tail domain phosphorylation; i.e. assembly and KSP phosphorylation in axons depends on prior dephosphorylation of head domain sites. Deregulation of this process leads to pathological accumulations of phosphorylated NFs in the soma as seen in some neurodegenerative disorders. To test this hypothesis, we studied the effect of PKA phosphorylation of the NF-M head domain on phosphorylation of tail domain KSP sites. In rat cortical neurons we showed that head domain phosphorylation of endogenous NF-M by forskolin-activated PKA inhibits NF-M tail domain phosphorylation. To demonstrate the site specificity of PKA phosphorylation and its effect on tail domain phosphorylation, we transfected NIH3T3 cells with NF-M mutated at PKA-specific head domain serine residues. Epidermal growth factor stimulation of cells with mutant NF-M in the presence of forskolin exhibited no inhibition of NF-tail domain phosphorylation compared with the wild type NF-M-transfected cells. This is consistent with our hypothesis that transient phosphorylation of NF-M head domains inhibits tail domain phosphorylation and suggests this as one of several mechanisms underlying topographic regulation. C1 NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Pant, HC (reprint author), NINDS, Neurochem Lab, NIH, Bldg 36,Rm 4D04,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 59 TC 36 Z9 36 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 27 PY 2003 VL 278 IS 26 BP 24026 EP 24032 DI 10.1074/jbc.M303079200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 692AR UT WOS:000183638600104 PM 12695506 ER PT J AU Benyamini, H Gunasekaran, K Wolfson, H Nussinov, R AF Benyamini, H Gunasekaran, K Wolfson, H Nussinov, R TI beta(2)-microglobulin amyloidosis: Insights from conservation analysis and fibril modelling by protein docking techniques SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE beta(2)-microglobulin; docking algorithm; amyloidosis; sequence conservation; fibril modelling ID HUMAN BETA-2-MICROGLOBULIN REVEALS; DISULFIDE BOND; IN-VITRO; SHAPE COMPLEMENTARITY; IMMUNOGLOBULIN FOLD; MOLECULAR-DYNAMICS; BINDING-SITE; SH3 DOMAIN; CONFORMATIONS; ORGANIZATION AB Current data suggest that globular domains may form amyloids via different mechanisms. Nevertheless, there are indications that the initiation of the process takes place invariably in the less stable segments of a protein domain. We have studied the sequence and structural conservation of beta(2)-microglobulin that deposits into fibrils in dialysis-related amyloidosis. The dataset includes 51 high-resolution non-redundant structures of the antibody constant domain-like proteins (Cl) and 132 related sequences. We describe a set of 30 conserved residues. Among them, 23 are conserved structurally, 16 are conserved sequentially and nine are conserved both sequentially and structurally. Strands A (12-18), G (91-95) and D (45-55) are the less conserved and stable segments of the domain, while strands B (22-28), C (36-41), E (62-70) and F (78-83) are the conserved and stable segments. We find that the conserved residues form a cluster with a network of interactions. The observed pattern of conservation is consistent with experimental data including H/D exchange, urea denaturation and limited proteolysis that suggest that strands A and G do not participate in the amyloid fibril. Additionally, the low conservation of strand D is consistent with the observation that this strand may acquire different conformations as seen m crystal structures of bound and isolated beta(2)-microglobulin. We used a docking technique to suggest a model for a fibril via stacking Of beta(2)-microglobulin monomers. Our analysis suggests that the favored monomer building block for fibril elongation is the conformation of the isolated beta(2)-microglobulin, without the beta-bulge on strand D and without strands A and G participating in the fibril beta-sheet structure. This monomer retains all the conserved residues and their network of interactions, increasing the likelihood of its existence in solution. The inter-strand interaction between the two (monomer) building blocks forms a new continuous beta-sheet such that addition of monomers results in a fibril model that has the characteristic cross-beta structure. (C) 2003 Elsevier Science Ltd. All rights reserved . C1 Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. NCI, Lab Expt & Computat Biol, Frederick, MD 21702 USA. Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Sch Comp Sci, IL-69978 Tel Aviv, Israel. NCI, SAIC, Bas Res Program, Lab Expt & Computat Biol, Frederick, MD 21702 USA. RP Nussinov, R (reprint author), Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RI Wolfson, Haim/A-1837-2011 FU NCI NIH HHS [N01-CO-12400] NR 58 TC 26 Z9 27 U1 0 U2 1 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUN 27 PY 2003 VL 330 IS 1 BP 159 EP 174 DI 10.1016/S0022-2836(03)00557-6 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 693XZ UT WOS:000183744800014 PM 12818210 ER PT J AU Kasckow, JW Aguilera, G Mulchahey, JJ Sheriff, S Herma, JP AF Kasckow, JW Aguilera, G Mulchahey, JJ Sheriff, S Herma, JP TI In vitro regulation of corticotropin-releasing hormone SO LIFE SCIENCES LA English DT Article; Proceedings Paper CT Symposium on Stimulants and Other Drugs of Abuse and Their Effects on Neuropeptides and the Peptidergic Systems CY JUN 27-29, 2002 CL MARCO ISL, FLORIDA DE corticotropin-releasing hormone; in vitro; culture; amygdala; hypothalamus; stress ID MESSENGER-RIBONUCLEIC-ACID; RAT HYPOTHALAMUS INVITRO; PITUITARY-ADRENAL AXIS; FACTOR CRF RELEASE; KC CELL-LINE; PARAVENTRICULAR NUCLEUS; NITRIC-OXIDE; CARBON-MONOXIDE; ANTERIOR-PITUITARY; RESTRAINT STRESS AB Studies involving regulation of corticotropin-releasing hormone (CRH) in vitro have been used to validate findings obtained in vivo and more importantly have been used as model systems to better understand signalling mechanisms responsible for the expression of the CRH gene and peptide. Many in vitro studies examining CRH have utilized hypothalamic tissue while a few have focused on the amygdala. Clonal cell lines have also been utilized as models of central nervous system CRH neurons. Stimuli that have been implicated in regulating hypothalamic CRH regulation in vitro include protein kinase A (PKA) and protein kinase C (PKC) activators, glucocorticoids, biogenic amines, cytokines and the gaseous neurotransmitters. Amygdalar CRH levels in vitro are affected by some of the same stimuli that regulate hypothalamic CRH; however there is evidence supporting differential regulation of CRH in these two brain regions by some of the same stimuli. Only a few studies in aggregate have investigated signal transduction mechanisms and these studies have focused on PKA- and glucocorticoid-mediated changes in CRH expression. Thus, much more investigative work in better understanding CRH regulation in vitro is needed. (C) 2003 Elsevier Science Inc. All rights reserved. C1 VAMC, Psychiat Serv 116A, Cincinnati, OH 45220 USA. Univ Cincinnati, Sch Med, Dept Psychiat, Cincinnati, OH 45267 USA. Univ Cincinnati, Program Neurosci, Cincinnati, OH 45267 USA. NICHHD, Dev Endocrinol Branch, Sect Endocrine Physiol, NIH, Bethesda, MD 20892 USA. Phase 2 Discovery Inc, Cincinnati, OH 45219 USA. Univ Cincinnati, Coll Med, Dept Surg, Cincinnati, OH 45267 USA. RP Kasckow, JW (reprint author), VAMC, Psychiat Serv 116A, 3200 Vine St, Cincinnati, OH 45220 USA. RI Herman, James/D-4960-2015 OI Herman, James/0000-0003-3571-2406 FU NIMH NIH HHS [K01 MH001545-01] NR 83 TC 16 Z9 17 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 JUN 27 PY 2003 VL 73 IS 6 BP 769 EP 781 DI 10.1016/S0024-3205(03)00409-0 PG 13 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 692MH UT WOS:000183664500014 PM 12801598 ER PT J AU Klausner, RD Fauci, AS Corey, L Nabel, GJ Gayle, H Berkley, S Haynes, BF Baltimore, D Collins, C Douglas, RG Esparza, J Francis, DP Ganguly, NK Gerberding, JL Johnston, MI Kazatchkine, MD McMichael, AJ Makgoba, MW Pantaleo, G Piot, P Shao, YM Tramont, E Varmus, H Wasserheit, JN AF Klausner, RD Fauci, AS Corey, L Nabel, GJ Gayle, H Berkley, S Haynes, BF Baltimore, D Collins, C Douglas, RG Esparza, J Francis, DP Ganguly, NK Gerberding, JL Johnston, MI Kazatchkine, MD McMichael, AJ Makgoba, MW Pantaleo, G Piot, P Shao, YM Tramont, E Varmus, H Wasserheit, JN TI The need for a global HIV vaccine enterprise SO SCIENCE LA English DT Editorial Material C1 Bill & Melinda Gates Fdn, Seattle, WA 98102 USA. NIAID, Div AIDS, NIH, Vaccine & Prevent Res Program, Bethesda, MD 20892 USA. NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. Fred Hutchinson Canc Res Ctr, HIV Vaccine Trials Network, Program Infect Dis, Seattle, WA 98109 USA. Univ Washington, Dept Lab Med, Seattle, WA 98109 USA. Int AIDS Vaccine Initiat, New York, NY 10038 USA. Duke Univ, Sch Med, Durham, NC 27710 USA. CALTECH, Pasadena, CA 91125 USA. AIDS Vaccine Advocacy Coalit, New York, NY 10011 USA. Sequella Global TB Fdn, Rockville, MD 20850 USA. WHO, UNAIDS, Joint UN Programme HIV AIDS, HIV Vaccine Initiat, Geneva 27, Switzerland. VaxGen Inc, Brisbane, CA 94005 USA. Indian Council Med Res, New Delhi 110029, India. Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. ANRS, F-75013 Paris, France. Univ Oxford, MRC, Human Immunol Unit, Weatherall Inst Mol Med, Oxford OX3 9DS, England. Univ Natal, ZA-4041 Durban, South Africa. Univ Lausanne, CHU Vaudois, Div Immunol & Allergy, CH-1011 Lausanne, Switzerland. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Klausner, RD (reprint author), Bill & Melinda Gates Fdn, Seattle, WA 98102 USA. RI Pantaleo, Giuseppe/K-6163-2016 NR 2 TC 144 Z9 149 U1 0 U2 5 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUN 27 PY 2003 VL 300 IS 5628 BP 2036 EP 2039 DI 10.1126/science.1086916 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 694KZ UT WOS:000183774900028 PM 12829768 ER PT J AU De Sandre-Giovannoli, A Bernard, R Cau, P Navarro, C Amiel, J Boccaccio, I Lyonnet, S Stewart, CL Munnich, A Le Merrer, M Levy, N AF De Sandre-Giovannoli, A Bernard, R Cau, P Navarro, C Amiel, J Boccaccio, I Lyonnet, S Stewart, CL Munnich, A Le Merrer, M Levy, N TI Lamin A truncation in Hutchinson-Gilford progeria SO SCIENCE LA English DT Article ID DISEASE C1 Fac Med Timone, INSERM, U491, Marseille, France. Hop La Timone, Dept Med Genet, Marseille, France. Hop Necker Enfants Malad, INSERM, U393, Paris, France. Hop Conception, Biol Cellulaire Lab, Marseille, France. NCI, Can & Dev Biol Lab, Frederick, MD 21702 USA. RP Levy, N (reprint author), Fac Med Timone, INSERM, U491, Marseille, France. RI De Sandre-Giovannoli, Annachiara/L-5759-2016; LEVY, Nicolas/J-1632-2014; Cau, Pierre/M-3541-2016 OI De Sandre-Giovannoli, Annachiara/0000-0002-2324-2462; LEVY, Nicolas/0000-0001-5171-6365; NR 3 TC 595 Z9 611 U1 10 U2 67 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUN 27 PY 2003 VL 300 IS 5628 BP 2055 EP 2055 DI 10.1126/science.1084125 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 694KZ UT WOS:000183774900035 PM 12702809 ER PT J AU Frey, SE Newman, FK Yan, LH Belshe, RB AF Frey, SE Newman, FK Yan, LH Belshe, RB TI Response to smallpox vaccine in persons immunized in the distant past SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID RECOMBINANT AB Context There is renewed interest in use of smallpox vaccine due to the potential for a bioterrorist attack. This would involve vaccinating health care workers who were previously vaccinated. Objective To evaluate the use of diluted vaccinia virus in vaccination of previously vaccinated (non-naive) participants. Design, Setting, and Participants Eighty non-naive participants, aged 3 2 to 60 years, were randomized in a single-blinded study to receive either undiluted or diluted (1:3.2, 1:10, or 1:32) doses of smallpox vaccine. A comparison group, aged 18 to 31 years, of 10 vaccinia-naive participants received undiluted vaccine. Participants were enrolled between April 1 and May 15, 2002, at the National Institute of Allergy and infectious Diseases Vaccine and Treatment Evaluation Unit at Saint Louis University, St Louis, Mo. Intervention Smallpox vaccine was administered by scarification using 15 skin punctures in the deltoid region of the arm. Main Outcome Measures Presence of a major reaction, defined as a vesicular or pustular lesion or area of palpable induration surrounding a central lesion following vaccination, and measures, of viral shedding and antibody titers. Results Initial vaccination resulted in a major reaction in 64 of 80 non-naive participants Ninety-five percent of non-naive participants had major reactions in the undiluted group, 90% in the 1:3.2 dilution group, 81% in the 1:10 dilution group, and 52.6% in the 1:32 dilution group. All (n=10) of the vaccinia-naive participants had major reactions. Compared with vaccinia-naive participants, non-naive participants had significantly smaller skin lesions (P=.04) and significantly less incidence of fever (P=.02). Preexisting antibody was present in 76 of 80 non-naive participants. Antibody responses were significantly higher and occurred more rapidly in the non-naive participants compared with the vaccinia-naive participants (P=.002 for day 28 and P=.003 for 6 months). Vaccinia-naive participants shed virus from the vaccination site 2 to 6 days longer and had significantly higher peak mean viral titers when compared with the non-naive participants (P=.002). Conclusions Previously vaccinated persons can be successfully revaccinated with diluted (less than or equal to1:10) smallpox vaccine. Fewer adverse reactions were observed in this study of non-naive participants when compared with events in vaccinia-naive participants, which may be due to immunologic memory. C1 St Louis Univ, Hlth Sci Ctr, Sch Med, Dept Med,Div Infect Dis & Immunol, St Louis, MO 63110 USA. NIAID, Vaccine & Treatment Evaluat Unit, St Louis, MO USA. EMMES Corp, Rockville, MD USA. RP Frey, SE (reprint author), St Louis Univ, Hlth Sci Ctr, Sch Med, Dept Med,Div Infect Dis & Immunol, 3635 Vista Ave,FDT-8N, St Louis, MO 63110 USA. FU NIAID NIH HHS [N01-AI-45150] NR 12 TC 78 Z9 78 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 25 PY 2003 VL 289 IS 24 BP 3295 EP 3299 DI 10.1001/jama.289.24.3295 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 693EX UT WOS:000183704600024 PM 12824212 ER PT J AU Wright, ME Fauci, AS AF Wright, ME Fauci, AS TI Smallpox immunization in the 21st century - The old and the new SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID VACCINATION C1 NIAID, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, NIH, Dept Hlth & Human Serv, Bldg 31,Room 7A03,MSC 2520, Bethesda, MD 20892 USA. NR 13 TC 4 Z9 4 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 25 PY 2003 VL 289 IS 24 BP 3306 EP 3308 DI 10.1001/jama.289.24.3306 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 693EX UT WOS:000183704600027 PM 12824215 ER PT J AU Shiloach, J Santambien, P Trinh, L Schapman, A Boschetti, E AF Shiloach, J Santambien, P Trinh, L Schapman, A Boschetti, E TI Endostatin capture from Pichia pastoris culture in a fluidized bed - From on-chip process optimization to application SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE chip technology; Pichia pastoris; fluidized bed; yeast; endostatin; proteins ID PROTEIN EXPRESSION; ADSORPTION; ANGIOGENESIS; CHROMATOGRAPHY; GROWTH AB One of the characteristics of the methylothrophic yeast Pichia pastoris is its ability to grow to a very high cell density. Biomass concentrations of 300-400 g wet mass/l are common. It is therefore obvious that the recovery processes of extracellular proteins from this microorganism should take into account the effect of high biomass content. Separation by filtration and/or centrifugation is possible but these steps are cumbersome and can affect the protein recovery. The use of fluidized beds is attractive proteins capture option since it eliminates the biomass while capturing the desired protein. Zirconia-based resins possess unique properties which make them appropriate for processing high biomass concentrations in an expanded bed mode. The beads are particularly heavy (density is 3.2 g/ml) and small (75 mum) and therefore can accommodate high fluidization velocity and high mass transport. Specific operating conditions for effective capture of expressed protein have to be determined. This determination is generally time consuming and requires relatively large amount of feedstock for the lab trials. To avoid multiple chromatographic trials in columns, optimal conditions of adsorption and elution were determined by ProteinChip technology coupled with mass spectrometry. This technology involves flat chip surfaces functionalized as chromatographic beads where it is possible to adsorb and desorb proteins. Four different functional groups (strong anion-exchange, weak cation-exchange, hydrophobic and metal chelate) were tested and the retained proteins were analyzed directly by mass spectrometry. The weak cation-exchange group was chosen for further work. The Zirconia-based weak cation-exchange sorbent (CM HyperZ) was evaluated for binding capacity in a packed column and then for capturing endostatin from crude feed stock. Based on the previously determined conditions; 45 1 of culture containing approximately 15 kg of biomass (wet mass) and 3 g endostatin were applied on an expanded bed at a flow-rate of 535 cm/h, yielding 80% of the endostatin and removing approximately 80% of foreign proteins. (C) 2003 Elsevier Science B.V. All rights reserved. C1 BioSepra SA, Ciphergen Biosyst, F-95800 Christophe, France. NIDDK, Biotechnol Unit, Bethesda, MD USA. RP Santambien, P (reprint author), BioSepra SA, Ciphergen Biosyst, 48 Ave Genottes,BP 8347,Cergy St, F-95800 Christophe, France. NR 17 TC 10 Z9 11 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD JUN 25 PY 2003 VL 790 IS 1-2 BP 327 EP 336 DI 10.1016/S1570-0232(03)00097-7 PG 10 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 684MT UT WOS:000183211700025 PM 12767341 ER PT J AU Zhang, FL Lucke, C Baier, LJ Sacchettini, JC Hamilton, JA AF Zhang, FL Lucke, C Baier, LJ Sacchettini, JC Hamilton, JA TI Solution structure of human intestinal fatty acid binding protein with a naturally-occurring single amino acid substitution (A54T) that is associated with altered lipid metabolism SO BIOCHEMISTRY LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; HELIX-LESS VARIANT; INSULIN-RESISTANCE; ESCHERICHIA-COLI; CODON-54 POLYMORPHISM; NMR-SPECTROSCOPY; ABORIGINAL CANADIANS; PLASMA-LIPOPROTEINS; LYSINE RESIDUES; LIGAND-BINDING AB The human intestinal fatty acid binding protein (I-FABP) belongs to a family of intracellular lipid binding proteins. This 15 kDa protein binds dietary long-chain fatty acids in the cytosol of enterocytes. A naturally-occurring nucleotide polymorphism at codon 54, which produces either an alanine-containing (A54) or a threonine-containing (T54) protein, has been identified. These two I-FABP forms display differential binding and transport of fatty acids across cells, and their alleles are associated with in vivo insulin resistance and/or altered lipid metabolism in several human populations. The three-dimensional solution structure of the more common A54 form was previously determined in our lab. A direct comparison between human A54 and T54 I-FABP has now been performed to help elucidate the structural origins of their physiological distinctions. The solution structure of T54 I-FABP is highly homologous to that of A54 I-FABP. with the same overall three-dimensional fold that includes an antiparallel beta-clam motif. Chemical shift differences between the two proteins suggest only minor local structural changes within the "portal region" and no significant alterations elsewhere. Hence, the slightly stronger binding of fatty acids to T54 I-FABP does not originate from residues in direct contact with the bound fatty acid. Instead, it appears that the larger Thr(54) side chain affects the passage of the ligand through the entry portal. Structural details of this portal region will be discussed in view of the influence residue 54 exerts on the functional properties of human I-FABP. C1 Boston Univ, Sch Med, Dept Physiol & Biophys, Boston, MA 02118 USA. Univ Frankfurt, Inst Biophys Chem, D-60439 Frankfurt, Germany. NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77845 USA. RP Hamilton, JA (reprint author), Boston Univ, Sch Med, Dept Physiol & Biophys, 715 Albany St,W302, Boston, MA 02118 USA. OI Hamilton, James/0000-0002-4747-7071 FU NHLBI NIH HHS [HL26335]; NIGMS NIH HHS [GM45859] NR 69 TC 21 Z9 29 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 JUN 24 PY 2003 VL 42 IS 24 BP 7339 EP 7347 DI 10.1021/bi0273617 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 691UT UT WOS:000183624800008 PM 12809489 ER PT J AU Cappola, TP Cope, L Cernetich, A Barouch, LA Minhas, K Irizarry, RA Parmigiani, G Durrani, S Lavoie, T Hoffman, EP Ye, SQ Garcia, JGN Hare, JM AF Cappola, TP Cope, L Cernetich, A Barouch, LA Minhas, K Irizarry, RA Parmigiani, G Durrani, S Lavoie, T Hoffman, EP Ye, SQ Garcia, JGN Hare, JM TI Deficiency of different nitric oxide synthase isoforms activates divergent transcriptional programs in cardiac hypertrophy SO PHYSIOLOGICAL GENOMICS LA English DT Article DE ventricular remodeling; mice; knockout; gene expression profiling; genomics ID CONGESTIVE-HEART-FAILURE; IN-VIVO; OXIDATIVE STRESS; VENTRICULAR HYPERTROPHY; PRESSURE-OVERLOAD; EXPRESSION; GENE; HYPERTENSION; GROWTH; MICE AB Decreased nitric oxide synthase (NOS) activity induces left ventricular hypertrophy (LVH), but the transcriptional pathways mediating this effect are unknown. We hypothesized that specific NOS isoform deletion (NOS3 or NOS1) would activate different transcriptional programs in LVH. We analyzed cardiac expression profiles (Affymetrix MG-U74A) from NOS-/- mice using robust multi-array average (RMA). Of 12,422 genes analyzed, 47 genes were differentially expressed in NOS3(-/-) and 67 in NOS1(-/-) hearts compared with wild type (WT). Only 16 showed similar changes in both NOS-/- strains, most notably decreased heat-shock proteins (HSP10, 40, 70, 86, 105). Hypertrophied NOS1(-/-) hearts had unique features, including decreased myocyte-enriched calcineurin interacting protein and paradoxical downregulation of fetal isoforms (alpha-skeletal actin and brain natriuretic peptide). Cluster analyses demonstrated that NOS1 deletion caused more pronounced changes in the myocardial transcriptome than did NOS3 deletion, despite similar cardiac phenotypes. These findings suggest that the transcriptional basis for LVH varies depending on the inciting biochemical stimulus. In addition, NOS isoforms appear to play distinct roles in modulating cardiac structure. C1 NHLBI, Program Genom Applicat HopGene, Bethesda, MD 20205 USA. Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21287 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21287 USA. Childrens Natl Med Ctr, Ctr Med Genet, Washington, DC 20010 USA. RP Hare, JM (reprint author), Johns Hopkins Univ Hosp, Div Cardiol, 600 N Wolfe St,Carnegie 568, Baltimore, MD 21287 USA. RI Garcia, Joe/E-8862-2010 FU NHLBI NIH HHS [1U01-HL-066583, 5R01-HL-065455] NR 37 TC 24 Z9 26 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD JUN 24 PY 2003 VL 14 IS 1 BP 25 EP 34 DI 10.1152/physiolgenomics.00156.2002 PG 10 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 693HN UT WOS:000183711500004 PM 12709511 ER PT J AU Lindvall, O McKay, R AF Lindvall, O McKay, R TI Brain repair by cell replacement and regeneration SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID EMBRYONIC STEM-CELLS; PARKINSONS-DISEASE; DOPAMINE NEURONS; TRANSPLANTATION; DIFFERENTIATION; RECOVERY; NEUROGENESIS; PRECURSORS; PROGENITOR; PATIENT C1 Univ Lund Hosp, Wallenberg Neurosci Ctr, Dept Clin Neurosci, S-22184 Lund, Sweden. NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP McKay, R (reprint author), Univ Lund Hosp, Wallenberg Neurosci Ctr, Dept Clin Neurosci, Solvegatan 17 BMC A-11, S-22184 Lund, Sweden. NR 21 TC 26 Z9 28 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 24 PY 2003 VL 100 IS 13 BP 7430 EP 7431 DI 10.1073/pnas.1332673100 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 695TE UT WOS:000183845800006 PM 12810949 ER PT J AU Beard, BC Wilson, SH Smerdon, MJ AF Beard, BC Wilson, SH Smerdon, MJ TI Suppressed catalytic activity of base excision repair enzymes on rotationally positioned uracil in nucleosomes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chromatin; glycosylase; DNA polymerase beta; apyrmidinic/apurinic endonuclease ID DNA-POLYMERASE-BETA; GLUCOCORTICOID RESPONSE ELEMENT; RIBOSOMAL-RNA GENE; CORE PARTICLES; CYTOSINE DEAMINATION; CHROMATIN; SEQUENCE; SITE; MECHANISM; PROTEIN AB The majority of DNA in eukaryotic cells exists in the highly condensed structural hierarchy of chromatin, which presents a challenge to DNA repair enzymes in that recognition, incision, and restoration of the original sequence at most sites must take place within these structural constraints. To test base excision repair (BER) activities on chromatin substrates, an in vitro system was developed that uses human uracil DNA glycosylase (UDG), apyrimidinic/apurinic endonuclease (APE), and DNA polymerase beta (pol beta) on homogeneously damaged, rotationally positioned DNA in nucleosomes. We find that UDG and APE carry out their combined catalytic activities with reduced efficiency on nucleosome substrates (approximate to10% of that on naked DNA). Furthermore, these enzymes distinguish between two different rotational settings of the lesion on the histone surface, showing a 2- to 3-fold difference in activity between uracil facing "toward" and "away from" the histories. However, UDG and APE will digest such substrates to completion in a concentration-dependent manner. Conversely, the synthesis activity of pol 13 is inhibited completely by nucleosome substrates and is independent of enzyme concentration. These results suggest that the first two steps of BER, IUDG and APE, may occur "unassisted" in chromatin, whereas downstream factors in this pathway (i.e., pol beta) may require nucleosome remodeling for efficient DNA BER in at least some regions of chromatin in eukaryotic cells. C1 Washington State Univ, Sch Mol Biosci, Dept Biochem & Biophys, Pullman, WA 99164 USA. Natl Inst Environm Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Smerdon, MJ (reprint author), Washington State Univ, Sch Mol Biosci, Dept Biochem & Biophys, Pullman, WA 99164 USA. FU NIEHS NIH HHS [ES04106, R01 ES004106] NR 61 TC 84 Z9 84 U1 2 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 24 PY 2003 VL 100 IS 13 BP 7465 EP 7470 DI 10.1073/pnas.1330328100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 695TE UT WOS:000183845800013 PM 12799467 ER PT J AU Moskovitz, J Stadtman, ER AF Moskovitz, J Stadtman, ER TI Selenium-deficient diet enhances protein oxidation and affects methionine sulfoxide reductase (MsrB) protein level in certain mouse tissues SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE methionine oxidation; selenoprotein; aging; oxidative stress ID SUBSTRATE STEREOSPECIFICITY; ESCHERICHIA-COLI; MESSENGER-RNA; EXPRESSION; CELLS; SELENOPROTEIN; STRESS; DAMAGE; PURIFICATION; INCREASE AB Mammals contain two methionine sulfoxide (MetO) reductases, MsrA and MsrB, that catalyze the thioredoxin-dependent reduction of the S-Met:0 and R-MetO derivatives, respectively, to methionine. The major mammalian MsrB is a selenoprotein (except in the heart). Here, we show that there is a loss of MsrB activity in the MsrA(-/-) mouse that correlates with parallel losses in the levels of MsrB mRNA and MsrB protein, suggesting that MsrA might have a role in MsrB transcription. Moreover, mice that were grown on a selenium-deficient (SD) diet showed a substantial decrease in the levels of MsrB-catalytic activity, MsrB protein, and MsrB mRNA in liver and kidney tissues of both WT and MsrA(-/-) mouse strains. Whereas no significant protein-Meto could be detected in tissue proteins of young mature mice grown on, a selenium-adequate diet, growth on the SD diet led to substantial accumulations of MetO in proteins and also of protein carbonyl derivatives in the liver, kidney, cerebrum, and cerebellum, respectively. In addition, accumulation of protein-MetO derivatives increased with age in tissues of mice fed with a selenium-adequate diet. It should be pointed out that even though the total Msr level is at least 2-fold higher in WT than in MsrA(-/-) mice, SD diet causes an equal elevation of protein-MetO (except in brain cerebellum) and carbonyl levels in both strains, suggesting involvement of other selenoproteins in regulation of the level of cellular protein-MetO accumulation. Furthermore, the development of the "tip-toe" walking behavior previously observed in the MsrA(-/-) mice occurred earlier when they were fed with the SD diet. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Moskovitz, J (reprint author), NHLBI, Biochem Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 32 TC 64 Z9 70 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 24 PY 2003 VL 100 IS 13 BP 7486 EP 7490 DI 10.1073/pnas.1332607100 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 695TE UT WOS:000183845800017 PM 12792026 ER PT J AU Ben-Menachem, G Kubler-Kielb, J Coxon, B Yergey, A Schneerson, R AF Ben-Menachem, G Kubler-Kielb, J Coxon, B Yergey, A Schneerson, R TI A newly discovered cholesteryl galactoside from Borrelia burgdorferi SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LYME-DISEASE; QUANTITATIVE DETERMINATION; MYCOPLASMA-FERMENTANS; STRUCTURAL-ANALYSIS; MASS-SPECTROMETRY; RAPID METHOD; CHROMATOGRAPHY; MEMBRANES; STEROLS AB Two major glycolipids, which comprise approximate to36% of the total lipid mass from Borrelia burgdorferi, the etiological agent of Lyme disease, were investigated. We determined the fatty acid type, sugar identity, anomeric configuration, and substituent type and position. The structures were identified as cholesteryl 6-O-acyl-beta-D-galactopyranoside (B. burgdorferi glycolipid 1, BbGL-1), and 1,2-di-O-acyl-3-O-alpha-D-galactopyranosyl-sn-glycerol (BbGL-11). The major fatty acids Were palmitate and oleate. The structures were corroborated by gas-liquid chromatography MS, matrix-assisted laser desorption/ionization time-of-flight spectroscopy, fast atom bombardment MS, detailed NMR spectrometry, and metabolic labeling. This is a previously undescribed demonstration of a cholesteryl galactoside in bacteria. Lipopolysaccharide was not detected in B. burgdorferi. The two glycolipids have several properties suggesting they may function as lipopolysaccharide: both are main components of the bacterial membrane, surface exposed, and have a three-domain structure. BbGL-1 elicited specific antibodies in mice and rabbits, and BbGL-11 elicited antibodies that reacted with both glycolipids. C1 NICHHD, Dev & Mol Immun Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. Polish Acad Sci, Inst Immunol & Expt Therapy, PL-53114 Wroclaw, Poland. RP Ben-Menachem, G (reprint author), NICHHD, Dev & Mol Immun Lab, NIH, Bethesda, MD 20892 USA. NR 25 TC 95 Z9 98 U1 1 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 24 PY 2003 VL 100 IS 13 BP 7913 EP 7918 DI 10.1073/pnas.1232451100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 695TE UT WOS:000183845800090 PM 12799465 ER PT J AU Kitabatake, Y Hikida, T Watanabe, D Pastan, I Nakanishi, S AF Kitabatake, Y Hikida, T Watanabe, D Pastan, I Nakanishi, S TI Impairment of reward-related learning by cholinergic cell ablation in the striatum SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TRANSGENIC MICE; BASAL GANGLIA; COMPARTMENTAL ORGANIZATION; HUMAN ACETYLCHOLINESTERASE; DELAYED ALTERNATION; PREFRONTAL CORTEX; NUCLEUS-ACCUMBENS; AXON-TERMINALS; T-MAZE; RAT AB The striatum in the basal ganglia-thalamocortical circuitry is a key neural substrate that is implicated in motor balance and procedural learning. The projection neurons in the striatum are dynamically modulated by nigrostriatal dopaminergic input and intrastriatal cholinergic input. The role of intrastriatal acetylcholine (ACh) in learning behaviors, however, remains to be fully clarified. In this investigation, we examine the involvement of intrastriatal ACh in different categories of learning by selectively ablating the striatal cholinergic neurons with use of immunotoxin-mediated cell targeting. We show that selective ablation of cholinergic neurons in the striatum impairs procedural learning in the tone-cued T-maze memory task. Spatial delayed alternation in the T-maze learning test is also impaired by cholinergic cell elimination. In contrast, the deficit in striatal ACh transmission has no effect on motor learning in the rota-rod test or spatial learning in the Morris water-maze test or on contextual- and tone-cued conditioning fear responses. We also report that cholinergic cell elimination adaptively upregulates nicotinic ACh receptors not only within the striatum but also in the cerebral cortex and substantia nigra. The present investigation indicates that cholinergic modulation in the local striatal circuit plays a pivotal role in regulation of neural circuitry involving reward-related procedural learning and working memory. C1 Kyoto Univ, Fac Med, Dept Biol Sci, Kyoto 6068501, Japan. NCI, Mol Biol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Nakanishi, S (reprint author), Kyoto Univ, Fac Med, Dept Biol Sci, Kyoto 6068501, Japan. NR 33 TC 75 Z9 79 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 24 PY 2003 VL 100 IS 13 BP 7965 EP 7970 DI 10.1073/pnas.1032899100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 695TE UT WOS:000183845800099 PM 12802017 ER PT J AU Sztalryd, C Xu, GH Dorward, H Tansey, JT Contreras, JA Kimmel, AR Londos, C AF Sztalryd, C Xu, GH Dorward, H Tansey, JT Contreras, JA Kimmel, AR Londos, C TI Perilipin A is essential for the translocation of hormone-sensitive lipase during lipolytic activation SO JOURNAL OF CELL BIOLOGY LA English DT Article DE lipolysis; adipocytes; ADRP/adipophilin; HSL; lipid storage droplets ID LIPID STORAGE DROPLET; PROTEIN-KINASE; MEDIATED LIPOLYSIS; 3T3-L1 ADIPOCYTES; CELLS; DIFFERENTIATION; SYSTEM; LINES; MOUSE; ALPHA AB A key step in lipolytic activation of adipocytes is the translocation of hormone-sensitive lipase (HSL) from the cytosol to the surface of the lipid storage droplet. Adipocytes from perilipin-null animals have an elevated basal rate of lipolysis compared with adipocytes from Wild-type mice, but fail to respond maximally to lipolytic stimuli. This defect is downstream of the p-adrenergic receptor-adenylyl cyclase complex. Now, we show that HSL is basally associated with lipid droplet surfaces at a low level in pefilipin nulls, but that stimulated translocation from the cytosol to lipid droplets is absent in adipocytes derived from embryonic fibroblasts of perilipin-null mice. We have also reconstructed the HSL translocation reaction in the nonadipocyte Chinese hamster ovary cell line by introduction of GFP-tagged HSL with and without perilipin A. On activation of protein kinase A, HSL-GFP translocates to lipid droplets only in cells that express fully phosphory-latable perilipin A, confirming that perilipin is required to elicit the HSL translocation reaction. Moreover, in Chinese hamster ovary cells that express both HSL and perilipin A, these two proteins cooperate to produce a more rapidly accelerated lipolysis than do cells that express either of these proteins alone, indicating that lipolysis is a concerted reaction mediated by both protein kinase A-phosphorylated HSL and perilipin A. C1 NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. Lund Univ, Sect Mol Signaling, Dept Cell & Mol Biol, SE-22184 Lund, Sweden. RP Londos, C (reprint author), NIDDKD, Cellular & Dev Biol Lab, NIH, Bldg 6,Rm B1-32A,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 23 TC 309 Z9 327 U1 2 U2 20 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD JUN 23 PY 2003 VL 161 IS 6 BP 1093 EP 1103 DI 10.1083/jcb.200210169 PG 11 WC Cell Biology SC Cell Biology GA 695JM UT WOS:000183827400010 PM 12810697 ER PT J AU Kim, M Park, CH Lee, MS Carlson, BA Hatfield, DL Lee, BJ AF Kim, M Park, CH Lee, MS Carlson, BA Hatfield, DL Lee, BJ TI A novel TBP-interacting zinc finger protein represses transcription by inhibiting the recruitment of TFIIA and TFIIB SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE chromatin immunoprecipitation; FAX; TBP; transcription; transcriptional repressor; Xenopus laevis; zinc finger protein ID TATA-BINDING PROTEIN; RNA-POLYMERASE-II; TRNA(SEC) GENE; IN-VITRO; COMPLEXES; PROMOTER; FAMILY; KRUPPEL AB We isolated a novel gene encoding a zinc finger protein from Xenopus laevis, designated NZFP that interacts with the TATA-binding protein (TBP). NZFP contains a highly conserved sequence designated finger associated box (FAX) and SUMO-1 consensus-binding motifs at the N-terminal half and 10 C2H2 type zinc finger motifs at the C-terminal half, respectively. Deletion mutants of NZFP fused with the Gal4 DNA binding domain were used to determine the function of NZFP during gene transcription by transfecting them into a Xenopus kidney cell line. Both full-length NZFP and the FAX domain repressed transcription activity by 3-5-fold. Moreover, an in vitro pull-down assay showed that the C-terminal core domain of TBP makes direct contact with the N-terminal portion of NZFP. We also found through chromatin immunoprecipitation experiments that the interaction between NZFP and TBP inhibits binding of TFIIA and TFIIB. These data strongly suggest that the repression by NZFP occurs through its binding to both DNA and TBP and the resulting NZFIP-TBP-promoter complex inhibits preinitiation complex assembly by preventing binding of TFIIA and TFIIB. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Seoul Natl Univ, Sch Biol Sci, Mol Genet Lab, Seoul 151742, South Korea. NCI, Sect Mol Biol Selenium, Basic Res Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Lee, BJ (reprint author), Seoul Natl Univ, Sch Biol Sci, Mol Genet Lab, Seoul 151742, South Korea. NR 28 TC 5 Z9 6 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 20 PY 2003 VL 306 IS 1 BP 231 EP 238 DI 10.1016/S0006-291X(03)00939-2 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 692TT UT WOS:000183676900037 PM 12788093 ER PT J AU Jayakumar, R Kusiak, JW Chrest, FJ Demehin, AA Murali, J Wersto, RP Nagababu, E Ravi, L Rifkind, JM AF Jayakumar, R Kusiak, JW Chrest, FJ Demehin, AA Murali, J Wersto, RP Nagababu, E Ravi, L Rifkind, JM TI Red cell perturbations by amyloid beta-protein SO BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS LA English DT Article DE amyloid fibril; red cell; oxidative stress; biotin; flow cytometry; membrane ID RADICAL OXIDATIVE STRESS; ALZHEIMERS-DISEASE; HYDROGEN-PEROXIDE; HEME DEGRADATION; HIPPOCAMPAL-NEURONS; SOLUBLE FORM; BASIC FGF; PEPTIDE; MODEL; PLASMA AB Amyloid beta-protein (Abeta) accumulation in brain is thought to be important in causing the neuropathology of Alzheimer's disease (AD). Abeta interactions with both neurons and microglial cells play key roles in AD. Since vascular deposition of Abeta is also implicated in AD, the interaction of red cells with these toxic aggregates gains importance. However, the effects of A interactions with red blood cells are less well understood. Synthetic amyloid beta-protein (1-40) was labeled with biotin and preincubated at 37 degreesC for 4, 14 and 72 h to produce fibrils. Flow cytometry was used to study the binding of these fibrils to red cells. The amyloid fibrils had a high affinity for the red cell with increased binding for the larger fibrils produced by longer preincubation. Bovine serum albumin (BSA) did not reverse the binding, but actually resulted in a more efficient binding of the Abeta fibrils to the red cells. The interaction of Abeta with red cells increased the mean cell volume and caused the cells to become more spherical. This effect was greater for the longer fibrils. At the same time the interaction of Abeta with red cells produced an increase in their fluorescence measured after 16-h incubation at 37 degreesC. This increase in fluorescence is attributed to the formation of fluorescent heme degradation products. The effect of prior hemoglobin oxidation, catalase inhibition and glutathione peroxidase inhibition indicated that the amyloid-induced oxidative damage to the red cell involved hydrogen peroxide-induced heme degradation. These results suggest that amyloid interactions with the red cell may contribute to the pathology of AD. Published by Elsevier B.V. C1 NIA, Gerontol Res Ctr, Mol Dynam Sect, Baltimore, MD 21224 USA. Cent Leather Res Inst, Bioorgan Lab, Madras, Tamil Nadu, India. NIA, Res Resources Branch, Baltimore, MD 21224 USA. RP Rifkind, JM (reprint author), NIA, Gerontol Res Ctr, Mol Dynam Sect, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM rifkindj@grc.nia.nih.gov NR 57 TC 40 Z9 40 U1 2 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4165 J9 BBA-GEN SUBJECTS JI Biochim. Biophys. Acta-Gen. Subj. PD JUN 20 PY 2003 VL 1622 IS 1 BP 20 EP 28 DI 10.1016/S0304-4165(03)00101-6 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 728GK UT WOS:000185709300004 PM 12829257 ER PT J AU Tsutsui, T Tamura, Y Yagi, E Someya, H Hori, I Metzler, M Barrett, JC AF Tsutsui, T Tamura, Y Yagi, E Someya, H Hori, I Metzler, M Barrett, JC TI Cell-transforming activity and mutagenicity of 5 phytoestrogens in cultured mammalian cells SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE mammalian cells; transformation; phytoestrogens ID PROTEIN-TYROSINE KINASE; BREAST-CANCER CELLS; NEOPLASTIC TRANSFORMATION; TOPOISOMERASE ACTIVITY; PHYTO-ESTROGENS; GENISTEIN; INDUCTION; ISOFLAVONE; EXPOSURE; GROWTH AB For the simultaneous assessment of in vitro carcinogenicity and mutagenicity of phytoestrogens, the abilities of 5 phytoestrogens, daidzein, genistein, biochanin A, prunetin, and coumestrol, to induce cell transformation and genetic effects were examined using the Syrian hamster embryo (SHE) cell model. Cellular growth was inhibited by all phytoestrogens in a concentration-related manner. The growth inhibitory effect of the compounds was ranked: genistein, prunetin > coumestrol > biochanin A > daidzein, which did not correspond to their apoptosis-inducing abilities. Morphological transformation in SHE cells was elicited by all phytoestrogens, except, prunetin. The transforming activities were ranked as follows: genistein > coumestrol > daidzein > biochanin A. Somatic mutations in SHE cells at the Na+/K+ ATPase and hprt loci were induced only by genistein, coumestrol, or daidzein. Chromosome aberrations were induced by genistein or coumestrol, and aneuploidy in the near diploid range was occurred by genistein or biochanin A. Genistein, biochanin A or daidzein induced DNA adduct formation in SHE cells with the abilities: genistein > biochanin A > daidzein. Prunetin was negative for any of these genetic endpoints. Our results provide evidence that genistein, coumestrol, daidzein and biochanin A induce cell transformation in SHE cells and that the transforming activities of these phytoestrogens correspond to at least 2 of the mutagenic effects by each phytoestrogen, i.e., gene mutations, chromosome aberrations, aneuploidy or DNA adduct formation, suggesting the possible involvement of mutagenicity in the initiation of phytoestrogen-induced carcinogenesis. (C) 2003 Wiley-Liss, Inc. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Nippon Dent Univ Tokyo, Dept Pharmacol, Sch Dent, Tokyo, Japan. Univ Karlsruhe, Inst Food Chem & Toxicol, Karlsruhe, Germany. NCI, Lab Biosyst & Canc, Bethesda, MD 20892 USA. RP Barrett, JC (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 39 TC 14 Z9 17 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUN 20 PY 2003 VL 105 IS 3 BP 312 EP 320 DI 10.1002/ijc.11046 PG 9 WC Oncology SC Oncology GA 678HN UT WOS:000182861400004 PM 12704663 ER PT J AU Ciolino, H MacDonald, C Memon, O Dankwah, M Yeh, GC AF Ciolino, H MacDonald, C Memon, O Dankwah, M Yeh, GC TI Dehydroepiandrosterone inhibits the expression of carcinogen-activating enzymes in vivo SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE DHEA; cytochrome p450 1A1/1A2; DMBA; EROD ID SPONTANEOUS TUMORIGENESIS; DHEA; LIVER; MICE; RAT; DNA; 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN; CHEMOPREVENTION; METABOLITES; MECHANISM AB We investigated the effect of the steroid hormone dehydroepiandrosterone (DHEA) on the hepatic expression and activity of carcinogen-activating enzymes, the cytochromes P450 (CYP) 1A1, 1A2 and 1B1, in Sprague-Dawley rats. In animals fed DHEA at 200 or 400 mg/kg body weight every other day for 2 weeks prior to exposure to the aryl hydrocarbon dimethylbenz[a]anthracene (DMBA, 5 mg/kg), there was a dose-dependent decrease in hepatic CYP activity, as measured by ethoxyresorufin-O (EROD) assay, from 37.1 to 22.9 and 14.7 pmoles/min/10 mug microsomes, respectively. DHEA did not directly inhibit microsomal EROD activity, however, leading us to investigate its effects on enzyme expression. To test this, we examined protein and mRNA levels of the enzymes. Western blot for CYP1A1 and CYP1A2 showed that DHEA inhibited the increase in hepatic CYP1A1 and CYP1A2 enzyme levels that are normally induced by DMBA. DMBA-induced increase in expression of CYP1A1, CYP1A2 and CYP1B1 mRNA was similarly blunted in DHEA-treated animals. DHEA was also able to significantly reduce the basal expression of CYP1A1 and CYP1A2 but not of CYP1B1. These results indicate that DHEA regulates the expression and, hence, the activity of hepatic carcinogen-activating enzymes in vivo, and this may be an important mechanism of its chemopreventive activity. Published 2003 Wiley-Liss, Inc.(dagger) C1 NCI, Cellular Def & Carcinogenesis Sect, Basic Res Lab, Frederick, MD 21702 USA. RP Ciolino, H (reprint author), NCI, Cellular Def & Carcinogenesis Sect, Basic Res Lab, Bldg 538,Room 141, Frederick, MD 21702 USA. NR 22 TC 11 Z9 12 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 JUN 20 PY 2003 VL 105 IS 3 BP 321 EP 325 DI 10.1002/ijc.11075 PG 5 WC Oncology SC Oncology GA 678HN UT WOS:000182861400005 PM 12704664 ER PT J AU Harrigan, JA Opresko, PL von Kobbe, C Kedar, PS Prasad, R Wilson, SH Bohr, VA AF Harrigan, JA Opresko, PL von Kobbe, C Kedar, PS Prasad, R Wilson, SH Bohr, VA TI The Werner syndrome protein stimulates DNA polymerase beta strand displacement synthesis via its helicase activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BASE EXCISION-REPAIR; FUNCTIONAL INTERACTION; REPEAT SEQUENCE; WRN PROTEIN; HUMAN-CELLS; INTERACTS; BINDING; COMPLEX; DELTA; 3'->5'-EXONUCLEASE AB Werner syndrome is a hereditary premature aging disorder characterized by genomic instability. Genetic analysis and protein interaction studies indicate that the defective gene product (WRN) may play an important role in DNA replication, recombination, and repair. DNA polymerase beta (polbeta) is a central participant in both short and long-patch base excision repair (BER) pathways, which function to process most spontaneous, alkylated, and oxidative DNA damage. We report here a physical interaction between WRN and pol beta, and using purified proteins reconstitute of a portion of the long-patch BER pathway to examine a potential role for WRN in this repair response. We demonstrate that WRN stimulates pol beta strand displacement DNA synthesis and that this stimulation is dependent on the helicase activity of WRN. In addition, a truncated WRN protein, containing primarily the helicase domain, retains helicase activity and is sufficient to mediate the stimulation of pol beta. The WRN helicase also unwinds a BER substrate, providing evidence that WRN plays a role in unwinding DNA repair intermediates. Based on these findings, we propose a novel mechanism by which WRN may mediate pol beta-directed long-patch BER. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. OI Opresko, Patricia/0000-0002-6470-2189 NR 57 TC 79 Z9 79 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 20 PY 2003 VL 278 IS 25 BP 22686 EP 22695 DI 10.1074/jbc.M213103200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 689QF UT WOS:000183503900069 PM 12665521 ER PT J AU Vishnyakova, TG Bocharov, AV Baranova, IN Chen, ZG Remaley, AT Csako, G Eggerman, TL Patterson, AP AF Vishnyakova, TG Bocharov, AV Baranova, IN Chen, ZG Remaley, AT Csako, G Eggerman, TL Patterson, AP TI Binding and internalization of lipopolysaccharide by Cla-1, a human orthologue of rodent scavenger receptor B1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HIGH-DENSITY-LIPOPROTEIN; SELECTIVE LIPID UPTAKE; BACTERIAL LIPOPOLYSACCHARIDE; SR-BI; ADRENOCORTICAL-CELLS; APOPTOTIC THYMOCYTES; PLASMA-LIPOPROTEINS; HDL CHOLESTEROL; KUPFFER CELLS; ENDOTOXIN AB Scavenger receptor, class B, type I (SR-BI) mediates selective uptake of high density lipoprotein (HDL) cholesteryl ester. SR-BI recognizes HDL, low density lipoprotein (LDL), exchangeable apolipoproteins, and protein-free lipid vesicles containing negatively charged phospholipids. Lipopolysaccharides (LPS) are highly glycosylated anionic phospholipids contributing to septic shock. Despite significant structural similarities between anionic phospholipids and LPS, the role of SR-BI in LPS uptake is unknown. Cla-1, the human SR-BI orthologue, was determined to be a LPS-binding protein and endocytic receptor mediating the binding and internalization of lipoprotein-free, monomerized LPS. LPS strongly competed with HDL, lipid-free apoA-I and apoA-II for HDL binding to the mouse RAW cells. Stably transfected HeLa cells expressing Cla-1-bound LPS with a K-d of about 16 mug/ml, and had a 3-4-fold increase in binding capacity and LPS uptake. Bodipy-labeled LPS uptake was found to initially accumulate in the plasma membrane and subsequently in a perinuclear region identified predominantly as the Golgi complex. Bodipy-LPS and Alexa-apoA-I had staining that colocalized on the cell surface and intracellularly indicating similar transport mechanisms. When associated with HDL, LPS uptake was increased in Cla-1 overexpressing HeLa cells by 5-10-fold. Cla-1-associated H-3-LPS uptake exceeded I-125-apolipoprotein uptake by 5-fold indicating a selective LPS uptake. Upon interacting with Cla-1 overexpressing HeLa cells, the complex (Bodipy-LPS/Alexa 488 apolipoprotein-labeled HDL) bound and was internalized as a holoparticle. Intracellularly, LPS and apolipoproteins were sorted to different intracellular compartments. With LPS-associated HDL, intracellular LPS colocalized predominantly with transferrin, indicating delivery to an endocytic recycling compartment. Our study reveals a close similarity between Cla-1-mediated selective LPS uptake and the recently described selective lipid sorting by rodent SR-BI. In summary, Cla-1 was found to bind and internalize monomerized and HDL-associated LPS, indicating that Cla-1 may play important role in septic shock by affecting LPS cellular uptake and clearance. C1 NIH, Dept Lab Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NHLBI, NIH, Bethesda, MD 20892 USA. NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. RP Bocharov, AV (reprint author), NIH, Dept Lab Med, Warren G Magnuson Clin Ctr, Bldg 10, Bethesda, MD 20892 USA. NR 51 TC 80 Z9 82 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 20 PY 2003 VL 278 IS 25 BP 22771 EP 22780 DI 10.1074/jbc.M211032200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 689QF UT WOS:000183503900080 PM 12651854 ER PT J AU Rutkai, E Dorgai, L Sirot, R Yagil, E Weisberg, RA AF Rutkai, E Dorgai, L Sirot, R Yagil, E Weisberg, RA TI Analysis of insertion into secondary attachment sites by phage lambda and by int mutants with altered recombination specificity SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE site-specific recombination; lysogeny; phage HK022; tyrosine recombinase; evolution ID BACTERIOPHAGE-LAMBDA; ESCHERICHIA-COLI; STRAND EXCHANGE; IDENTIFYING DETERMINANTS; CRYSTAL-STRUCTURE; COLIPHAGE-LAMBDA; BINDING-SITES; DNA; INTEGRASE; SEQUENCE AB When phage lambda lysogenizes a cell that lacks the primary bacterial attachment site, integrase catalyzes insertion of the phage chromosome into one of many secondary sites. Here, we characterize the secondary sites that are preferred by wild-type lambda and by lambda int mutants with altered insertion specificity. The sequences of these secondary sites resembled that of the primary site: they contained two imperfect inverted repeats flanking a short spacer. The imperfect inverted repeats of the primary site bind integrase, while the 7 bp spacer, or overlap region, swaps strands with a complementary sequence in the phage attachment site during recombination. We found substantial sequence conservation in the imperfect inverted repeats of secondary sites, and nearly perfect conservation in the leftmost three bases of the overlap region. By contrast, the rightmost bases of the overlap region were much more variable. A phage with an altered overlap region preferred to insert into secondary sites with the corresponding bases. We suggest that this difference between the left and right segments is a result of the defined order of strand exchanges during integrase-promoted recombination. This suggestion accounts for the unexpected segregation pattern of the overlap region observed after insertion into several secondary-sites. Some of the altered specificity int mutants differed from wild-type, in secondary site preference, but we were unable to identify simple sequence motifs that account for these differences. We propose that insertion into secondary sites is a step in the evolutionary change of phage insertion specificity and present a model of how this might occur. Published by Elsevier Science Ltd. C1 NICHHD, Mol Genet Sect, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. Bay Zoltan Inst Biotechnol, H-6726 Szeged, Hungary. Tel Aviv Univ, Dept Biochem, IL-69978 Tel Aviv, Israel. RP Weisberg, RA (reprint author), NICHHD, Mol Genet Sect, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. NR 56 TC 10 Z9 10 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUN 20 PY 2003 VL 329 IS 5 BP 983 EP 996 DI 10.1016/S0022-2836(03)00442-X PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 692QK UT WOS:000183671600013 PM 12798688 ER PT J AU Schotte, F Lim, MH Jackson, TA Smirnov, AV Soman, J Olson, JS Phillips, GN Wulff, M Anfinrud, PA AF Schotte, F Lim, MH Jackson, TA Smirnov, AV Soman, J Olson, JS Phillips, GN Wulff, M Anfinrud, PA TI Watching a protein as it functions with 150-ps time-resolved X-ray crystallography SO SCIENCE LA English DT Article ID LIGAND-BINDING; CARBONMONOXY-MYOGLOBIN; CONFORMATIONAL RELAXATION; CRYSTAL-STRUCTURE; PHOTODISSOCIATION; DYNAMICS; CO; INTERMEDIATE; CAVITIES; MOTIONS AB We report picosecond time-resolved x-ray diffraction from the myoglobin (Mb) mutant in which Leu(29) is replaced by Phe (L29F mutant). The frame-by-frame structural evolution, resolved to 1.8 angstroms, allows one to literally "watch" the protein as it executes its function. Time-resolved mid-infrared spectroscopy of flash-photolyzed L29F MbCO revealed a short-lived CO intermediate whose 140-ps lifetime is shorter than that found in wild-type protein by a factor of 1000. The electron density maps of the protein unveil transient conformational changes far more dramatic than the structural differences between the carboxy and deoxy states and depict the correlated side-chain motion responsible for rapidly sweeping CO away from its primary docking site. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Pusan Natl Univ, Dept Chem, Pusan 609735, South Korea. Harvard Univ, Sch Med, Boston, MA 02115 USA. Rice Univ, Dept Biochem & Cell Biol, Houston, TX 77251 USA. Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. European Synchrotron Radiat Facil, F-38043 Grenoble, France. RP Schotte, F (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. OI Olson, John/0000-0002-0760-5403 FU NHLBI NIH HHS [HL47020]; NIAMS NIH HHS [AR40252]; NIGMS NIH HHS [GM35649] NR 22 TC 529 Z9 537 U1 6 U2 77 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUN 20 PY 2003 VL 300 IS 5627 BP 1944 EP 1947 DI 10.1126/science.1078797 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 691RN UT WOS:000183619400046 PM 12817148 ER PT J AU Sundaram, R Sun, YP Walker, CM Lemonnier, FA Jacobson, S Kaumaya, PTP AF Sundaram, R Sun, YP Walker, CM Lemonnier, FA Jacobson, S Kaumaya, PTP TI A novel multivalent human CTL peptide construct elicits robust cellular immune responses in HLA-A*0201 transgenic mice: implications for HTLV-1 vaccine design SO VACCINE LA English DT Article DE HTLV-1 CTL epitopes; multivalent peptide; antigen presentation/processing; HLA-A*0201/D-b transgenic mice ID CYTOTOXIC T-LYMPHOCYTES; LEUKEMIA-VIRUS TYPE-1; PHASE-I TRIAL; TROPICAL SPASTIC PARAPARESIS; DOUBLE KNOCKOUT MICE; LYMPHOPROLIFERATIVE DISEASE; DIRECT VISUALIZATION; MULTIPLE EPITOPES; PERIPHERAL-BLOOD; ANTIGEN AB Cytotoxic T-lymphocytes are critical in the clearance of chronic viral infections such as HTLV-1. Peptide-based vaccines may have potential application in invoking antiviral CTL responses. In the development of vaccination strategies, it is becoming increasingly important to elicit a broad immune response against several epitopes simultaneously that may provide large population coverage. In the present study, we addressed this issue, namely the processing and presentation of multiple CTL epitopes simultaneously for the generation of multispecific CTL responses. We designed a novel multivalent peptide consisting of three HLA-A*0201 restricted CTL epitopes, with intervening double arginine residues in tandem. These epitopes were derived from the HTLV-1 regulatory protein Tax, which is an attractive target for vaccine development against HTLV-1. Arginine residues were included to provide cleavage sites for proteasomes, to generate the intended MHC Class I ligands. Proteasomal digestion studies and mass spectrometry analysis showed cleavage of the multivalent construct to generate the individual epitopes. Immunization of HLA-A*0201 transgenic mice with this construct efficiently elicited cellular responses to each intended epitope in vivo, further validating the applicability of this approach. These data may have potential in the development of immunotherapeutic strategies for the treatment of HTLV-1 disease and in the future design of multivalent subunit peptide vaccines. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 Ohio State Univ, Dept Obstet & Gynecol, Tzagournis Med Res Facil, Columbus, OH 43210 USA. Ohio State Univ, Coll Med, Columbus, OH 43210 USA. Ohio State Univ, Arthur G James Comprehens Canc Ctr, Columbus, OH 43210 USA. Ohio State Univ, Ctr Retrovirus Res, Columbus, OH 43210 USA. Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. Ohio State Univ, Dept Microbiol, Columbus, OH 43210 USA. Ohio State Univ, Dept Pediat, Columbus, OH 43210 USA. Procter & Gamble Co, Miami Valley Labs, Corp Res Div, Cincinnati, OH 45253 USA. Inst Pasteur, Unite Immunite Cellularie Antiviral, F-75724 Paris 15, France. NINDS, Viral Immunol Sect, NIH, Bethesda, MD 20892 USA. RP Kaumaya, PTP (reprint author), Ohio State Univ, Dept Obstet & Gynecol, Tzagournis Med Res Facil, Suite 316,420W 12th Ave, Columbus, OH 43210 USA. FU PHS HHS [A140302] NR 57 TC 21 Z9 21 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUN 20 PY 2003 VL 21 IS 21-22 BP 2767 EP 2781 DI 10.1016/S0264-410X(03)00179-8 PG 15 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 693GT UT WOS:000183709300014 PM 12798617 ER PT J AU Gilbert, PB Chiu, YL Allen, M Lawrence, DN Chapdu, C Israel, H Holman, D Keefer, MC Wolff, M Frey, SE AF Gilbert, PB Chiu, YL Allen, M Lawrence, DN Chapdu, C Israel, H Holman, D Keefer, MC Wolff, M Frey, SE CA NIAID HIV Vaccine Trials Network TI Long-term safety analysis of preventive HIV-1 vaccines evaluated in AIDS vaccine evaluation group NIAID-sponsored Phase I and II clinical trials SO VACCINE LA English DT Article DE adverse events; HIV vaccine trial; long-term follow-up; peptide; recombinant canarypox; subunit; vaccinia; adjuvants ID GP160 RECOMBINANT VACCINIA; VIRUS TYPE-1 VACCINE; CANDIDATE VACCINE; IMMUNE-RESPONSES; SERONEGATIVE VOLUNTEERS; NEUTRALIZING ANTIBODY; PEPTIDE IMMUNOGEN; CANARYPOX VACCINE; NAIVE ADULTS; ENVELOPE AB This report evaluates long-term safety data from 3189 human immunodeficiency virus type 1 (HIV-1) uninfected, healthy volunteers who were enrolled into 51 National Institute of Allergy and Infectious Diseases (NIAID)- sponsored Phase I and II multicentred, randomized, double-blind trials of recombinant HIV-1 subunit vaccines (23 studies), synthetic peptide vaccines (7 studies), live vaccinia-vector recombinant envelope vaccines (7 studies), canarypox vector recombinant vaccines (13 studies), a DNA vaccine (1 study), and a Salmonella-vector vaccine (1 study). During the 12,340 person-years of follow-up, participants were monitored for adverse events including immune dysfunction/autoimmunity, anaphylaxis, cancer, death, and vaccine allergy. The analysis provides evidence that a preparation of a C4-V3 polypeptide vaccine emulsified in incomplete Freund's caused serious toxicity, but otherwise no safety problems considered serious were identified for any of the vaccines and adjuvants studied. These data serve to solidify the growing safety base of current vaccine technologies utilized in candidate vaccines for HIV-1 infection. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 St Louis Univ, Hlth Sci Ctr, Div Infect Dis & Immunol, St Louis, MO 63103 USA. Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA USA. NIAID, Vaccine Clin Res Branch, Vaccine & Prevent Res Program, Div Aids, Bethesda, MD USA. Univ Rochester, Med Ctr, Dept Med, Infect Dis Unit, Rochester, NY 14642 USA. EMMES Corp, Rockville, MD USA. RP Frey, SE (reprint author), St Louis Univ, Hlth Sci Ctr, Div Infect Dis & Immunol, 3635 Vista Ave, St Louis, MO 63103 USA. OI Allen, Mary/0000-0001-8163-0714 FU NIAID NIH HHS [N01-AI-05063, 5-U01 AI-46703, 5-U01 AI-46747, N01-AI-05061, N01-AI-05062, N01-AI-05065, N01-AI-45207, N01-AI-45208, N01-AI-45209, N01-AI-45210, N01-AI-45211, N01-AI-52500, N01-AI-82500] NR 37 TC 43 Z9 48 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUN 20 PY 2003 VL 21 IS 21-22 BP 2933 EP 2947 DI 10.1016/S0264-410X(03)00158-0 PG 15 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 693GT UT WOS:000183709300034 PM 12798637 ER PT J AU Hoshino, Y Jones, RW Ross, J Kapikian, AZ AF Hoshino, Y Jones, RW Ross, J Kapikian, AZ TI Construction and characterization of rhesus monkey rotavirus (MMU18006)- or bovine rotavirus (UK)-based serotype G5, G8, G9 or G10 single VP7 gene substitution reassortant candidate vaccines SO VACCINE LA English DT Article DE rotavirus vaccine; single VP7 gene substitution reassortant; rotavirus G5, G8, G9 or G10 ID GROUP-A ROTAVIRUS; LONG RNA ELECTROPHEROTYPE; YOUNG-CHILDREN; MOLECULAR CHARACTERIZATION; MONOCLONAL-ANTIBODIES; HOSPITALIZED CHILDREN; ACUTE GASTROENTERITIS; BRAZILIAN CHILDREN; ACUTE DIARRHEA; UNITED-STATES AB Group A rotaviruses are the single most important etiologic agents of severe diarrhea of infants and young children worldwide and have been estimated to be responsible for approximately 650,000-800,000 deaths annually in children <5-year-old in the developing countries. Thus, the development of a safe and effective rotavirus vaccine has been a global public health goal. Epidemiologic surveillance of rotavirus VP7 (G) serotypes-genotypes conducted in various populations throughout the world has repeatedly shown that approximately 90% of the typeable rotavirus isolates belong to G1-G4. For these reasons, we have developed a rhesus rotavirus (RRV)-based or bovine rotavirus (UK)-based quadrivalent vaccine which is designed to provide antigenic coverage for G1-G4. More recently, G serotypes-genotypes other than G1-G4, including G5, G8-G10, have been detected in various parts of the world. Although the occurrence of such uncommon G types, except for G9, has been focal, still, in order to "be ready and prepared", we have constructed and characterized eight additional reassortant rotavirus vaccines, each of which bears a single human or bovine VP7 gene encoding G serotype 5, 8, 9 or 10 specificity and the remaining 10 genes of RRV strain MMU18006 or bovine rotavirus strain UK. These candidate vaccines could be evaluated singly in special populations or in combination with a RRV- or an UK-based quadrivalent vaccine to broaden its G serotype specificity. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 NIAID, Epidemiol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Hoshino, Y (reprint author), NIAID, Epidemiol Sect, Infect Dis Lab, NIH, Bldg 50,Room 6308,50 S Dr,MSC 8026, Bethesda, MD 20892 USA. NR 89 TC 18 Z9 22 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 JUN 20 PY 2003 VL 21 IS 21-22 BP 3003 EP 3010 DI 10.1016/S0264-410X(03)00120-8 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 693GT UT WOS:000183709300041 PM 12798644 ER PT J AU Jendrek, S Little, SF Hem, S Mitra, G Giardina, S AF Jendrek, S Little, SF Hem, S Mitra, G Giardina, S TI Evaluation of the compatibility of a second generation recombinant anthrax vaccine with aluminum-containing adjuvants SO VACCINE LA English DT Article DE anthrax; vaccine; aluminum-containing adjuvant ID PROTECTIVE ANTIGEN; BACILLUS-ANTHRACIS; MODEL ANTIGENS; GUINEA-PIGS; PROTEINS; ADSORPTION; EFFICACY AB Recombinant protective antigen (rPA) is the active pharmaceutical ingredient in a second generation anthrax vaccine undergoing pre-clinical evaluation. This rPA vaccine differs from the currently licensed vaccine, anthrax vaccine adsorbed (AVA), in that the sole component is a recombinant form of protective antigen (PA). Unlike AVA the rPA vaccine contains no lethal factor (LF) or edema factor (EF), components of the two bipartite toxins, nor many other Bacillus anthracis-related contaminating proteins that are present in AVA. The proposed clinical protocol involves adsorption of the rPA to an aluminum-based adjuvant. The adsorptive characteristics of rPA and two aluminum-containing adjuvants were examined in a physiological buffer with and without EDTA. Based on the pI of rPA (pI = 5.6) and the zero charge point of aluminum hydroxide adjuvant (11.5) and aluminum phosphate adjuvant (4.5), it was predicted and demonstrated that rPA bound in a more efficient manner to aluminum hydroxide adjuvant than to aluminum phosphate adjuvant in the physiological buffer. Binding of the rPA to the aluminum hydroxide adjuvant was decreased by increasing amounts of phosphate in the buffer. The adsorptive capacity for rPA onto aluminum hydroxide adjuvant in the physiological buffer and in water were calculated to be 0.46 mg rPA/mg aluminum in DPBS and 0.73 mg rPA/mg aluminum in water. This study also demonstrated that upon desorption from the aluminum hydroxide adjuvant the rPA was physically intact and free of detectable aggregates. Further, the eluted material was biologically active in an in vitro cytotoxicity assay. Desorption was only possible after an overnight incubation of 2-8 degreesC and not after a room temperature incubation reflecting increased contact with the aluminum hydroxide adjuvant over time. These data suggest that the interaction between rPA and aluminum hydroxide adjuvant is predominantly electrostatic in character. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 NCI, SAIC Frederick Inc, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. USA, Med Res Inst Infect Dis, Bacteriol Dic, Frederick, MD 21702 USA. Purdue Univ, Dept Ind & Phys Pharm, W Lafayette, IN 47907 USA. RP Jendrek, S (reprint author), NCI, SAIC Frederick Inc, Frederick Canc Res & Dev Ctr, Bldg 320, Frederick, MD 21702 USA. FU PHS HHS [N01-C0-12400] NR 24 TC 34 Z9 40 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUN 20 PY 2003 VL 21 IS 21-22 BP 3011 EP 3018 DI 10.1016/S0264-410X(03)00109-9 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 693GT UT WOS:000183709300042 PM 12798645 ER PT J AU Disbrow, GL Sunitha, I Baker, CC Hanover, J Schlegel, R AF Disbrow, GL Sunitha, I Baker, CC Hanover, J Schlegel, R TI Codon optimization of the HPV-16 E5 gene enhances protein expression SO VIROLOGY LA English DT Article ID HUMAN-PAPILLOMAVIRUS TYPE-16; GROWTH-FACTOR RECEPTOR; INTEGRAL MEMBRANE-PROTEIN; E5 TRANSFORMING PROTEIN; OPEN READING FRAME; HUMAN KERATINOCYTES; ENDOPLASMIC-RETICULUM; SYNTHETIC PEPTIDES; GENE-EXPRESSION; ONCOPROTEIN AB The human papillomavirus type 16 (HPV-16) E5 protein is an 83-amino-acid, hydrophobic polypeptide that has been localized to intracellular membranes when overexpressed in COS-1 cells. While the HPV-16 E5 protein appears to modulate endosomal pH and signal transduction pathways. genetic analysis of its biological activities has been hampered by low (usually nondetectable) levels of expression in stable cell lines. Sequence analysis of the native HPV-16 E5 gene revealed that infrequent-use codons are used for 33 of its 83 amino acids and, in an effort to optimize E5 expression, we converted these codons to those more common in mammalian genes. The modified gene, 16E5*, generated protein levels that were six- to ninefold higher than those of wild-type HPV-16 E5, whereas the levels of mRNA were unchanged. 16E5* protein was detectable in keratinocytes by immunoblotting, immunoprecipitation, and immunofluorescence techniques and formed disulfide-dependent dimers and higher-order oligomers. Unlike the bovine papillomavirus E5 protein, which is present in the Golgi. 16E5* was localized primarily to the endoplasmic reticulum and its expression reduced the in vitro life span of keratinocytes. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Georgetown Univ, Med Ctr, Sch Med, Dept Pathol, Washington, DC 20057 USA. NCI, Ctr Canc Res, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Schlegel, R (reprint author), Georgetown Univ, Med Ctr, Sch Med, Dept Pathol, Preclin Sci Bldg,Room GR10C, Washington, DC 20057 USA. FU NCI NIH HHS [R10 CA53371] NR 58 TC 52 Z9 56 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JUN 20 PY 2003 VL 311 IS 1 BP 105 EP 114 DI 10.1016/S0042-6822(03)00129-6 PG 10 WC Virology SC Virology GA 699EL UT WOS:000184042900012 PM 12832208 ER PT J AU Nandi, JS Tikute, SA Chhangani, AK Potdar, VA Tiwari-Mishra, M Ashtekar, RA Kumari, J Walimbe, A Mohnot, SM AF Nandi, JS Tikute, SA Chhangani, AK Potdar, VA Tiwari-Mishra, M Ashtekar, RA Kumari, J Walimbe, A Mohnot, SM TI Natural infection by simian retrovirus-6 (SRV-6) in Hanuman langurs (Semnopithecus entellus) from two different geographical regions of India SO VIROLOGY LA English DT Article ID PFIZER MONKEY VIRUS; NUCLEOTIDE-SEQUENCE; IMMUNODEFICIENCY-SYNDROME; ENVELOPE GLYCOPROTEIN; CELL EPITOPES; T-CELL; MACAQUES; AIDS; TUMOR; PROTEIN AB We have previously reported natural infection of Hanuman langurs (Semnopithecus entellus) from Lucknow, India by a novel simian retrovirus, SRV-6, a beta-retrovirus (type D retrovirus). Here we describe infection by a closely related SRV-6 in an isolated feral population of Hanuman langurs from Jodhpur in the Northwestern desert region of India. Serological analyses, using in-house ELISA and WB, genomic amplification, and sequencing of env region (gp70 and gp20) of the viral genome were carried out. SRV-6-infected langurs from the two regions were serologically cross-reactive. The env gene was used for phylogenetic analyses, being the most variable part of a retroviral genome. The surface glycoproteins (gp70) were almost identical between the two SRV-6 isolates and related to but distinct from equivalent regions from other exogenous SRVs. We could sequence the transmembrane glycoprotein gp20 from SRV-6 infecting the Jodhpur langurs, which was again shown to be related to but unique compared to the other known SRVs. The study suggests that natural infection by related strains of SRV-6 occurs in wild langurs from different parts of India. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Natl Inst Virol, Dept Retroviral, Pune 411001, Maharashtra, India. JNV Univ, Dept Zool, Primate Res Ctr, Jodhpur, Rajasthan, India. Natl Inst Virol, Comp Sect, Dept Retrovirol, Pune 411001, Maharashtra, India. RP Nandi, JS (reprint author), NIAID, Mol Microbiol Lab, Twinbrook Facil 2, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. NR 45 TC 8 Z9 9 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JUN 20 PY 2003 VL 311 IS 1 BP 192 EP 201 DI 10.1016/S0042-6822(03)00187-9 PG 10 WC Virology SC Virology GA 699EL UT WOS:000184042900020 PM 12832216 ER PT J AU Teufel, A Wong, EA Mukhopadhyay, M Malik, N Westphal, H AF Teufel, A Wong, EA Mukhopadhyay, M Malik, N Westphal, H TI FoxP4, a novel forkhead transcription factor SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION LA English DT Article DE development; winged helix; kidney cancer; gut ID ALVEOLAR RHABDOMYOSARCOMA; PROTEIN; GENE; HEAD; DISRUPTION; ALIGNMENT; DATABASE; CLONING; FUSION; TISSUE AB Forkhead proteins have been demonstrated to play key roles in embryonic development, cell cycle regulation, and oncogenesis. We report the characterization of a new forkhead transcription factor, which is a member of the FoxP subfamily. In adult tissues FoxP4 is expressed in heart, brain, lung, liver, kidney, and testis. By Northern hybridization, very low levels of FoxP4 expression were found as early as E7 during embryonic development. Embryonic expression was highest at Ell and subsequently decreased at E15 and E17. In situ hybridization revealed expression of FoxP4 in the developing lung and gut, suggesting a role for FoxP4 during the development of these organs. In addition, FoxP4 was found to be significantly reduced in patients with kidney tumors. Lastly, FoxP4 matches an uncharacterized human EST that has previously been shown to be down-regulated in larynx carcinoma. (C) 2003 Elsevier Science B.V. All rights reserved. C1 NICHD, Lab Mammalian Genes & Dev, NICHHD, NIH, Bethesda, MD 20892 USA. Virginia Polytech Inst & State Univ, Dept Anim & Poultry Sci, Blacksburg, VA 24061 USA. RP Westphal, H (reprint author), NICHD, Lab Mammalian Genes & Dev, NICHHD, NIH, Bldg 6B,Room 413,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 27 TC 40 Z9 41 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4781 J9 BBA-GENE STRUCT EXPR JI Biochim. Biophys. Acta-Gene Struct. Expression PD JUN 19 PY 2003 VL 1627 IS 2-3 BP 147 EP 152 DI 10.1016/S0167-4781(03)00074-5 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 694DN UT WOS:000183758700011 PM 12818433 ER PT J AU Cao, JJ Kulkarni, SS Husbands, SM Bowen, WD Williams, W Kopajtic, T Katz, JL George, C Newman, AH AF Cao, JJ Kulkarni, SS Husbands, SM Bowen, WD Williams, W Kopajtic, T Katz, JL George, C Newman, AH TI Dual probes for the dopamine transporter and sigma(1) receptors: novel piperazinyl alkyl-bis(4 '-fluorophenyl)amine analogues as potential cocaine-abuse therapeutic agents SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CONDITIONED PLACE PREFERENCE; MONOAMINE TRANSPORTERS; 1-<2-ETHYL>-4-(3-PHENYLPROPYL)PIPERAZINES GBR-12935; PIPERIDINE ANALOGS; RIMCAZOLE ANALOGS; LIGANDS; BINDING; DERIVATIVES; AFFINITY; 1-<2-(DIPHENYLMETHOXY)ETHYL>-4-(3-PHENYLPROPYL)PIPERAZINES AB Both dopamine uptake inhibitors and sigma(1) receptor antagonists have been implicated as potential pharmacotherapeutics for the treatment of cocaine abuse. While the dopamine uptake inhibitors may share with cocaine neurochemical mechanisms underlying reinforcing properties, sigma(1) antagonists have been shown to attenuate some behavioral actions and toxic side effects associated with cocaine overdose. Rimcazole, a sigma(1) receptor antagonist that binds to the DAT (K-i = 224 nM), is not behaviorally cocaine-like and attenuates some of the behavioral actions of cocaine. To determine the roles of both DAT and sigma(1) receptors in the behavioral actions of rimcazole, a series of analogues was synthesized. Initial studies identified two analogues. (1 and 4) that showed high to moderate affinities for both DAT and sigma(1) receptors and failed to show cocaine-like discriminative stimulus (DS) effects. A second series of bis(4'-fluorophenyl)amine analogues have now been prepared in which the most potent DAT compound, 19 (K-i = 8.5 nM), was selective over serotonin transporter (SERT/DAT = 94), norepinephrine transporter (NET/DAT = 63), and sigma(1) receptor binding (sigma(1)/DAT = 44). In addition, two other analogues 10 and 17 showed superior selectivity for DAT over SERT (170- and 140-fold, respectively) and DAT over NET (219- and 190-fold, respectively) but were essentially equipotent at DAT and sigma(1) receptors (10; K-i = 77 and 124 nM, respectively, 17; K-i = 28 and 13 nM, respectively). CoMFA studies at both DAT and sigma(1) receptors were performed to examine structural requirements for optimal binding at these two targets as well as to assess differences between them. Behavioral evaluation of analogues with varying affinities for both DAT and sigma(1) receptors may provide a novel approach toward designing medications for cocaine abuse. C1 NIDA, IRP, Med Chem Sect, Baltimore, MD 21224 USA. NIDA, IRP, Psychobiol Sect, Baltimore, MD 21224 USA. NIDDK, Med Chem Lab, NIH, Bethesda, MD 20892 USA. USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. RP Newman, AH (reprint author), NIDA, IRP, Med Chem Sect, Baltimore, MD 21224 USA. EM anewman@intra.nida.nih.gov RI Husbands, Stephen/D-5926-2011 NR 29 TC 22 Z9 24 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUN 19 PY 2003 VL 46 IS 13 BP 2589 EP 2598 DI 10.1021/jm030008u PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 689UN UT WOS:000183511500006 PM 12801223 ER PT J AU Lee, K Zhang, MC Liu, HP Yang, DJ Burke, TR AF Lee, K Zhang, MC Liu, HP Yang, DJ Burke, TR TI Utilization of a beta-aminophosphotyrosyl mimetic in the design and synthesis of macrocyclic Grb2 SH2 domain-binding peptides SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PHOSPHATE-CONTAINING LIGANDS; AMINO-ACIDS; SIGNAL-TRANSDUCTION; INHIBITORS; PROTEIN; AGENTS AB Grb2 SH2 domains are protein-docking modules that exert important functions in both normal and pathogenic signal transduction processes. Development of synthetic Grb2 SH2 domain binding ligands is being pursued by several groups as potential new therapies for a variety of diseases, including certain cancers. In these efforts, macrocyclization has been successfully utilized to take advantage of preferential recognition by Grb2 SH2 domains of ligands in beta-bend conformations. Recent examples of this approach include olefin-metathesis-derived macrocycles that employ ring closure at the beta-position of key pTyr-mimicking residues. In the current study, a novel phosphatase-stable beta-amino-pTyr mimetic designated "Pmp(beta)" was utilized to prepare variants of previously reported olefin-metathesis-derived macrocycles. An initial set of simplified cyclic peptides lacking key naphthyl side chain functionality was first synthesized to determine optimum ring size, with results indicating that a four-unit ning-closing segment was appropriate. On the basis of these findings, macrolactamization was undertaken with a more highly functionalized, naphthyl-containing gamma-amino acid analogue. The resulting cyclic beta-amino peptide is the first of a new class of pTyr-mimetic-containing ligands that may have utility in the development of antagonists of both Grb2 SH2 domains and other pTyr-dependent signaling systems. C1 NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA. RP Burke, TR (reprint author), NCI, Med Chem Lab, Ctr Canc Res, NIH, POB B,Bldg 376,Boyles St, Frederick, MD 21702 USA. EM tburke@helix.nih.gov RI Burke, Terrence/N-2601-2014 NR 39 TC 16 Z9 18 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUN 19 PY 2003 VL 46 IS 13 BP 2621 EP 2630 DI 10.1021/jm030049q PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 689UN UT WOS:000183511500009 PM 12801226 ER PT J AU Choi, Y Kang, JH Lewin, NE Blumberg, PM Lee, J Marquez, VE AF Choi, Y Kang, JH Lewin, NE Blumberg, PM Lee, J Marquez, VE TI Conformationally constrained analogues of diacylglycerol. 19. Synthesis and protein kinase C binding affinity of diacylglycerol lactones bearing an N-hydroxylamide side chain SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article AB The structures of N-hydroxylamides 1a and 1b, previously reported by Lee et al. in J. Med. Chem. 2001, 44, 4309-4312 as strong protein kinase C (PK-C) ligands, were incorrect and correspond instead to esters 2a and 2b, respectively. Here, we report the synthesis and complete characterization of 1a and 1b together with the associated biological activity in terms of PK-C binding affinity. C1 NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Seoul Natl Univ, Coll Pharm, Med Chem Lab, Kwanak Ku, Seoul 151742, South Korea. RP Marquez, VE (reprint author), NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. EM marquezv@dc37a.nci.nih.gov RI Choi, Yongseok/F-8375-2012 OI Choi, Yongseok/0000-0002-3622-3439 NR 4 TC 16 Z9 16 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 JUN 19 PY 2003 VL 46 IS 13 BP 2790 EP 2793 DI 10.1021/jm030082c PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 689UN UT WOS:000183511500024 PM 12801241 ER PT J AU Sakai, T Larsen, M Yamada, KM AF Sakai, T Larsen, M Yamada, KM TI Fibronectin requirement in branching morphogenesis SO NATURE LA English DT Article ID CELL-MATRIX ADHESIONS; SALIVARY-GLAND; SUBMANDIBULAR-GLAND; EPITHELIUM; CADHERIN; SURFACE; LUNG AB Many organs, including salivary glands, lung and kidney, are formed during embryonic development by epithelial branching. In branching morphogenesis, repetitive epithelial cleft and bud formation create the complex three-dimensional branching structures characteristic of many organs(1-3). Although the mechanisms are poorly understood, one might involve the site-specific accumulation of some regulatory protein. Here we show that the extracellular matrix protein fibronectin(4,5) is essential for cleft formation during the initiation of epithelial branching. Fibronectin messenger RNA and fibrils appeared transiently and focally in forming cleft regions of submandibular salivary-gland epithelia, accompanied by an adjacent loss of cadherin localization. Decreasing the fibronectin concentration by using small interfering RNA and inhibition by anti-fibronectin or anti-integrin antibodies blocked cleft formation and branching. Exogenous fibronectin accelerated cleft formation and branching. Similar effects of fibronectin suppression and augmentation were observed in developing lung and kidney. Mechanistic studies revealed that fibrillar fibronectin can induce cell-matrix adhesions on cultured human salivary epithelial cells with a local loss of cadherins at cell-cell junctions. Thus, fibronectin expression is required for cleft formation in branching morphogenesis associated with the conversion of cell-cell adhesions to cell-matrix adhesions. 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, Bethesda, MD 20892 USA. OI Yamada, Kenneth/0000-0003-1512-6805; Larsen, Melinda/0000-0002-5026-2012 NR 30 TC 287 Z9 291 U1 1 U2 25 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 19 PY 2003 VL 423 IS 6942 BP 876 EP 881 DI 10.1038/nature01712 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 691BQ UT WOS:000183585300048 PM 12815434 ER PT J AU Putcha, GV Le, SY Frank, S Besirli, CG Clark, K Chu, BY Alix, S Youle, RJ LaMarche, A Maroney, AC Johnson, EM AF Putcha, GV Le, SY Frank, S Besirli, CG Clark, K Chu, BY Alix, S Youle, RJ LaMarche, A Maroney, AC Johnson, EM TI JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis SO NEURON LA English DT Article ID N-TERMINAL KINASE; CEREBELLAR GRANULE CELLS; BCL-2 FAMILY MEMBERS; CYTOCHROME-C RELEASE; SYMPATHETIC NEURONS; CEP-1347 KT7515; PHOSPHATIDYLINOSITOL 3-KINASE; INDUCE APOPTOSIS; DEATH PATHWAY; RELATIVE BIM AB Trophic factor deprivation (TFD) activates c-Jun N-terminal kinases (JNKs), culminating in coordinate AP1- dependent transactivation of the BH3-only BCL-2 proteins BIMEL and HRK, which in turn are critical for BAX-dependent cytochrome c release, caspase activation, and apoptosis. Here, we report that TFD caused not only induction but also phosphorylation of BIMEL. Mitochondrially localized JNKs but not upstream activators, like mixed-lineage kinases (MLKs) or mitogen-activated protein kinase kinases (MKKs), specifically phosphorylated BIMEL at Ser65, potentiating its proapoptotic activity. Inhibition of the JNK pathway attenuated BIMEL expression, prevented BIMEL phosphorylation, and abrogated TFD-induced apoptosis. Conversely, activation of this pathway promoted BIMEL expression and phosphorylation, causing BIM- and BAX-dependent cell death. Thus, JNKs regulate the proapoptotic activity of BIMEL during TFD, both transcriptionally and posttranslationally. C1 Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Mol Biol & Pharmacol, St Louis, MO 63110 USA. Cephalon Inc, W Chester, PA 19380 USA. NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Upstate USA, Lake Placid, NY 12946 USA. RP Johnson, EM (reprint author), Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. FU NIA NIH HHS [R37AG-12947]; NINDS NIH HHS [R01NS38651] NR 53 TC 366 Z9 374 U1 1 U2 8 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JUN 19 PY 2003 VL 38 IS 6 BP 899 EP 914 DI 10.1016/S0896-6273(03)00355-6 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 693AA UT WOS:000183691400010 PM 12818176 ER PT J AU Fruchter, O AF Fruchter, O TI Aspiration of barium - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID SULFATE ASPIRATION; TRACT C1 NIH, Bethesda, MD 20892 USA. RP Fruchter, O (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 19 PY 2003 VL 348 IS 25 BP 2582 EP 2583 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 690YC UT WOS:000183577200031 ER PT J AU Hollander, MC Poola-Kella, S Fornace, AJ AF Hollander, MC Poola-Kella, S Fornace, AJ TI Gadd34 functional domains involved in growth suppression and apoptosis SO ONCOGENE LA English DT Article DE Gadd34; PEG-3; apoptosis ID DAMAGE-INDUCIBLE GENE; DNA-DAMAGE; PROTEIN GADD34; ARREST; INTERACTS; SEQUENCE; SIGNALS; PEG-3; CELLS AB Gadd34 (also known as MyD116) was originally described as a growth arrest and DNA damage-inducible gene. Increased expression of Gadd34 was subsequently found to correlate with apoptosis, and forced overexpression of the protein leads to apoptosis. Gadd34 protein modulates protein phosphatase type 1 activity through both direct binding to the protein, as well as through binding to other proteins that also modulate phosphatase activity. In addition, Gadd34 has a region of homology with the herpes simplex virus type 1 ICP34.5 protein that is involved in the prevention of apoptosis in infected cells. Recently it was reported that a novel rat Gadd34-related gene, PEG-3, was upregulated in transformed cells, and that forced expression of this gene led to increased tumorigenic potential of cells implanted into nude mice and increased angiogenesis of these tumors. We have found, however, that PEG-3 does not exist in normal rat cells, which have a single diploid complement of Gadd34. Sequence analysis of the rat Gadd34 gene and comparison with PEG-3 indicates that PEG-3 is most likely a mutant of Gadd34 that perhaps arose as a result of transformation. This finding suggests that truncated Gadd34 may interfere with normal Gadd34 function in transfected cells. However, human Gadd34 lacking the viral homology domain does not interfere with normal Gadd34-induced apoptosis in cultured cells. This suggests that viral similarity sequences may be required for Gadd34-mediated functions other than apoptosis. C1 NCI, Basic Res Lab, NIH, Bethesda, MD 20892 USA. RP Hollander, MC (reprint author), NCI, Basic Res Lab, NIH, Bldg 37,Room 6144, Bethesda, MD 20892 USA. RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X NR 20 TC 26 Z9 32 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 19 PY 2003 VL 22 IS 25 BP 3827 EP 3832 DI 10.1038/sj.onc.1206567 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 691NH UT WOS:000183612000001 PM 12813455 ER PT J AU Bierie, B Nozawa, M Renou, JP Shillingford, JM Morgan, F Oka, T Taketo, MM Cardiff, RD Miyoshi, K Wagner, KU Robinson, GW Hennighausen, L AF Bierie, B Nozawa, M Renou, JP Shillingford, JM Morgan, F Oka, T Taketo, MM Cardiff, RD Miyoshi, K Wagner, KU Robinson, GW Hennighausen, L TI Activation of beta-catenin in prostate epithelium induces hyperplasias and squamous transdifferentiation SO ONCOGENE LA English DT Article DE beta-catenin; cell identity; transdifferentiation; neoplasia; prostate ID HAIR FOLLICLE MORPHOGENESIS; MAMMARY-GLAND; TERMINAL DIFFERENTIATION; SIGNALING PATHWAYS; GROWTH-FACTOR; STEM-CELLS; EXPRESSION; MICE; GENE; CANCER AB The Wnt/beta-catenin signaling pathway is critical for normal mammalian development, the specification of epidermal cells and neoplastic transformation of intestinal epithelium. However, precise molecular information regarding cell-specific responses to beta-catenin signaling has been limited. This question was addressed using a mouse model in which exon 3 of the beta-catenin gene was deleted in several cell types with loxP-mediated recombination utilizing a Cre transgene under control of the mouse mammary tumor virus-long terminal repeat (MMTV-LTR). The stabilization of beta-catenin in prostate epithelium resulted in hyperplasias and extensive transdifferentiation into epidermal-like structures, which expressed keratins 1 and 6, filaggrin, loricrin and involucrin. The cell-specific loss of NKCC1 protein and reduced nuclear Stat5a is further suggestive of a loss of prostate epithelial characteristics. In addition to the prostate, hyperplasias and squamous metaplasias were detected in epithelia of the epididymis, vas deferens, coagulating gland, preputial gland and salivary gland. However, and in contrast to a recent study, no lesions reminiscent of high-grade prostate intraepithelial neoplasia were detected. Since beta-catenin was activated in several cell types and impinged upon the viability of these mice, it was not possible to evaluate the cumulative effect over more than 3 months. To assess long-term consequences of beta-catenin activation, mutant and control prostate tissues were transplanted into the mammary fat pads of wild-type males. Notably, squamous metaplasias, intra-acinous hyperplasia and possible neoplastic transformation were observed after a total of 18 weeks of beta-catenin stimulation. This suggests that the transdifferentiation into squamous metaplasias is an early response of endoderm-derived cells to beta-catenin, and that the development of intra-acinous hyperplasias or neoplastic foci is a later event. C1 NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. Inst Natl Rech Agron, Jouy En Josas, France. Kyoto Univ, Grad Sch Med, Dept Pharmacol, Kyoto 6068501, Japan. Univ Calif Davis, Ctr Comparat Med, Davis, CA 95616 USA. Univ Tokushima, Dept Biochem, Sch Dent, Tokushima 7708504, Japan. Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Nebraska Med Ctr, Omaha, NE USA. RP Hennighausen, L (reprint author), NIDDK, Lab Genet & Physiol, NIH, Bldg 8,Room 101, Bethesda, MD 20892 USA. RI Wagner, Kay-Uwe/B-6044-2009; Robinson, Gertraud/I-2136-2012 NR 53 TC 83 Z9 89 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 19 PY 2003 VL 22 IS 25 BP 3875 EP 3887 DI 10.1038/sj.onc.1206426 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 691NH UT WOS:000183612000007 PM 12813461 ER PT J AU Pedersen, TX Leethanakul, C Patel, V Mitola, D Lund, LR Dano, K Johnsen, M Gutkind, JS Bugge, TH AF Pedersen, TX Leethanakul, C Patel, V Mitola, D Lund, LR Dano, K Johnsen, M Gutkind, JS Bugge, TH TI Laser capture microdissection-based in vivo genomic profiling of wound keratinocytes identifies similarities and differences to squamous cell carcinoma SO ONCOGENE LA English DT Review DE cDNA arrays; gene expression; keratinocytes; laser capture microdissection; squamous cell carcinoma; wound healing ID GAP-JUNCTION PROTEINS; HUMAN EPIDERMAL-KERATINOCYTES; INTERFERON-GAMMA RECEPTORS; MOUSE SKIN CARCINOGENESIS; HEAT-SHOCK PROTEINS; NF-KAPPA-B; GROWTH-FACTOR; GENE-EXPRESSION; TRANSCRIPTION FACTOR; MOLECULAR-CLONING AB Keratinocytes undergo a dramatic phenotypic conversion during reepithelialization of skin wounds to become hyperproliferative, migratory, and invasive. This transient healing response phenotypically resembles malignant transformation of keratinocytes during squamous cell carcinoma progression. Here we present the first analysis of global changes in keratinocyte gene expression during skin wound healing in vivo, and compare these changes to changes in gene expression during malignant conversion of keratinized epithelium. Laser capture microdissection was used to isolate RNA from wound keratinocytes from incisional mouse skin wounds and adjacent normal skin keratinocytes. Changes in gene expression were determined by comparative cDNA array analyses, and the approach was validated by in situ hybridization. The analyses identified 48 candidate genes not previously associated with wound reepithelialization. Furthermore, the analyses revealed that the phenotypic resemblance of wound keratinocytes to squamous cell carcinoma is mimicked at the level of gene expression, but notable differences between the two tissue-remodeling processes were also observed. The combination of laser capture microdissection and cDNA array analysis provides a powerful new tool to unravel the complex changes in gene expression that underlie physiological and pathological remodeling of keratinized epithelium. C1 Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. Rigshosp, Finsen Lab, DK-2100 Copenhagen O, Denmark. Natl Inst Dent & Craniofacial Res, Mol Carcinogenesis Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Bugge, TH (reprint author), Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Unit, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Room 211, Bethesda, MD 20892 USA. RI Gutkind, J. Silvio/A-1053-2009; Johnsen, Morten/L-8016-2014; OI Johnsen, Morten/0000-0003-3763-2362; Pedersen, Tanja Xenia/0000-0003-2515-3022 NR 137 TC 55 Z9 55 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 19 PY 2003 VL 22 IS 25 BP 3964 EP 3976 DI 10.1038/sj.onc.1206614 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 691NH UT WOS:000183612000016 PM 12813470 ER PT J AU Kessler, RC Berglund, P Demler, O Jin, R Koretz, D Merikangas, KR Rush, AJ Walters, EE Wang, PS AF Kessler, RC Berglund, P Demler, O Jin, R Koretz, D Merikangas, KR Rush, AJ Walters, EE Wang, PS TI The epidemiology of major depressive disorder - Results from the National Comorbidity Survey Replication (NCS-R). SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID INTERNATIONAL DIAGNOSTIC INTERVIEW; RANDOMIZED CONTROLLED TRIAL; IMPULSE-CONTROL DISORDERS; UNITED-STATES; PRIMARY-CARE; PSYCHIATRIC-DISORDERS; MENTAL-DISORDERS; QUALITY IMPROVEMENT; ANXIETY DISORDERS; BIPOLAR DISORDER AB Context Uncertainties exist about prevalence and correlates of major depressive disorder (MDD). Objective To present nationally representative data on prevalence and correlates of MDD by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, and on study patterns and correlates of treatment and treatment adequacy from the recently completed National Comorbidity Survey Replication (NCS-R). Design Face-to-face household survey,conducted from February 2001 to December 2002. Setting The 48 contiguous United States. Participants Household residents ages 18 years or older (N =9090) who responded to the NCS-R survey. Main Outcome Measures Prevalence and correlates of MDD using the World Health Organization's (WHO) Composite International Diagnostic Interview (CIDI), 12-month severity with the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR), the Sheehan Disability Scale (SDS), and the WHO disability assessment scale (WHO-DAS). Clinical reinterviews used the Structured Clinical Interview for DSM-IV. Results The prevalence of CIDI MDD for lifetime was 16.2% (95% confidence interval [CI], 15.1-17.3) (32.6-35.1 million US adults) and for 12-month was 6.6% (95% CI; 5.9-7.3) (13.1-14.2 million US adults). Virtually all CIDI 12-month cases were independently classified as clinically significant using the QIDS-SR, with 10.4% mild, 38.6% moderate, 38.0% severe, and 12.9% very severe. Mean episode duration was 16 weeks (95% Cl, 15.1-17.3). Role impairment as measured by SIDS was substantial as indicated by 59.3 % of 12-month cases with severe or very severe role impairment. Most lifetime (72.1 %) and 12-month (78.5%) cases had comorbid CIDI/DSM-IV disorders, with MDD only rarely primary. Although 51.6% (95% Cl, 46.1-57.2) of 12-month cases received health care treatment for MDD, treatment was adequate in only 41.9% (95% Cl, 35.9-47.9) of these cases, resulting in 21.7% (95% Cl, 18.1-25.2) of 12-month MDD being adequately treated. Sociodemographic correlates of treatment were far less numerous than those of prevalence. Conclusions Major depressive disorder is a common disorder, widely distributed in the population, and usually associated with substantial symptom severity and role impairment. While the recent increase in treatment is encouraging, inadequate treatment is a serious concern. Emphasis on screening and expansion of treatment needs to be accompanied by a parallel emphasis on treatment quality improvement. C1 Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. Univ Michigan, Inst Social Res, Ann Arbor, MI USA. NIMH, Div Mental Dosorders Behav Res & AIDS, Rockville, MD 20857 USA. NIMH, Intramural Res Program, Rockville, MD 20857 USA. Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Kessler, RC (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. RI Culwell, M. Shaun/F-5156-2010; OI Rush, Augustus/0000-0003-2004-2382 FU NIMH NIH HHS [U01-MH60220] NR 79 TC 3661 Z9 3792 U1 36 U2 412 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 18 PY 2003 VL 289 IS 23 BP 3095 EP 3105 DI 10.1001/jama.289.23.3095 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 690QM UT WOS:000183560400024 PM 12813115 ER PT J AU Berkman, LF Blumenthal, J Burg, M Carney, RM Catellier, D Cowan, MJ Czajkowski, SM DeBusk, R Hosking, J Jaffe, A Kaufmann, PG Mitchell, P Norman, J Powell, LH Raczynski, JM Schneiderman, N AF Berkman, LF Blumenthal, J Burg, M Carney, RM Catellier, D Cowan, MJ Czajkowski, SM DeBusk, R Hosking, J Jaffe, A Kaufmann, PG Mitchell, P Norman, J Powell, LH Raczynski, JM Schneiderman, N CA Writing Comm ENRICHD Investigators TI Effects of treating depression and low-perceived social support on clinical events after myocardial infarction - The enhancing recovery in coronary heart disease patients (ENRICHD) randomized trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID SEROTONIN REUPTAKE INHIBITORS; ARTERY DISEASE; MAJOR DEPRESSION; UNSTABLE ANGINA; MORTALITY RISK; A BEHAVIOR; FOLLOW-UP; PROGNOSIS; SURVIVAL; SYMPTOMS AB Context Depression and low perceived social support (LPSS) after myocardial infarction (MI) are associated with higher morbidity and mortality, but little is known about whether this excess risk can be reduced through treatment. Objective To determine whether mortality and recurrent infarction are reduced by. treatment of depression and LPSS with cognitive behavior therapy (CBT), supplemented with a selective serotonin reuptake inhibitor (SSRI) antidepressant when indicated, in patients enrolled within 28 days after MI. Design, Setting, and Patients Randomized clinical trial conducted from October 1996 to April 2001 in 2481 MI patients (1084 women, 1397 men) enrolled from 8 clinical centers. Major or minor depression was diagnosed by modified Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and severity by the 17-item Hamilton Rating Scale for Depression (HRSD); LPSS was determined by the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Social Support Instrument (ESSI). Random allocation was to usual medical care or CBT-based psychosocial intervention. Intervention Cognitive behavior therapy was initiated at a median of 17 days after the index MI for a median of 11 individual sessions throughout 6 months, plus group therapy when feasible, with SSRIs for patients scoring higher than 24 on the HRSD or having a less than 50% reduction in Beck Depression Inventory scores after 5 weeks. Main Outcome Measures Composite primary end point of death or recurrent MI; secondary outcomes included change in HRSD (for depression),or ESSI scores (for LPSS) at 6 months. Results Improvement in psychosocial outcomes at 6 months favored treatment: mean (SD) change in HRSD score, -10.1 (7.8) in the depression and psychosocial intervention group vs -8.4 (7.7) in the depression and usual care group (P<.001); mean (SD) change in ESSI score, 5.1 (5.9) in the LPSS and psychosocial intervention group vs 3.4 (6.0) in the LPSS and usual care group (P<.001). After an average follow-up of 29 months, there was no significant difference in event-free survival between-usual care (75.9%) and psychosocial intervention (75.8%). There were also no differences in survival between the psychosocial intervention and usual care arms in any of the 3 psychosocial risk groups (depression, LPSS, and depression and LPSS patients). Conclusions The intervention did not increase event-free survival. The intervention improved depression and social isolation, although the relative improvement in the psychosocial intervention group compared with the usual care group was less than expected due to substantial improvement in usual care patients. C1 Univ N Carolina, ENRICHD Coordinating Ctr, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC 27514 USA. Harvard Univ, Boston, MA 02115 USA. Duke Univ, Durham, NC USA. Yale Univ, New Haven, CT USA. Washington Univ, St Louis, MO USA. Univ Calif Los Angeles, Los Angeles, CA USA. NHLBI, Bethesda, MD 20892 USA. Stanford Univ, Palo Alto, CA 94304 USA. Mayo Clin, Rochester, MN USA. Univ Washington, Seattle, WA 98195 USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. Univ Alabama, Birmingham, AL USA. Univ Miami, Coral Gables, FL 33124 USA. RP Czajkowski, SM (reprint author), Univ N Carolina, ENRICHD Coordinating Ctr, Dept Biostat, Collaborat Studies Coordinating Ctr, CB 8030,137 E Franklin St, Chapel Hill, NC 27514 USA. FU NHLBI NIH HHS [N01-HC-55147, N01-HC-55140, N01-HC-55141, N01-HC-55142, N01-HC-55143,, N01-HC-55144, N01-HC-55145, N01-HC-55146, N01-HC-55148] NR 67 TC 941 Z9 958 U1 4 U2 74 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 18 PY 2003 VL 289 IS 23 BP 3106 EP 3116 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 690QM UT WOS:000183560400025 PM 12813116 ER PT J AU Bremner, JD Vythilingam, M Ng, CK Vermetten, E Nazeer, A Oren, DA Berman, RM Charney, DS AF Bremner, JD Vythilingam, M Ng, CK Vermetten, E Nazeer, A Oren, DA Berman, RM Charney, DS TI Regional brain metabolic correlates of alpha-methylparatyrosine-induced depressive symptoms - Implications for the neural circuitry of depression SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID CEREBRAL BLOOD-FLOW; ANTIDEPRESSANT-INDUCED REMISSION; ADRENERGIC-RECEPTOR BINDING; SUBGENUAL PREFRONTAL CORTEX; RECURRENT MAJOR DEPRESSION; TRYPTOPHAN-DEPLETION; LOCUS-COERULEUS; SUICIDE VICTIMS; GERIATRIC DEPRESSION; HIPPOCAMPAL VOLUME AB Context We previously used positron emission tomography (PET) measurement of brain metabolism with (18)fluorodeoxyglucose to show that patients receiving selective serotonin reuptake inhibitors (SSRIs) who have a tryptophan depletion-induced return of depressive symptoms have an acute decrease in metabolism in orbitofrontal cortex, dorsolateral prefrontal cortex, and thalamus. Many patients with depression in remission while taking norepinephrine reuptake inhibitors (NRIs) (but not SSRIs) experience a return of depressive symptoms with depletion of norepinephrine and dopamine using alpha-methylparatyrosine (AMPT). Objective To assess brain metabolic correlates of AMPT administration in patients with depression in remission while receiving NRIs. Design, Setting, and Participants Randomized, controlled, double-blind trial in which 18 patients recruited in 1997-2000 from the general community who had depression in remission while taking NRIs had PET imaging in a psychiatric research unit following AMPT and placebo administration. Interventions After initial medication with desipramine and follow-up until response, patients underwent active AMPT (five 1-g doses administered orally over 28 hours) and placebo (diphenhydramine hydrochloride, five 50- mg doses administered similarly) catecholamine depletion challenges in randomized order of assignment, after which PET imaging was performed on day 3 of each condition. Both study conditions were performed 1 week apart. Main Outcome Measures Regional brain metabolism rates in patients with and without AMPT-induced return of depressive symptoms. Results AMPT-induced return of depressive symptoms was experienced by 11 of the 18 patients and led to decreased brain metabolism in a number of cortical areas, with the greatest magnitude of effects in orbitofrontal (P=.002) and dorsolateral prefrontal (P=.03) cortex and thalamus (P=.006). Increased resting metabolism in prefrontal and limbic areas predicted vulnerability to return of depressive symptoms. Conclusions Different neurochemical systems that mediate depression may have effects on a common brain circuitry. Baseline metabolism in successfully treated depressed patients may predict vulnerability to future episodes of depression. C1 Emory Univ, Sch Med, Dept Psychiat, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Dept Behav Sci, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Dept Radiol, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Emory Ctr Positron Emiss Tomog, Atlanta, GA 30322 USA. Atlanta Vet Affairs Med Ctr, Decatur, GA USA. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Univ Louisville, Dept Radiol, Louisville, KY 40292 USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. RP Bremner, JD (reprint author), Emory Univ Hosp, PET Ctr Nucl Med, 1256 Briarcliff Rd, Atlanta, GA 30306 USA. RI Bremner, James/B-1632-2013; OI Vermetten, Eric/0000-0003-0579-4404 FU NIMH NIH HHS [R01 MH056120, 1R01MH56120, R01 MH056120-12] NR 101 TC 80 Z9 81 U1 6 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 18 PY 2003 VL 289 IS 23 BP 3125 EP 3134 DI 10.1001/jama.289.23.3125 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 690QM UT WOS:000183560400027 PM 12813118 ER PT J AU Insel, TR Charney, DS AF Insel, TR Charney, DS TI Research on major depression - Strategies and priorities SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID DISORDERS; MOOD; PREVENTION; DISCOVERY; SUICIDE; IMPACT C1 NIMH, Mood & Anxiety Disorders Res Program, Bethesda, MD 20892 USA. RP Insel, TR (reprint author), NIMH, Mood & Anxiety Disorders Res Program, 6001 Execut Blvd,Room 8235, Bethesda, MD 20892 USA. NR 20 TC 53 Z9 57 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 18 PY 2003 VL 289 IS 23 BP 3167 EP 3168 DI 10.1001/jama.289.23.3167 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 690QM UT WOS:000183560400032 PM 12813123 ER PT J AU Pawlosky, RJ Flanagan, VP Doherty, RF AF Pawlosky, RJ Flanagan, VP Doherty, RF TI A mass spectrometric validated high-performance liquid chromatography procedure for the determination of folates in foods SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE food analysis; 5-methyltetrahydrofolic acid; folic acid; mass spectrometry; HPLC; isotope dilution ID FOLIC-ACID; COMBINED AFFINITY; MONOGLUTAMATES; DERIVATIVES; VEGETABLES; LIVER; MILK AB A series of five food reference materials (RM) that had certified values of folate concentrations and five frozen food samples were analyzed for 5-methyltetrahydrofolic acid (5-MTHFA) and folic acid (FA) using a high-performance liquid chromatography (HPLC) method with fluorescence detection that was validated using an HPLC mass spectrometry (MS) method with electrospray ionization. Identical sample specimens were extracted and analyzed in triplicate using both instrumental methods, and a comparison was made of the mean values of 5-MTHFA and FA resulting from these determinations. The analytes were isolated on either a high capacity strong anion exchange solid phase extraction column (HPLC method) or a phenyl Bond Elut column (MS method) prior to analyses. For quantification of the analytes by MS, C-13-labeled 5-MTHFA and FA were added to samples as internal standards prior to enzymatic digestion and conversion of the polyglutamate forms of 5-MTHFA to the monoglutamic acid. Quantification of FA and 5-MTHFA using the HPLC analysis was carried out using external standards. With the exception of one RM (pig liver), the values established for 5-MTHFA using these methods were highly comparable. In determining the variance associated with these two procedures, it was observed that the mean relative standard error for 5-MTHFA was 12 (range, 2-27%) and 11% (range, 5-25%) for the HPLC and MS methods, respectively. FA was detected in only three of the samples, and the values obtained for it by either method were similar. This is the first paper that describes a mass spectrometric method used in the validation of an HPLC determination of food folates across a wide range of sample matrixes. The comparable values for 5-MTHFA and FA suggest that HPLC analysis with fluorescent detection may be used to accurately quantify folates present in a variety of food matrixes. C1 USDA ARS, Beltsville Human Nutr Res Ctr, Food Composit Lab, Beltsville, MD 20705 USA. RP Pawlosky, RJ (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, Room 114,12420 Parklawn Dr, Rockville, MD 20851 USA. NR 20 TC 22 Z9 23 U1 3 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD JUN 18 PY 2003 VL 51 IS 13 BP 3726 EP 3730 DI 10.1021/jf034017n PG 5 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA 689UJ UT WOS:000183511100006 PM 12797734 ER PT J AU Karlsson, T Popham, JM Long, JR Oyler, N Drobny, GP AF Karlsson, T Popham, JM Long, JR Oyler, N Drobny, GP TI A study of homonuclear dipolar recoupling pulse sequences in solid-state nuclear magnetic resonance SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ANGLE-SPINNING NMR; INTERNUCLEAR DISTANCE MEASUREMENTS; MOLECULAR TORSIONAL ANGLE; DOUBLE-QUANTUM EXCITATION; ROTATIONAL RESONANCE; MAGIC-ANGLE; EXCHANGE SPECTROSCOPY; CRYSTAL-STRUCTURE; PEPTIDE; ACIDS AB Dipolar recoupling pulse sequences are of great importance in magic angle spinning solid-state NMR. Recoupling sequences are used for excitation of double-quantum coherence, which, in turn, is employed in experiments to estimate internuclear distances and molecular torsion angles. Much effort is spent on the design of recoupling sequences that are able to produce double-quantum coherence with high efficiency in demanding spin systems, i.e., spin systems with small dipole-dipole couplings and large chemical-shift anisotropies (CSAs). The sequence should perform robustly under a variety of experimental conditions. This paper presents experiments and computer calculations that extend the theory of double-quantum coherence preparation from the strong coupling/small CSA limit to the weak coupling limit. The 6 performance of several popular dipole-dipole recoupling sequences-DRAWS, POST-C7, SPC-5, R14(2)(6), and R22(4)(9)-are compared. It is found that the optimum performance for several of these sequences, in the weak coupling/large CSA limit, varies dramatically, with respect to the sample spinning speed, the magnitude and orientation of the CSAs, and the magnitude of dipole-dipole couplings. It is found that the efficiency of double-quantum coherence preparation by gamma-encoded sequences departs from the predictions of first-order theory. The discussion is supported by density-matrix calculations. C1 Univ Washington, Dept Chem, Seattle, WA 98195 USA. Univ Florida, Dept Biochem & Mol Biol, Gainesville, FL 32611 USA. NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Drobny, GP (reprint author), Univ Washington, Dept Chem, Seattle, WA 98195 USA. FU NIGMS NIH HHS [R01-GM5891403] NR 61 TC 44 Z9 45 U1 3 U2 24 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUN 18 PY 2003 VL 125 IS 24 BP 7394 EP 7407 DI 10.1021/ja0294360 PG 14 WC Chemistry, Multidisciplinary SC Chemistry GA 689QB UT WOS:000183503500049 PM 12797814 ER PT J AU Welch, DR Hunter, KW AF Welch, DR Hunter, KW TI A new member of the growing family of metastasis suppressors identified in prostate cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID TUMOR-METASTASIS; ENDOTHELIAL-CELLS; SECONDARY SITE; GROWTH-FACTORS; PROGRESSION; DORMANCY; PROTEIN; GENES; PROLIFERATION; VASCULATURE C1 Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. Univ Alabama, Ctr Comprehens Canc, Birmingham, AL 35294 USA. NCI, Lab Populat Genet, Ctr Canc Res, Bethesda, MD 20892 USA. RP Welch, DR (reprint author), Univ Alabama, Dept Pathol, 1670 Univ Blvd,Volker Hall,G-038, Birmingham, AL 35294 USA. RI Welch, Danny/B-7310-2009 OI Welch, Danny/0000-0002-1951-4947 FU NCI NIH HHS [CA62168, CA88728, CA89109] NR 48 TC 19 Z9 19 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUN 18 PY 2003 VL 95 IS 12 BP 839 EP 841 PG 3 WC Oncology SC Oncology GA 690NY UT WOS:000183556300002 PM 12813161 ER PT J AU Terry, PD Jain, M Miller, AB Howe, GR Rohan, TE AF Terry, PD Jain, M Miller, AB Howe, GR Rohan, TE TI Glycemic load, carbohydrate intake, and risk of colorectal cancer in women: A prospective cohort study SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID COLON-CANCER; INSULIN RESPONSES; DEATH RATES; INDEX; GLUCOSE; OBESITY AB Mounting evidence suggests that high circulating levels of insulin might be associated with increased colorectal cancer risk. The glycemic effects of diets high in refined starch may increase colorectal cancer risk by affecting insulin and/or insulin-like growth factor-I levels. We examined the association between dietary intake and colorectal cancer risk in a cohort of 49 124 women participating in a randomized, controlled trial of screening for breast cancer in Canada. Linkages to Canadian mortality and cancer databases yielded data on mortality and cancer incidence up to December 31, 2000. During an average 16.5 years of follow-up, we observed 616 incident cases of colorectal cancer (436 colon cancers, 180 rectal cancers). gate ratios for colorectal cancer for the highest versus the lowest quintile level were 1.05 (95% confidence interval [CI] = 0.73 to 1.53; P-trend = .94) for glycemic load, 1.01 (95% CI = 0.68 to 1.51; P-trend = .66) for total carbohydrates, and 1.03 (95% CI = 0.73 to 1.44; P-trend = .71) for total sugar. Our data do not support the hypothesis that diets high in glycemic load, carbohydrates, or sugar increase colorectal cancer risk. C1 Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. Ontario Minist Hlth & Long Term Care, Integrated Policy & Planning Div, Toronto, ON, Canada. Univ Toronto, Dept Publ Hlth Sci, Toronto, ON, Canada. Univ Toronto, Dept Publ Hlth Sci, Toronto, ON, Canada. Deutsch Krebsforschungszentrum, Div Clin Epidemiol, D-6900 Heidelberg, Germany. Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. RP Terry, PD (reprint author), NIEHS, Epidemiol Branch, POB 12233,MD A3-05, Res Triangle Pk, NC 27709 USA. NR 17 TC 51 Z9 51 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUN 18 PY 2003 VL 95 IS 12 BP 914 EP 916 PG 3 WC Oncology SC Oncology GA 690NY UT WOS:000183556300014 PM 12813175 ER PT J AU Gardner, P AF Gardner, P TI A need to update and revise the pneumococcal vaccine recommendations for adults SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID DISEASE C1 NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Gardner, P (reprint author), NIH, Fogarty Int Ctr, Bldg 31,Room B2C02, Bethesda, MD 20892 USA. NR 10 TC 9 Z9 9 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUN 17 PY 2003 VL 138 IS 12 BP 999 EP 1000 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 690YM UT WOS:000183578100010 PM 12809459 ER PT J AU Wang, TJ Larson, MG Levy, D Vasan, RS Leip, EP Wolf, PA D'Agostino, RB Murabito, JM Kannel, WB Benjamin, EJ AF Wang, TJ Larson, MG Levy, D Vasan, RS Leip, EP Wolf, PA D'Agostino, RB Murabito, JM Kannel, WB Benjamin, EJ TI Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality - The Framingham Heart Study SO CIRCULATION LA English DT Article DE arrhythmia; fibrillation, atrial; heart failure; mortality ID PROGNOSTIC-SIGNIFICANCE; SINUS RHYTHM; RISK; CARDIOMYOPATHY; DYSFUNCTION; SURVIVAL; TRIAL AB Background-Atrial fibrillation (AF) and congestive heart failure (CHF) frequently occur together, but there is limited information regarding their temporal relations and the combined influence of these conditions on mortality. Methods and Results-We studied participants in the Framingham Study with new-onset AF or CHF. Multivariable Cox proportional hazards models with time-dependent variables were used to evaluate whether mortality after AF or CHF was affected by the occurrence and timing of the other condition. Hazard ratios (HRs) were adjusted for time period and cardiovascular risk factors. During the study period, 1470 participants developed AF, CHF, or both. Among 382 individuals with both conditions, 38% had AF first, 41% had CHF first, and 21% had both diagnosed on the same day. The incidence of CHF among AF subjects was 33 per 1000 person-years, and the incidence of AF among CHF subjects was 54 per 1000 person-years. In AF subjects, the subsequent development of CHF was associated with increased mortality (men: HR 2.7; 95% CI, 1.9 to 3.7; women: HR 3.1; 95% CI, 2.2 to 4.2). Similarly, in CHF subjects, later development of AF was associated with increased mortality (men: HR 1.6; 95% CI, 1.2 to 2.1; women: HR 2.7, 95% CI, 2.0 to 3.6). Preexisting CHF adversely affected survival in individuals with AF, but preexisting AF was not associated with adverse survival in those with CHF. Conclusions-Individuals with AF or CHF who subsequently develop the other condition have a poor prognosis. Additional studies addressing the pathogenesis, prevention, and optimal management of the joint occurrence of AF and CHF appear warranted. C1 Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02118 USA. Boston Univ, Sch Med, Neurol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02118 USA. NHLBI, Bethesda, MD 20892 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. RP Benjamin, EJ (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. OI Larson, Martin/0000-0002-9631-1254; Murabito, Joanne/0000-0002-0192-7516; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [K24 HL-04334-01A1, N01-HC-25195]; NINDS NIH HHS [5RO1-NS-17950] NR 27 TC 729 Z9 766 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 17 PY 2003 VL 107 IS 23 BP 2920 EP 2925 DI 10.1161/01.CIR.0000072767.89944.6E PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 691NQ UT WOS:000183612700010 PM 12771006 ER PT J AU Lin, CM Fu, HQ Martinovsky, M Bouhassira, E Aladjem, MI AF Lin, CM Fu, HQ Martinovsky, M Bouhassira, E Aladjem, MI TI Dynamic alterations of replication timing in mammalian cells SO CURRENT BIOLOGY LA English DT Article ID BETA-GLOBIN LOCUS; ORIGIN RECOGNITION COMPLEX; DNA-REPLICATION; CONTROL REGION; ASYNCHRONOUS REPLICATION; CHROMOSOME CONDENSATION; CHROMATIN STRUCTURE; ACTIVATION REGION; GENE-EXPRESSION; YEAST AB Background: The eukaryotic genome is divided into distinct replication timing domains, which are activated during S phase in a strictly conserved order. Cellular differentiation can alter replication timing in some loci, but recent experiments yielded conflicting data regarding the relationship between gene expression and replication timing. The genetic and epigenetic determinants of replication timing in mammalian cells have yet to be elucidated. Results: We developed a mammalian experimental system in which the timing of DNA replication can be altered in a controlled manner. This system utilizes sequences from the human beta-globin locus that exhibit orientation-dependent transcriptional silencing when inserted into the murine genome. We found that before insertion, the murine target site replicated late during S phase. After insertion, replication timing depended on the orientation of the transgene. In a transcription-permissive orientation, the transgene and flanking sequences replicated early. In the reverse (silencing-prone) orientation, these sequences replicated late. Early replication correlated with histone modifications of the transgene chromatin but could be observed in the absence of the beta-globin promoter. Importantly, the replication timing switch did not require a replication origin within the transgene. Conclusions: Transgene insertions into mammalian heterochromatin can alter the timing of DNA replication at the insertion site. This differentiation-independent replication timing switch did not necessitate insertion of an active promoter or a replication origin. These observations suggest that the timing of DNA replication can be manipulated by changes in DNA sequence, but that the determinants of replication timing are distinct from the sequences that specify replication initiation sites. C1 NCI, Ctr Canc Res, Lab Mol Pharmacol, NIH, Bethesda, MD 20892 USA. Albert Einstein Coll Med, Bronx, NY 10461 USA. RP Aladjem, MI (reprint author), NCI, Ctr Canc Res, Lab Mol Pharmacol, NIH, Bethesda, MD 20892 USA. RI Aladjem, Mirit/G-2169-2010 OI Aladjem, Mirit/0000-0002-1875-3110 NR 48 TC 45 Z9 46 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JUN 17 PY 2003 VL 13 IS 12 BP 1019 EP 1028 DI 10.1016/S0960-9822(03)00382-8 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 691CV UT WOS:000183588000020 PM 12814547 ER PT J AU Stevens, B AF Stevens, B TI Glia: much more than the neuron's side-kick SO CURRENT BIOLOGY LA English DT Editorial Material C1 NICHD, Sect Nervous Syst Dev & Plast, NIH, Bethesda, MD 20892 USA. RP Stevens, B (reprint author), NICHD, Sect Nervous Syst Dev & Plast, NIH, Bldg 49,Room 5A78,MSC 4495,49 Convent Dr, Bethesda, MD 20892 USA. NR 7 TC 1 Z9 1 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JUN 17 PY 2003 VL 13 IS 12 BP R469 EP R472 DI 10.1016/S0960-9822(03)00404-4 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 691CV UT WOS:000183588000008 PM 12814563 ER PT J AU Kafkafi, N Pagis, M Lipkind, D Mayo, CL Bemjamini, Y Golani, I Elmer, GI AF Kafkafi, N Pagis, M Lipkind, D Mayo, CL Bemjamini, Y Golani, I Elmer, GI TI Darting behavior: a quantitative movement pattern designed for discrimination and replicability in mouse locomotor behavior SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE inbred strains; exploratory behavior; open-field behavior; locomotor behavior; cocaine; amphetamine; C57BL/6; DBA/2; SEE ID RATS RATTUS-NORVEGICUS; FALSE DISCOVERY RATE; EXPLORATORY-BEHAVIOR/; HIPPOCAMPAL-FORMATION; DOPAMINE TRANSPORTER; DEFENSIVE BEHAVIORS; LOW RESPONDERS; AMPHETAMINE; COCAINE; STRAINS AB In the open-field behavior of rodents, Software for Exploring Exploration (SEE) can be used for an explicit design of behavioral endpoints with high genotype discrimination and replicability across laboratories. This ability is demonstrated here in the development of a measure for darting behavior. The behavior of two common mouse inbred strains, C57BL/6J (B6) and DBA/2J (D2), was analyzed across three different laboratories, and under the effect of cocaine or amphetamine. "Darting" was defined as having higher acceleration during progression segments while moving less during stops. D2 mice darted significantly more than B6 mice in each laboratory, despite being significantly less active. These differences were maintained following cocaine administration (up to 20 mg/kg) and only slightly altered by amphetamine (up to 5 mg/kg) despite a several fold increase in activity. The replicability of darting behavior was confirmed in additional experiments distinct from those used for its design. The strategy leading to the darting measure may be used to develop additional discriminative and replicable endpoints of open-field behavior. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Johns Hopkins Bayview Med Ctr, Natl Inst Drug Abuse, NIH, Baltimore, MD 21224 USA. Univ Maryland, Sch Med, Psychiat Res Ctr, Dept Psychiat, Baltimore, MD 21224 USA. Tel Aviv Univ, Dept Zool, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Dept Stat, IL-69978 Tel Aviv, Israel. RP Kafkafi, N (reprint author), Johns Hopkins Bayview Med Ctr, Natl Inst Drug Abuse, NIH, 5500 Nathan Shock Dr,Bldg C, Baltimore, MD 21224 USA. EM nkafkafi@intra.nida.nih.gov FU NINDS NIH HHS [1 R01 NS40234-01] NR 43 TC 34 Z9 34 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD JUN 16 PY 2003 VL 142 IS 1-2 BP 193 EP 205 DI 10.1016/S0166-4328(03)00003-2 PG 13 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 692UX UT WOS:000183679600021 PM 12798281 ER PT J AU de Mora, JF Esteban, LM Burks, DJ Nunez, A Garces, C Garcia-Barrado, MJ Iglesias-Osma, MC Moratinos, J Ward, JM Santos, E AF de Mora, JF Esteban, LM Burks, DJ Nunez, A Garces, C Garcia-Barrado, MJ Iglesias-Osma, MC Moratinos, J Ward, JM Santos, E TI Ras-GRF1 signaling is required for normal beta-cell development and glucose homeostasis SO EMBO JOURNAL LA English DT Article DE cell growth; beta-cells; differentiation; insulin; Ras-GRF1 ID EXCHANGE FACTOR; INSULIN-SECRETION; RAS ACTIVATOR; MOUSE GROWTH; H-RAS; EXPRESSION; MICE; DISRUPTION; PROTEIN; CALCIUM AB Development of diabetes generally reflects an inadequate mass of insulin-producing beta-cells. beta-cell proliferation and differentiation are regulated by a variety of growth factors and hormones, including insulin-like growth factor I (IGF-I). GRF1 is a Ras-guanine nucleotide exchange factor known previously for its restricted expression in brain and its role in learning and memory. Here we demonstrate that GRF1 is also expressed in pancreatic islets. Interestingly, our GRF1-deficient mice exhibit reduced body weight, hypoinsulinemia and glucose intolerance owing to a reduction of beta-cells. Whereas insulin resistance is not detected in peripheral tissues, GRF1 knockout mice are leaner due to increased lipid catabolism. The reduction in circulating insulin does not reflect defective glucose sensing or insulin production but results from impaired beta-cell proliferation and reduced neogenesis. IGF-I treatment of isolated islets from GRF1 knockouts fails to activate critical downstream signals such as Akt and Erk. The observed phenotype is similar to manifestations of preclinical type 2 diabetes. Thus, our observations demonstrate a novel and specific role for Ras-GRF1 pathways in the development and maintenance of normal beta-cell number and function. C1 Univ Salamanca, Ctr Invest Canc, IBMCC, CSIC, E-37008 Salamanca, Spain. Univ Salamanca, Inst Neurociencias Castilla & Leon, E-37008 Salamanca, Spain. Univ Salamanca, Dept Fisiol & Farmacol, E-37008 Salamanca, Spain. Univ Autonoma Madrid, Unidad Lipidos, Fdn Jimenez Diaz, E-28049 Madrid, Spain. NCI, Frederick, MD 21702 USA. RP Santos, E (reprint author), Univ Salamanca, Ctr Invest Canc, IBMCC, CSIC, E-37008 Salamanca, Spain. RI Iglesias-Osma, Maria Carmen/B-1641-2013; Garcia Barrado, Maria Jose/L-4852-2014 OI Iglesias-Osma, Maria Carmen/0000-0002-2206-9119; Garcia Barrado, Maria Jose/0000-0003-2552-5973 NR 42 TC 45 Z9 47 U1 1 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD JUN 16 PY 2003 VL 22 IS 12 BP 3039 EP 3049 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 693NV UT WOS:000183724400016 ER PT J AU Rayasam, GV Wendling, O Angrand, PO Mark, M Niederreither, K Song, L Lerouge, T Hager, GL Chambon, P Losson, R AF Rayasam, GV Wendling, O Angrand, PO Mark, M Niederreither, K Song, L Lerouge, T Hager, GL Chambon, P Losson, R TI NSD1 is essential for early post-implantation development and has a catalytically active SET domain SO EMBO JOURNAL LA English DT Article DE gastrulation; gene disruption; HMTase; nuclear receptor cofactor; SET domain ID HISTONE METHYLATION; FUNCTIONAL-CHARACTERIZATION; TRANSCRIPTIONAL REGULATION; NUCLEAR RECEPTORS; CONTAINING GENE; METHYLTRANSFERASE; EXPRESSION; PROTEIN; H3; CHROMATIN AB The nuclear receptor-binding SET domain-containing protein (NSD1) belongs to an emerging family of proteins, which have all been implicated in human malignancy. To gain insight into the biological functions of NSD1, we have generated NSD1-deficient mice by gene disruption. Homozygous mutant NSD1 embryos, which initiate mesoderm formation, display a high incidence of apoptosis and fail to complete gastrulation, indicating that NSD1 is a developmental regulatory protein that exerts function(s) essential for early post-implantation development. We have also examined the enzymatic potential of NSD1 and found that its SET domain possesses intrinsic histone methyltransferase activity with specificity for Lys36 of histone H3 (M-K36) and Lys20 of histone H4 (H4K20). C1 NIH, Lab Receptor Biol & Gene Express, Bethesda, MD 20892 USA. Baylor Coll Med, Dept Med, Ctr Cardiovasc Dev, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol & Cellular Biol, Ctr Cardiovasc Dev, Houston, TX 77030 USA. Coll France, ULP, INSERM, CNRS,Inst Genet & Biol Mol & Cellulaire, F-67404 Illkirch Graffenstaden, France. Cellzome AG, D-69117 Heidelberg, Germany. RP Chambon, P (reprint author), NIH, Lab Receptor Biol & Gene Express, Bldg 10, Bethesda, MD 20892 USA. NR 40 TC 184 Z9 193 U1 1 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD JUN 16 PY 2003 VL 22 IS 12 BP 3153 EP 3163 DI 10.1093/emboj/cdg288 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 693NV UT WOS:000183724400027 PM 12805229 ER PT J AU Bosselut, R Guinter, TI Sharrow, SO Singer, A AF Bosselut, R Guinter, TI Sharrow, SO Singer, A TI Unraveling a revealing paradox: Why major histocompatibility complex I-signaled thymocytes "Paradoxically" appear as CD4(+)8(lo) transitional cells during positive selection of CD8(+) T cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE lineage commitment; kinetic signaling; coreceptor reversal; positive selection ID TRANSGENIC MICE; LINEAGE COMMITMENT; GENE-EXPRESSION; THYMIC SELECTION; ANTIGEN RECEPTOR; CD4 GENE; DIFFERENTIATION; CORECEPTOR; MODEL; LYMPHOCYTES AB The mechanism by which T cell receptor specificity deternimes the outcome of the CD4/CD8 lineage decision in the thymus is not known. An important clue is the fact that major histocompatibility complex (NMHC)-I-signaled thymocytes paradoxically appear as CD4(+)8(10) transitional cells during their differentiation into CD8(+) T cells. Lineage commitment is generally thought to occur at the CD4(+)8(+) (double positive) stage of differentiation and to result in silencing of the opposite coreceptor gene. From this perspective, the appearance of MHC-I-signaled thymocytes as CD4(+)8(10) cells would be due to effects on CD8 surface protein expression, not CD8 gene expression. But contrary to this perspective, this study demonstrates that MHC-I-signaled thymocytes appear as CD4(+)8(10) cells because of transient down-regulation of CD8 gene expression, not because of changes in CD8 surface protein expression or distribution. This study also demonstrates that initial cessation of CD8 gene expression in MHC-I-signaled thymocytes is not necessarily indicative of commitment to the CD4(+) T cell lineage, as such thymocytes retain the potential to differentiate into CD8(+)T cells. These results challenge classical concepts of lineage commitment but fulfill predictions of the kinetic signaling model. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Lab Immune Cell Biol, Bethesda, MD 20892 USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Room 4B36, Bethesda, MD 20892 USA. NR 49 TC 41 Z9 41 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUN 16 PY 2003 VL 197 IS 12 BP 1709 EP 1719 DI 10.1084/jem.20030170 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 691RJ UT WOS:000183619000011 PM 12810689 ER PT J AU Reina-San-Martin, B Difilippantonio, S Hanitsch, L Masilamani, RF Nussenzweig, A Nussenzweig, MC AF Reina-San-Martin, B Difilippantonio, S Hanitsch, L Masilamani, RF Nussenzweig, A Nussenzweig, MC TI H2AX is required for recombination between immunoglobulin switch regions but not for intra-switch region recombination or somatic hypermutation SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE class switch recombination; somatic hypermutation; activation-induced cytidine dealminase; H2AX; non-homologous end joining ID DOUBLE-STRAND BREAKS; DNA-POLYMERASE-ETA; MISMATCH REPAIR PROTEIN; CYTIDINE DEAMINASE AID; HEAVY-CHAIN SWITCH; HISTONE H2AX; B-CELLS; MICE DEFICIENT; CIRCULAR DNA; IN-VIVO AB Changes in chromatin structure induced by posttranslational modifications of histones are important regulators of genomic function. Phosphorylation of histone H2AX promotes DNA repair and helps maintain genomic stability. Although B cells lacking H2AX show impaired class switch recombination (CSR), the precise role of H2AX in CSR and somatic hypermutation (SHM) has not been defined. We show that H2AX is not required for SHM, suggesting that the processing of DNA lesions leading to SHM is fundamentally different from CSR. Impaired CSR in H2AX(-/-) B cells is not due to alterations in switch region transcription, accessibility, or aberrant joining. In the absence of H2AX, short-range intra-switch region recombination proceeds normally while long-range inter-switch region recombination is impaired. Our results suggest a role for H2AX in regulating the higher order chromatin remodeling that facilitates switch region synapsis. C1 Rockefeller Univ, Dept Mol Immunol HHMI, Lab Mol Immunol, New York, NY 10021 USA. Rockefeller Univ, Howard Hughes Med Inst, New York, NY USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Nussenzweig, MC (reprint author), Rockefeller Univ, Dept Mol Immunol HHMI, Lab Mol Immunol, RRB Rm 470,Box 220,1230 York Ave, New York, NY 10021 USA. RI Reina-San-Martin, Bernardo/I-9484-2016 OI Reina-San-Martin, Bernardo/0000-0003-2083-6166 NR 89 TC 190 Z9 191 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUN 16 PY 2003 VL 197 IS 12 BP 1767 EP 1778 DI 10.1084/jem.20030569 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 691RJ UT WOS:000183619000016 PM 12810694 ER PT J AU Pinn, VW AF Pinn, VW TI Expanding the frontiers of women's health research - US style SO MEDICAL JOURNAL OF AUSTRALIA LA English DT Editorial Material ID ESTROGEN PLUS PROGESTIN C1 US Dept HHS, Off Res Womens Hlth, NIH, Bethesda, MD 20892 USA. RP Pinn, VW (reprint author), US Dept HHS, Off Res Womens Hlth, NIH, Bldg 1,Room 201, Bethesda, MD 20892 USA. NR 21 TC 5 Z9 5 U1 0 U2 0 PU AUSTRALASIAN MED PUBL CO LTD PI SYDNEY PA LEVEL 1, 76 BERRY ST, SYDNEY, NSW 2060, AUSTRALIA SN 0025-729X J9 MED J AUSTRALIA JI Med. J. Aust. PD JUN 16 PY 2003 VL 178 IS 12 BP 598 EP 599 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 694UY UT WOS:000183794200001 PM 12797843 ER PT J AU Tadic, D Linders, JTM Flippen-Anderson, JL Jacobson, AE Rice, KC AF Tadic, D Linders, JTM Flippen-Anderson, JL Jacobson, AE Rice, KC TI Probes for narcotic receptor mediated phenomena. Part 31: Synthesis of rac-(3R,6aS,11aS)-2-methyl-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzof uro[2,3-c]azocine-10-ol, and azocine-8-ol, the ortho-c and the para-c oxide-bridged phenylmorphan isomers SO TETRAHEDRON LA English DT Article DE oxide-bridged phenylmorphans; opioid receptor ligand; methanobenzofuro[2.3-c]azocines synthesis; X-ray diffraction studies ID PHENOLIC HYDROXYL-GROUPS; MORPHINE; 5-(META-HYDROXYPHENYL)MORPHAN AB Two of the 12 possible oxide-bridged phenylmorphans, were synthesized, rac-(3R,6aS,11aS)-2-methyl-1,3,4,5,6,11a-hexahydro2H-3,6a-methanobenzofuro[2,3-c]azocine-10-ol (7) (the ortho-c compound), and rac-(3R,6aS, 11aS)-2-methyl-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocine-8-ol (8) (the para-c compound). Single-crystal X-ray diffraction studies indicated that the dihedral angle between the least squares planes through the phenyl ring and the atoms C-1, C-11a, C-12, and C-3 in the piperidine ring in both 7(.)CHCl(3) and 8(.)HBr was 6.9degrees. The C-12-C-6a-C-6b-C-10a torsion angle was found to be 139.3degrees for both compounds. The angular relationship between the phenolic ring and the piperidine ring in phenylmorphans that interact with specific opioid receptors as agonists or antagonists is of considerable theoretical interest. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 NIDDKD, Dept Hlth & Human Serv, Lab Med Chem, NIH, Bethesda, MD 20892 USA. USN, Res Lab, Lab Struct Matter, Washington, DC 20375 USA. RP Rice, KC (reprint author), NIDDKD, Dept Hlth & Human Serv, Lab Med Chem, NIH, Bethesda, MD 20892 USA. EM kr21f@nih.gov NR 16 TC 14 Z9 14 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4020 J9 TETRAHEDRON JI Tetrahedron PD JUN 16 PY 2003 VL 59 IS 25 BP 4603 EP 4614 DI 10.1016/S0040-4020(03)00659-8 PG 12 WC Chemistry, Organic SC Chemistry GA 691LX UT WOS:000183608700014 ER PT J AU Jugessur, A Wilcox, AJ Lie, RT Murray, JC Taylor, JA Ulvik, A Drevon, CA Vindenes, HA Abyholm, FE AF Jugessur, A Wilcox, AJ Lie, RT Murray, JC Taylor, JA Ulvik, A Drevon, CA Vindenes, HA Abyholm, FE TI Exploring the effects of methylenetetrahydrofolate reductase gene variants C677T and A1298C on the risk of orofacial clefts in 261 Norwegian case-parent triads SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE abnormalities; cleft lip; cleft palate; folic acid; genes; genetic predisposition to disease; haplotypes; vitamins ID NEURAL-TUBE DEFECTS; FOLIC-ACID SUPPLEMENTATION; MATERNAL VITAMIN USE; BIRTH-DEFECTS; ORAL CLEFTS; 5,10-METHYLENETETRAHYDROFOLATE REDUCTASE; PERICONCEPTIONAL SUPPLEMENTATION; MULTIVITAMIN SUPPLEMENTATION; COMMON MUTATION; OFFSPRING GENES AB Folic acid and the methylenetetrahydrofolate reductase (MTHFR) gene have both been implicated in the etiology of orofacial clefts. The authors selected 261 case-parent triads (173 cases with cleft lip with or without cleft palate (CL/P) and 88 cases with cleft palate only (CPO)) from a Norwegian population-based study of orofacial clefts (May 1996-1998). A case-parent triad design was used to examine whether MTHFR variants C677T and A1298C, and their haplotypes, are risk factors for orofacial clefts. Among CL/P cases, the child's genotype at C677T or A1298C did not influence the risk. However, children of mothers carrying the C677T variant allele had a lower risk of CL/P. For CPO, children carrying the C677T variant allele had about a twofold increased risk, whereas the mother's genotypes did not contribute to the risk. The haplotype-based transmission/disequilibrium test showed that except for 677T/1298A (p = 0.06), none of the other haplotypes showed evidence of excess transmission to the offspring. The authors also explored interaction of C677T with maternal use of folic acid among children with CPO. Surprisingly, the risk associated with the child's carrying either CT or TT was higher (fourfold) when the mother used folic acid. These findings suggest a possible role of MTHFR and folic acid in the causation of orofacial clefts, but the strength and direction of these effects remain to be clarified. C1 Haukeland Univ Hosp, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway. Univ Bergen, Sect Med Stat, Bergen, Norway. Univ Bergen, Med Birth Registry Norway, Bergen, Norway. NIEHS, Epidemiol Branch, Durham, NC USA. Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. Univ Bergen, Bergen, Norway. Univ Oslo, Inst Nutr Res, Oslo, Norway. Haukeland Univ Hosp, Dept Plast Surg, N-5021 Bergen, Norway. Univ Oslo, Rikshosp, Dept Plast Surg, N-0027 Oslo, Norway. RP Jugessur, A (reprint author), Haukeland Univ Hosp, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway. RI Drevon, Christian /F-6012-2010; OI Wilcox, Allen/0000-0002-3376-1311; taylor, jack/0000-0001-5303-6398 FU NIDCR NIH HHS [DE08559] NR 53 TC 52 Z9 62 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2003 VL 157 IS 12 BP 1083 EP 1091 DI 10.1093/aje/kwg097 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 690BY UT WOS:000183528500005 PM 12796044 ER PT J AU Saydah, SH Loria, CM Eberhardt, MS Brancati, FL AF Saydah, SH Loria, CM Eberhardt, MS Brancati, FL TI Abnormal glucose tolerance and the risk of cancer death in the United States SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE diabetes mellitus; glucose tolerance test; mortality; neoplasms; nutrition surveys ID FACTOR-BINDING PROTEIN-1; GROWTH-FACTOR-I; COLORECTAL-CANCER; DIABETES-MELLITUS; INSULIN-RESISTANCE; PROSTATE-CANCER; PLASMA-GLUCOSE; BREAST-CANCER; FOLLOW-UP; HELSINKI POLICEMEN AB Although abnormal glucose tolerance is a well-established risk factor for cardiovascular disease, its relation to cancer risk is less certain. Therefore, the authors performed a prospective cohort study using data from the Second National Health and Nutrition Examination Survey and the Second National Health and Nutrition Examination Survey Mortality Study to determine this relation. This analysis focused upon a nationally representative sample of 3,054 adults aged 30-74 years who underwent an oral glucose tolerance test at baseline (1976-1980). Deaths were identified by searching national mortality files through 1992. Adults were classified as having either previously diagnosed diabetes (n = 247), undiagnosed diabetes (n = 180), impaired glucose tolerance (n = 477), or normal glucose tolerance (n = 2250). There were 195 cancer deaths during 40,024 person-years of follow-up. Compared with those having normal glucose tolerance, adults with impaired glucose tolerance had the greatest adjusted relative hazard of cancer mortality (relative hazard = 1.87, 95% confidence interval (CI): 1.06, 3.31), followed by those with undiagnosed diabetes (relative hazard = 1.31, 95% CI: 0.48, 3.56) and diabetes (relative hazard = 1.13, 95% CI: 0.49, 2.62). These data suggest that, in the United States, impaired glucose tolerance is an independent predictor for cancer mortality. C1 Social & Sci Syst Inc, Silver Spring, MD 20910 USA. Johns Hopkins Bloomberg Sch Publ lth, Dept Epidemiol, Baltimore, MD USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Off Anal Epidemiol & Hlth Promot, Natl Ctr Hlth Stat, Hyattsville, MD USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. RP Saydah, SH (reprint author), Social & Sci Syst Inc, 8757 Georgia Ave,12th Floor, Silver Spring, MD 20910 USA. FU NHLBI NIH HHS [T32 HL07024-26] NR 59 TC 109 Z9 117 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2003 VL 157 IS 12 BP 1092 EP 1100 DI 10.1093/aje/kwg100 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 690BY UT WOS:000183528500006 PM 12796045 ER PT J AU Saftlas, AF Levine, RJ Klebanoff, MA Martz, KL Ewell, MG Morris, CD Sibai, BM AF Saftlas, AF Levine, RJ Klebanoff, MA Martz, KL Ewell, MG Morris, CD Sibai, BM TI Abortion, changed paternity, and risk of preeclampsia in nulliparous women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE abortion, induced; abortion, spontaneous; paternity; pre-eclampsia; pregnancy ID PREGNANCY-INDUCED HYPERTENSION; PRE-ECLAMPSIA; LAST PREGNANCY; PARTNER; CALCIUM; FETAL; DONOR; SPERM; TRIAL AB A prior birth confers a strong protective effect against preeclampsia, whereas a prior abortion confers a weaker protective effect. Parous women who change partners in a subsequent pregnancy appear to lose the protective effect of a prior birth. This study (Calcium for Preeclampsia Prevention Trial, 1992-1995) examines whether nulliparous women with a prior abortion who change partners also lose the protective effect of the prior pregnancy. A cohort analysis was conducted among participants in this large clinical trial of calcium supplementation to prevent preeclampsia. Subjects were nulliparous, had one prior pregnancy or less, delivered after 20 weeks' gestation, and were interviewed at 5-21 weeks about prior pregnancies and paternity. Women without a history of abortion served as the reference group in logistic regression analyses. Women with a history of abortion who conceived again with the same partner had nearly half the risk of preeclampsia (adjusted odds ratio = 0.54, 95 percent confidence interval: 0.31, 0.97). In contrast, women with an abortion history who conceived with a new partner had the same risk of preeclampsia as women without a history of abortion (adjusted odds ratio = 1.03, 95 percent confidence interval: 0.72, 1.47). Thus, the protective effect of a prior abortion operated only among women who conceived again with the same partner. An immune-based etiologic mechanism is proposed, whereby prolonged exposure to fetal antigens from a previous pregnancy protects against preeclampsia in a subsequent pregnancy with the same father. C1 Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. Emmes Corp, Potomac, MD USA. Oregon Hlth Sci Univ, Div Med Informat & Outcomes Res, Portland, OR 97201 USA. Univ Cincinnati, Coll Med, Dept Obstet & Gynecol, Cincinnati, OH 45267 USA. RP Saftlas, AF (reprint author), Univ Iowa, Coll Publ Hlth, Gen Hosp, Dept Epidemiol, Room C-21F, Iowa City, IA 52242 USA. FU NICHD NIH HHS [N01-HD-1-3123, N01-HD-1-3121, N01-HD-1-3122, N01-HD-1-3124, N01-HD-1-3125, N01-HD-1-3126, N01-HD-2-3154, N01-HD-5-3246, R29-HD-325790] NR 31 TC 67 Z9 70 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2003 VL 157 IS 12 BP 1108 EP 1114 DI 10.1093/aje/kwg101 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 690BY UT WOS:000183528500008 PM 12796047 ER PT J AU Michaud, DS Giovannucci, E Willett, WC Colditz, GA Fuchs, CS AF Michaud, DS Giovannucci, E Willett, WC Colditz, GA Fuchs, CS TI Dietary meat, dairy products, fat, and cholesterol and pancreatic cancer risk in a prospective study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cholesterol; dairy products; fats; meat; pancreatic neoplasms ID PAST MEDICAL HISTORY; NUTRITIONAL FACTORS; DIABETES-MELLITUS; PROSTATE-CANCER; NUTRIENT INTAKE; COLON-CANCER; CARCINOGENESIS; ALCOHOL; QUESTIONNAIRE; CONSUMPTION AB Case-control studies suggest that meat and cholesterol intakes may be related to elevated risks of pancreatic cancer. Few prospective studies have examined associations between diet and pancreatic cancer, although in one recent study saturated fat consumption was related to higher risk. In a cohort of US women, the authors confirmed 178 pancreatic cancer cases over 18 years of follow-up. A mailed 61-item food frequency questionnaire was self-administered at baseline, and health and lifestyle variables were updated biennially. Analyses were performed using Cox proportional hazards models to adjust for potential confounders. Intakes of total fat, different types of fats, and cholesterol were not associated with pancreatic cancer risk. Similarly, total meat, red meat, and dairy products were not related to risk. Individual food items contributing to intakes of total meat and dairy products, as well as fish and eggs, did not reveal any specific association. Updating dietary exposures by using questionnaires from 1980, 1984, 1986, and 1990 produced similar findings. The authors' data do not support previous findings that meat or saturated fat intakes are related to pancreatic cancer risk. Future prospective studies should examine the influence of cooking practices as well as other dietary habits on the risk of pancreatic cancer. C1 NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA USA. RP Michaud, DS (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS-320 MSC 7232, Rockville, MD 20892 USA. RI Michaud, Dominique/I-5231-2014; Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU NCI NIH HHS [CA87969, CA 86102] NR 53 TC 91 Z9 93 U1 1 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2003 VL 157 IS 12 BP 1115 EP 1125 DI 10.1093/aje/kwg098 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 690BY UT WOS:000183528500009 PM 12796048 ER PT J AU Datta, K Neumann, RD Winters, TA AF Datta, K Neumann, RD Winters, TA TI A protocol for separation and isolation of small and/or large DNA fragments with high yield using CL4B Sepharose SO ANALYTICAL BIOCHEMISTRY LA English DT Editorial Material ID PURIFICATION; BROMIDE C1 NIH, Warren Grant Magnuson Clin Ctr, Dept Nucl Med, Bethesda, MD 20892 USA. RP Winters, TA (reprint author), NIH, Warren Grant Magnuson Clin Ctr, Dept Nucl Med, 10 Ctr Dr, Bethesda, MD 20892 USA. NR 4 TC 5 Z9 5 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD JUN 15 PY 2003 VL 317 IS 2 BP 284 EP 287 DI 10.1016/S0003-2697(03)00168-4 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 685ZF UT WOS:000183294400023 PM 12758272 ER PT J AU Lukashev, DE Smith, PT Caldwell, CC Ohta, A Apasov, SG Sitkovsky, MV AF Lukashev, DE Smith, PT Caldwell, CC Ohta, A Apasov, SG Sitkovsky, MV TI Analysis of A2a receptor-deficient mice reveals no significant compensatory increases in the expression of A2b, A1, and A3 adenosine receptors in lymphoid organs SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE adenosine; adenosine receptors; inflammation; cyclic AMP ID INFLAMED SITES; IMMUNE-SYSTEM; INFLAMMATION; PROTECTION; GENE; TRANSCRIPTION; ARTHRITIS; ISCHEMIA; PROTEINS; RELEASE AB Although recent genetic and pharmacologic in vivo studies of acute inflammation models in mice demonstrated that the cyclic AMP-elevating A2a receptor plays a non-redundant role in protection from excessive acute inflammatory tissue damage and in the down-regulation of proinflammatory cytokine production, it remained to be established whether genetic deficiency of the A2a receptor is accompanied by a compensatory up-regulation of the cAMP-elevating A2b receptor and/or other adenosine receptors. Here, we show that most of the cAMP response to adenosine is abolished in lymphoid tissues of A2a receptor-deficient mice, although some response remains in splenocytes. No significant changes were observed in A2b, A1, and A3 mRNA levels in the thymus or lymph nodes of A2a receptor-deficient mice, but small increases in mRNA expression of these receptors were detected in the spleen. These data suggest that regulation of the expression of A2b, A1, and A3 receptors is not affected significantly by the absence of A2a receptors and may provide further explanation of earlier in vivo observations of increased tissue damage and of longer persistence of proinflammatory cytokines in animals with inactivated A2a receptors. (C) 2003 Elsevier Science Inc. All rights reserved. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Sitkovsky, MV (reprint author), NIAID, Immunol Lab, NIH, 10 Ctr Ctr,Room 11N-256, Bethesda, MD 20892 USA. RI Lukashev, Dmitriy/F-8133-2010; OI Caldwell, Charles/0000-0003-1692-4550 NR 25 TC 44 Z9 44 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 JUN 15 PY 2003 VL 65 IS 12 BP 2081 EP 2090 DI 10.1016/S0006-2952(03)00158-8 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 691DE UT WOS:000183588900019 PM 12787889 ER PT J AU Little, RF Pittaluga, S Grant, N Steinberg, SM Kavlick, MF Mitsuya, H Franchini, G Gutierrez, M Raffeld, M Jaffe, ES Shearer, G Yarchoan, R Wilson, WH AF Little, RF Pittaluga, S Grant, N Steinberg, SM Kavlick, MF Mitsuya, H Franchini, G Gutierrez, M Raffeld, M Jaffe, ES Shearer, G Yarchoan, R Wilson, WH TI Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology SO BLOOD LA English DT Article ID NON-HODGKINS-LYMPHOMA; B-CELL LYMPHOMA; AIDS-RELATED LYMPHOMAS; PROGNOSTIC-SIGNIFICANCE; INTENSIVE CHEMOTHERAPY; HISTOGENETIC SUBSETS; VIRUS-INFECTION; EXPRESSION; PROTEIN; P53 AB The outcome of acquired immunodeficiency syndrome-related lymphomas (ARLs) has improved since the era of highly active antiretroviral therapy, but median survival remains low. We studied dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) with suspension of antiretroviral therapy in 39 newly diagnosed ARLs and examined protein expression profiles associated with drug resistance and histogenesis, patient immunity, and HIV dynamics and mutations. The expression profiles from a subset of ARL cases were also compared with a matched group of similarly treated HIV-negative cases. Complete remission was achieved in 74% of patients, and at 53 months median follow-up, disease-free and overall survival are 92% and 60%, respectively. Following reinstitution of antiretroviral therapy after chemotherapy, the CD4(+) cells recovered by 12 months and the viral loads decreased below baseline by 3 months. Compared with HIV-negative cases, the ARL cases had lower bcl-2 and higher CD10 expression, consistent with a germinal center origin and good prognosis, but were more likely to be highly proliferative and to express p53, adverse features with standard chemotherapy. Unlike HIV-negative cases, p53 overexpression was not associated with a poor outcome, suggesting different pathogenesis. High tumor proliferation did not correlate with poor outcome and may partially explain the high activity of dose-adjusted EPOCH. The results suggest that the improved immune function associated with highly active antiretroviral therapy (HAART) may have led to a shift in pathogenesis away from lymphomas of postgerminal center origin, which have a poor prognosis. These results suggest that tumor pathogenesis is responsible for the improved outcome of ARLs in the era of HAART. (C) 2003 by The American Society of Hematology. C1 NCI, CCR, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Wilson, WH (reprint author), NCI, CCR, Expt Transplantat & Immunol Branch, NIH, Bldg 10,Rm 12-N-226, Bethesda, MD 20892 USA. EM wilsonw@mail.nih.gov NR 43 TC 198 Z9 205 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 15 PY 2003 VL 101 IS 12 BP 4653 EP 4659 DI 10.1182/blood-2002-11-3589 PG 7 WC Hematology SC Hematology GA 689FV UT WOS:000183481700011 PM 12609827 ER PT J AU Klion, AD Noel, P Akin, C Law, MA Gilliland, DG Cools, J Metcalfe, DD Nutman, TB AF Klion, AD Noel, P Akin, C Law, MA Gilliland, DG Cools, J Metcalfe, DD Nutman, TB TI Elevated serum tryptase levels identify a subset of patients with a myeloproliferative variant of idiopathic hypereosinophilic syndrome associated with tissue fibrosis, poor prognosis, and imatinib responsiveness SO BLOOD LA English DT Article ID MAST-CELL TRYPTASE; C-KIT; T-CELLS; MASTOCYTOSIS; EXPRESSION; EOSINOPHILIA; DISEASE; DISORDERS; PROTEINS; MUTATION AB Since serum tryptase levels are elevated in some patients with myeloproliferative disorders, we examined their utility in identifying a subset of patients with hypereosinophilic syndrome (HES) and an underlying myeloproliferative disorder. Elevated serum tryptase levels (> 11.5 ng/mL) were present in 9 of 15 patients with HIES and were associated with other markers of myeloproliferation, including elevated B-12 levels and splenomegaly. Although bone marrow biopsies in these patients showed increased numbers of CD25(+) mast cells and atypical spindle-shaped mast cells, patients with HES and elevated serum tryptase could be distinguished from patients with systemic mastocytosis and eosinophilia by their clinical manifestations, the absence of mast cell aggregates, the lack of a somatic KIT mutation, and the presence of the recently described fusion of the Fip1-like 1 (FIP1L1) gene to the platelet-derived growth factor receptor alpha gene (PDGFRA). Patients with HES and elevated serum tryptase were more likely to develop fibro-proliferative end organ damage, and 3 of 9 died within 5 years of diagnosis in contrast to 0 of 6 patients with normal serum tryptase levels. All 6 patients with HES and elevated tryptase treated with imatinib demonstrated a clinical and hematologic response. In summary, elevated serum tryptase appears to be a sensitive marker of a myeloproliferative variant of HES that is characterized by tissue fibrosis, poor prognosis, and imatinib responsiveness. (C) 2003 by The American Society of Hematology. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Div Hematol, Boston, MA 02115 USA. RP Klion, AD (reprint author), NIAID, Parasit Dis Lab, NIH, Bldg 4,Rm 126, Bethesda, MD 20892 USA. EM aklion@nih.gov OI Klion, Amy/0000-0002-4986-5326; Cools, Jan/0000-0001-6626-5843; Akin, Cem/0000-0001-6301-4520 NR 35 TC 230 Z9 238 U1 2 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 15 PY 2003 VL 101 IS 12 BP 4660 EP 4666 DI 10.1182/blood-2003-01-0006 PG 7 WC Hematology SC Hematology GA 689FV UT WOS:000183481700012 PM 12676775 ER PT J AU Jin, YX Knudsen, E Wang, L Bryceson, Y Damaj, B Gessani, S Maghazachi, AA AF Jin, YX Knudsen, E Wang, L Bryceson, Y Damaj, B Gessani, S Maghazachi, AA TI Sphingosine 1-phosphate is a novel inhibitor of T-cell proliferation SO BLOOD LA English DT Article ID NATURAL-KILLER-CELLS; HETEROTRIMERIC G-PROTEINS; HUMAN DENDRITIC CELLS; LYSOPHOSPHATIDIC ACID; RECEPTORS EDG-1; SPHINGOSINE-1-PHOSPHATE; KINASE; LYMPHOCYTES; ACTIVATION; LYSOPHOSPHOLIPIDS AB Sphingosine 1-phosphate (S1P) is a pleiotropic lysosphingophospholipid stored and secreted by platelets. Using reverse transcription-polymerase chain reaction and flow cytometric analyses, we determined the expression of SIP receptors (S1P(1), S1P(3), S1P(4), and S1P(5)) in peripheral blood T cells. T cells were induced to proliferate in the presence of phorbol 12-myristate 13-acetate (PMA) plus ionomycin, anti-CD3 plus anti-CD28, and allogeneic immature or mature dendritic cells. This activity was inhibited by the addition of S1P. Enhanced T-cell proliferation was observed when these cells were stimulated with the same stimuli, but were incubated in serum-free media (SFM). Addition of S1P to SFM inhibited the stimulation of T cells induced by T-cell stimuli, suggesting that S1P is an important inhibitory molecule present in the serum. T-cell proliferation was also inhibited by the addition of dilhydrosphingosine 1-phosphate (DHS1P), sphingosine, and ceramide; however, the latter 2 sphingolipids required higher concentrations than S1P. Pretreatment of T cells with pertussis toxin (PTX) blocked the inhibitory effect of S1P on activation with PMA plus ionomycin, but not on activation with anti-CD3 plus anti-CD28. This is corroborated with the down-regulation of SIP, in T cells stimulated with anti-CD3 plus anti-CD28. Similarly, PTX did not affect the inhibitory effect of SIP on T-cell proliferation when dendritic cells were used as stimuli. Further, SIP or DHS1P but not ceramide or sphingosine enhanced rather than decreased secretion of interleukin 2 and interferon gamma by T cells stimulated with anti-CD3 plus anti-CD28. These results show differential effects of SIP on polyclonal T-cell proliferation and cytokine secretion. (Blood. 2003;101:4909-4915). C1 Univ Oslo, Dept Anat & Physiol, Inst Basic Med Sci, Oslo, Norway. NIAID, Immunogenet Lab, NIH, Rockville, MD USA. BioQuant, San Diego, CA USA. Inst Super Sanita, Rome, Italy. RP Maghazachi, AA (reprint author), Univ Oslo, Dept Anat, POB 1105 Blindern, N-0317 Oslo, Norway. EM azzam.maghazachi@basalmed.uio.no RI Conti, Lucia/C-3159-2009; Gessani, Sandra/K-5151-2016; OI Gessani, Sandra/0000-0002-8451-0758; Bryceson, Yenan/0000-0002-7783-9934 NR 33 TC 58 Z9 61 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 15 PY 2003 VL 101 IS 12 BP 4909 EP 4915 DI 10.1182/blood-2002-09-2962 PG 7 WC Hematology SC Hematology GA 689FV UT WOS:000183481700048 PM 12586615 ER PT J AU Wiestner, A Rosenwald, A Barry, TS Wright, G Davis, RE Henrickson, SE Zhao, H Ibbotson, RE Orchard, JA Davis, Z Stetler-Stevenson, M Raffeld, M Arthur, DC Marti, GE Wilson, WH Hamblin, TJ Oscier, DG Staudt, LM AF Wiestner, A Rosenwald, A Barry, TS Wright, G Davis, RE Henrickson, SE Zhao, H Ibbotson, RE Orchard, JA Davis, Z Stetler-Stevenson, M Raffeld, M Arthur, DC Marti, GE Wilson, WH Hamblin, TJ Oscier, DG Staudt, LM TI ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile SO BLOOD LA English DT Article ID V-H GENES; CD38 EXPRESSION; B-CELLS; GENOMIC ABERRATIONS; PROGNOSTIC-FACTORS; MUTATIONAL STATUS; ANTIGEN; CHAIN; PHENOTYPE; SURVIVAL AB The presence or absence of somatic mutations in the expressed immunoglobulin heavy chain variable regions (IgVH) of chronic lymphocytic leukemia (CLL) cells provides prognostic information. Patients whose leukemic cells express unmutated IgVH regions (Ig-unmutated CLL) often have progressive disease, whereas patients whose leukemic cells express mutated IgVH regions (Ig-mutated CLL) more often have an indolent disease. Given the difficulty in performing IgVH sequencing in a routine diagnostic laboratory, this prognostic distinction is currently unavailable to most patients. Pilot gene expression profiling studies in patients with CLL identified genes that were differentially expressed between the Ig-unmutated and Ig-mutated CLL subtypes. Here, we have profiled an expanded cohort of 107 patients and show that ZAP-70 is the gene that best distinguishes the CLL subtypes. Ig-unmutated CLL expressed ZAP-705.54-fold more highly than Ig-mutated CLL (P < 10(-21)). ZAP-70 expression correctly predicted IgVH mutation status in 93% of patients. ZAP-70 expression and IgVH mutation status were comparable in their ability to predict time to treatment requirement following diagnosis. In 7 patients, ZAP-70 expression and IgVH mutation status were discordant: 4 Ig-mutated CLLs had high ZAP-70 expression and 3 Ig-unmutated CLLs had low ZAP-70 expression. Among these ZAP-70 "outliers," those with Ig-mutated CLL had clinical features that are uncharacteristic of this CLL subtype: 2 required early treatment and 2 used a mutated VH3-21 gene, an IgVH gene that has been associated with progressive disease. We developed reverse transcriptase-polymerase chain reaction and immunohistochemical assays for ZAP-70 expression that can be applied clinically and would yield important prognostic information for patients with CLL. (Blood. 2003;101:4944-4951). C1 NCI, Metab Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, Biometr Res Branch, NIH, Bethesda, MD USA. Royal Boumemouth Hosp, Dept Hematol, Bournemouth, Dorset, England. US FDA, Ctr Biol Evaluat & Res, Off Cellular Tissue & Gene Therapies, Bethesda, MD USA. NCI, Div Clin Sci, Med Branch, NIH, Bethesda, MD USA. RP Staudt, LM (reprint author), NCI, Metab Branch, Canc Res Ctr, NIH, Bldg 10,Rm 4N114, Bethesda, MD 20892 USA. EM lstaudt@mail.nih.gov NR 48 TC 507 Z9 531 U1 0 U2 8 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 15 PY 2003 VL 101 IS 12 BP 4944 EP 4951 DI 10.1182/blood-2002-10-3306 PG 8 WC Hematology SC Hematology GA 689FV UT WOS:000183481700053 PM 12595313 ER PT J AU Lee, TH Kim, SU Yu, SL Kim, SH Park, DS Moon, HB Dho, SH Kwon, KS Kwon, HJ Han, YH Jeong, S Kang, SW Shin, HS Lee, KK Rhee, SG Yu, DY AF Lee, TH Kim, SU Yu, SL Kim, SH Park, DS Moon, HB Dho, SH Kwon, KS Kwon, HJ Han, YH Jeong, S Kang, SW Shin, HS Lee, KK Rhee, SG Yu, DY TI Peroxiredoxin II is essential for sustaining life span of erythrocytes in mice SO BLOOD LA English DT Article ID GLUTATHIONE-PEROXIDASE; MEMBRANE SKELETON; HYDROGEN-PEROXIDE; OXIDATIVE STRESS; HEMOLYTIC-ANEMIA; BETA-ACTIN; PROTEIN; GENE; DEFICIENCY; MUTATION AB Peroxiredoxins (Prxs) are a family of antioxidant proteins that reduce peroxide levels by using reducing agents such as thioredoxin. These proteins were characterized to have a number of cellular functions, including cell proliferation and differentiation and protection of specific proteins from oxidative damage. However, the physiological roles of the peroxiredoxins have not been determined. To clarify the physiological relevance of this protein type, we generated a mouse model deficient in Prx II, which is abundantly expressed in all types of cells. The Prx II-/- mice were healthy in appearance and fertile. However, they had splenomegaly caused by the congestion of red pulp with hemosiderin accumulation. Heinz bodies were detected in their peripheral blood, and morphologically abnormal cells were elevated in the dense red blood cell (RBC) fractions, which contained markedly higher levels of reactive oxygen species (ROS). The Prx II-/- mice had significantly decreased hematocrit levels, but increased reticulocyte counts and erythropoletin levels, indicative of a compensatory action to maintain hematologic homeostasis in the mice. In addition, a labeling experiment with the thiol-modifying reagent biotinylated iodoacetamide (BIAM) in Prx II-/- mice revealed that a variety of RBC proteins were highly oxidized. Our results suggest that Prx II-/- mice have hemolytic anemia and that Prx II plays a major role in protecting RBCs from oxidative stress in mice. (C) 2003 by The American Society of Hematology. C1 Korea Res Inst Biosci & Biotechnol, Lab Dev & Differentiat, Funct Proteom Lab, Taejon 305333, South Korea. Wonkwang Univ, Sch Med, Dept Pathol, Iksan, South Korea. Wonkwang Univ, Sch Med, Dept Lab Med, Iksan, South Korea. Ewha Womans Univ, Ctr Cell Signalling Res, Seodaemoon Gu, Seoul, South Korea. Ewha Womans Univ, Div Mol Life Sci, Seodaemoon Gu, Seoul, South Korea. Korea Inst Sci & Technol, Natl Creat Res Initiat Ctr Calcium & Learning, Seoul 130650, South Korea. NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. RP Yu, DY (reprint author), Korea Res Inst Biosci & Biotechnol, Lab Dev & Differentiat, Funct Proteom Lab, Taejon 305333, South Korea. EM dyyu10@kribb.re.kr RI Park, Do-Sim/B-6594-2013 OI Park, Do-Sim/0000-0002-6001-4223 NR 30 TC 232 Z9 245 U1 2 U2 10 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 15 PY 2003 VL 101 IS 12 BP 5033 EP 5038 DI 10.1182/blood-2002-08-2548 PG 6 WC Hematology SC Hematology GA 689FV UT WOS:000183481700066 PM 12586629 ER PT J AU Bethge, WA Wilbur, DS Storb, R Hamlin, DK Santos, EB Brechbiel, MW Fisher, DR Sandmaier, BM AF Bethge, WA Wilbur, DS Storb, R Hamlin, DK Santos, EB Brechbiel, MW Fisher, DR Sandmaier, BM TI Selective T-cell ablation with bismuth-213-labeled anti-TCR alpha beta as nonmyeloablative conditioning for allogeneic canine marrow transplantation SO BLOOD LA English DT Article ID TOTAL-BODY IRRADIATION; MIXED HEMATOPOIETIC CHIMERISM; IDENTICAL LITTERMATE DOGS; MONOCLONAL-ANTIBODY; BONE-MARROW; PHARMACOLOGICAL IMMUNOSUPPRESSION; MYELODYSPLASTIC SYNDROME; ANTI-CD45 ANTIBODY; MYELOID-LEUKEMIA; GRAFT-REJECTION AB Two major immunologic barriers, the host-versus-graft (HVG) and graft-versus-host (GVH) reactions, have to be overcome for successful allogeneic hematopoietic cell transplantation. T cells were shown to be primarily involved in these barriers in the major histocompatibility complex identical setting. We hypothesized that selective ablation of T cells using radioimmunotherapy together with postgrafting immunosuppression would suffice to ensure stable allogeneic engraftment. We had described a canine model of nonmyeloablative marrow transplantation in which host immune reactions were impaired by a single dose of 200 cGy total body irradiation (TBI), and both GVH and residual HVG reactions were controlled by postgrafting immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP). Here, we substituted the a-emitter bismuth-213 (Bi-213) linked to a monoclonal antibody (mAb) against T-cell receptor (TCR) alphabeta, using the metal-binding chelate diethylenetriaminepentaacetic acid (DTPA) derivative cyclohexyl-(CHX)-A", for 200 cGy TBI. Biodistribution studies using a gamma-emitting indium-111-labeled anti-TCRalphabeta mAb showed uptake primarily in blood, marrow, lymph nodes, spleen, and liver. Four dogs were treated with 0.13 to 0.46 mg/kg TCRalphabeta mAb labeled with 3.7 to 5.6 mCi/kg (137-207 MBq/kg) Bi-213. The treatment was administered in 6 injections on days -3 and -2 followed by transplantation of dog leukocyte antigen-identical marrow on day 0 and postgrafting immunosuppression with MMF/CSP. The therapy was well tolerated except for elevations of transaminases that were transient in all but one of the dogs. No other organ toxicities or signs of graft-versus-host disease were noted. The dogs had prompt allogeneic hematopoietic engraftment and achieved stable mixed donor-host hematopoietic chimerism with donor contributions ranging from 5% to 55% after more than 30 weeks of follow up. (C) 2003 by The American Society of Hematology. C1 Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. Univ Washington, Dept Radiat Oncol, Seattle, WA 98195 USA. NCI, NIH, Bethesda, MD 20892 USA. Pacific NW Natl Lab, Richland, WA USA. RP Sandmaier, BM (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, 1100 Fairview Ave N,D1-100,POB 19024, Seattle, WA 98109 USA. EM bsandmai@fhcrc.org FU NCI NIH HHS [CA15704, CA78902, P01 CA078902]; NHLBI NIH HHS [HL36444] NR 45 TC 42 Z9 43 U1 1 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 15 PY 2003 VL 101 IS 12 BP 5068 EP 5075 DI 10.1182/blood-2002-12-3867 PG 8 WC Hematology SC Hematology GA 689FV UT WOS:000183481700071 PM 12609833 ER PT J AU Chen, ZM O'Shaughnessy, MJ Gramaglia, I Panoskaltsis-Mortari, A Murphy, WJ Narula, S Roncarolo, MG Blazar, BR AF Chen, ZM O'Shaughnessy, MJ Gramaglia, I Panoskaltsis-Mortari, A Murphy, WJ Narula, S Roncarolo, MG Blazar, BR TI IL-10 and TGF-beta induce alloreactive CD4(+)CD25(-) T cells to acquire regulatory cell function SO BLOOD LA English DT Article ID GROWTH-FACTOR-BETA; VERSUS-HOST-DISEASE; EFFECTOR FUNCTION; EX-VIVO; TOLERANCE INDUCTION; PERIPHERAL-BLOOD; ORAL TOLERANCE; IN-VITRO; MICE; INTERLEUKIN-10 AB We previously reported that interleukin-10 (IL-10) and transforming growth factor (TGF)-beta treatment of primary mixed lymphocyte reaction (MLR) cultures resulted in secondary alloantigen-specific hyporesponsiveness and protection from graft-versus-host disease (GVHD) lethality. Here, we report that CD4(+) T cells recovered from the IL-10- and TGF-beta-treated primary MLR cultures have immunoregulatory function. Tolerized cells significantly inhibited proliferation of naive alloreactive CD4(+) T cells in a primary MLR. Inhibition of the naive alloresponse was observed with as few as 1 tolerized cell to 10 naive responder cells. Tolerized cells were able to significantly reduce GVHD lethality when injected with naive alloreactive CD4(+) T cells into major histocombatibility class (MHC) II disparate recipients. Rigorous CD25 depletion of the primary MLR had no effect on generation of a regulatory capacity, suggesting that the regulatory cells likely originated from CD4(+)CD25(-) T cells. Immune suppression was mediated independently of IL-10 and TGF-beta production, as neutralizing antibodies for IL-10, IL-10R, and TGF-beta were unable to revert suppression, and IL-10-deficient CD4(+) T cells were able to mediate in vitro and in vivo suppression. The generation of immunoregulatory cells from a CD4(+)CD25(-) population during tolerization with IL-10 and TGF-beta provides an additional mechanism to prevent GVHD lethality by T cells that may escape full tolerance induction. (C) 2003 by The American Society of Hematology. C1 Univ Minnesota, Ctr Canc, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Pediat, Div Bone Marrow Transplantat, Minneapolis, MN 55455 USA. Sci Applicat Int Corp, Frederick, MD USA. NCI, Lab Leukocyte Biol, Frederick Canc Res & Dev Ctr, Frederick, MD USA. Schering Plough Res Inst, Kenilworth, NJ USA. HSR, TIGET, San Raffaele Telethon Inst, Milan, Italy. RP Blazar, BR (reprint author), Univ Minnesota, Ctr Canc, Minneapolis, MN 55455 USA. EM blaza001@tc.umn.edu OI RONCAROLO, Maria Grazia/0000-0002-2193-9186 FU NHLBI NIH HHS [R01 HL63452, 2R37HL56067]; NIAID NIH HHS [P01 AI-35225, R01 AI 34495]; NIGMS NIH HHS [T32 GM08244-15]; Telethon [TGT03F01, TGT06S01] NR 37 TC 131 Z9 138 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 15 PY 2003 VL 101 IS 12 BP 5076 EP 5083 DI 10.1182/blood-2002-09-2798 PG 8 WC Hematology SC Hematology GA 689FV UT WOS:000183481700072 PM 12609834 ER PT J AU Sigurdson, AJ Doody, MM Rao, RS Freedman, DM Alexander, BH Hauptmann, M Mohan, AK Yoshinaga, S Hill, DA Tarone, R Mabuchi, K Ron, E Linet, MS AF Sigurdson, AJ Doody, MM Rao, RS Freedman, DM Alexander, BH Hauptmann, M Mohan, AK Yoshinaga, S Hill, DA Tarone, R Mabuchi, K Ron, E Linet, MS TI Cancer incidence in the US radiologic technologists health study, 1983-1998 SO CANCER LA English DT Article DE cohort; epidemiology; methods; occupation; women; radiation; risk factors ID CURRENT MORTALITY RATES; ATOMIC-BOMB SURVIVORS; UNITED-STATES; PHYSICIAN SPECIALISTS; BRITISH RADIOLOGISTS; PROSPECTIVE COHORT; RISK; RADIATION; REGISTRY; PROFESSIONALS AB BACKGROUND. Workers exposed to low doses of radiation can provide information regarding cancer risks that are of public concern. However, characterizing risk at low doses requires large populations and ideally should include a large proportion of women, both of which rarely are available. METHODS. Among 90,305 radiologic technologists in the U.S. (77% women) who were followed during 1983-1998, data concerning incident cancer occurrence was obtained from mailed questionnaires and from death records. Standardized incidence ratios (SIRs) were computed using age-specific, gender-specific, race-specific, and calendar year-specific cancer rates from the Surveillance, Epidemiology, and End Results Program. RESULTS. The SIR for all cancers in both genders combined was 1.04 (95% confidence interval [95% CI], 1.00-1.07; n = 3292 technologists). Female technologists had an elevated risk for all solid tumors combined (SIR = 1.06; 95% Cl, 1.02-1.10; n = 2168 women) and for breast cancers (SIR = 1.16; 95% Cl, 1.09-1.23; n = 970 women), melanoma (SIR = 1.66; 95% Cl, 1.43-1.89; n = 181 women), and thyroid cancers (SIR = 1.54; 95% Cl, 1.24-1.83; n = 107 women). Male technologists experienced a decreased risk for solid tumors (SIR = 0.92; 95% CI, 0.85-0.98; n = 755 men); however, melanoma (SIR = 1.39; 95% CI; 1.00-1.79; n = 56 men) and thyroid cancers (SIR = 2.23; 95% CI, 1.29-3.59; n = 17 men) were increased. Among both genders, the risks were decreased for buccal cavity/pharyngeal cancers (SIR = 0.73; 95% CI, 0.55-0.90; n 54 technologists), rectal cancers (SIR = 0.62; 95% Cl 0.48-0.76; n = 53 technologists), and lung cancers (SIR = 0.77, 95% Cl, 0.70-0.85; n = 307 technologists). CONCLUSIONS. The elevated risk for breast cancer may have been related to occupational radiation exposure. The observed excesses of melanoma and thyroid cancers may reflect, at least in part, earlier detection among medical workers with easy access to health care. Published 2003 by the American Cancer Society. C1 NCI, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Biostat Branch, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. Univ Minnesota, Div Environm & Occupat Hlth, Minneapolis, MN USA. Natl Inst Radiol Sci, Environm Radiat Protect Res Grp, Chiba 260, Japan. RP Sigurdson, AJ (reprint author), NCI, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, Dept Hlth & Human Serv,NIH, 6120 Execut Blvd,EPS 7092,MSC 7238, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CP-51016, N01-CP-15673, N02-CP-81005, N02-CP-81121] NR 43 TC 121 Z9 121 U1 5 U2 14 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JUN 15 PY 2003 VL 97 IS 12 BP 3080 EP 3089 DI 10.1002/cncr.11444 PG 10 WC Oncology SC Oncology GA 686WC UT WOS:000183343100021 PM 12784345 ER PT J AU Wingo, PA Cardinez, CI Landis, SH Greenlee, RT Ries, LAG Anderson, RN Thun, MJ AF Wingo, PA Cardinez, CI Landis, SH Greenlee, RT Ries, LAG Anderson, RN Thun, MJ TI Long-term trends in cancer mortality in the United States, 1930-1998 SO CANCER LA English DT Review DE neoplasm; mortality; surveillance; trends ID ORAL-CONTRACEPTIVE USE; FATAL COLON-CANCER; INTERPRETING TRENDS; PROSTATE-CANCER; BREAST-CANCER; SURVEILLANCE SERIES; OVARIAN-CANCER; PROSPECTIVE COHORT; PANCREATIC-CANCER; COLORECTAL-CANCER C1 Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30341 USA. NCI, Bethesda, MD 20892 USA. Amer Canc Soc, Dept Epidemiol & Surveillance Res, Natl Home Off, Atlanta, GA 30329 USA. RP Wingo, PA (reprint author), Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, 4770 Buford Highway NE,Mailstop K-53, Atlanta, GA 30341 USA. NR 110 TC 166 Z9 189 U1 1 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JUN 15 PY 2003 VL 97 IS 12 SU S BP 3133 EP + DI 10.1002/cncr.11380 PG 135 WC Oncology SC Oncology GA 687XX UT WOS:000183403200001 PM 12784323 ER PT J AU Aleman, C Annereau, JP Liang, XJ Cardarelli, CO Taylor, B Yin, JJ Aszalos, A Gottesman, MM AF Aleman, C Annereau, JP Liang, XJ Cardarelli, CO Taylor, B Yin, JJ Aszalos, A Gottesman, MM TI P-glycoprotein, expressed in multidrug resistant cells, is not responsible for alterations in membrane fluidity or membrane potential SO CANCER RESEARCH LA English DT Article ID TUMOR-CELLS; MOTIONAL FREEDOM; CARCINOMA-CELLS; TRANSPORTER; DEPOLYMERIZATION; INHIBITORS; ADRIAMYCIN; APOPTOSIS; PROTEINS; PACKING AB Expression of P-glycoprotein (P-gp), the multidrug resistance (MDR) 1 gene product, can lead to MDR in tumors. However, the physiological role of P-gp in normal tissues is not well understood. Previous studies on multidrug-resistant cells have suggested changes in membrane fluidity and membrane potential associated with P-gp expression, but interpretation of these studies is difficult, because most experimental cells have been selected for long periods in the presence of cytotoxic drugs and may have other host alterations. Therefore, we created two cell lines in which a transfected human MDR1 cDNA is repressed by tetracycline and induced in the absence of tetracycline. One cell line was derived from a mouse embryonic fibroblast cultured from a double (mdr1a/1b) knockout mouse, and the other was from a human HeLa cell line. Analysis of the kinetics of expression of P-gp showed that the mRNA had a half-life of similar to4 h, and the protein had a half-life of similar to16 h. P-gp cell surface expression (measured with monoclonal antibody MRK-16) and P-gp function (measured with a fluorescent substrate, rhodamine 123) was characterized by using fluorescence-activated cell sorting. No differences in membrane potential using the fluorescent probe oxonol or in membrane "fluidity" using fluorescent anisotropy probe or electron spin resonance probe were observed in the tet-repressible P-gp-expressing cells. In contrast, several drug-selected cells that express P-gp showed an increase in membrane fluidity and membrane potential. These results suggest that expression of P-gp per se has little effect on membrane fluidity or membrane potential, and it does not have H+ pump activity. The changes. in these parameters observed in drug-selected cells must reflect other host adaptations to drug selection. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, FACS Core Facil, NIH, Bethesda, MD 20892 USA. Ctr Food Safety & Appl Nutr, Instrumentat & Biophys Branch, College Pk, MD 20740 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. RI Yin, Jun Jie /E-5619-2014 NR 38 TC 51 Z9 52 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 2003 VL 63 IS 12 BP 3084 EP 3091 PG 8 WC Oncology SC Oncology GA 691CG UT WOS:000183586800016 PM 12810633 ER PT J AU Ng, SSW Gutschow, M Weiss, M Hauschildt, S Teubert, U Hecker, TK Luzzio, FA Kruger, EA Eger, K Figg, WD AF Ng, SSW Gutschow, M Weiss, M Hauschildt, S Teubert, U Hecker, TK Luzzio, FA Kruger, EA Eger, K Figg, WD TI Antiangiogenic activity of N-substituted and tetrafluorinated thalidomide analogues SO CANCER RESEARCH LA English DT Article ID NECROSIS-FACTOR-ALPHA; PHASE-II TRIAL; CYCLOOXYGENASE-2 EXPRESSION; CONGENITAL ABNORMALITIES; BREAST-CANCER; RENAL-CELL; ANGIOGENESIS; INHIBITOR; GROWTH AB Inhibition of angiogenesis is currently perceived as one of the promising strategies in the treatment of cancer. The antiangiogenic property of thalidomide has inspired a second wave of research on this teratogenic drug. Previous studies from our group and others demonstrated that metabolites of thalidomide are responsible for the drug's pharmacological actions. On the basis of the structures of these metabolites, we synthesized 118 thalidomide analogues. Preliminary screening selected 7 of these 118 analogues for more extensive testing in the current study. In the rat aortic ring assay, all 4 analogues in the N-substituted class and 2 of the 3 analogues in the tetrafluorinated class significantly inhibited microvessel outgrowth at 12.5-200 muM. Thalidomide failed to block angiogenesis at similar concentrations. Subsequently, the effects of these analogues on human umbilical vein endothelial cell proliferation and tube formation were determined. Those analogues showing antiangiogenicity in the rat aortic ring assay also demonstrated antiproliferative action in human umbilical vein endothelial cells. Cell proliferation was not affected by thalidomide. Interestingly, all 7 analogues as well as thalidomide suppressed tube formation. Two tetrafluorinated analogues consistently showed the highest potency and efficacy in all three assays. The in vivo toxicity of representative analogues from each class was also evaluated. Taken together, our results support the further development and evaluation of novel thalidomide analogues as antiangiogenic agents. C1 NCI, Mol Pharmacol Sect, Canc Therapeut Branch, NIH, Bethesda, MD 20892 USA. Univ Bonn, Inst Pharmaceut, Poppelsdorf, D-5300 Bonn, Germany. Univ Leipzig, Inst Pharm, Leipzig, Germany. Univ Leipzig, Inst Zool, Dept Immunobiol, Leipzig, Germany. Univ Louisville, Dept Chem, Louisville, KY 40292 USA. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, Canc Therapeut Branch, NIH, Bldg 10,Room 5A01,MSC 1910,9000 Rockville Pike, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 NR 31 TC 66 Z9 66 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 2003 VL 63 IS 12 BP 3189 EP 3194 PG 6 WC Oncology SC Oncology GA 691CG UT WOS:000183586800030 PM 12810647 ER PT J AU Rajendra, R Gounder, MK Saleem, A Schellens, JHM Ross, DD Bates, SE Sinko, P Rubin, EH AF Rajendra, R Gounder, MK Saleem, A Schellens, JHM Ross, DD Bates, SE Sinko, P Rubin, EH TI Differential effects of the breast cancer resistance protein on the cellular accumulation and cytotoxicity of 9-aminocamptothecin and 9-nitrocamptothecin SO CANCER RESEARCH LA English DT Article ID PHASE-II TRIAL; METASTATIC COLORECTAL-CARCINOMA; ORGANIC ANION TRANSPORTER; PLANT ANTITUMOR AGENTS; ACUTE MYELOID-LEUKEMIA; MULTIDRUG-RESISTANCE; TOPOISOMERASE-I; ANTILEUKEMIC ACTIVITY; CAMPTOTHECIN ANALOGS; CONTINUOUS-INFUSION AB Breast cancer resistance protein (BCRP)/MXR/ABCG2 is a new member of the family of ATP-dependent drug efflux proteins. Whereas overexpression of another member of this family, P-glycoprotein, minimally affects the cytotoxicity of camptothecins (CPTs), overexpression of wildtype as well as certain mutant BCRPs confers resistance to CPT analogues that are used clinically, including topotecan and irinotecan. Relatively little is known regarding the effects of BCRP on other CPT analogues. We now report studies of 9-aminocamptothecin (9-AC) and 9-nitrocamptothecin (9-NC) using mammalian cells stably transfected with constructs expressing a variety of efflux proteins, including wild-type BCRP and a mutant BCRP that contains a threonine rather than an arginine at position 482 (R482T). The results indicate that overexpression of either P-glycoprotein, multidrug resistance protein type 1, or multidrug resistance protein type 2 has little, effect on the cytotoxicity of 9-NC or 9-AC. By contrast, overexpression of either wild-type or R482T BCRP confers resistance to 9-AC, but not to 9-NC. Furthermore, overexpression of wild-type or mutant BCRP is associated with reduced intracellular accumulation of 9-AC, but not 9-NC. In addition, immunoblotting studies indicate that whereas increased BCRP expression is evident in cells selected for resistance to irinotecan, BCRP expression is not detectable in two different cell lines selected for resistance to 9-NC. Taken together, these findings suggest that wild-type as well as R482T BCRP mediates cellular efflux of 9-AC but not 9-NC. Furthermore, the results suggest that polar groups at the 9 or 10 position of the CPT A ring facilitate interaction with BCRP and have implications for the clinical development of new CPT analogues. C1 Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Pharmacol, New Brunswick, NJ 08901 USA. Rutgers State Univ, Sch Pharm, Dept Pharmaceut, Piscataway, NJ 08855 USA. Netherlands Canc Inst, Amsterdam, Netherlands. Univ Maryland, Sch Med, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. Baltimore Vet Affairs Hosp, Baltimore, MD USA. NCI, Canc Therapeut Branch, Bethesda, MD 20892 USA. RP Rubin, EH (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Pharmacol, 195 Little Albany St, New Brunswick, NJ 08901 USA. FU NCI NIH HHS [R01-CA77545, R21-CA094583]; NIGMS NIH HHS [R01-GM59170] NR 51 TC 54 Z9 60 U1 1 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 JUN 15 PY 2003 VL 63 IS 12 BP 3228 EP 3233 PG 6 WC Oncology SC Oncology GA 691CG UT WOS:000183586800035 PM 12810652 ER PT J AU Lin, X Zhang, FJ Bradbury, CM Kaushal, A Li, L Spitz, DR Aft, RL Gius, D AF Lin, X Zhang, FJ Bradbury, CM Kaushal, A Li, L Spitz, DR Aft, RL Gius, D TI 2-deoxy-D-glucose-induced cytotoxicity and radiosensitization in tumor cells is mediated via disruptions in thiol metabolism SO CANCER RESEARCH LA English DT Article ID CARCINOMA MCF-7/ADR CELLS; DEPRIVATION-INDUCED CYTOTOXICITY; GLUCOSE DEPRIVATION; OXIDATIVE STRESS; CANCER-CELLS; GLUTATHIONE DISULFIDE; HYDROGEN-PEROXIDE; GENE-EXPRESSION; RADIATION; KINASE AB Exposure to ionizing radiation is believed to cause cell injury via the production of free radicals that are thought to induce oxidative damage. It has been proposed that exposure to agents that enhance oxidative stress-induced injury by disrupting thiol metabolism may sensitize cells to the cytotoxic effects of ionizing radiation. Recently, it has been shown that glucose deprivation selectively induces cell injury in transformed human cells via metabolic oxidative stress (J. Biol. Chem., 273: 5294-5299; Ann. N.Y. Acad. Sci., 899. 349-362), resulting in profound disruptions in thiol metabolism. Because 2-deoxy-D-glucose (2DG) is a potent inhibitor of glucose metabolism thought to mimic glucose deprivation in vivo, the hypothesis that exposure to 2DG might be capable of inducing radiosensitization in transformed cells via perturbations in thiol metabolism was tested. When HeLa cells were exposed to 2DG (4-10 nM) for 4-72 h, cell survival decreased (20-90%) in a dose- and time-dependent fashion. When HeLa cells were treated with 6 mm 2DG for 16 h before ionizing radiation exposure, radiosensitization was observed with a sensitizer enhancement ratio of 1.4 at 10% isosurvival. Treatment with 2DG was also found to cause decreases in intracellular total glutathione content (50%). Simultaneous treatment with the thiol antioxidant N-acetyleysteine (NAC; 30 mm) protected HeLa cells against the cytotoxicity and radiosensitizing effects of 2DG, without altering radiosensitivity in the absence of 2DG. Furthermore, treatment with NAC partially reversed the 2DG-induced decreases in total glutathione content, as well as augmented intracellular cysteine content. Finally, the cytotoxicity and radiosensitizing effects of 2DG were more pronounced in v-Fos-transforined versus non-transformed immortalized rat cells, and this radiosensitization was also inhibited by treatment with NAC. These results support the hypothesis that exposure to 2DG causes cytotoxicity and radiosensitization via a mechanism involving perturbations in thiol metabolism and allows for the speculation that these effects may he more pronounced in transformed versus normal cells. C1 NCI, Radiat Oncol Branch, Radiat Oncol Sci Program, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Edward Mallinckrodt Inst Radiol, Sect Canc Biol, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. Univ Iowa, Free Rad & Radiat Biol Program, Dept Radiat Oncol, Med Labs B180, Iowa City, IA USA. RP Gius, D (reprint author), NCI, Radiat Oncol Branch, Radiat Oncol Sci Program, Ctr Canc Res,NIH, Bldg 10,Room B3B69, Bethesda, MD 20892 USA. FU NCI NIH HHS [P01 CA66081, 1 K08 CA72602-01, P01 CA75556, P20 CA91709]; NHLBI NIH HHS [R01 HL51469] NR 28 TC 98 Z9 101 U1 2 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 JUN 15 PY 2003 VL 63 IS 12 BP 3413 EP 3417 PG 5 WC Oncology SC Oncology GA 691CG UT WOS:000183586800061 PM 12810678 ER PT J AU Dass, K Shoham, S Monsein, L Conville, PS Witebsky, FG Lucey, DR AF Dass, K Shoham, S Monsein, L Conville, PS Witebsky, FG Lucey, DR TI "Too numerous to count" lesions on magnetic resonance images of the brain - Tuberculomas in the brain with meningitis SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; POLYMERASE CHAIN-REACTION; MYCOBACTERIUM-TUBERCULOSIS; COMPLEX C1 Washington Hosp Ctr, Infect Dis Serv, Washington, DC 20010 USA. Washington Hosp Ctr, Dept Radiol, Washington, DC 20010 USA. NIH, Warren G Magnuson Clin Ctr, Dept Lab Med, Microbiol Serv, Bethesda, MD 20892 USA. RP Dass, K (reprint author), Washington Hosp Ctr, Infect Dis Serv, Washington, DC 20010 USA. NR 14 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 15 PY 2003 VL 36 IS 12 BP 1545 EP + PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 688WJ UT WOS:000183460000007 PM 12807095 ER PT J AU Cortez, KJ Walsh, TJ Bennett, JE AF Cortez, KJ Walsh, TJ Bennett, JE TI Successful treatment of coccidioidal meningitis with voriconazole SO CLINICAL INFECTIOUS DISEASES LA English DT Article AB A previously healthy 47-year-old man with coccidioidal meningitis had fluconazole treatment failure and developed severe symptoms, multiple cranial nerve palsies, and brainstem inflammation visible on magnetic resonance imaging (MRI). High-dose voriconazole therapy resulted in gradual resolution of almost all signs and symptoms, normalization of cerebrospinal fluid, and clearing of brain-stem edema seen on MRI. The patient had photosensitivity after 10 weeks of treatment, but this improved when the voriconazole dose was lowered. Continuous voriconazole therapy kept coccidioidal meningitis in complete remission in this patient for 12 years. C1 NIAID, Clin Mycol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Bennett, JE (reprint author), NIAID, Clin Mycol Sect, Clin Invest Lab, NIH, Rm 11C304,10 Ctr Dr, Bethesda, MD 20892 USA. NR 9 TC 67 Z9 72 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 15 PY 2003 VL 36 IS 12 BP 1619 EP 1622 DI 10.1086/375235 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 688WJ UT WOS:000183460000019 PM 12802765 ER PT J AU O'Grady, NP AF O'Grady, NP TI Dedicated catheter lumens for parenteral nutrition - Reply SO CLINICAL INFECTIOUS DISEASES LA English DT Letter C1 NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP O'Grady, NP (reprint author), NIH, Dept Crit Care Med, Bldg 10,Rm 7D43,10 Ctr Dr,MSC 1662, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 15 PY 2003 VL 36 IS 12 BP 1626 EP 1626 DI 10.1086/375092 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 688WJ UT WOS:000183460000024 ER PT J AU Klebanoff, MA Guise, JM Carey, JC AF Klebanoff, MA Guise, JM Carey, JC TI Treatment recommendations for bacterial vaginosis in pregnant women SO CLINICAL INFECTIOUS DISEASES LA English DT Letter ID PREVENT PRETERM DELIVERY; METRONIDAZOLE; VAGINALIS; BIRTH C1 NICHHD, NIH, Div Epidemiol Stat & Prevent Res, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR USA. Maricopa Integrated Hlth Syst & Med Professionals, Dept Obstet & Gynecol, Phoenix, AZ USA. RP Klebanoff, MA (reprint author), NICHHD, NIH, Div Epidemiol Stat & Prevent Res, Dept Hlth & Human Serv, 6100 Execut Blvd,Rm 7B05,MSC 7510, Bethesda, MD 20892 USA. OI Carey, J Christopher/0000-0002-1625-3948 NR 9 TC 7 Z9 8 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 15 PY 2003 VL 36 IS 12 BP 1630 EP 1631 DI 10.1086/375271 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 688WJ UT WOS:000183460000029 PM 12802775 ER PT J AU Cheng, AW Wang, SQ Cai, JL Rao, MS Mattson, MP AF Cheng, AW Wang, SQ Cai, JL Rao, MS Mattson, MP TI Nitric oxide acts in a positive feedback loop with BDNF to regulate neural progenitor cell proliferation and differentiation in the mammalian brain SO DEVELOPMENTAL BIOLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; LONG-TERM POTENTIATION; RAT CEREBRAL-CORTEX; CNS STEM-CELLS; NEUROTROPHIC FACTOR; SYNAPTIC PLASTICITY; DIETARY RESTRICTION; NEURONAL DIVERSITY; PRECURSOR CELLS; UP-REGULATION AB Nitric oxide (NO) is believed to act as an intercellular signal that regulates synaptic plasticity in mature neurons. We now report that NO also regulates the proliferation and differentiation of mouse brain neural progenitor cells (NPCs). Treatment of dissociated mouse cortical neuroepithelial cluster cell cultures with the NO synthase inhibitor L-NAME or the NO scavenger hemoglobin increased cell proliferation and decreased differentiation of the NPCs into neurons, whereas the NO donor sodium nitroprusside inhibited NPC proliferation and increased neuronal differentiation. Brain-derived neurotrophic factor (BDNF) reduced NPC proliferation and increased the expression of neuronal NO synthase (nNOS) in differentiating neurons. The stimulatory effect of BDNF on neuronal differentation of NPC was blocked by L-NAME and hemoglobin, suggesting that NO produced by the latter cells inhibited proliferation and induced neuronal differentiation of neighboring NPCs. A similar role for NO in regulating the switch of neural stem cells from proliferation to differentiation in the adult brain is suggested by data showing that NO synthase inhibition enhances NPC proliferation and inhibits neuronal differentiation in the subventricular zone of adult mice. These findings identify NO as a paracrine messenger stimulated by neurotrophin signaling in newly generated neurons to control the proliferation and differentiation of NPC, a novel mechanism for the regulation of developmental and adult neurogenesis. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NIA, Gerontol Res Ctr, Neurosci Lab, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Gerontol Res Ctr, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 62 TC 189 Z9 200 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 15 PY 2003 VL 258 IS 2 BP 319 EP 333 DI 10.1016/S0012-1606(03)00120-9 PG 15 WC Developmental Biology SC Developmental Biology GA 692TP UT WOS:000183676600007 PM 12798291 ER PT J AU Liu, K AF Liu, K TI The case for cancer immunotherapy SO DRUG DISCOVERY TODAY LA English DT Editorial Material ID METASTATIC MELANOMA; CHEMOTHERAPY PLUS; LYMPHOCYTES; LEUKEMIA C1 NCI, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Liu, K (reprint author), NCI, Canc Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6446 J9 DRUG DISCOV TODAY JI Drug Discov. Today PD JUN 15 PY 2003 VL 8 IS 12 BP 530 EP 531 AR PII S1359-6446(03)02727-2 DI 10.1016/S1359-6446(03)02727-2 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 690WE UT WOS:000183572800006 PM 12821297 ER PT J AU Taylor, JP Taye, AA Campbell, C Kazemi-Esfarjani, P Fischbeck, KH Min, KT AF Taylor, JP Taye, AA Campbell, C Kazemi-Esfarjani, P Fischbeck, KH Min, KT TI Aberrant histone acetylation, altered transcription, and retinal degeneration in a Drosophila model of polyglutamine disease are rescued by CREB-binding protein SO GENES & DEVELOPMENT LA English DT Article DE polyglutamine; Drosophila; CREB-binding protein (CBP); histone acetylation; gene expression analysis; retinal degeneration ID EXPANDED POLYGLUTAMINE; HUNTINGTONS-DISEASE; NEURODEGENERATION; TOXICITY; SUPPRESSION; GENES; CBP; ACETYLTRANSFERASES; SEQUESTRATION; PATHOGENESIS AB Sequestration of the transcriptional coactivator CREB-binding protein (CBP), a histone acetyltransferase, has been implicated in the pathogenesis of polyglutamine expansion neurodegenerative disease. We used a Drosophila model to demonstrate that polyglutamine-induced neurodegeneration is accompanied by a defect in histone acetylation and a substantial alteration in the transcription profile. Furthermore, we demonstrate complete functional and morphological rescue by up-regulation of endogenous Drosophila CBP (dCBP). Rescue of the degenerative phenotype is associated with eradication of polyglutamine aggregates, recovery of histone acetylation, and normalization of the transcription profile. These findings suggest that histone acetylation is an early target of polyglutamine toxicity and indicate that transcriptional dysregulation is an important part of the pathogenesis of polyglutamine-induced neurodegeneration. C1 NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. SUNY Buffalo, Ctr Neurosci, Dept Physiol & Biophys, Buffalo, NY 14214 USA. SRA Int Inc, Rockville, MD 20852 USA. RP Min, KT (reprint author), NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. EM mink@ninds.nih.gov OI min, kyung-tai/0000-0003-0983-4258 FU NINDS NIH HHS [K22 NS 44125, K22 NS044125] NR 32 TC 92 Z9 93 U1 0 U2 4 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUN 15 PY 2003 VL 17 IS 12 BP 1463 EP 1468 DI 10.1101/gad.1087503 PG 6 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 692WH UT WOS:000183682900004 PM 12815067 ER PT J AU Hummer, G Kevrekidis, IG AF Hummer, G Kevrekidis, IG TI Coarse molecular dynamics of a peptide fragment: Free energy, kinetics, and long-time dynamics computations SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID BIFURCATION-ANALYSIS; ALANINE DIPEPTIDE; OPTIMAL PREDICTION; AQUEOUS-SOLUTION; CONFORMATIONAL TRANSITIONS; GLOBAL BIFURCATIONS; INFREQUENT EVENTS; RATE CONSTANTS; RARE EVENTS; MEAN FORCE AB We present a "coarse molecular dynamics'' approach and apply it to studying the kinetics and thermodynamics of a peptide fragment dissolved in water. Short bursts of appropriately initialized simulations are used to infer the deterministic and stochastic components of the peptide motion parametrized by an appropriate set of coarse variables. Techniques from traditional numerical analysis (Newton-Raphson, coarse projective integration) are thus enabled; these techniques help analyze important features of the free-energy landscape (coarse transition states, eigenvalues and eigenvectors, transition rates, etc.). Reverse integration of coarse variables backward in time can assist escape from free energy minima and trace low-dimensional free energy surfaces. To illustrate the coarse molecular dynamics approach, we combine multiple short (0.5 ps) replica simulations to map the free energy surface of the "alanine dipeptide'' in water, and to determine the similar to1/(1000 ps) rate of interconversion between the two stable configurational basins corresponding to the alpha-helical and extended minima. (C) 2003 American Institute of Physics. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Princeton Univ, Princeton, NJ 08544 USA. RP Hummer, G (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 68 TC 152 Z9 153 U1 0 U2 22 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD JUN 15 PY 2003 VL 118 IS 23 BP 10762 EP 10773 DI 10.1063/1.1574777 PG 12 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 683AJ UT WOS:000183124300045 ER PT J AU Mancinelli, R Ceccanti, M Guiducci, MS Sasso, GF Sebastiani, G Attilia, ML Allen, JP AF Mancinelli, R Ceccanti, M Guiducci, MS Sasso, GF Sebastiani, G Attilia, ML Allen, JP TI Simultaneous liquid chromatographic assessment of thiamine, thiamine monophosphate and thiamine diphosphate in human erythrocytes: a study on alcoholics SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE alcohol-related problems; thiamine ID PHOSPHATE-ESTERS; TRANSKETOLASE ACTIVITY; DIFFERENT ORGANS; INVIVO KINETICS; BLOOD; DEFICIENCY; PYROPHOSPHATE; DEPHOSPHORYLATION; PHOSPHORYLATION; ELUTION AB An isocratic HPLC procedure for the assessment of thiamine (T), thiamine monophosphate (TMP) and thiamine diphosphate (TDP) in human erythrocytes is described. Several aspects of the procedure make it suitable for both clinical and research purposes: limits of detection and quantification of 1 and 2.5 nmol/l, respectively, recovery of 102% on average (range 93-112%), intra- and inter-day precisions within 5 and 9%, respectively, total elution time 15 min. This analytical methodology was applied to a case-control study on erythrocyte samples from 103 healthy subjects and 36 alcohol-dependent patients at risk of thiamine deficiency. Mean control values obtained were: T = 89.6 +/- 22.7 nmol/l, TMP = 4.4 +/- 6.6 nmol/l and TDP = 222.23 +/- 56.3 nmol/l. T and TDP mean values of alcoholics were significantly lower than those of control cases: T = 69.4 +/- 35.9 nmol/l (P < 0.001) and TDP = 127.4 +/- 62.5 nmol/l (p < 10(-5)). The diagnostic role of TDP was evaluated and a significant role for thiamine was established in the study of alcohol related problems. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Ist Super Sanita, Dept Clin Biochem, I-00161 Rome, Italy. Univ Roma La Sapienza, Alcohol Liver Dis Unit, Rome, Italy. NIAAA, Washington, DC USA. RP Ceccanti, M (reprint author), Via Giovanni Lanza 172, I-00184 Rome, Italy. OI CECCANTI, Mauro/0000-0001-9981-8715 NR 32 TC 51 Z9 52 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD JUN 15 PY 2003 VL 789 IS 2 BP 355 EP 363 DI 10.1016/S1570-0232(03)00139-9 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 679VB UT WOS:000182941700016 PM 12742126 ER PT J AU Harlan, LC Hankey, BF AF Harlan, LC Hankey, BF TI The surveillance, epidemiology, and end-results program database as a resource for conducting descriptive epidemiologic and clinical studies SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID BREAST-CANCER; WOMEN C1 NCI, Bethesda, MD 20892 USA. RP Harlan, LC (reprint author), NCI, Bethesda, MD 20892 USA. NR 10 TC 60 Z9 60 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 15 PY 2003 VL 21 IS 12 BP 2232 EP 2233 DI 10.1200/JCO.2003.94.023 PG 2 WC Oncology SC Oncology GA 690TG UT WOS:000183564800003 PM 12805320 ER PT J AU Anderson, WF Chu, KC Chang, S AF Anderson, WF Chu, KC Chang, S TI Inflammatory breast carcinoma and noninflammatory locally advanced breast carcinoma: Distinct clinicopathologic entities? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CANCER INCIDENCE; OVARIAN-CANCER; SURVEILLANCE; EPIDEMIOLOGY; WOMEN; RISK; SURVIVAL; PROGRAM; AGE AB Purpose: Inflammatory breast carcinoma (IBC) and noninflammatory locally advanced breast carcinoma (LABC) are both associated with poor prognosis; however, whether they are distinct clinicopathologic entities remains controversial. Materials and Methods: To determine whether IBC and LABC were different, we compared tumor characteristics, prognosis, and age-specific incidence rate patterns in the Surveillance, Epidemiology, and End-Results program. An age of 50 years served as a surrogate marker for menopause. Results: Younger age at diagnosis, poorer tumor grade, and negative estrogen receptors (ERs) were more predictive of IBC (n = 2,237) than of LABC in = 7,985). Breast carcinoma survival was worse for patients with IBC than for those with LARC (log-rank test, P < .0001). Age-specific incidence rates for IBC increased until 50 years and then flattened, whereas rates for LABC increased for all ages. When rates for LABC were stratified by estrogen receptor-positive (ERP) and -negative (ERN) expression, rates for ERP and ERN diverged, that is, rates for ERP increased with advancing age, whereas rates for ERN flattened after 50 years. When rates for IBC were stratified by ER expression, rates for both ERP and ERN flattened after 50 years of age. Conclusion: IBC and LABC seemed to be distinct biologic entities, as indicated by different prognostic factor profiles and age-specific incidence rate patterns. Rates that increased before 50 years and then stabilized, possibly indicated that premenopausal exposures had a greater effect on maintaining rates for IBC than for LABC. C1 NCI, Div Canc Prevent, EPN, Bethesda, MD 20892 USA. NCI, Ctr Reduce Canc Hlth Disparities, Bethesda, MD 20892 USA. RP Anderson, WF (reprint author), NCI, Div Canc Prevent, EPN, Room 2144,6130 Execut Blvd, Bethesda, MD 20892 USA. NR 40 TC 82 Z9 87 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 15 PY 2003 VL 21 IS 12 BP 2254 EP 2259 DI 10.1200/JCO.2003.07.082 PG 6 WC Oncology SC Oncology GA 690TG UT WOS:000183564800007 PM 12805323 ER PT J AU Fine, HA Wen, PY Maher, EA Viscosi, E Batchelor, T Lakhani, N Figg, WD Purow, BW Borkowf, CB AF Fine, HA Wen, PY Maher, EA Viscosi, E Batchelor, T Lakhani, N Figg, WD Purow, BW Borkowf, CB TI Phase II trial of thalidomide and carmustine for patients with recurrent high-grade gliomas SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; LEWIS LUNG-CARCINOMA; TUMOR-GROWTH; RADIATION-THERAPY; IN-VIVO; MALIGNANT GLIOMAS; BRAIN-TUMORS; 1ST RELAPSE; ANGIOGENESIS; ANGIOSTATIN AB Purpose: The use of thalidomide as an antiangiogenic agent has met with only limited success in the treatment of malignant gliomas. On the basis of preclinical data demonstrating synergistic antitumor activity when antiangiogenic agents are combined with cytotoxic agents, we explored the clinical activity of the combination of thalidomide and carmustine (BCNU) in patients with recurrent high-grade gliomas. Patients and Methods: Patients with a histologic diagnosis of high-grade glioma and radiographic evidence of tumor progression after standard surgery, radiation, and chemotherapy were eligible for the study. Patients received BCNU 200 mg/m(2) on day 1 of every 6-week cycle, and 800 mg/d of thalidomide that was escalated to a maximal dose of 1,200 mg/d as tolerated. Results: A total of 40 patients (38 with glioblastomas, two with anaplastic gliomas) were accrued to the study. The combination of thalidomide and BCNU was well tolerated; mild myelosuppression and mild to moderate sedation were the most common side effects. The median progression-free survival (100 days) and the objective radiographic response rate (24%) for patients with glioblastoma compared favorably with data from historical controls. Conclusion: This is one of the first clinical trials to evaluate the strategy of combining a putative antiangiogenic agent with a cytotoxic agent in patients with primary brain tumors. Our data demonstrate that thalidomide in combination with BCNU is well tolerated and has antitumor activity in patients with recurrent high-grade gliomas. Although the combination seems to be more active than either agent alone, such conclusions await confirmatory trials. C1 NCI, Neurooncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NINDS, NIH, Bethesda, MD 20892 USA. NCI, Canc Therapeut Branch, NIH, Bethesda, MD 20892 USA. NCI, Canc Prevent Branch, NIH, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Dept Neurol, Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Fine, HA (reprint author), NCI, Neurooncol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,MSC 1911,Bldg 10,Room 12S245, Bethesda, MD 20892 USA. EM hfine@mail.nih.gov RI Figg Sr, William/M-2411-2016 NR 37 TC 111 Z9 116 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 15 PY 2003 VL 21 IS 12 BP 2299 EP 2304 DI 10.1200/JCO.2003.08.045 PG 6 WC Oncology SC Oncology GA 690TG UT WOS:000183564800014 PM 12805330 ER PT J AU Schnipper, LE Atkins, M Beveridge, RA Brenner, D Bunn, P Coleman, E Comis, RL Einhorn, L Emanuel, E Fields, S Forastiere, A Gordon, BG Halberg, F Haluska, F Hortobagyi, G Kolker, A Miller, LL Norton, L Sallan, S Scherr, S Niederhuber, JE Baggstrom, MQ Balducci, L Bosserman, LD Bosworth, LL Brose, M Come, SE Cripe, LD Fisch, M Gesme, D Goldstein, N Gordon, BG Gostout, B Gralow, J Grunberg, SM Haluska, FG Hortobagyi, GN Klimberg, VS Kuzel, T Lessin, LS Pazdur, R Pfister, DG Raghavan, D Runowicz, CD Schnipper, LE Schuchter, LM Schwartz, BS Sigal, EV Stovall, E Ward, JH Zwelling, LA AF Schnipper, LE Atkins, M Beveridge, RA Brenner, D Bunn, P Coleman, E Comis, RL Einhorn, L Emanuel, E Fields, S Forastiere, A Gordon, BG Halberg, F Haluska, F Hortobagyi, G Kolker, A Miller, LL Norton, L Sallan, S Scherr, S Niederhuber, JE Baggstrom, MQ Balducci, L Bosserman, LD Bosworth, LL Brose, M Come, SE Cripe, LD Fisch, M Gesme, D Goldstein, N Gordon, BG Gostout, B Gralow, J Grunberg, SM Haluska, FG Hortobagyi, GN Klimberg, VS Kuzel, T Lessin, LS Pazdur, R Pfister, DG Raghavan, D Runowicz, CD Schnipper, LE Schuchter, LM Schwartz, BS Sigal, EV Stovall, E Ward, JH Zwelling, LA CA Amer Soc Clin Oncology TI American Society of Clinical Oncology policy statement: Oversight of clinical research SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article AB Well-publicized lapses in the review or implementation of clinical research studies have raised public questions about the integrity of the clinical research process. Public trust in the integrity of research is critical not only for funding and participation in clinical trials but also for confidence in the treatments that result from the trials. The questions raised by these unfortunate cases pose an important opportunity to reassess the clinical trials oversight system to ensure the integrity of clinical research and the safety of those who enroll in clinical trials. Since its inception, the American Society of Clinical Oncology (ASCO) has worked for the advancement of cancer treatments through clinical research and to help patients gain prompt access to scientifically excellent and ethically unimpeachable clinical trials. As an extension of its mission, ASCO is affirming with this policy statement the critical importance of a robust review and oversight system to ensure that clinical trials participants give fully informed consent and that their safety is a top priority. Ensuring the integrity of research cannot be stressed enough because of its seminal connection to the advancement of clinical cancer treatment. The overall goal of this policy is to enhance public trust in the cancer clinical trials process. To achieve this, the following elements are essential: 1. Ensure safety precautions for clinical trial participants and their fully informed consent. 2. Ensure the validity and integrity of scientific research. 3. Enhance the educational training of clinical scientists and research staff to ensure the highest standards of research conduct. 4. Promote accountability and responsibility among all those involved in clinical research (not just those serving on institutional review boards [IRBs], but also institutional officials, researchers, sponsors, and participants) and ensure support for an effective oversight process. 5. Enhance the professional and public understanding of clinical research oversight. 6. Enhance the efficiency and cost-effectiveness of the clinical research oversight system. This policy statement makes recommendations in several areas that serve as principles to support an improved system of oversight for clinical research. ASCO will work with all parties involved in the clinical research system to develop the steps necessary to implement these recommendations. Centralized Trial Review: A large percentage of oncology clinical trials are coordinated through the National Cancer Institute's (NCI) system of cooperative groups, which already incorporates centralized scientific review. As such, there is a tremendous opportunity to employ a centralized mechanism to provide ethical review by highly trained IRB members, allowing local IRBs to take advantage of the financial and time efficiencies that central review provides. Centralized review boards (CRBs) would also contribute consistency and efficiency to the process. Once successfully completed, the review would represent an approval to open the protocol at all of the institutions that have subscribed to the centralized review system. Local IRBs would be able to devote time usually spent on initial review to ongoing monitoring of the trial taking place at their institution. Considering the enormous size and complexity of the clinical research enterprise, ASCO envisions multiple CRBs, which could be distributed as regional review boards. Central review will use a single protocol and consent form, and monitor and evaluate adverse events (AEs) on a global basis, eliminating many of the time-consuming steps for the local IRB. Global monitoring and assessment of AEs has real potential to enhance trial participants' safety by giving local institutions more information on the overall trial and enabling them to devote more time to ongoing review of the trial onsite. Use of a CRB also has real potential to reduce the costs of clinical trial oversight by allowing local IRBs to eliminate the costs of initial review. These efficiencies will likely lead to institutions redirecting funds toward monitoring ongoing trials. Although a CRB has potential to improve the efficiency of the process, a CRB could also have tremendous ability to delay valuable trials. Checks and balances must be included in the newly devised system to ensure timely review and appeals of CRB actions. ASCO proposes the advent of a new pilot program for centralizing review of clinical trials. It requires clear engagement of all stakeholders in planning the experiment, clear articulation of the goals, and assurance of federal regulatory protection for institutions choosing to participate. If successful, this CRB pilot project could be expanded to include multi-institutional industry-sponsored research. Education and Training. Education and training are critical to the ultimate success of an improved oversight system. All members of the research team should receive comprehensive education on conducting scientifically and ethically valid clinical research. The curriculum should also include information an the prevailing local and federal regulations that pertain to the clinical trials process. IRB members should also receive ongoing education and training in the review of clinical research protocols. IRB training should pay particular attention to nonscientific members to give them the toots necessary to speak on behalf of research participants. ASCO should develop a curriculum that focuses on the proper conduct of human research and emphasize ethically sound clinical research in the context of its Annual Meeting. Informed Consent: Investigators and review boards have specific roles to play in ensuring the education of trial participants through the informed consent process, both when they are considering trial enrollment and as they participate in the trial. Review boards and investigators should focus primarily on the informed consent process, rather than the informed consent documents. Federal Oversight: The federal government has an important role to play in the oversight of clinical research. This role should be expanded to cover all research, not just that which is funded by the federal government or conducted with the oversight of the Food and Drug Administration (FDA). The Department of Health and Human Services (HHS) Office for Human Research Protections (OHRP) and the FDA should provide dear regulatory support and guidance for local institutions that choose to employ a CRB. In the case, of the pilot CRB discussed in this policy statement, it should serve as the preferred option for the cancer cooperative group clinical trials. Ideally, the federal government should unify and streamline its regulations for the oversight of clinical research. Resources Supporting Clinical Research Infrastructure: An effective oversight process demands the highest quality scientific and ethical review and onsite monitoring of the safety of trial participants. This can only be accomplished by the involvement of an experienced IRB that receives funding, resources, and institutional support enabling it to fulfill its mandate. Conflict of interest: Critical to the integrity of research is the absence of bias in the process. ASCO strongly recommends the adoption of standards for the identification, management, and, where appropriate, elimination of conflicts of interests, whether they are actual, potential, or apparent. C1 Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Inova Fairfax Hosp, Alexandria, VA USA. Univ Michigan, Med Ctr, Ann Arbor, MI USA. Univ Colorado, Ctr Canc, Denver, CO 80262 USA. Canc Care Inc, New York, NY USA. Eastern Cooperat Oncol Grp, Philadelphia, PA USA. Indiana Univ, Canc Pavil, Indianapolis, IN 46204 USA. NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. Amgen Inc, Thousand Oaks, CA 91320 USA. Johns Hopkins Univ, Ctr Oncol, Baltimore, MD 21205 USA. Univ Nebraska, Med Ctr, Omaha, NE USA. Marin Canc Inst, Greenbrae, CA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Ovarian Canc Natl Alliance, Washington, DC USA. Pharmacia Corp, Peapack, NJ USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Natl Coalit Canc Survivorship, Silver Spring, MD USA. Amer Soc Clin Oncol Canc Policy & Clin Affairs, Alexandria, VA 22314 USA. NR 11 TC 32 Z9 33 U1 1 U2 15 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 15 PY 2003 VL 21 IS 12 BP 2377 EP 2386 DI 10.1200/JCO.2003.04.026 PG 10 WC Oncology SC Oncology GA 690TG UT WOS:000183564800025 ER PT J AU Bruinooge, SS AF Bruinooge, SS CA ASCO TI American Society of Clinical Oncology policy statement update: Genetic testing for cancer susceptibility SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID INFORMED CONSENT; ADOLESCENTS; EXPRESSION; EDUCATION; CHILDREN; TISSUE AB As the leading organization representing cancer specialists involved in patient care and clinical research, the American Society of Clinical Oncology (ASCO) reaffirms its commitment to integrating cancer risk assessment and management, including molecular analysis of cancer predisposition genes, into the practice of oncology and preventive medicine. The primary goal of this effort is to foster expanded access to, and continued advances in, medical care provided to patients and families affected by hereditary cancer syndromes. The 1996 ASCO Statement on Genetic Testing for Cancer Susceptibility set forth specific recommendations relating to clinical practice, research needs, educational opportunities, requirement for informed consent, indications for genetic testing, regulation of laboratories, and protection from discrimination, as well as access to and reimbursement for cancer genetics services. In updating this Statement, ASCO endorses the following principles: Indications for Genetic Testing: ASCO recommends that genetic testing be offered when 1) the individual has personal or family history features suggestive of a genetic cancer susceptibility condition, 2) the test can be adequately interpreted, and 3) the results will aid in diagnosis or influence the medical or surgical management of the patient or family members at hereditary risk of cancer. ASCO recommends that genetic testing only be done in the setting of pre- and post-test counseling, which should include discussion of possible risks and benefits of cancer early detection and prevention modalities. Special Issues in Testing Children for Cancer Susceptibility: ASCO recommends that the decision to offer testing to potentially affected children should take into account the availability of evidence-based risk-reduction strategies and the probability of developing a malignancy during childhood. Where risk-reduction strategies are available or cancer predominantly develops in childhood, ASCO believes that the scope of parental authority encompasses the eight to decide for or against testing. In the absence of increased risk of a childhood malignancy, ASCO recommends delaying genetic testing until an individual is of sufficient age to make an informed decision regarding such tests. As in other areas of pediatric care, the clinical cancer genetics professional should be an advocate for the best interests of the child. Counseling About Medical Management After Testing. ASCO recommends that oncologists include in pre- and post-test counseling the discussion of possible risks and benefits of cancer early-detection and prevention modalities, some of which have presumed but unproven efficacy for individuals at increased hereditary risk of cancer. Regulation of Genetic Testing: ASCO recommends strengthening regulatory oversight of laboratories that provide clinical cancer predisposition tests. These quality assurance mechanisms should include oversight of the reagents used in genetic testing, interlaboratory comparisons of reference samples, standardization of laboratory genetic test reports, and proficiency testing. Protection From Insurance and Employment Discrimination: ASCO supports establishing a federal law to prohibit discrimination by health insurance providers and employers on the basis of an individual's inherited susceptibility to cancer. Protections against genetic discrimination should apply to those with group coverage, those with individual health insurance policies, and the uninsured. Coverage of Services: ASCO supports efforts to ensure that all individuals at significantly increased risk of hereditary cancer have access to appropriate genetic counseling, testing, screening, surveillance, and all related medical and surgical interventions, which should be covered without penalty by public and private third-party payers. Confidentiality and Communication of Familial Risk. ASCO recommends that providers make concerted efforts to protect the confidentiality of genetic information. However, they should remind patients of the importance of communicating test results to family members, as part of pretest counseling and informed consent discussions. ASCO believes that the cancer care provider's obligations (if any) to at-risk relatives are best fulfilled by communication of familial risk to the person undergoing testing, emphasizing the importance of sharing this information with family members so that they may also benefit. Educational Opportunities in Genetics: ASCO is committed to continuing to provide educational opportunities for physicians and other health care providers regarding the methods of cancer risk assessment, the clinical characteristics of hereditary cancer susceptibility syndromes, and the range of issues related to genetic testing, including pre- and post-test genetic counseling, and risk management, so that health professionals may responsibly integrate the care of persons at increased genetic risk of cancer into the practice of clinical and preventive oncology. Special Issues Relating to Genetic Research on Human Tissues. ASCO recommends that all researchers proposing to use or store human biologic specimens for genetic studies should consult either the responsible institutional review board (IRS) or a comparable body specifically constituted to assess human tissue research, to determine the requirements for protection specific to the study under consideration. This consultation should take place before the project is initiated. The determination of the need for informed consent or authorization in such studies should depend on whether the research involves tests for genetic markers of known clinical significance and whether research data will be linked to protected health information, as well as other considerations specific to the study proposed. Special attention should also be paid to 1) whether future research findings Will be disclosed to the research participants, 2) whether future contact of participants is planned, 3) whether and how protected health information about the tissue donors will, be stared, and what will happen to study specimens after the trial ends. In addition, ASCO affirms the right of people contributing tissue to a databank to rescind their permission, in accordance with federal privacy regulations. C1 Amer Soc Clin Oncol, Alexandria, VA 22314 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Albert Einstein Coll Med, Oakland, CA USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NCI, NIH, Rockville, MD USA. Univ Michigan, Ann Arbor, MI 48109 USA. Marin Canc Inst, Greenbrae, CA USA. James Canc Hosp & Res Inst, Columbus, OH USA. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Amer Coll Med Genet, Bethesda, MD USA. Univ Penn, Ctr Canc, Philadelphia, PA 19104 USA. City Hope Natl Med Ctr, Duarte, CA 91010 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. RP Bruinooge, SS (reprint author), Amer Soc Clin Oncol, 1900 Duke St,Suite 200, Alexandria, VA 22314 USA. NR 24 TC 367 Z9 373 U1 1 U2 22 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 15 PY 2003 VL 21 IS 12 BP 2397 EP 2406 DI 10.1200/JCO.2003.03.189 PG 10 WC Oncology SC Oncology GA 690TG UT WOS:000183564800028 ER PT J AU Malaspina, A Moir, S Kottilil, S Hallahan, CW Ehler, LA Liu, SY Planta, MA Chun, TW Fauci, AS AF Malaspina, A Moir, S Kottilil, S Hallahan, CW Ehler, LA Liu, SY Planta, MA Chun, TW Fauci, AS TI Deleterious effect of HIV-1 plasma viremia on B cell costimulatory function SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; T-CELLS; INFECTED INDIVIDUALS; CD86 EXPRESSION; ANTIBODY-RESPONSE; GERMINAL-CENTERS; LYMPHOID-TISSUE; ACTIVATION; RECEPTOR; VIRUS AB HIV infection leads to numerous immunologic defects, including impaired B cell function. An effective Immoral response requires bidirectional interactions between B cells and CD4(+) T cells, critical of which are interactions between CD80/CD86 expressed on activated B cells and CD28 expressed on responder CD4(+) T cells. In the present study, we examined the effect of active HIV replication on B cell costimulatory function. Induction of CD80/CD86 on B cells following B cell receptor and CD40 triggering and responsiveness of CD4(+) T cells to activated B cells were investigated in a system where B cells of HIV-infected patients were compared concurrently to B cells of HIV-negative donors. In contrast to HIV-aviremic patients, B cells of HIV-viremic patients were ineffective at stimulating CD4(+) T cells, as measured by the induction of activation markers and proliferation. The importance of interactions of CD80/CD86 and CD28 in activating CD4(+) T cells was clear; the ablation of a normal response following the addition of neutralizing anti-CD86/CD80 Abs mirrored the response of CD4(+) T cells to B cells of HIV-viremic patients, while the addition of exogenous CD28 ligands partially restored the poor CD4(+) T cell response to the B cells of HIV-viremic. patients. Ineffective B cell costimulatory function in HIV-viremic patients was associated with low induction of CD80/CD86 expression on B cells. Our findings further delineate the scope of defects associated with cognate B cell-CD4(+) T cell interactions in HIV infection and suggest that therapeutic interventions designed to enhance CD28-dependent costimulatory pathways may help restore immune functions. C1 NIAID, Immunoregulat Lab, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Moir, S (reprint author), NIAID, Immunoregulat Lab, Dept Hlth & Human Serv, NIH, Bldg 10,Room 6A02,10 Ctr Dr, Bethesda, MD 20892 USA. NR 43 TC 70 Z9 74 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2003 VL 170 IS 12 BP 5965 EP 5972 PG 8 WC Immunology SC Immunology GA 688AZ UT WOS:000183411100020 PM 12794123 ER PT J AU Liu, KB Abrams, SI AF Liu, KB Abrams, SI TI Alterations in Fas expression are characteristic of, but not solely responsible for, enhanced metastatic competence SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LYMPHOCYTE-MEDIATED CYTOTOXICITY; FLICE-INHIBITORY PROTEIN; LIGAND INTERACTIONS; IMMUNE ESCAPE; T-CELLS; ANTIGEN; TUMORS; APOPTOSIS; INDUCTION; DISEASE AB Dysregulation of the Fas pathway has been implicated in tumor progression; however, how alterations in Fas expression influence metastatic behavior remains unresolved. In this study, we investigated the link between Fas expression and metastatic capacity in two mouse tumor models: one was a sarcoma, which was used to analyze the consequences of loss of Fas function in experimental pulmonary metastases, and the other was a mammary carcinoma, where Fas expression was examined in matched pairs of primary and metastatic cell lines as well as by immunohistochemistry of tissues taken from primary and metastatic sites of spontaneous tumor development. In the sarcoma model, a Fas-resistant/refractory subline was produced in vitro from the parental line by biologic selection against Fas-responsive cells, and it was then compared with the poorly metastatic parental line and to an in vivo-derived subline that was highly metastatic for growth in the lungs. In both tumor models, an inverse correlation was demonstrated between Fas expression and metastatic phenotype. Subsequent studies in the sarcoma model revealed that although the Fas-resistant/refractory subline displayed significant metastatic ability, the parental line from which it was derived exhibited little to no additional metastatic activity if experimentally rendered Fas-resistant by molecular-based strategies or transplanted into a Fas ligand-deficient host. Therefore, these findings suggested that down-regulation of Fas was associated with the metastatic phenotype, but alterations in Fas expression alone were insufficient for acquisition of full metastatic potential. Rather, the ability of such Fas-resistant neoplastic subpopulations to achieve metastatic competence apparently required co-possession of additional malignant characteristics. C1 NCI, Ctr Canc Res, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. RP Abrams, SI (reprint author), NCI, Ctr Canc Res, Tumor Immunol & Biol Lab, Bldg 10,Room 5B46,10 Ctr Dr, Bethesda, MD 20892 USA. OI Liu, Kebin/0000-0003-1965-7240 NR 20 TC 20 Z9 21 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2003 VL 170 IS 12 BP 5973 EP 5980 PG 8 WC Immunology SC Immunology GA 688AZ UT WOS:000183411100021 PM 12794124 ER PT J AU Aringer, M Hofmann, SR Frucht, DM Chen, M Centola, M Morinobu, A Visconti, R Kastner, DL Smolen, JS O'Shea, JJ AF Aringer, M Hofmann, SR Frucht, DM Chen, M Centola, M Morinobu, A Visconti, R Kastner, DL Smolen, JS O'Shea, JJ TI Characterization and analysis of the proximal Janus kinase 3 promoter SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; COMPLETE GENOMIC ORGANIZATION; PROTEIN-TYROSINE KINASES; NATURAL-KILLER-CELLS; COMMON GAMMA-CHAIN; MICE LACKING JAK3; T-CELLS; TRANSCRIPTION FACTORS; MOLECULAR-CLONING; INTERLEUKIN-2 DEFICIENT AB Janus kinase 3 (Jak3) is a nonreceptor tyrosine kinase essential for signaling via cytokine receptors that comprise the common gamma-chain (gammac), i.e., the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Jak3 is preferentially expressed in hemopoietic cells and is up-regulated upon cell differentiation and activation. Despite the importance of Jak3 in lymphoid development and immune function, the mechanisms that govern its expression have not been defined. To gain insight into this issue, we set out to characterize the Jak3 promoter. The 5'-untranslated region of the Jak3 gene is interrupted by a 3515-bp intron. Upstream of this intron and the transcription initiation site, we identified an similar to1-kb segment that exhibited lymphoid-specific promoter activity and was responsive to TCR signals. Truncation of this fragment revealed that core promoter activity resided in a 267-bp fragment that contains putative Sp-1, AP-1, Ets, Stat, and other binding sites. Mutation of the AP-1 sites significantly diminished, whereas mutation of the Ets sites abolished, the inducibility of the promoter construct. Chromatin immunoprecipitation assays showed that histone acetylation correlates with mRNA expression and that Ets-1/2 binds this region. Thus, transcription factors that bind these sites, especially Ets family members, are likely to be important regulators of Jak3 expression. C1 NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. Univ Vienna, Dept Rheumatol, Vienna, Austria. RP O'Shea, JJ (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, 10 Ctr Dr,MSC-1820,Bldg 10,Room 9N252, Bethesda, MD 20892 USA. RI Visconti, Roberta/C-5299-2009 NR 55 TC 18 Z9 21 U1 1 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2003 VL 170 IS 12 BP 6057 EP 6064 PG 8 WC Immunology SC Immunology GA 688AZ UT WOS:000183411100031 PM 12794134 ER PT J AU Faure, M Barber, DF Takahashi, SM Jin, T Long, EO AF Faure, M Barber, DF Takahashi, SM Jin, T Long, EO TI Spontaneous clustering and tyrosine phosphorylation of NK cell inhibitory receptor induced by ligand binding SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; DROSOPHILA-MELANOGASTER CELLS; CLASS-I MOLECULES; COMPLEX CLASS-I; IMMUNE SYNAPSE; CD28-MEDIATED CYTOTOXICITY; CYTOLYTIC INTERACTIONS; TARGET-CELLS; CUTTING EDGE; HLA-C AB Inhibition of NK cell cytotoxicity by killer cell Ig-like receptors (KIR) depends on phosphorylation of cytoplasmic tyrosines in KIR, which recruit tyrosine phosphatase Src homology protein tyrosine phosphatase 1. It is not clear how KIR, whose function lies downstream of a tyrosine kinase, succeeds in blocking proximal NK cell activation signals upon binding HLA class I on target cells. Here we show that mixing NK cells with insect cells expressing HLA-C was sufficient to induce clustering of KIR, and phosphorylation of KIR and SHP-1. Transient phosphorylation of KIR was detected in the presence of pervanadate, an inhibitor of protein tyrosine phosphatases, at suboptimal concentration. Phosphorylation of KIR was specifically induced by ligand binding because it was detected only when HLA-C was loaded with a peptide that permits KIR binding. KIR phosphorylation was not dependent on ICAM-1-mediated adhesion and was not blocked by inhibition of actin polymerization, but required Zn2+. Fluorescence resonance energy transfer between HLA-C molecules revealed close molecular interactions induced by KIR binding. These results demonstrate tight clustering of KIR and rapid KIR phosphorylation induced simply by binding to HLA-C. The unique property of KIR to become phosphorylated in the absence of adhesion and of actin cytoskeleton rearrangement explains how KIR can efficiently block early activation signals during NK-target cell contacts. C1 NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Long, EO (reprint author), NIAID, Immunogenet Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. RI Barber, Domingo/G-1257-2010; Long, Eric/G-5475-2011 OI Barber, Domingo/0000-0001-8824-5405; Long, Eric/0000-0002-7793-3728 NR 54 TC 44 Z9 44 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2003 VL 170 IS 12 BP 6107 EP 6114 PG 8 WC Immunology SC Immunology GA 688AZ UT WOS:000183411100037 PM 12794140 ER PT J AU Lai, WC Zhou, M Shankavaram, U Peng, G Wahl, LM AF Lai, WC Zhou, M Shankavaram, U Peng, G Wahl, LM TI Differential regulation of lipopolysaccharide-induced monocyte matrix metalloproteinase (MMP)-1 and MMP-9 by p38 and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CYTOSOLIC PHOSPHOLIPASE A(2); PROSTAGLANDIN-H SYNTHASE-2; INFLAMMATORY CYTOKINES; EXPRESSION; INHIBITION; INDUCTION; COLLAGENASE; PATHWAYS; STRESS; SUPPRESSION AB Signal transduction events in monocyte matrix metalloproteinase (MMIP) production have been shown to include a PGE(2)-cAMP-dependent step. To determine earlier pathway components, we examined the role of mitogen-activated protein kinases (MAPKs) in the regulation of monocyte MMP-1 and MMP-9, two major MMPs induced by LPS. Stimulation with LPS resulted in the activation of the extracellular signal-regulated kinase 1 and 2 (ERK1/2) and mitogen-activated kinase p38. The p38-specific inhibitor SB203580 suppressed p38 activity and MMP-1 mRNA and protein, but increased ERK activity and MMP-9 mRNA and protein. In contrast, the MAPK kinase 1/2-specific inhibitor PD98059 inhibited MMP-1 and MMP-9. However, both MAPK inhibitors decreased the production of cyclooxygenase-2 and PGE(2), but only the inhibition of MMP-1 by SB203580 was reversed by PGE(2) or dibutyryl cAMP. Examination of the effect of these MAPK inhibitors on the promoters of MMP-1 and MMP-9 revealed that PD98059 inhibited the binding of transcription factors to all of the MMP promoter-specific complementary oligonucleotides tested. However, SB203580 only inhibited the binding of MMP-1-specific CREB and SP 1 oligonucleotides, which was reversed by PGE(2). Additionally, SB203580 enhanced transcription factor binding to the oligonucleotides complementary to a NF-kappaB site in the promoter of MMP-9. Thus, LPS induction of MMP-1 production by monocytes is regulated by both ERK1/2 and p38, whereas MMP-9 stimulation occurred mainly through the ERK1/2 pathway. Moreover, p38 regulates MMP-1 mainly through a PGE(2)-dependent pathway, whereas ERK1/2-mediated MMP-1 and MMP-9 production involves the activation of additional MNIP promoter sites through a PGE(2)-independent mechanism. C1 Natl Inst Dent & Craniofacial Res, Immunopathol Sect, NIH, Bethesda, MD 20892 USA. RP Wahl, LM (reprint author), Natl Inst Dent & Craniofacial Res, Immunopathol Sect, NIH, 30 Convent Dr,Bldg 30,Rm 325, Bethesda, MD 20892 USA. NR 26 TC 118 Z9 128 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 JUN 15 PY 2003 VL 170 IS 12 BP 6244 EP 6249 PG 6 WC Immunology SC Immunology GA 688AZ UT WOS:000183411100053 PM 12794156 ER PT J AU Liu, KB Abrams, SI AF Liu, KB Abrams, SI TI Coordinate regulation of IFN consensus sequence-binding protein and caspase-1 in the sensitization of human colon carcinoma cells to Fas-mediated apoptosis by IFN-gamma SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTERFERON-GAMMA; IN-VIVO; RECEPTOR SUPERFAMILY; LIGAND INTERACTIONS; TUMOR-DEVELOPMENT; GENE-EXPRESSION; IMMUNE-SYSTEM; T-CELLS; INDUCTION; ANTIGEN AB Interferon-gamma is thought to be essential for the regulation of antitumor reactions. However, the degree of responsiveness of malignant cells to IFN-gamma may have a profound influence on the overall efficacy of an antitumor response. In this study, we examined the molecular basis by which IFN-gamma differentially sensitized human primary and metastatic colon carcinoma cells to Fas-mediated apoptosis. To that end, we analyzed IFN-gamma-induced gene expression at the genome scale, followed by an analysis of the expression and function of specific genes associated with IFN-gamma- and Fas-mediated signaling. We found that although both cell populations exhibited a similar gene expression profile at the genome scale in response to IFN-gamma, the expression intensities of the IFN-gamma-regulated genes were much greater in the primary tumor. Noteworthily, two genes, one involved in IFN-gamma-mediated signaling, IFN consensus sequence-binding protein (ICSBP), and one involved in Fas-mediated signaling, caspase-1, were clearly shown to be differentially induced between the two cell lines. In the primary tumor cells, the expression of ICSBP and caspase-1 was strongly induced in response to IFN-gamma; whereas they were weakly to nondetectable in the metastatic tumor cells. Functional studies demonstrated that both caspase-1 and ICSBP were involved in Fas-mediated apoptosis following IFN-gamma sensitization, but proceeded via two distinct pathways. This study also reports for the first time the expression of ICSBP in a nonhemopoietic tumor exhibiting proapoptotic properties. Overall, in a human colon carcinoma cell model, we identified important functional contributions of two IFN-gamma-regulated genes, ICSBP and caspase-1, in the mechanism of Fas-mediated death. C1 NCI, Ctr Canc Res, Lab Tumor Immunol & Biol, NIH, Bethesda, MD 20892 USA. RP Abrams, SI (reprint author), NCI, Ctr Canc Res, Lab Tumor Immunol & Biol, NIH, Bldg 10,Rm 5B46,10 Ctr Dr, Bethesda, MD 20892 USA. OI Liu, Kebin/0000-0003-1965-7240 NR 43 TC 34 Z9 34 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2003 VL 170 IS 12 BP 6329 EP 6337 PG 9 WC Immunology SC Immunology GA 688AZ UT WOS:000183411100063 PM 12794166 ER PT J AU Chakraborty, M Abrams, SI Camphausen, K Liu, KB Scott, T Coleman, CN Hodge, JW AF Chakraborty, M Abrams, SI Camphausen, K Liu, KB Scott, T Coleman, CN Hodge, JW TI Irradiation of tumor cells up-regulates Fas and enhances CTL lytic activity and CTL adoptive immunotherapy SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN CARCINOEMBRYONIC ANTIGEN; CEA TRANSGENIC MICE; IONIZING-RADIATION; CYTOTOXIC LYMPHOCYTES; CANCER-IMMUNOTHERAPY; RECOMBINANT VACCINES; INDUCED EXPRESSION; ENDOTHELIAL-CELLS; IMMUNE-RESPONSES; CARCINOMA-CELLS AB CD8(+) CTL play important roles against malignancy in both active and passive immunotherapy. Nonetheless, the success of antitumor CTL responses may be improved by additional therapeutic modalities. Radiotherapy, which has a long-standing use in treating neoplastic disease, has been found to induce unique biologic alterations in cancer cells affecting Fas gene expression, which, consequently, may influence the overall lytic efficiency of CTL. Here, in a mouse adenocarcinoma cell model, we examined whether exposure of these tumor cells to sublethal doses of irradiation 1) enhances Fas expression, leading to more efficient CTL killing via Fas-dependent mechanisms in vitro; and 2) improves antitumor activity in vivo by adoptive transfer of these Ag-specific CTL. Treatment of carcinoembryonic Ag-expressing MC38 adenocarcinoma cells with irradiation (20 Gy) in vitro enhanced Fas expression at molecular, phenotypic, and functional levels. Furthermore, irradiation sensitized these targets to Ag-specific CTL killing via the Fas/Fas ligand pathway. We examined the effect of localized irradiation of s.c. growing tumors on the efficiency of CTL adoptive immunotherapy. Irradiation caused up-regulation of Fas by these tumor cells in situ, based on immunohistochemistry. Moreover, localized irradiation of the tumor significantly potentiated tumor rejection by these carcinoembryonic Ag-specific CTL. Overall, these results showed for the first time that 1) regulation of the Fas pathway in tumor cells by irradiation plays an important role in their sensitization to Ag-specific CTL; and 2) a combination regimen of tumor-targeted irradiation and CTL promotes more effective antitumor responses in vivo, which may have implications for the combination of immunotherapy and radiation therapy. C1 NCI, Canc Res Ctr, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Hodge, JW (reprint author), NCI, Canc Res Ctr, Tumor Immunol & Biol Lab, NIH, 10 Ctr Dr,Bldg 10,Rm 8B09,MSC 1750, Bethesda, MD 20892 USA. RI Hodge, James/D-5518-2015; OI Hodge, James/0000-0001-5282-3154; Liu, Kebin/0000-0003-1965-7240 NR 60 TC 186 Z9 192 U1 0 U2 9 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2003 VL 170 IS 12 BP 6338 EP 6347 PG 10 WC Immunology SC Immunology GA 688AZ UT WOS:000183411100064 PM 12794167 ER PT J AU Novellino, L Renkvist, N Rini, F Mazzocchi, A Rivoltini, L Greco, A Deho, P Squarcina, P Robbins, PF Parmiani, G Castelli, C AF Novellino, L Renkvist, N Rini, F Mazzocchi, A Rivoltini, L Greco, A Deho, P Squarcina, P Robbins, PF Parmiani, G Castelli, C TI Identification of a mutated receptor-like protein tyrosine phosphatase kappa as a novel, class IIHLA-restricted melanoma antigen SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD4(+) T-CELLS; CLASS-II MOLECULES; R-PTP-KAPPA; ANTITUMOR IMMUNITY; TUMOR-ANTIGENS; HIGH-FREQUENCY; LYMPHOCYTES; PEPTIDE; GENE; RESPONSES AB Recent studies increasingly point to a pivotal role of CD4(+) T cells in human anti-tumor immune response. Here we show that lymphocytes purified from a tumor-infiltrated lymph node of a melanoma patient that had remained disease free for 10 years after surgical resection of a lymph node metastasis comprised oligoclonal class II HLA-restricted CD4(+) T cells recognizing the autologous tumor cells in vitro. In fact, the CD4(+) T cell clones isolated from these lymphocytes displayed a tumor-specific, cytotoxic activity in addition to a Th1-like cytokine profile. By a genetic approach, a peptide derived from a mutated receptor-like protein tyrosine phosphatase kappa was identified as a novel HLA-DR10-restricted epitope for all the melanoma-specific CD4(+) T cell clones. The immunogenic peptide was shown to contain the mutated residue that was crucial for T cell recognition and activation. Moreover, a systemic immunity against the mutated peptide was detectable in the patient's peripheral blood T lymphocytes obtained during the disease-free period of follow-up. These findings further support the relevance of CD4(+) T cells directed against mutated epitopes in tumor immunity and provide the rationale for a possible usage of mutated, tumor-specific Ags for immunotherapy of human cancer. C1 Ist Nazl Tumori, Unit Immunotherapy Human Tumors, I-20133 Milan, Italy. Ist Nazl Tumori, Unit Mol Mech Tumor Growth & Progress, I-20133 Milan, Italy. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Castelli, C (reprint author), Ist Nazl Tumori, Unit Immunotherapy Human Tumors, Via Venezian 1, I-20133 Milan, Italy. RI Greco, Angela/C-1953-2017; castelli, chiara/K-6899-2012; OI Greco, Angela/0000-0003-2994-0349; castelli, chiara/0000-0001-6891-8350; Rivoltini, Licia/0000-0002-2409-6225 NR 42 TC 25 Z9 25 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2003 VL 170 IS 12 BP 6363 EP 6370 PG 8 WC Immunology SC Immunology GA 688AZ UT WOS:000183411100067 PM 12794170 ER PT J AU Petraitis, V Petraitiene, R Sarafandi, AA Keleher, AM Lyman, CA Casler, HE Sein, T Groll, AH Becher, J Avila, NA Walsh, TJ AF Petraitis, V Petraitiene, R Sarafandi, AA Keleher, AM Lyman, CA Casler, HE Sein, T Groll, AH Becher, J Avila, NA Walsh, TJ TI Combination therapy in treatment of experimental pulmonary aspergillosis: Synergistic interaction between an antifungal triazole and an echinocandin SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID INVASIVE FUNGAL-INFECTIONS; GUINEA-PIG MODEL; AMPHOTERICIN-B; IN-VITRO; DISSEMINATED CANDIDIASIS; CASPOFUNGIN ACETATE; FILAMENTOUS FUNGI; MICAFUNGIN FK463; ITRACONAZOLE; EFFICACY AB Invasive pulmonary aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Simultaneous inhibition of fungal cell-wall and cell-membrane biosynthesis may result in synergistic interaction against Aspergillus fumigatus. We studied the antifungal activity of micafangin, a new echinocandin, in combination with ravuconazole, a second-generation triazole, against experimental invasive pulmonary aspergillosis in persistently neutropenic rabbits. This combination led to significant reductions in mortality (P less than or equal to .001), residual fungal burden (P less than or equal to .05), and serum galactomannan antigenemia (P less than or equal to .01), compared with either agent alone. Combination therapy also resulted in reduction (P less than or equal to .05) of organism-mediated pulmonary injury and of pulmonary infiltrates detected by thoracic computed tomography (P less than or equal to .001). No toxicity was observed with the echinocandin-triazole combination. An MTT hyphal damage assay demonstrated significant in vitro synergistic interaction between the antifungal triazole and the echinocandin. The combination of an antifungal triazole and echinocandin may represent a new strategy for treatment of invasive pulmonary aspergillosis. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Radiol, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Surg Serv, Vet Resources Program,Off Res Serv, Bethesda, MD 20892 USA. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bldg 10,Rm 13N240,10 Ctr Dr, Bethesda, MD 20892 USA. NR 49 TC 161 Z9 166 U1 1 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 15 PY 2003 VL 187 IS 12 BP 1834 EP 1843 DI 10.1086/375420 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 693NA UT WOS:000183722600002 PM 12792859 ER PT J AU Bishop, LR Kovacs, JA AF Bishop, LR Kovacs, JA TI Quantitation of anti-Pneumocystis jiroveci antibodies in healthy persons and immunocompromised patients SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID MAJOR SURFACE GLYCOPROTEIN; VIRUS-INFECTED PATIENTS; CARINII; RESPONSES; GENES; HUMANS AB To facilitate studies of the epidemiology of Pneumocystis jiroveci infection in both healthy persons and immunocompromised patients, we developed a quantitative ELISA with recombinant major surface glycoprotein (MSG) fragment MSG-14, a P. jiroveci-specific protein that includes a highly conserved region of the MSG protein family. By immunoblot, all samples reacted with the carboxyl portion of MSG-14; by ELISA, immunocompromised patients with Pneumocystis pneumonia (PCP) who were immunocompromised for reasons other than AIDS, had higher antibody levels than did either patients with AIDS with PCP (P = .01) or healthy persons (P = .005). Longitudinal observations of 8 patients with AIDS showed no correlation between time of diagnosis of Pneumocystis infection and change in antibody levels. Eleven percent (4/35) of healthy persons demonstrated a >4-fold change in antibody titers during 1 year of observation. This ELISA assay allows quantitation of anti-P. jiroveci antibodies in human serum samples and should be useful in better understanding the epidemiology of P. jiroveci infection in humans. C1 NIH, Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Kovacs, JA (reprint author), Bldg 10,Rm 7D43,MSC 1662, Bethesda, MD 20892 USA. NR 15 TC 30 Z9 30 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 15 PY 2003 VL 187 IS 12 BP 1844 EP 1848 DI 10.1086/375354 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 693NA UT WOS:000183722600003 PM 12792860 ER PT J AU Kalayjian, RC Landay, A Pollard, RB Taub, DD Gross, BH Francis, IR Sevin, A Pu, MY Spritzler, J Chernoff, M Namkung, A Fox, L Martinez, A Waterman, K Fiscus, SA Sha, B Johnson, D Slater, S Rousseau, F Lederman, MM AF Kalayjian, RC Landay, A Pollard, RB Taub, DD Gross, BH Francis, IR Sevin, A Pu, MY Spritzler, J Chernoff, M Namkung, A Fox, L Martinez, A Waterman, K Fiscus, SA Sha, B Johnson, D Slater, S Rousseau, F Lederman, MM CA Adult AIDS Clin Trials Grp 5015 5113 TI Age-related immune dysfunction in health and in human immunodeficiency virus (HIV) disease: Association of age and HIV infection with naive CD8(+) cell depletion, reduced expression of CD28 on CD8(+) cells, and reduced thymic volumes SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 14th International AIDS Conference CY JUL 07-12, 2001 CL BARCELONA, SPAIN ID ACTIVE ANTIRETROVIRAL THERAPY; T-CELLS; LYMPHOCYTE SUBSETS; PERIPHERAL-BLOOD; ACTIVATION; APOPTOSIS; AIDS; SURVIVAL; ADULTS; SEROCONVERSION AB Older age is a strong predictor of accelerated human immunodeficiency virus (HIV) disease progression. We investigated the possible immunologic basis of this interaction by comparing older (greater than or equal to45 years) and younger (less than or equal to30 years) HIV-infected adults with simultaneously enrolled, aged-matched, healthy volunteers. Cross-sectional comparisons suggested age-associated reductions in naive CD8(+) cells and in the expression of CD28(+) on CD8(+) cells among both HIV-infected subjects and control subjects. Opposite patterns of CD4(+) and CD8(+) cell differences were apparent between these subject groups. HIV infection, but not age, was associated with impairments in delayed-type hypersensitivity responses, lymphoproliferation, and spontaneous apoptosis and with alterations in expression of chemokine receptors CCR5 and CXCR4. Reduced thymic volumes were associated with age and with HIV infection among younger, but not older, subjects. Because of their common association with age and HIV disease, naive CD8(+) cell depletion, diminished CD28 expression on CD8(+) cells, and reduced thymic volumes are possible correlates of the interaction of age with HIV disease. C1 Metrohlth Med Ctr, Div Infect Dis, Cleveland, OH 44109 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Rush Med Coll, Chicago, IL 60612 USA. Univ Calif Davis, Sacramento, CA 95817 USA. Univ So Calif, Los Angeles, CA USA. NIA, Baltimore, MD 21224 USA. NIA, Rockville, MD USA. NIH, Div AIDS, Rockville, MD USA. Social & Sci Syst, Rockville, MD USA. Univ Michigan, Ann Arbor, MI 48109 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Texas, Galveston, TX 77555 USA. Univ N Carolina, Chapel Hill, NC USA. Triangle Pharmaceut Inc, Durham, NC 27707 USA. RP Kalayjian, RC (reprint author), Metrohlth Med Ctr, Div Infect Dis, 2500 Metrohlth Dr, Cleveland, OH 44109 USA. FU NCRR NIH HHS [M01 RR00080]; NIAID NIH HHS [AI-38858, AI-36219, AI-25879] NR 47 TC 81 Z9 82 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 15 PY 2003 VL 187 IS 12 BP 1924 EP 1933 DI 10.1086/375372 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 693NA UT WOS:000183722600012 PM 12792869 ER PT J AU Morris, L Martin, DJ Bredell, H Nyoka, SN Sacks, L Pendle, S Page-Shipp, L Karp, CL Sterling, TR Quinn, TC Chaisson, RE AF Morris, L Martin, DJ Bredell, H Nyoka, SN Sacks, L Pendle, S Page-Shipp, L Karp, CL Sterling, TR Quinn, TC Chaisson, RE TI Human immunodeficiency virus-1 RNA levels and CD4 lymphocyte counts, during treatment for active tuberculosis, in South African patients SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HIV-INFECTION; IMMUNE ACTIVATION; LOAD; EXPRESSION; MARKERS; DISEASE; IMPACT; TYPE-1; RATES; CCR5 AB During 6 months of treatment, we measured human immunodeficiency virus (HIV)-1 virus loads, CD4 T cell counts, and immune activation markers, in 111 HIV-1-infected patients with active tuberculosis (TB). The median virus load (baseline, 5.58 log(10) copies/mL) significantly increased at 1 month (5.71 log(10) copies/mL), then returned to near-baseline levels at 3 months (5.40 log(10) copies/mL) and at 6 months (5.36 log(10) copies/mL). In contrast, the median CD4 counts increased at I month (186/mm(3)), at 3 months (238/mm(3)), and at 6 months (239/mm(3)). CD4 counts and virus loads did not change during therapy. Expression of CD38 and HLA-DR remained high throughout treatment, whereas plasma levels of interleukin-6 decreased over time. C1 Johns Hopkins Univ, Ctr TB Res, Baltimore, MD 21231 USA. NIAID, Bethesda, MD 20892 USA. Natl Inst Communicable Dis, AIDS Virus Res Unit, Johannesburg, South Africa. Sizwe Infect Dis Hosp, Johannesburg, South Africa. Goldfields W Hosp, Westonaria, South Africa. RP Chaisson, RE (reprint author), Johns Hopkins Univ, Ctr TB Res, 424 N Bond St, Baltimore, MD 21231 USA. OI , Lynn/0000-0003-3961-7828 FU FIC NIH HHS [2 D 43 TW000010]; PHS HHS [K24-01637] NR 24 TC 56 Z9 57 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 15 PY 2003 VL 187 IS 12 BP 1967 EP 1971 DI 10.1086/375346 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 693NA UT WOS:000183722600018 PM 12792875 ER PT J AU Hoffman, AF Oz, M Caulder, T Lupica, CR AF Hoffman, AF Oz, M Caulder, T Lupica, CR TI Functional tolerance and blockade of long-term depression at synapses in the nucleus accumbens after chronic cannabinoid exposure SO JOURNAL OF NEUROSCIENCE LA English DT Article DE marijuana; Delta(9)-THC; nucleus accumbens; synaptic plasticity; drug abuse; tolerance ID SYNAPTIC TRANSMISSION; RAT-BRAIN; MICE; DELTA(9)-TETRAHYDROCANNABINOL; RECEPTORS; STRIATUM; LOCALIZATION; NEUROBIOLOGY; HIPPOCAMPUS; ENHANCEMENT AB The rewarding properties of the psychoactive constituents of marijuana, termed "cannabinoids," may reflect actions on synaptic transmission in the nucleus accumbens (NAc). Furthermore, long-term changes in these synapses may support the addictive process. Excitatory and inhibitory synapses are acutely inhibited by cannabinoids in the NAc, and endogenous cannabinoids (endocannabinoids) play a critical role in the expression of long-term depression (LTD) of excitatory cortical afferents in this structure. Because humans often use marijuana for prolonged periods, we examined the impact of long-term cannabinoid exposure on synaptic processes in an animal model. Electrophysiological recordings in rat brain slices containing the NAc were performed after chronic exposure to vehicle solution, Delta(9)-tetrahydrocannabinol (THC), or the cannabinoid agonist R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-(1-naphthalenyl)methanone mesylate (WIN55,212-2). Extracellular glutamatergic postsynaptic potentials and whole-cell GABAergic IPSCs were concentration-dependently inhibited by WIN55,212-2 in slice's from naive or vehicle-treated animals. However, the sensitivity to WIN55,212-2 was diminished in chronic agonist-treated animals. In addition, cross-tolerance to the inhibitory effect of the mu-opioid agonist Tyr-D-Ala(2), N-CH3-Phe(4) Gly-ol-enkephalin was observed. Endocannabinoid-mediated LTD was initiated via electrical stimulation (5 min, 10 Hz) of glutamatergic afferents to the NAc and was completely blocked by the cannabinoid receptor antagonist SR141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide] in vehicle-treated animals. LTD was not observed in brain slices from rats chronically treated with Delta(9)-THC or WIN55,212-2. These data demonstrate that long-term exposure to the active ingredient of marijuana blocks synaptic plasticity in the NAc and reduces the sensitivity of GABAergic and glutamatergic synapses to both cannabinoids and opioids. C1 NIDA, US Dept HHS, Intramural Res Program,Cellular Neurobiol Branch, Sect Cellular Neurophysiol,NIH, Baltimore, MD 21224 USA. RP Lupica, CR (reprint author), NIDA, US Dept HHS, Intramural Res Program,Cellular Neurobiol Branch, Sect Cellular Neurophysiol,NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Oz, Murat/E-2148-2012; yu, yan/C-2322-2012; Hoffman, Alexander/H-3035-2012 OI Hoffman, Alexander/0000-0002-2676-0628 NR 30 TC 119 Z9 126 U1 1 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 JUN 15 PY 2003 VL 23 IS 12 BP 4815 EP 4820 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 696MY UT WOS:000183891700005 PM 12832502 ER PT J AU Tang, A Bungay, PM Gonzales, RA AF Tang, A Bungay, PM Gonzales, RA TI Characterization of probe and tissue factors that influence interpretation of quantitative microdialysis experiments for dopamine SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE dopamine; microdialysis; nucleus accumbens; tissue resistance; calcium-dependence; no-net-flux ID NUCLEUS-ACCUMBENS; EXTRACELLULAR DOPAMINE; EXTRACTION FRACTION; 3,4-DIHYDROXYPHENYLACETIC ACID; INTRACEREBRAL MICRODIALYSIS; MASS-TRANSFER; AMINO-ACIDS; RAT-BRAIN; RELEASE; STRIATUM AB Two quantitative methods, the Lonnroth (no-net-flux) and variation of perfusion flow rate methods, were used to investigate the influence of the probe and tissue on dopamine microdialysis measurements. In vivo measurements were made in the nucleus accumbens of awake, freely moving rats on two consecutive days of dialysis. The results of the no-net-flux study showed that there was no statistically significant difference in extraction fraction at a perfusion flow rate of 2.0 mul/min between in vitro in a well-stirred solution and in vivo measured during 2 days of continuous dialysis. Also, varying the perfusate flow rate over the range 0.25-2.0 mul/ min produced a variation in the extraction fraction that was the same in vitro and in vivo. These results indicate that the extraction fraction for dopamine over the 2 days was dominated by the properties of the probe. The negligible influence of the tissue on dopamine extraction fraction was probably due to the high basal activity of the dopamine transporter in vivo. Therefore, the extraction fraction is unlikely to be sensitive to increases in dopamine uptake in the vicinity of the probe. The apparent extracellular dopamine concentration increased by 37% on the second day of dialysis while the calcium-dependence of basal dialysate dopamine levels declined by 20%. These findings are consistent with a decrease in physiological viability of the dopamine nerve terminals surrounding the probe during a long-term experiment. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Univ Texas, Coll Pharm, Div Pharmacol & Toxicol, Austin, TX 78712 USA. NIH, Div Bioengn & Phys Sci, Off Res Serv, Bethesda, MD 20892 USA. RP Tang, A (reprint author), Univ Texas, Coll Pharm, Div Pharmacol & Toxicol, Austin, TX 78712 USA. FU NIAAA NIH HHS [AA07471, AA11852] NR 36 TC 30 Z9 31 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD JUN 15 PY 2003 VL 126 IS 1 BP 1 EP 11 DI 10.1016/S0165-0270(03)00003-7 PG 11 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 691HM UT WOS:000183600100001 PM 12788497 ER PT J AU Sokolov, BP Jiang, LX Trivedi, NS Aston, C AF Sokolov, BP Jiang, LX Trivedi, NS Aston, C TI Transcription profiling reveals mitochondrial, ubiquitin and signaling systems abnormalities in postmortem brains from subjects with a history of alcohol abuse or dependence SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE microarray; substance abuse; alcoholism; psychiatric disorders ID GENE-EXPRESSION DIFFERENCES; RAT PERIVENOUS HEPATOCYTES; MAJOR DEPRESSION; FRONTAL-CORTEX; ETHANOL-CONSUMPTION; MICROARRAY ANALYSIS; ANGELMAN-SYNDROME; PLANUM TEMPORALE; ANXIETY DISORDER; PANIC DISORDER AB Alcohol abuse is a common human disorder with high rate of comorbidity with other psychiatric disorders. To identify candidate mechanisms for alcohol abuse, the expression of 12,626 genes was measured in postmortem temporal cortex from 11 subjects with a history of alcohol abuse or dependence, with or without other psychiatric diagnoses and compared pairwise with the expression in 11 nonalcoholic subjects matched for the other psychiatric diagnoses and demographics. Genes were defined to have altered expression in alcohol abuse if: 1) the gene showed decreased expression in at least 10 of 11 subjects with alcohol abuse, or showed increased expression in at least 10 of 11 subjects with this diagnosis compared to matched non-abusers (P < 0.007, chi(2)test); or 2) the difference in the mean abuser/non-abuser ratio for the gene from value of 1.0 was significant at P < 0.05 (one sample t-test). In subjects with a history of alcohol abuse or dependence, 163 genes were changed significantly. The most abundant and consistent changes were in gene families encoding mitochondrial proteins, the ubiquitin system, and signal transduction. These alterations indicate disturbances in energy metabolism and multiple signaling mechanisms in the temporal cortex of subjects with a history of alcohol abuse or dependence. We hypothesize that these mechanisms may be related to alcohol abuse traits or long-term effects of alcohol. (C) 2003 Wiley-Liss, Inc. C1 NIDA, Mol Neuropsychiat Branch, NIH, DHHS, Baltimore, MD 21224 USA. Wyeth Res, Neurosci Discovery Res, Princeton, NJ USA. RP Sokolov, BP (reprint author), NIDA, Mol Neuropsychiat Branch, NIH, DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 56 TC 77 Z9 77 U1 3 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD JUN 15 PY 2003 VL 72 IS 6 BP 756 EP 767 DI 10.1002/jnr.10631 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 687MQ UT WOS:000183381000011 PM 12774316 ER PT J AU Oh, JD Chartisathian, K Ahmed, SM Chase, TN AF Oh, JD Chartisathian, K Ahmed, SM Chase, TN TI Cyclic AMP responsive element binding protein phosphorylation and persistent expression of levodopa-induced response alterations in unilateral nigrostriatal 6-OHDA lesioned rats SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE Parkinson's disease; 6-hydroxydopamine lesion; striatum; CREB phosphorylation; protein kinase A; motor response alterations ID LONG-TERM POTENTIATION; NMDA RECEPTOR SUBUNITS; MESSENGER-RNA LEVELS; KINASE-A INHIBITOR; L-DOPA TREATMENT; PARKINSONS-DISEASE; INDUCED DYSKINESIAS; GENE-EXPRESSION; TYROSINE PHOSPHORYLATION; CREB PHOSPHORYLATION AB Activation of cAMP responsive element binding protein (CREB) has been increasingly implicated in the formation and maintenance of long-term memory. To elucidate molecular mechanisms that underlie the persisting alterations in motor response occurring with levodopa (L-dopa) treatment of parkinsonian patients, we evaluated the time course of these changes in relation to the activation of striatal CREB in 6-hydroxydopamine (6-OHDA) lesioned animals. Three weeks of twice-daily L-dopa treatment reduced the duration of the rotational response to acute L-dopa challenge in hemiparkinsonian rats, which lasted about 5 weeks after withdrawal of chronic L-dopa therapy. This shortened response duration, resembling human wearing-off fluctuations, was associated with a marked increase in Ser-133 phosphorylated CREB (pCREB) immunoreactivity in medium spiny neurons in dorsolateral striatum in response to acute dopaminomimetic challenge. Intermittent treatment with the D1 receptor-preferring agonist SKF 38393, but not the D2 receptor-preferring agonist quinpirole, produced a similar rise in CREB phosphorylation. The time course of changes in CREB phosphorylation correlated with the time course of changes in motor behavior after cessation of chronic L-dopa therapy. Both the altered motor response duration and the degree of CREB phosphorylation were attenuated by the intrastriatal administration of CREB antisense or protein kinase A inhibitor Rp-cAMPS. The results suggest that region-specific Ser-133 CREB phosphorylation in D1 receptor containing spiny neurons contributes to the persistence of the motor response alterations produced by intermittent stimulation of striatal dopaminergic receptors. (C) 2003 Wiley-Liss, Inc. C1 NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. Cent Michigan Univ, Dept Psychol, Mt Pleasant, MI 48859 USA. RP Chase, TN (reprint author), NINDS, Expt Therapeut Branch, NIH, 10 Ctr Dr,Rm 5C211,MSC 1406, Bethesda, MD 20892 USA. OI Ahmed, Syed Mukhtar/0000-0002-9183-9957 NR 65 TC 20 Z9 23 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 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD JUN 15 PY 2003 VL 72 IS 6 BP 768 EP 780 DI 10.1002/jnr.10629 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 687MQ UT WOS:000183381000012 PM 12774317 ER PT J AU Nelson, R Bender, AM Connaughton, VP AF Nelson, R Bender, AM Connaughton, VP TI Stimulation of sodium pump restores membrane potential to neurons excited by glutamate in zebrafish distal retina SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID WHITE PERCH RETINA; NA+-K+ PUMP; HORIZONTAL CELLS; BIPOLAR CELLS; GOLDFISH RETINA; KAINATE RECEPTOR; PHARMACOLOGICAL CHARACTERIZATION; NA,K-ATPASE ALPHA; IONIC CURRENTS; CARP RETINA AB Glutamate either depolarizes or hyperpolarizes retinal neurons. Those are the initial and primary effects. Using a voltage probe (oxonol, DiBaC(4) (5)) to study dissociated zebrafish retinal neurons, we find a secondary, longer-term effect: a post-excitatory restoration of membrane potential, termed after-hyperpolarization (AHP). AHP occurs only in neurons that are depolarized by glutamate and typically peaks about 5 min after glutamate application. AHP is seen in dissociated horizontal cells (HCs) and hyperpolarizing, or OFF type, bipolar cells (HBCs). These cells commonly respond with only an AHP component. AHP never occurs in depolarizing, or ON type, bipolar cells (DBCs), which are cell types hyperpolarized by glutamate. AHP is blocked by 6-cyano7-nitroquinoxaline-2,3-dione (CNQX). It is evoked by kainate, AMPA and the AMPA-selective agonist (S)-5-fluorowillardiine, but not by NMDA, D-aspartate, the kainate-selective agonist SYM 2081 or by DL-2-amino-4-phosphonobutyric acid (DL-AP4). Cells with exclusively AHP responses are tonically depolarized. Resting potentials can be restored by nifedipine, suggesting a tonic, depolarizing action of L-type Ca2+ channels. However AHP is not blocked by nifedipine and is insensitive to [Cl-](o). AHP is blocked by Li-0(+) substitution for Na-0(+) and by ouabain. A mechanism is proposed in which Na+ entering through ionotropic AMPA channels stimulates Na+,K+-ATPase, which, by electrogenic action, restores membrane potential, generating the AHP response. Patterns of ATPase immunoreactivity support localization in the outer plexiform layer (OPL) as cone pedicles, HCs and BCs were positively labelled. Labelling was weaker in the inner plexiform layer (IPL) than in nuclear layers, though two IPL bands of immunoreactive BC terminals could be discerned, one in sublamina a and the other in sublamina b. Persistent stimulation of distal retina by photoreceptor glutamate may induce increased expression and activity of Na+,K-ATPase, with a consequent impact on distal glutamate responses. C1 NINDS, Basic Neurosci Program, NIH, Bethesda, MD 20892 USA. American Univ, Dept Biol, Washington, DC 20016 USA. RP Nelson, R (reprint author), NINDS, Basic Neurosci Program, NIH, Bldg 36 Room 2C02,36 Convent Dr MSC 4066, Bethesda, MD 20892 USA. NR 59 TC 11 Z9 11 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4221 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD JUN 15 PY 2003 VL 549 IS 3 BP 787 EP 800 DI 10.1113/jphysiol.2003.042051 PG 14 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 695DE UT WOS:000183815200012 PM 12730339 ER PT J AU Fay, MP Pfeiffer, R Cronin, KA Le, CX Feuer, EJ AF Fay, MP Pfeiffer, R Cronin, KA Le, CX Feuer, EJ TI Age-conditional probabilities of developing cancer SO STATISTICS IN MEDICINE LA English DT Article DE competing risks; gamma confidence interval; hypothetical cohort; lifetime risk; surveillance; vital rates ID RATES AB We propose an estimator of the probability of developing a disease in a given age range, conditional on never having developed the disease prior to the beginning of the age range. Our estimator improves the one described by Wun, Merrill and Feuer (Lifetime Data Analysis 1998; 4, 169-186) that is currently used by the U.S. National Cancer Institute for the SEER Cancer Statistics Review. Both estimators use cross-sectional disease rates and provide an interpretation of these rates in terms of the age-conditional probability of developing disease in a hypothetical cohort. The difficulty of this problem is that rates are not available per person-years alive and disease free, but only per person-years alive. Wun et al. used ad hoc methods to handle this problem which did not properly account for competing risks, did not provide a measure of variability, and only allowed age ranges using prespecified 5-year age intervals. Here we solve the problem under a unified competing risks framework, which allows the calculation of the age-conditional probabilities for any age range. We generalize gamma confidence intervals to apply to our new statistic. Although our new method provides estimates which are numerically similar to that of Wun et al., this paper provides a comprehensive theoretical basis for estimation and inference about the age-conditional probability of developing a disease. Published in 2003 by John Wiley Sons, Ltd. C1 NCI, Bethesda, MD 20892 USA. US FDA, CDER, Div Biometr 3, Rockville, MD 20850 USA. RP Fay, MP (reprint author), NCI, 6116 Execut Blvd,Suite 504,MSC 8317, Bethesda, MD 20892 USA. RI Fay, Michael/A-2974-2008; Pfeiffer, Ruth /F-4748-2011; OI Fay, Michael P./0000-0002-8643-9625 FU Intramural NIH HHS [Z99 AI999999] NR 9 TC 58 Z9 58 U1 0 U2 3 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD JUN 15 PY 2003 VL 22 IS 11 BP 1837 EP 1848 DI 10.1002/sim.1428 PG 12 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 679AP UT WOS:000182899100005 PM 12754719 ER PT J AU Lonser, RR Glenn, GM Walther, M Chew, EY Libutti, SK Linehan, WM Oldfield, EH AF Lonser, RR Glenn, GM Walther, M Chew, EY Libutti, SK Linehan, WM Oldfield, EH TI von Hippel-Lindau disease SO LANCET LA English DT Review ID TUMOR-SUPPRESSOR GENE; CENTRAL-NERVOUS-SYSTEM; RENAL-CELL CARCINOMA; ENDOTHELIAL GROWTH-FACTOR; SPORADIC CEREBELLAR HEMANGIOBLASTOMAS; ENDOLYMPHATIC SAC TUMORS; VHL GENE; PAPILLARY CYSTADENOMA; GERMLINE MUTATIONS; NEUROENDOCRINE TUMORS AB von Hippel-Lindau disease is a heritable multisystem cancer syndrome that is associated with a germline mutation of the VHL tumour suppressor gene on the short arm of chromosome 3. This disorder is not rare (about one in 36 000 livebirths) and Is Inherited as a highly penetrant autosomal dominant trait (le, with a high individual risk of disease). Affected individuals are at risk of developing various benign and malignant tumours of the central nervous system, kidneys, adrenal glands, pancreas, and reproductive adnexal organs. Because of the complexities associated with management of the various types of tumours in this disease, treatment is multidisciplinary. We present an overview of the clinical aspects, management, and treatment options for von Hippel-Lindau disease. C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NEI, Clin Trials Branch, NIH, Bethesda, MD 20892 USA. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Lonser, RR (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,Room 5D37, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 EY999999] NR 98 TC 596 Z9 624 U1 4 U2 36 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUN 14 PY 2003 VL 361 IS 9374 BP 2059 EP 2067 DI 10.1016/S0140-6736(03)13643-4 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 689JT UT WOS:000183488900025 PM 12814730 ER PT J AU Spacek, LA Griswold, M Quinn, TC Moore, RD AF Spacek, LA Griswold, M Quinn, TC Moore, RD TI Total lymphocyte count and hemoglobin combined in an algorithm to initiate the use of highly active antiretroviral therapy in resource-limited settings SO AIDS LA English DT Article DE algorithms; antiretroviral therapy; CD4 cell count; HIV-1; total lymphocyte count ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-INFECTED PATIENTS; UGANDAN ADULTS; CD4 COUNTS; ANEMIA; PERCENTAGE; EPISODES; COHORT AB Objective: To develop clinical algorithms that improve the sensitivity of surrogate markers to initiate the use of highly active antiretroviral therapy (HAART) in resource-limited settings. Design: A retrospective evaluation of total lymphocyte counts (TLC) and hemoglobin to predict the CD4 lymphocyte count. Methods: A total of 3269 members of the Johns Hopkins HIV observational cohort contributed 22 690 paired observations of CD4 lymphocyte counts and TLC. Two methods were used to evaluate the effect of combining TLC and hemoglobin to predict CD4 cell counts below 200 cells/mm(3) before the initiation of HAART in 1451 participants; 55.3% of participants had CD4 cell counts below 200 cells/mm(3). Results: TLC below 1200 cells/mm(3) and hemoglobin below 12 g/dl significantly predicted CD4 cell counts below 200 cells/mm(3). For TLC alone sensitivity was 70.7% and specificity was 81.7%. For both men and women, we chose a TLC lower cutoff point of 1200 cells/mm(3), an upper cutoff point of 2000 cells/mm(3), and hemoglobin of 12 g/dI. For men, method I generated sensitivity of 78.0% and specificity of 77.5%. Method II improved specificity to 81.8%. For women, method I increased sensitivity to 85.6% and decreased specificity to 64.1 %. Method II improved specificity to 81.4%. Conclusion: TLC below 1200 cells/mm(3) were associated with CD4 cell counts below 200 cells/mm(3) as in the WHO guidelines, but sensitivity was low. Adding hemoglobin to TLC increased sensitivity, thereby reducing the risk of false-negative results. Our model may serve as a template for the development of algorithms to initiate the use of HAART in resource-limited settings. (C) 2003 Lippincott Williams Wilkins. C1 Johns Hopkins Univ, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21205 USA. Johns Hopkins Bloomberg Sch Hyg & Publ Hlth, Dept Biostat, Baltimore, MD USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Spacek, LA (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Div Infect Dis, 1830 E Monument St,Room 401, Baltimore, MD 21205 USA. EM lspacek@jhmi.edu FU NIAID NIH HHS [T32-AI07451]; NIDA NIH HHS [K24-DA00432, R01-DA11602] NR 20 TC 38 Z9 42 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUN 13 PY 2003 VL 17 IS 9 BP 1311 EP 1317 DI 10.1097/01.aids.0000060369.78202.66 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 699QK UT WOS:000184067300005 PM 12799552 ER PT J AU Pinto, LA Grene, E Baker, R Mac Trubey, C Torres, N Trivett, M Shearer, GM AF Pinto, LA Grene, E Baker, R Mac Trubey, C Torres, N Trivett, M Shearer, GM TI HIV inhibitory activity generated by antigen-stimulated cord blood leukocytes SO AIDS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; REVERSE TRANSCRIPTION; REPLICATION; TRANSMISSION; INFECTION; GAMMA; CELLS AB Leukocytes from adult peripheral blood generate HIV-inhibitory soluble factors after stimulation with influenza A virus or allogeneic leukocytes. Leukocytes from neonates and adults exhibit immunological differences, and it is not known whether cord blood leukocytes secrete antiviral molecules after these types of stimulation. Our findings that cord blood mononuclear cells can generate soluble HIV-inhibitory factor(s), after antigenic stimulation, may have implications for understanding the host defence mechanisms of HIV-1 vertical transmission and the development of potential vaccine adjuvants. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. INOVA Fairfax Hosp Children, Falls Church, VA USA. NCI Frederick, SAIC Frederick, Intramural Res Support Program, Frederick, MD USA. RP Pinto, LA (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CO-56000] NR 18 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 JUN 13 PY 2003 VL 17 IS 9 BP 1389 EP 1392 DI 10.1097/01.aids.0000060403.18106.28 PG 4 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 699QK UT WOS:000184067300014 PM 12799561 ER PT J AU Bai, YW AF Bai, YW TI Hidden intermediates and levinthal paradox in the folding of small proteins SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Editorial Material DE protein folding; hidden intermediates; Levinthal paradox; Native-state hydrogen exchange ID STATE HYDROGEN-EXCHANGE; ON-PATHWAY INTERMEDIATE; CYTOCHROME-C; KINETIC EVIDENCE; BUNDLE PROTEIN; MECHANISM; STABILITY; BARRIERS; BARNASE; MODEL AB It has Iona been suggested that existence of partially folded intermediates may be essential for proteins to fold in a biologically meaningful time scale. Although partially folded intermediates have been commonly observed in larger proteins, they are generally not detectable in the kinetic folding of smaller proteins (similar to100 amino acids or less). Recent native-state hydrogen exchange studies suggest that partially folded intermediates may exist behind the rate-limiting transition state in small proteins and evade detection by conventional kinetic methods. Published by Elsevier Science (USA). C1 NCI, Biochem Lab, Bethesda, MD 20892 USA. RP Bai, YW (reprint author), NCI, Biochem Lab, Bldg 37,Room 6114E, Bethesda, MD 20892 USA. NR 38 TC 36 Z9 36 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 13 PY 2003 VL 305 IS 4 BP 785 EP 788 DI 10.1016/S0006-291X(03)00800-3 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 690YR UT WOS:000183578500001 PM 12767898 ER PT J AU Francischetti, IMB Mather, TN Ribeiro, JMC AF Francischetti, IMB Mather, TN Ribeiro, JMC TI Cloning of a salivary gland metalloprotease and characterization of gelatinase and fibrin(ogen)lytic activities in the saliva of the Lyme disease tick vector Ixodes scapularis SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Ixodes seapularis; Borrelia burgdorferi; tick; hematophagy; collagen; fibrinogen; fibrino(gen)olytic; ADAM; reprolysin; blood-sucking ID LEECH HAEMENTERIA-GHILIANII; SNAKE-VENOM; EVOLUTIONARY FAMILIES; HEMENTIN; SIALOME; DAMMINI; IDENTIFICATION; PURIFICATION; PROTEINS AB The full-length sequence of tick salivary gland cDNA coding for a protein similar to metalloproteases (NIP) of the reprolysin family is reported. The Ixodes scapularis NIP is a 488 amino acid (aa) protein containing pre- and pro-enzyme domains, the zinc-binding motif HExxHxxGxxH common to metalloproteases, and a cysteine-rich region. In addition, the predicted amino-terminal sequences of I. scapularis MPs were found by Edman degradation of PVDF-transferred SDS/PAGE-separated tick saliva proteins, indicating that these putative enzymes are secreted. Furthermore, saliva has a metal-dependent proteolytic activity towards gelatin, fibrin(ogen). and fibronectin, but not collagen or laminin. Accordingly, L scapularis saliva has a rather specific metalloprotease similar to the hemorrhagic proteases of snake venoms. This is the first description of such activity in tick saliva and its role in tick feeding and Borrelia transmission is discussed. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NIAID, Med Entomol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Univ Rhode Isl, Ctr Vector Borne Dis, Kingston, RI 02881 USA. RP Francischetti, IMB (reprint author), NIAID, Med Entomol Sect, Parasit Dis Lab, NIH, Room 126,Bldg 4,4 Ctr Dr,MSC 0425, Bethesda, MD 20892 USA. OI Ribeiro, Jose/0000-0002-9107-0818 FU Intramural NIH HHS [Z01 AI000810-11, Z99 AI999999]; NIAID NIH HHS [R01 AI 37230, R01 AI037230] NR 30 TC 92 Z9 95 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 13 PY 2003 VL 305 IS 4 BP 869 EP 875 DI 10.1016/S0006-291X(03)00857-X PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 690YR UT WOS:000183578500014 PM 12767911 ER PT J AU Fujimoto, M Maezawa, Y Yokote, K Joh, K Kobayashi, K Kawamura, H Nishimura, M Roberts, AB Saito, Y Mori, S AF Fujimoto, M Maezawa, Y Yokote, K Joh, K Kobayashi, K Kawamura, H Nishimura, M Roberts, AB Saito, Y Mori, S TI Mice lacking Smad3 are protected against streptozotocin-induced diabetic glomerulopathy SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE diabetic glomerulopathy; fibronectin; Smad3; transforming growth factor beta; type IV collagen ID GROWTH-FACTOR-BETA; MATRIX GENE-EXPRESSION; TGF-BETA; MESANGIAL CELLS; HIGH GLUCOSE; AUTOCRINE ACTIVATION; IV COLLAGEN; II RECEPTOR; KIDNEY; MOUSE AB Transforming growth factor-beta (TGF-beta) has been implicated in the development of diabetic glomerulopathy. In order to evaluate a role of Smad3, one of the major signaling molecules downstream of TGF-beta, in the pathogenesis of diabetic glomerulopathy, Smad3-null mice were made diabetic with streptozotocin injection and analyzed 4 weeks after induction of diabetes. Electron microscopy revealed that the thickness of glomerular basement membrane (GBM) in wild-type diabetic mice was significantly higher than that in non-diabetic mice, whereas no appreciable GBM thickening was found in Smad3-null diabetic mice. Urinary albumin excretion was dramatically increased in wild-type diabetic mice, whereas Smad3-null diabetic mice did not show any overt albuminuria. Northern blotting revealed that mRNA levels of fibronectin and alpha3 chain of type IV collagen (alpha3Col4) in renal cortex of wild-type diabetic mice were approximately twice as much as those of non-diabetic mice, whereas their mRNA levels were not increased in Smad3-null diabetic mice. Real-time polymerase chain reaction (PCR) also confirmed diabetes-induced upregulation of fibronectin and alpha3Col4 in glomeruli of wild-type mice. Glomerular expression of TGF-beta1, as assessed by real-time PCR, was enhanced to a similar degree in wild-type and smad3-null diabetic mice, indicating that the observed differences between wild-type and Smad3-null mice are not attributable to difference in the expression of TGF-beta1. These data clearly demonstrate a critical role of Smad3 in the early phase of diabetic glomerulopathy. This may be due at least partly to the present findings that diabetes-induced upregulation of fibronectin and alpha3Col4 is dependent on Smad3 function. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Chiba Univ, Grad Sch Med, Dept Clin Cell Biol & Med, Chiba 2608670, Japan. Sakura Natl Hosp, Dept Pathol, Sakura, Chiba 2858765, Japan. Sakura Natl Hosp, Dept Internal Med, Sakura, Chiba 2858765, Japan. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Yokote, K (reprint author), Chiba Univ, Grad Sch Med, Dept Clin Cell Biol & Med, 1-8-1 Inohana, Chiba 2608670, Japan. NR 30 TC 100 Z9 107 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 13 PY 2003 VL 305 IS 4 BP 1002 EP 1007 DI 10.1016/S0006-291X(03)00885-4 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 690YR UT WOS:000183578500033 PM 12767930 ER PT J AU Bae, JS Jang, MK Hong, SH An, WG Choi, YH Do Kim, H Cheong, JH AF Bae, JS Jang, MK Hong, SH An, WG Choi, YH Do Kim, H Cheong, JH TI Phosphorylation of NF-kappa B by calmodulin-dependent kinase IV activates anti-apoptotic gene expression SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE NF-kappa B; calmodulin-dependent kinase; apoptosis; phosphorylation ID PROTEIN-KINASES; CELL-DEATH; INHIBITION; ALPHA; TRANSACTIVATION; TRANSCRIPTION; CASCADE; COMPLEX; CANCER; DOMAIN AB We previously presented that calmodulin-dependent kinase IV (CaMKIV) mutually interacts with NF-kappaB and phosphorylates it directly, inducing the increased transcriptional regulation dependent on NF-kappaB target genes [J. Biol. Chem. 276 (2001) 20005]. Here, we show that Ser(535) residue is phosphorylated by CaMKIV. S535A mutant of p65 was specifically defective in transactivation of NF-kappaB target gene expression induced by CaMKIV. While coexpression of active CaMKIV with wild-type p65 led to a recovery from etoposide-induced apoptosis and an increase of Bcl-2 protein in cells, cells expressing S535A mutant did not. Taken together these results suggest that phosphorylated NF-kappaB p65 on Ser(535) by CaMKIV increases NF-kappaB target gene expression, including antiapoptotic gene, hence leading to inhibition of apoptosis. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Pusan Natl Univ, Dept Mol Biol, Pusan 609735, South Korea. NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. Kyungpook Natl Univ, Dept Biol, Taegu 702701, South Korea. Dong Eui Univ, Coll Oriental Med, Dept Biochem, Pusan 614054, South Korea. RP Cheong, JH (reprint author), Pusan Natl Univ, Dept Mol Biol, Pusan 609735, South Korea. NR 27 TC 29 Z9 30 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 13 PY 2003 VL 305 IS 4 BP 1094 EP 1098 DI 10.1016/S0006-291X(03)00869-6 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 690YR UT WOS:000183578500047 PM 12767944 ER PT J AU Taltavull, JF Chefer, VI Shippenberg, TS Kiyatkin, EA AF Taltavull, JF Chefer, VI Shippenberg, TS Kiyatkin, EA TI Severe brain hypothermia as a factor underlying behavioral immobility during cold-water forced swim SO BRAIN RESEARCH LA English DT Article DE distress/dysphoria; ventral striatum; brain cooling; sodium and calcium current; antidepressant drug ID ANTIDEPRESSANT TREATMENTS; DESPAIR TEST; TEMPERATURE; RATS; POTENTIALS; IMIPRAMINE; DOPAMINE AB Behavioral immobility during forced swim is usually considered a consequence of inescapable stress, and is used to screen antidepressant drugs. However, immobility in this test may also result from inhibition of neural functions because of brain hypothermia due to body cooling. To explore this possibility, we measured brain temperature dynamics during a 10-min forced swim in cold (25 degreesC) and warm (37 degreesC) water and correlated brain temperatures with behavioral changes. Cold water forced swim resulted in significant brain hypothermia (-6-7 degreesC) and immobility, while no immobility was observed during warm water forced swim, when brain temperature transiently, increased (0.5 degreesC) then decreased below baseline in the post-swim period. These data suggest that immobility, which rapidly develops during forced swim in cold water, may result from dramatic inhibition of neural functions because of severe brain hypothermia. (C) 2003 Elsevier Science B.V. All rights reserved. C1 NIDA, Intramural Res Program, Behav Neurosci Branch, Electophysiol Unit, Baltimore, MD 21224 USA. NIDA, Intramural Res Program, Integrat Neurosci Sect, Baltimore, MD 21224 USA. RP Kiyatkin, EA (reprint author), NIDA, Intramural Res Program, Behav Neurosci Branch, Electophysiol Unit, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 18 TC 29 Z9 29 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 13 PY 2003 VL 975 IS 1-2 BP 244 EP 247 DI 10.1016/S0006-8993(03)02695-7 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 686UL UT WOS:000183339300030 PM 12763614 ER PT J AU Grote, K Flach, I Luchtefeld, M Akin, E Holland, SM Drexler, H Schieffer, B AF Grote, K Flach, I Luchtefeld, M Akin, E Holland, SM Drexler, H Schieffer, B TI Mechanical stretch enhances mRNA expression and proenzyme release of matrix metalloproteinase-2 (MMP-2) via NAD(P)H oxidase-derived reactive oxygen species SO CIRCULATION RESEARCH LA English DT Article DE mechanical stretch; reactive oxygen species; NAD(P)H oxidase; p47(phox); matrix metalloproteinases ID SMOOTH-MUSCLE-CELLS; ANGIOTENSIN-II; IN-VITRO; ACTIVATION; ARTERIES; MATRIX-METALLOPROTEINASE-2; P47(PHOX); STRAIN; TISSUE; ALPHA AB Mechanical stretch is a hallmark of arterial hypertension and leads to vessel wall remodeling, which involves matrix metalloproteinases (MMPs). Because mechanical stretch is further capable of inducing reactive oxygen species (ROS) formation via the NAD(P)H oxidase, we assessed whether mechanical stretch enhances MMP expression and activity in a NAD(P)H oxidase-dependent manner. Therefore, vascular smooth muscle cells (VSMCs) isolated from C57BL/6 mice were exposed to cyclic mechanical stretch. The impact of ROS was assessed using VSMCs isolated from p47(phox-/-) mice, deficient for a NAD(P)H oxidase subunit responsible for ROS formation. Transcript levels were investigated by cDNA array and confirmed by RT-PCR. ROS formation was determined by DCF fluoroscopy and MMP-2 activity by zymography. Mechanical stretch of wild-type VSMCs resulted in a rapid ROS formation and p47(phox) membrane translocation that is followed by an increase in Nox-1 transcripts. ROS formation was completely abrogated in p47(phox-/-) VSMCs. cDNA array further revealed an increase of MMP-2 mRNA in response to mechanical stretch, which was validated by RT-PCR. Using p47(phox-/-) VSMCs, this increase in MMP-2 mRNA was completely blunted. mRNA expression of tissue inhibitor of MMP-2 TIMP-1 and TIMP-2 and membrane-type 1 MMP was unaffected by mechanical stretch. Gelatinolytic activity of pro-MMP-2 has been increased rapidly in wild-type VSMCs and was completely abolished in p47(phox-/-) VSMCs. These results indicate that mechanical stretch induces ROS formation via the NAD(P)H oxidase and thereby enhances MMP-2 mRNA expression and pro-MMP-2 release. These results are consistent with the notion that in arterial hypertension, reactive oxygen species are involved in vascular remodeling via MMP activation. The full text of this article is available online at http://www.circresaha.org. C1 Hannover Med Sch, Dept Cardiol & Angiol, D-3000 Hannover, Germany. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Schieffer, B (reprint author), Hannover Med Sch, Abt Kardiol & Angiol, Carl Neuberg Str 1, D-30625 Hannover, Germany. EM Schieffer.Bernhard@mh-hannover.de NR 32 TC 215 Z9 224 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD JUN 13 PY 2003 VL 92 IS 11 BP E80 EP E86 DI 10.1161/01.RES.0000077044.60138.7C PG 7 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 688WL UT WOS:000183460200015 PM 12750313 ER PT J AU Vazquez, G Wedel, BJ Trebak, M Bird, GS Putney, JW AF Vazquez, G Wedel, BJ Trebak, M Bird, GS Putney, JW TI Expression level of the canonical transient receptor potential 3 (TRPC3) channel determines its mechanism of activation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CAPACITATIVE CALCIUM-ENTRY; OPERATED CA2+ ENTRY; INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; SMOOTH-MUSCLE CELLS; TRISPHOSPHATE RECEPTOR; CATION CHANNELS; B-LYMPHOCYTES; DIACYLGLYCEROL; RELEASE; PROTEIN AB Studies on the mechanism of activation of canonical transient receptor potential ( TRPC) channels have often yielded conflicting results. In the current study, we have investigated the influence of expression level on the mode of regulation of TRPC3 channels. At relatively low levels of expression in DT40 chicken B- lymphocytes, TRPC3 was activated by the depletion of Ca2+ stores. Expression was increased by either transfecting with a 10- fold greater concentration of plasmid or transfecting with TRPC3 under control of a more efficient avian beta- actin promoter. At higher levels of expression, TRPC3 was no longer store- operated but could be activated through receptor- coupled phospholipase C. Under these expression conditions, TRPC3 was efficiently activated in DT40 cells lacking inositol 1,4,5- trisphosphate receptors. The Ca2+ store- operated channels formed upon expression of TRPC3 at limited levels were blocked by gadolinium; the receptor- activated channels formed upon expression of higher levels of TRPC3 were insensitive to gadolinium. These findings indicate that a single ion channel protein can form or contribute to the formation of channels regulated in two very distinct ways, i. e. either by phospholipase C- derived messengers or Ca2+ store- depletion. The mechanism of regulation of the channels depends on their level of expression. C1 NIEHS, Lab Signal Transduct, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), NIEHS, Lab Signal Transduct, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. RI Trebak, Mohamed/E-7405-2014 NR 33 TC 107 Z9 121 U1 2 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 13 PY 2003 VL 278 IS 24 BP 21649 EP 21654 DI 10.1074/jbc.M302162200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 687AT UT WOS:000183354200043 PM 12686562 ER PT J AU Vos, MD Martinez, A Ellis, CA Vallecorsa, T Clark, GJ AF Vos, MD Martinez, A Ellis, CA Vallecorsa, T Clark, GJ TI The pro-apoptotic Ras effector Nore1 may serve as a Ras-regulated tumor suppressor in the lung SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DISTINCT BINDING DOMAINS; EPIGENETIC INACTIVATION; CELL-GROWTH; K-RAS; PROTEIN; EXPRESSION; RASSF1A; DIFFERENTIATION; TRANSFORMATION; METHYLATION AB Ras oncoproteins mediate multiple biological effects by activating multiple effectors. Classically, Ras activation has been associated with enhanced cellular growth and transformation. However, activated forms of Ras may also inhibit growth by inducing senescence, apoptosis, and differentiation. Induction of apoptosis by Ras may be mediated by its effector RASSF1, which appears to function as a tumor suppressor. We now show that the Ras effector Nore1, which is structurally related to RASSF1, can also mediate a Ras-dependent apoptosis. Moreover, an analysis of Nore1 protein expression showed that it is frequently down-regulated in lung tumor cell lines and primary lung tumors. Like RASSF1, this correlates with methylation of the Nore1 promoter rather than gene deletion. Finally, re- introduction of Nore1, driven by its own promoter, impairs the growth in soft agar of a human lung tumor cell line. Consequently, we propose that the Ras effector Nore1 is a member of a family of Ras effector/tumor suppressors that includes RASSF1. C1 NCI, Dept Cell & Canc Biol, NIH, Rockville, MD 20850 USA. RP Clark, GJ (reprint author), NCI, Dept Cell & Canc Biol, NIH, 9610 Med Ctr Dr, Rockville, MD 20850 USA. RI Martinez, Alfredo/A-3077-2013 OI Martinez, Alfredo/0000-0003-4882-4044 NR 45 TC 79 Z9 88 U1 2 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 13 PY 2003 VL 278 IS 24 BP 21938 EP 21943 DI 10.1074/jbc.M211019200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 687AT UT WOS:000183354200079 PM 12676952 ER PT J AU Kubelka, J Eaton, WA Hofrichter, J AF Kubelka, J Eaton, WA Hofrichter, J TI Experimental tests of villin subdomain folding simulations SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE protein folding; villin headpiece; laser temperature jump ID BETA-HAIRPIN FORMATION; HEADPIECE SUBDOMAIN; COIL KINETICS; FAST EVENTS; PROTEIN; MODEL; DYNAMICS; DIFFUSION; HELIX; MECHANISMS AB We have used laser temperature-jump to investigate the kinetics and mechanism of folding the 35 residue subdomain of the villin headpiece. The relaxation kinetics are biphasic with a sub-microsecond phase corresponding to a helix-coil transition and a slower microsecond phase corresponding to overall unfolding/refolding. At 300 K, the folding time is 4.3(+/- 0.6) mus, making it the fastest folding, naturally occurring protein, with a rate close to the theoretical speed limit. This time is in remarkable agreement with the prediction of 5 (+11, - 3) mus by Zagrovic et al. from atomistic molecular dynamics simulations using an implicit solvent model. We test their prediction that replacement of the C-terminal phenylalanine residue with alanine will increase the folding rate by removing a transient non-native interaction. We find that the alanine substitution has no effect on the folding rate or on the equilibrium constant. Implications of this result for the validity of the simulated folding mechanism are discussed. Published by Elsevier Science Ltd. C1 NIDDKD, NIH, Phys Chem Lab, Bethesda, MD 20892 USA. RP Eaton, WA (reprint author), NIDDKD, NIH, Phys Chem Lab, MSC 0520,Bldg 5, Bethesda, MD 20892 USA. NR 41 TC 190 Z9 191 U1 3 U2 15 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUN 13 PY 2003 VL 329 IS 4 BP 625 EP 630 DI 10.1016/S0022-2836(03)00519-9 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 691HY UT WOS:000183601400001 PM 12787664 ER PT J AU Toth, A Kedei, N Wang, Y Blumberg, PM AF Toth, A Kedei, N Wang, Y Blumberg, PM TI Arachidonyl dopamine as a ligand for the vanilloid receptor VR1 of the rat SO LIFE SCIENCES LA English DT Article DE vanilloid receptor subtype 1 (VR1); capsaicin; anandamide; arachidonyl dopamine; resiniferatoxin (RTX) binding; Ca-45(2+) uptake; intracellular Ca2+ imaging; VR1-transfected CHO cells (CHO-VR1); desensitization; antagonism; agonism; calcium ID CANNABINOID-RECEPTOR; CAPSAICIN RECEPTORS; GANGLION NEURONS; ANANDAMIDE; PAIN; DESENSITIZATION; ACTIVATION; RESPONSES; CHANNEL; BRAIN AB The vanilloid receptor VR1 is a nonspecific Ca2+ channel, expressed in sensory neurons in the peripheral nervous system and in various brain regions, which is believed to be an important molecular integrator of several chemical (acid, vanilloids) and physical stimuli (heat) that cause pain. Recently, several endogenous ligands for VR1 have been identified such as arachidonyl ethanolamide (anandamide) and the more potent arachidonyl dopamine (AA-DO). Here, we further characterize AA-DO As a ligand for rat VR1, heterologously expressed in CHO and HEK293 cells. AA-DO inhibited the binding of [H-3]RTX to VR1 with a K-d value of 5.49 +/- 0.68 muM and with positive cooperativity (p = 1.89 +/- 0.27), indicating that AA-DO was about 5-fold more potent than anandamide in this system. The K-d (9.7 +/- 3.3 muM), and p values (1.54 +/- 0.04) for the binding of AA-DO to spinal cord membranes are in good correlation with the CHO-VR1 data. AA-DO stimulated Ca-45(2+) uptake on CHO-VR1 and HEK-VR1 cells with EC50 values of 4.76 +/- 1.43 and 7.17 +/- 1.64 muM and Hill coefficients of 1.28 +/- 0.11 and 1.13 +/- 0.13, respectively, consistent with the binding measurements. In contrast to anandamide, AA-DO induced virtually the same level of Ca-45(2+) uptake as did capsaicin (90 +/- 6.6% in the CHO cells expressing VR1 and 89.3 +/- 9.4% in HEK293 cells expressing VR1). In a time dependent fashion following activation, AA-DO partially desensitized VR1 both in 45Ca2+ uptake assays (IC50 = 3.24 +/- 0.84 muM, inhibition is 68.5 +/- 6.85%) as well as in Ca2+ imaging experiments (35.8 +/- 5.1% inhibition) using the CHO-VR1 system. The extent of desensitization was similar to that caused by capsaicin itself We conclude that AA-DO is a full agonist for VR1 with a potency in the low micromolar range and is able to significantly desensitize the cells in a time and dose dependent manner. Published by Elsevier Science Inc. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, Mol Mechanisms Tumor Promot Sect, NIH, Bethesda, MD 20892 USA. RP Blumberg, PM (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, Mol Mechanisms Tumor Promot Sect, NIH, Bldg 37,Rm 4048,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. RI Toth, Attila/F-4859-2010 OI Toth, Attila/0000-0001-6503-3653 NR 25 TC 41 Z9 44 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD JUN 13 PY 2003 VL 73 IS 4 BP 487 EP 498 DI 10.1016/S0024-3205(03)00310-2 PG 12 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 684ET UT WOS:000183193000010 PM 12759142 ER PT J AU Wu, XL Li, Y Crise, B Burgess, SM AF Wu, XL Li, Y Crise, B Burgess, SM TI Transcription start regions in the human genome are favored targets for MLV integration SO SCIENCE LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; RETROVIRAL INTEGRATION; GENE-THERAPY; DIRECTS INTEGRATION; DNA; MINICHROMOSOMES; ISLANDS; SITES AB Factors contributing to retroviral integration have been intractable because past studies have not precisely located genomic sites of proviruses in sufficient numbers for significant analysis. In this study, 903 murine leukemia virus (MLV) and 379 human immunodeficiency virus-1 (HIV-1) integrations in the human genome were mapped. The data showed that MLV preferred integration near the start of transcriptional units ( either upstream or downstream) whereas HIV-1 preferred integration anywhere in the transcriptional unit but not upstream of the transcriptional start. Defining different integration site preferences for retroviruses will have important rami. cations for gene therapy and may aid in our understanding of the factors directing the integration process. C1 NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Sci Applicat Int Corp, Frederick, MD 21702 USA. RP Burgess, SM (reprint author), NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. EM burgess@mail.nih.gov OI Burgess, Shawn/0000-0003-1147-0596 FU NCI NIH HHS [N01-CO-12400] NR 18 TC 897 Z9 952 U1 2 U2 15 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUN 13 PY 2003 VL 300 IS 5626 BP 1749 EP 1751 DI 10.1126/science.1083413 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 688WF UT WOS:000183459700052 PM 12805549 ER PT J AU Kang, JH Chung, HE Kim, SY Kim, Y Lee, J Lewin, NE Pearce, LV Blumberg, PM Marquez, VE AF Kang, JH Chung, HE Kim, SY Kim, Y Lee, J Lewin, NE Pearce, LV Blumberg, PM Marquez, VE TI Conformationally constrained analogues of diacylglycerol (DAG). Effect on protein kinase C (PK-C) binding by the isosteric replacement of Sn-1 and Sn-2 esters in DAG-lactones SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article ID 5-DISUBSTITUTED TETRAHYDRO-2-FURANONE TEMPLATE; PHORBOL ESTER; LIGANDS; AFFINITY; DESIGN AB In order to determine the importance of the two ester pharmacophores in high affinity, conformationally constrained DAG-lactones (Lac-1-5) as PK-C ligands, we have independently replaced the sn-1 and sn-2 carbonyl esters in these compounds by ketone (2, 10, 11), amide (3, 25-28), and hydroxyl (12, 13) isosteres. Although the ketone analogue of the sn-1 ester (2) exhibited comparable activity to the parent Lac-1 when taking into account the difference in lipophilicities, the other isosteres were significantly poorer PK-Ca ligands compared to the parent DAG-lactones. This study demonstrates that the ester functionality in DAG-lactone plays an important role in the ligand's capacity to form a strong hydrogen bond with Gly253 at the active site. The discrete K-i analysis from the sn-1 and sn-2 isosteres further confirms that the DAG-lactones bind preferentially to the C1-domain in the sn-2 binding mode, as previously suggested. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 Seoul Natl Univ, Coll Pharm, Med Chem Lab, Seoul 151742, South Korea. NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. NCI, Med Chem Lab, NIH, Frederick, MD 21701 USA. RP Lee, J (reprint author), Seoul Natl Univ, Coll Pharm, Med Chem Lab, Seoul 151742, South Korea. NR 17 TC 15 Z9 15 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 JUN 12 PY 2003 VL 11 IS 12 BP 2529 EP 2539 DI 10.1016/S0968-0896(03)00156-1 PG 11 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 683RU UT WOS:000183164000006 PM 12757721 ER PT J AU Nicholas, GM Eckman, LL Kovac, P Otero-Quintero, S Bewley, CA AF Nicholas, GM Eckman, LL Kovac, P Otero-Quintero, S Bewley, CA TI Synthesis of 1-D- and 1-L-myo-inosityl 2-N-acetamido-2-deoxy-alpha-glucopyranoside establishes substrate specificity of the Mycobacterium tuberculosis enzyme AcGI deacetylase SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article ID S-CONJUGATE AMIDASE; MYCOTHIOL BIOSYNTHESIS; THIOL; IDENTIFICATION; EXPRESSION; INHIBITORS; SMEGMATIS; SEQUENCE AB Mycothiol (MSH, 1-D-myo-inosityl 2-(N-acetyl-L-cysteinyl)amido-2-deoxy-alpha-D-glucopyrano side) is the principal low molecular weight thiol in actinomycetes. The enzyme 1-D-myo-inosityl 2-N-acetamido-2-deoxy-alpha-D-glucopyranoside deacetylase (AcGI deacetylase) is involved in the biosynthesis of MSH and forms the free amine 1-D-niyo-inosityl 2-amino-2-deoxy-alpha-D-glucopyranoside, which is used in the third of four steps of MSH biosynthesis. Here, we report the synthesis of two isomers of AcGL which contain either 1-L-myo-inositol or 1-D-myo-inositol. These synthetic products were used to investigate substrate specificity of the Mycobacterium tuberculosis enzyme AcGI deacetylase. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RP Bewley, CA (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NR 22 TC 16 Z9 17 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 JUN 12 PY 2003 VL 11 IS 12 BP 2641 EP 2647 DI 10.1016/S0968-0896(03)00154-8 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 683RU UT WOS:000183164000015 PM 12757730 ER PT J AU Hirai, T Subramaniam, S AF Hirai, T Subramaniam, S TI Structural insights into the mechanism of proton pumping by bacteriorhodopsin SO FEBS LETTERS LA English DT Review DE proton pump; conformational change; retinal energy transduction ID LIPIDIC CUBIC PHASES; X-RAY-DIFFRACTION; ANGSTROM RESOLUTION; ELECTRON CRYSTALLOGRAPHY; CONFORMATIONAL-CHANGES; EARLY INTERMEDIATE; MEMBRANE-PROTEINS; CRYSTAL-STRUCTURE; PURPLE MEMBRANE; M-STATE AB For over three decades, bacteriorhodopsin has served as a paradigm for the study of the mechanisms underlying ion pumping across biological membranes. It is perhaps among the simplest known ion pumps, which functions by converting light energy into an electrochemical gradient by pumping protons out of the cytoplasm. The combination of spectroscopic, biochemical and crystallographic studies on bacteriorhodopsin provides a unique opportunity to dissect the principal elements underlying the mechanism of transmembrane proton transport. Here, we provide a brief review of recent developments related to the determination of the structural changes during proton transport using crystallographic approaches. Taken together with previous spectroscopic and biochemical investigations, these studies allow the description of a detailed molecular mechanism of the main steps in vectorial proton transport by bacteriorhodopsin. (C) 2003 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved. C1 NCI, Biochem Lab, Bethesda, MD 20817 USA. RP Subramaniam, S (reprint author), NCI, Biochem Lab, Bethesda, MD 20817 USA. RI Hirai, Teruhisa/G-2105-2015 OI Hirai, Teruhisa/0000-0002-2114-8149 NR 47 TC 31 Z9 33 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUN 12 PY 2003 VL 545 IS 1 BP 2 EP 8 DI 10.1016/S0014-5793(03)00386-7 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 690WN UT WOS:000183573600002 PM 12788485 ER PT J AU Meis, PJ Klebanoff, M Thom, E Dombrowski, MP Sibai, B Moawad, AH Spong, CY Hauth, JC Miodovnik, M Varner, MW Leveno, KJ Caritis, SN Iams, JD Wapner, RJ Conway, D O'Sullivan, MJ Carpenter, M Mercer, B Ramin, SM Thorp, JM Peaceman, AM AF Meis, PJ Klebanoff, M Thom, E Dombrowski, MP Sibai, B Moawad, AH Spong, CY Hauth, JC Miodovnik, M Varner, MW Leveno, KJ Caritis, SN Iams, JD Wapner, RJ Conway, D O'Sullivan, MJ Carpenter, M Mercer, B Ramin, SM Thorp, JM Peaceman, AM CA Natl Inst Child Hlth Human Dev Mat TI Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID DOUBLE-BLIND; PREMATURE LABOR; HABITUAL ABORTION; BIRTH PREVENTION; CLINICAL-TRIALS; RISK-FACTORS; PROGESTERONE; PREGNANCY; WOMEN; PREDICTION AB Background: Women who have had a spontaneous preterm delivery are at greatly increased risk for preterm delivery in subsequent pregnancies. The results of several small trials have suggested that 17 alpha-hydroxyprogesterone caproate (17P) may reduce the risk of preterm delivery. Methods: We conducted a double-blind, placebo-controlled trial involving pregnant women with a documented history of spontaneous preterm delivery. Women were enrolled at 19 clinical centers at 16 to 20 weeks of gestation and randomly assigned by a central data center, in a 2:1 ratio, to receive either weekly injections of 250 mg of 17P or weekly injections of an inert oil placebo; injections were continued until delivery or to 36 weeks of gestation. The primary outcome was preterm delivery before 37 weeks of gestation. Analysis was performed according to the intention-to-treat principle. Results: Base-line characteristics of the 310 women in the progesterone group and the 153 women in the placebo group were similar. Treatment with 17P significantly reduced the risk of delivery at less than 37 weeks of gestation (incidence, 36.3 percent in the progesterone group vs. 54.9 percent in the placebo group; relative risk, 0.66 [95 percent confidence interval, 0.54 to 0.81]), delivery at less than 35 weeks of gestation (incidence, 20.6 percent vs. 30.7 percent; relative risk, 0.67 [95 percent confidence interval, 0.48 to 0.93]), and delivery at less than 32 weeks of gestation (11.4 percent vs. 19.6 percent; relative risk, 0.58 [95 percent confidence interval, 0.37 to 0.91]). Infants of women treated with 17P had significantly lower rates of necrotizing enterocolitis, intraventricular hemorrhage, and need for supplemental oxygen. Conclusions: Weekly injections of 17P resulted in a substantial reduction in the rate of recurrent preterm delivery among women who were at particularly high risk for preterm delivery and reduced the likelihood of several complications in their infants. C1 Wake Forest Univ, Dept Obstet & Gynecol, Winston Salem, NC 27157 USA. NICHHD, Bethesda, MD 20892 USA. George Washington Univ, Dept Biostat, Rockville, MD USA. Wayne State Univ, Detroit, MI USA. Univ Tennessee, Memphis, TN USA. Univ Chicago, Chicago, IL 60637 USA. Univ Alabama Birmingham, Birmingham, AL USA. Univ Cincinnati, Cincinnati, OH USA. Columbia Univ, New York, NY USA. Univ Utah, Salt Lake City, UT USA. Univ Texas San Antonio, SW Med Ctr, Dallas, TX USA. Univ Pittsburgh, Pittsburgh, PA USA. Ohio State Univ, Columbus, OH 43210 USA. Thomas Jefferson Univ, Philadelphia, PA 19107 USA. Univ Texas San Antonio, San Antonio, TX 78285 USA. Univ Miami, Miami, FL 33152 USA. Brown Univ, Providence, RI 02912 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Texas San Antonio, Houston, TX USA. Univ N Carolina, Chapel Hill, NC USA. Northwestern Univ, Chicago, IL 60611 USA. RP Meis, PJ (reprint author), Wake Forest Univ, Dept Obstet & Gynecol, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM pmeis@wfubmc.edu RI Varner, Michael/K-9890-2013; OI caritis, steve/0000-0002-2169-0712; Varner, Michael/0000-0001-9455-3973; Peaceman, Alan/0000-0002-4515-4850 FU NCRR NIH HHS [M01-RR-000080]; NICHD NIH HHS [HD27905, HD21410, HD21414, HD27860, HD27861, HD27869, HD27915, HD27917, HD34116, HD34122, HD34136, HD34208, HD34210, HD36801, HD40500, HD40512, HD40544, HD40560] NR 31 TC 729 Z9 748 U1 0 U2 13 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 12 PY 2003 VL 348 IS 24 BP 2379 EP 2385 DI 10.1056/NEJMoa035140 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 688HU UT WOS:000183428900003 PM 12802023 ER PT J AU Gallin, JI Alling, DW Malech, HL Wesley, R Koziol, D Marciano, B Eisenstein, EM Turner, ML DeCarlo, ES Starling, JM Holland, SM AF Gallin, JI Alling, DW Malech, HL Wesley, R Koziol, D Marciano, B Eisenstein, EM Turner, ML DeCarlo, ES Starling, JM Holland, SM TI Itraconazole to prevent fungal infections in chronic granulomatous disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID INVASIVE PULMONARY ASPERGILLOSIS; NEUTROPENIC PATIENTS; PHARMACOKINETICS; TRIMETHOPRIM; PROPHYLAXIS; THERAPY AB Background: Chronic granulomatous disease is a rare disorder in which the phagocytes fail to produce hydrogen peroxide. The patients are predisposed to bacterial and fungal infections. Prophylactic antibiotics and interferon gamma have reduced bacterial infections, but there is also the danger of life-threatening fungal infections. We assessed the efficacy of itraconazole as prophylaxis against serious fungal infections in chronic granulomatous disease. Methods: Thirty-nine patients at least 5 years old (6 female and 33 male; mean age, 14.9 years) were enrolled in a randomized, double-blind, placebo-controlled study. After the initially assigned treatment, each patient alternated between itraconazole and placebo annually. Patients 13 years of age or older and all patients weighing at least 50 kg received a single dose of 200 mg of itraconazole per day; those less than 13 years old or weighing less than 50 kg received a single dose of 100 mg per day. The primary end point was severe fungal infection, as determined by histologic results or culture. Results: One patient (who had not been compliant with the treatment) had a serious fungal infection while receiving itraconazole, as compared with seven who had a serious fungal infection while receiving placebo (P=0.10). No patient receiving itraconazole but five patients receiving placebo had a superficial fungal infection. No serious toxic effects were noted, although one patient had a rash and another had elevated results on liver-function tests; both of these effects resolved with the discontinuation of itraconazole. Conclusions: Itraconazole prophylaxis appears to be an effective and well-tolerated treatment that reduces the frequency of fungal infections in chronic granulomatous disease, but monitoring for long-term toxic effects is warranted. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Gallin, JI (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Rm 2C128, Bethesda, MD 20892 USA. NR 20 TC 162 Z9 178 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 12 PY 2003 VL 348 IS 24 BP 2416 EP 2422 DI 10.1056/NEJMoa021931 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 688HU UT WOS:000183428900007 PM 12802027 ER PT J AU Yang, HS Knies, JL Stark, C Colburn, NH AF Yang, HS Knies, JL Stark, C Colburn, NH TI Pdcd4 suppresses tumor phenotype in JB6 cells by inhibiting AP-1 transactivation SO ONCOGENE LA English DT Article DE Pdcd4; AP-1; c-Jun; c-Fos; transformation ID NF-KAPPA-B; C-JUN; TRANSCRIPTIONAL REGULATION; NEOPLASTIC TRANSFORMATION; HUMAN KERATINOCYTES; CYCLE PROGRESSION; ANTISENSE RNA; EXPRESSION; GROWTH; GENES AB Transformation suppressor Pdcd4 is downregulated in transformed (Tx) mouse epidermal JB6 RT101 cells relative to transformation-resistant (P-) and susceptible (P+) variants. Whether Pdcd4 downregulation is necessary not only to induce transformation but also to maintain tumor phenotypes has not been determined previously. In the present study, overexpression of Pdcd4 cDNA in stably transfected RT101 cells resulted in 40% fewer anchorage-independent colonies that were smaller in size than the vector control colonies, indicating that elevated Pdcd4 expression is sufficient to suppress tumor phenotype. Transient transfection of Pdcd4 expression plasmid and 4 x AP-1 reporter gene showed that activation of AP-1-dependent transcription was inhibited by Pdcd4 expression in a concentration-dependent manner. In contrast, Pdcd4 did not inhibit serum response element-dependent transcription, indicating specificity. In a Gal4 fusion assay, Pdcd4 specifically inhibited activation of c-Jun and c-Fos activation domains, but did not inhibit activation of JunB, JunD, Fra-1, or Fra-2. Gel mobility shift assay demonstrated that c-Jun is the major component detected in the AP-1 complex in RT101 cells. Previous studies suggested that AP-1 activity is required for maintaining the transformed phenotype in RT101 cells. Thus, Pdcd4 suppresses tumor phenotype by inhibiting AP-1-dependent transcription, possibly through inhibiting c-Jun and c-Fos activation. C1 Natl Canc Inst, Ctr Canc Res, Gene Regulat Sect, Frederick, MD 21702 USA. RP Yang, HS (reprint author), Natl Canc Inst, Ctr Canc Res, Gene Regulat Sect, Gene Regulat Sect,Bldg 567,Rm 180, Frederick, MD 21702 USA. RI Yang, Hsin-Sheng/A-6419-2008 NR 42 TC 117 Z9 128 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 12 PY 2003 VL 22 IS 24 BP 3712 EP 3720 DI 10.1038/sj.onc.12036433 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 690LQ UT WOS:000183551000005 PM 12802278 ER PT J AU Gabet, AS Mortreux, F Charneau, P Riou, P Duc-Dodon, M Wu, YL Jeang, KT Wattel, E AF Gabet, AS Mortreux, F Charneau, P Riou, P Duc-Dodon, M Wu, YL Jeang, KT Wattel, E TI Inactivation of hTERT transcription by Tax SO ONCOGENE LA English DT Article DE telomere; telomerase HTLV-1 hTERT oncogene; oncogenegic leukemogenesis ID T-CELL LEUKEMIA; VIRUS TYPE-1 TAX; COMPARATIVE GENOMIC HYBRIDIZATION; INHIBITS TELOMERASE ACTIVITY; HTLV-1 TAX; P53 GENE; IN-VIVO; BINDING ELEMENT; CANCER CELLS; CYCLE ARREST AB Telomerase expression is the hallmark of tumor cells in which this ribonucleoprotein complex preserves chromosome integrity by maintaining telomere length and thereby prevents cell death. However, recent data support a role of the combination of p53 and telomerase inactivation in initiating genetic instability that promotes malignant transformation. Through its pleiotropic effects on infected T-cell metabolism, the human T-cell leukemia virus type 1 (HTLV-1) oncoprotein Tax plays a central role in leukemogenesis. Here, we show that Tax inhibits human telomerase reverse transcriptase (hTERT) transcription, which is the rate-limiting factor of telomerase activity. This inhibitory effect, that occurs in competition with c-Myc through a canonical c-Myc binding site within the hTERT promoter, results in a decreased telomerase activity of Tax-expressing cells. This is the first demonstration of hTERT inhibition by an oncogene. Tax, which is only expressed in preleukemic cells, triggers infected T-cell cycle and keeps these cells cycling while inactivating p53. We propose that, in combination with these effects, h TER T repression by Tax at an early phase of carcinogenesis might contribute to the massive ploidy changes associated with the development of HTLV-1-associated malignancies. C1 Ctr Leon Berard, CNRS UMR 5537, Unite Oncogenese Viral, F-69373 Lyon 08, France. Inst Pasteur, Grp Virol Mol & Vector, F-75724 Paris, France. Fac Med Lyon Laennec, CNRS UMR 5537, F-69372 Lyon 8, France. NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. Hop Edouard Herriot, Hematol Serv, F-69437 Lyon 03, France. RP Wattel, E (reprint author), Univ Lyon 1, UMR5578 CNRS, Ctr Leon Berard, 28 Rue Laennec, F-69373 Lyon 08, France. RI Jeang, Kuan-Teh/A-2424-2008; mortreux, franck/M-5944-2014; Duc-Dodon, Madeleine/I-6580-2016 NR 59 TC 64 Z9 68 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 12 PY 2003 VL 22 IS 24 BP 3734 EP 3741 DI 10.1038/sj.onc.1206468 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 690LQ UT WOS:000183551000007 PM 12802280 ER PT J AU Ongusaha, PP Ouchi, T Kim, KT Nytko, E Kwak, JC Duda, RB Deng, CX Lee, SW AF Ongusaha, PP Ouchi, T Kim, KT Nytko, E Kwak, JC Duda, RB Deng, CX Lee, SW TI BRCA1 shifts p53-mediated cellular outcomes towards irreversible growth arrest SO ONCOGENE LA English DT Article DE BRCA1; p53; senescence; microarray; DNA damage ID DNA-DAMAGE RESPONSE; TRANSCRIPTIONAL ACTIVATION; ATAXIA-TELANGIECTASIA; GENE-EXPRESSION; FEEDBACK LOOP; P53; CYCLE; CHECKPOINT; REPAIR; GADD45 AB The tumor suppressor protein BRCA1 has been shown to enhance p53 transcription, whereas activated p53 represses BRCA1 transcription. To further understand the functional interaction of these proteins, we investigated the role of BRCA1 in p53-induced phenotypes. We found that BRCA1 when subjected to forced expression acts synergistically with wild-type p53, resulting in irreversible growth arrest, as shown by VhD mouse fibroblast cells expressing a temperature-sensitive mutant of p53. Furthermore, reintroduction of both BRCA1 and p53 into BRCA1(-/-)/p53(-/-) mouse embryonic fibroblasts markedly increased the senescence phenotype compared to that induced by Ill alone. In particular, we found that BRCA1 expression attenuated p53-mediated cell death in response to gamma-irradiation. Moreover, microarray screening of 11 000 murine genes demonstrated that a set of genes upregulated by p53 is enhanced by coexpression of BRCA1 and p53, suggesting that BRCA1 and p53 exert a promoter selectivity leading to a specific phenotype. Taken together, our results provide evidence that BRCA1 is involved in p53-mediated growth suppression rather than apoptosis. C1 Harvard Univ, Inst Med, Sch Med, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Canc Biol Program, Div Hematol Oncol, Boston, MA 02115 USA. CUNY Mt Sinai Sch Med, Derald H Ruttenberg Canc Ctr, New York, NY 10029 USA. Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA 02215 USA. NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Lee, SW (reprint author), Harvard Univ, Inst Med, Sch Med, Room 921,4 Blackfan Circle, Boston, MA 02115 USA. RI deng, chuxia/N-6713-2016 FU NCI NIH HHS [CA78356, CA80058, CA85214] NR 44 TC 32 Z9 33 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 12 PY 2003 VL 22 IS 24 BP 3749 EP 3758 DI 10.1038/sj.onc.1206439 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 690LQ UT WOS:000183551000009 PM 12802282 ER PT J AU Goldman, DP Berry, SH McCabe, MS Kilgore, ML Potosky, AL Schoenbaum, ML Schonlau, M Weeks, JC Kaplan, R Escarce, JJ AF Goldman, DP Berry, SH McCabe, MS Kilgore, ML Potosky, AL Schoenbaum, ML Schonlau, M Weeks, JC Kaplan, R Escarce, JJ TI Incremental treatment costs in National Cancer Institute-sponsored clinical trials SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID BREAST-CANCER; MEDICAL ONCOLOGISTS; BARRIERS; CARE; CHEMOTHERAPY; MULTICENTER; KNOWLEDGE; ATTITUDES AB Context Concern about additional costs for direct patient care impedes efforts to enroll patients in clinical trials. But generalizable evidence substantiating these concerns is lacking. Objective To assess the additional cost of treating cancer patients in the National Cancer Institute (NCI)-sponsored clinical trials in the United States across a range of trial phases, treatment modalities, and patient care settings. Design Retrospective cost study using a multistage, stratified, random sample of patients enrolled in 1 of 35 active phase 3 trials or phase 1 or any phase 2 trials between October 1, 1998, and December 31, 1999. Unadjusted and adjusted costs were compared and related to trial phase, institution type, and vital status. Setting and Participants A representative sample of 932 cancer patients enrolled in nonpediatric, NCI-sponsored clinical trials and 696 nonparticipants with a similar stage of disease not enrolled in a research protocol from 83 cancer clinical research institutions across the United States. Main Outcome Measures Direct treatment costs as measured using a combination of medical records, telephone survey, and Medicare claims data. Administrative and other research costs were excluded. Results The incremental costs of direct care in trials were modest. Over approximately a 2.5-year period, adjusted costs were 6.5% higher for trial participants than nonparticipants ($35418 vs $33248; P=.11). Cost differences for phase 3 studies were 3.5% (P=.22), lower than for phase 1 or 2 trials (12.8%; P=.20). Trial participants who died had higher costs than nonparticipants who died (17.9%; $39420 vs $33432, respectively; P=15). Conclusions Treatment costs for nonpediatric clinical trial participants are on average 6.5% higher than what they would be if patients did not enroll. This implies total incremental treatment costs for NCI-sponsored trials of $16 million in 1999. Incremental costs were higher for patients who died and who were in early phase studies although these findings deserve further scrutiny. Overall, the additional treatment costs of an open reimbursement policy for government-sponsored cancer clinical trials appear minimal. C1 RAND Corp, Hlth, Santa Monica, CA 90407 USA. RAND Corp, Stat, Santa Monica, CA 90407 USA. NCI, Off Educ & Special Initiat, Div Canc Control & Populat Sci, Washington, DC USA. NCI, Clin Invest Branch, Natl Canc Therapy Evaluat Program, Washington, DC USA. Univ Alabama, Dept Hlth Care Org & Policy, Birmingham, AL USA. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA USA. RP Goldman, DP (reprint author), RAND Corp, Hlth, 1700 Main St, Santa Monica, CA 90407 USA. NR 34 TC 34 Z9 34 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 11 PY 2003 VL 289 IS 22 BP 2970 EP 2977 DI 10.1001/jama.289.22.2970 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 687XZ UT WOS:000183403400020 PM 12799405 ER PT J AU Carreras, E Boix, E Rosenberg, HF Cuchillo, CM Nogues, MV AF Carreras, E Boix, E Rosenberg, HF Cuchillo, CM Nogues, MV TI Both aromatic and cationic residues contribute to the membrane-lytic and bactericidal activity of eosinophil cationic protein SO BIOCHEMISTRY LA English DT Article ID PRIMATE RIBONUCLEASE GENES; MAJOR BASIC-PROTEIN; SCHISTOSOMA-MANSONI; ANGSTROM RESOLUTION; CRYSTAL-STRUCTURE; MODEL MEMBRANES; LIPID BILAYERS; MECHANISM; PEPTIDES; TOXICITY AB Eosinophil cationic protein (ECP) and eosinophil derived neurotoxin (EDN) are proteins of the ribonuclease A (RNase A) superfamily that have developed biological properties related to the function of eosinophils. ECP is a potent cytotoxic molecule, and although the mechanism is still unknown this cytotoxic activity has been associated with its highly cationic character. Using liposome vesicles as a model, we have demonstrated that ECP tends to disrupt preferentially acidic membranes. On the basis of structure analysis, ECP variants modified at basic and hydrophobic residues have been constructed. Changes in the leakage of liposome vesicles by these ECP variants have indicated the role of both aromatic and basic specific amino acids in cellular membrane disruption. This is the case with the two tryptophans at positions 10 and 35, but not phenylalanine 76, and the two arginines 101 and 104. The bactericidal activity of both native ECP and point-mutated variants, tested against Escherichia coli and Staphylococcus aureus, suggests that basic amino acids play, in addition to the effect on the disruption of the cellular membrane, other roles such as specific binding on the surface of the bacteria cell. C1 Univ Autonoma Barcelona, Fac Ciencies, Dept Bioquim & Biol Mol, Bellaterra 08193, Spain. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Nogues, MV (reprint author), Univ Autonoma Barcelona, Fac Ciencies, Dept Bioquim & Biol Mol, Bellaterra 08193, Spain. RI Boix, Ester/B-9038-2012; Nogues, Victoria/H-6100-2015 OI Boix, Ester/0000-0003-1790-2142; Nogues, Victoria/0000-0002-7104-0961 NR 43 TC 73 Z9 76 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 10 PY 2003 VL 42 IS 22 BP 6636 EP 6644 DI 10.1021/bi0273011 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 685YW UT WOS:000183293100002 PM 12779318 ER PT J AU Peters, JM Aoyama, T Burns, AM Gonzalez, FJ AF Peters, JM Aoyama, T Burns, AM Gonzalez, FJ TI Bezafibrate is a dual ligand for PPAR alpha and PPAR beta: studies using null mice SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS LA English DT Article DE bezafibrate; peroxisome proliferator-activated receptor; gene expression ID PROLIFERATOR-ACTIVATED RECEPTOR; FATTY-ACID OXIDATION; MESSENGER-RNA LEVELS; ACYL-COA DEHYDROGENASE; APOLIPOPROTEIN C-III; IN-VIVO REGULATION; PEROXISOME-PROLIFERATOR; GENE-EXPRESSION; UNCOUPLING PROTEIN-3; ADIPOSE-TISSUE AB Bezafibrate is a known activator of peroxisome proliferator-activated receptors (PPARs) that can activate both PPARalpha and PPARbeta. To determine the role(s) of these receptors in mediating the biological effects of this chemical, the effect of bezafibrate was examined in PPARalpha-null and PPARbeta-null mice. Wild-type, PPARalpha-null, or PPARbeta-null mice were fed either a control diet or one containing 0.5% bezafibrate for 10 days. Bezafibrate feeding caused a significant increase in liver weight in wild-type and PPARbeta-null mice compared to controls, while liver weight was unchanged in bezafibrate-fed PPARalpha-null mice. Gonadal adipose stores were significantly smaller in wild-type and PPARbeta-null mice fed bezafibrate than in controls, and this effect was not found in similarly fed PPARalpha-null mice. Analysis of liver, white adipose tissue, and intestinal mRNAs showed that bezafibrate caused similar changes of mRNAs encoding lipid metabolizing enzymes in wild-type and PPARbeta-null mice compared to controls. Interestingly, in PPARalpha-null mice, bezafibrate also induced several mRNAs previously thought to be solely controlled by PPARalpha, showing that the effects of this drug are not exclusively modulated by this PPAR isoform. Western blot analysis of liver protein was consistent with changes in mRNA expression showing that the alterations in mRNA expression correlate with protein expression in this tissue. Results from these studies demonstrate that the effect of bezafibrate is mediated in large part by PPARalpha, although some changes in gene expression are dependent on PPARbeta. In contrast to other PPARalpha ligands such as WY-14,643, induction of some target genes by bezafibrate can also be modulated in the absence of a functional PPARalpha. Published by Elsevier Science B.V. C1 Penn State Univ, Dept Vet Sci, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. Shinshu Univ, Dept Aging Biochem, Sch Med, Nagano, Japan. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Peters, JM (reprint author), Penn State Univ, Dept Vet Sci, Ctr Mol Toxicol & Carcinogenesis, 226 Fenske Lab, University Pk, PA 16802 USA. RI Peters, Jeffrey/D-8847-2011 FU NCI NIH HHS [CA89607] NR 94 TC 72 Z9 73 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-1981 J9 BBA-MOL CELL BIOL L JI Biochim. Biophys. Acta Mol. Cell Biol. Lipids PD JUN 10 PY 2003 VL 1632 IS 1-2 BP 80 EP 89 DI 10.1016/S1388-1981(03)00065-9 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 688PY UT WOS:000183445600009 PM 12782154 ER PT J AU LeRoith, D Roberts, CT AF LeRoith, D Roberts, CT TI The insulin-like growth factor system and cancer SO CANCER LETTERS LA English DT Review DE insulin-like growth factor; insulin receptor; cancer ID FACTOR-I RECEPTOR; PROSTATE-SPECIFIC ANTIGEN; IGF-BINDING PROTEIN-3; HUMAN BREAST-CANCER; MESSENGER-RIBONUCLEIC-ACID; NF-KAPPA-B; COLORECTAL-CANCER; INHIBITS TUMORIGENESIS; CRYSTAL-STRUCTURE; AFRICAN-AMERICAN AB The insulin-like growth factor (IGF) family of ligands, binding proteins and receptors is an important growth factor system involved in both the development of the organism and the maintenance of normal function of many cells of the body. The system also has powerful anti-apoptotic effects. More recently, evidence has accrued to demonstrate that the IGFs play an important role in cancer. Individuals with serum IGF-II levels in the upper quartile of the normal range (and IGF binding protein-3 levels in the lower quartiles) have a relative risk for developing breast, prostate, colon and lung cancer. IGF-II is commonly expressed by tumor cells and may act as an autocrine growth factor; occasionally even reaching target tissues and causing tumor-induced hypoglycemia. The IGF-I receptor is commonly (though not always) overexpressed in many cancers, and many recent studies have identified new signaling pathways emanating from the IGF-I receptor that affect cancer cell proliferation, adhesion, migration and cell death; functions that are critical for cancer cell survival and metastases. In this review, many aspects of the IGF system and its relationship to cancer will be discussed. Published by Elsevier Science Ireland Ltd. C1 NIH, Diabet Branch, Bethesda, MD 20892 USA. Oregon Hlth Sci Univ, Dept Pediat, Portland, OR 97239 USA. RP LeRoith, D (reprint author), NIH, Diabet Branch, MSC 175,Room 8D12,Bldg 10, Bethesda, MD 20892 USA. OI Roberts, Charles/0000-0003-1756-5772 NR 66 TC 725 Z9 755 U1 4 U2 35 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 JUN 10 PY 2003 VL 195 IS 2 BP 127 EP 137 DI 10.1016/S0304-3835(03)00159-9 PG 11 WC Oncology SC Oncology GA 691WD UT WOS:000183628200001 PM 12767520 ER PT J AU Zhang, J Johnson, CD Hoffman, M AF Zhang, J Johnson, CD Hoffman, M TI Cervical cerclage in delayed interval delivery in a multifetal pregnancy: a review of seven case series SO EUROPEAN JOURNAL OF OBSTETRICS GYNECOLOGY AND REPRODUCTIVE BIOLOGY LA English DT Review DE cerclage; delayed interval delivery; multiple; pregnancy; triplet; twin ID MULTIPLE PREGNANCIES; TWIN PREGNANCIES; PRETERM DELIVERY; CONTROLLED TRIAL; TRIMESTER; SUTURE; WOMEN; RISK AB Objective: To examine whether cervical cerclage after the first delivery prolongs the inter-delivery interval in delayed interval deliveries. Study design: We identified 66 case reports and case series of delayed interval delivery published between 1880 and 2002. We selected seven case series that identified all cases of delayed interval delivery in their institutions during a specified period. Results: Despite routine use of broad-spectrum prophylactic antibiotics, the average incidence of clinical intrauterine infection after the first delivery was 36% (95% confidence interval (Cl): 26-46%). The incidence of maternal sepsis was 4.9% (95% Cl: 0.2-9.6%). Studies in which cerclage was infrequently used reported a shorter inter-delivery interval compared to studies where cerclage was used in all cases (median is equal to 9 days versus 26 days, respectively, P < 0.001) despite similar gestational ages at the first delivery, types of antibiotics, tocolytics, and incidence of infection. After controlling for other factors, the use of cerclage did not significantly increase the risk of intrauterine infection (adjusted relative risk = 1.1, 95% Cl: 0.4-3.5). Conclusion: Cervical cerclage after the first delivery is associated with a longer inter-delivery interval without increasing the risk of intrauterine infection. Published by Elsevier Science Ireland Ltd. C1 NICHD, Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Christiana Care Hlth Syst, Dept Obstet & Gynecol, Newark, DE USA. RP Zhang, J (reprint author), NICHD, Epidemiol Branch, NIH, NIH Bldg 6100,Room 7B03, Bethesda, MD 20892 USA. OI Hoffman, Matthew/0000-0002-2927-8693 NR 17 TC 22 Z9 28 U1 0 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0301-2115 J9 EUR J OBSTET GYN R B JI Eur. J. Obstet. Gynecol. Reprod. Biol. PD JUN 10 PY 2003 VL 108 IS 2 BP 126 EP 130 DI 10.1016/S0301-2115(02)00479-7 PG 5 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 687UE UT WOS:000183394700002 PM 12781398 ER PT J AU Takiguchi, M Achanzar, WE Qu, W Li, GY Waalkes, MP AF Takiguchi, M Achanzar, WE Qu, W Li, GY Waalkes, MP TI Effects of cadmium on DNA-(Cytosine-5) methyltransferase activity and DNA methylation status during cadmium-induced cellular transformation SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE cadmium; DNA methylation; DNA methyltransferase; transformation; carcinogenesis ID INDUCED MALIGNANT TRANSFORMATION; PROSTATE EPITHELIAL-CELLS; METALLOTHIONEIN-I GENE; C-MYC PROTOONCOGENES; NOBLE NBL/CR RAT; PROLIFERATIVE LESIONS; INJECTION SITE; CANCER; TUMORS; HYPOMETHYLATION AB Cadmium is a human carcinogen that likely acts via epigenetic mechanisms. Since DNA methylation alterations represent an important epigenetic event linked to cancer, the effect of cadmium on DNA methyltransferase (MeTase) activity was examined using in vitro (TRL1215 rat liver cells) and ex vivo (M.SssI DNA MeTase) systems. Cadmium effectively inhibited DNA MeTases in a manner that was noncompetitive with respect to substrate (DNA), indicating an interaction with the DNA binding domain rather than the active site. Based on these results, the effects of prolonged cadmium exposure on DNA MeTase and genomic DNA methylation in TRL1215 cells were studied. After I week of exposure to 0-2.5 muM cadmium, DNA MeTase activity was reduced (up to 40%) in a concentration-dependent fashion, while genomic DNA methylation showed slight but significant reductions at the two highest concentrations. After 10 weeks of exposure, the cells exhibited indications of transformation, including hyperproliferation, increased invasiveness, and decreased serum dependence. Unexpectedly, these cadmium-transformed cells exhibited significant increases in DNA methylation and DNA MeTase activity. These results indicate that, while cadmium is an effective inhibitor of DNA MeTase and initially induces DNA hypomethylation, prolonged exposure results in DNA hypermethylation and enhanced DNA MeTase activity. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NIEHS, Inorgan Carcinogenesis Sect, Lab Comparat Carcinogenesis, NCI, Res Triangle Pk, NC 27709 USA. RP Waalkes, MP (reprint author), NIEHS, Inorgan Carcinogenesis Sect, Lab Comparat Carcinogenesis, NCI, POB 12233,111 Alexander Dr,MD F0-09, Res Triangle Pk, NC 27709 USA. NR 59 TC 207 Z9 229 U1 0 U2 26 PU ACADEMIC PRESS INC ELSEVIER SCIENCE 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 JUN 10 PY 2003 VL 286 IS 2 BP 355 EP 365 DI 10.1016/S0014-4827(03)00062-4 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 682QY UT WOS:000183104400018 PM 12749863 ER PT J AU Bettinotti, MP Panelli, MC Ruppe, E Mocellin, S Phan, GQ White, DE Marincola, FM AF Bettinotti, MP Panelli, MC Ruppe, E Mocellin, S Phan, GQ White, DE Marincola, FM TI Clinical and immunological evaluation of patients with metastatic melanoma undergoing immunization with the HLA-Cw*0702-associated epitope MAGE-A12 : 170-178 SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE melanoma; immunotherapy; MAGE; immune response ID TUMOR-INFILTRATING LYMPHOCYTES; PEPTIDE VACCINATION; MONONUCLEAR-CELLS; T-LYMPHOCYTES; GENE MAGE-3; IN-VIVO; EXPRESSION; ANTIGENS; IDENTIFICATION; REGRESSION AB Patients with metastatic melanoma who expressed HLA-Cw*0702 and whose tumors had demonstrable MAGE-A12 expression were immunized with the peptide MAGE-A12: 170-178 administered subcutaneously in incomplete Freund's adjuvant (IFA). The peptide was administered either every week or every 3 weeks for 4 cycles. Patients were evaluated for toxicity and for immunologic and clinical response to peptide immunization. Pre-treatment fine needle aspirates were obtained to document MAGE-A 12 expression for enrollment. MAGE-A12 mRNA was identified in 62% of specimens. Nine patients were selected for vaccination based on MAGE-A12 expression and the presence of HLA-Cw*0702. The immune response was monitored both by tetrameric HLA-Cw*0702/MAGE-A12:170-178 complexes and by analysis of interferon-gamma mRNA transcription using a quantitative real-time polymerase chain reaction assay after peptide-specific stimulation. The samples consisted of circulating lymphocytes analyzed ex vivo or after 10 to 14 days of in vitro sensitization. One of 9 patients sustained an ongoing partial clinical response. No convincing evidence of enhancement of the systemic immune response against MAGE-A 12: 170-178 could be documented. Because of the modest immunological and clinical results, the present protocol has been discontinued as new routes of administration are being considered. (C) 2003 Wiley-Liss, Inc. C1 NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. NCI, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), NIH, Ctr Clin, Dept Transfus Med, Bldg 10,Room 1C711,10 Ctr Dr MSC 1502, Bethesda, MD 20892 USA. NR 28 TC 31 Z9 32 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 JUN 10 PY 2003 VL 105 IS 2 BP 210 EP 216 DI 10.1002/ijc.11045 PG 7 WC Oncology SC Oncology GA 669PK UT WOS:000182359500010 PM 12673681 ER PT J AU Dalakas, MC Clark, WM AF Dalakas, MC Clark, WM TI Strokes, thromboembolic events, and IVIg - Rare incidents blemish an excellent safety record SO NEUROLOGY LA English DT Editorial Material ID DOSE INTRAVENOUS IMMUNOGLOBULIN C1 NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. RP Dalakas, MC (reprint author), NINDS, Neuromuscular Dis Sect, NIH, Bldg 10,Room 4N248,10 Ctr Dr MSC, Bethesda, MD 20892 USA. NR 10 TC 47 Z9 47 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUN 10 PY 2003 VL 60 IS 11 BP 1736 EP 1737 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 688DT UT WOS:000183418400003 PM 12796522 ER PT J AU Markovic-Plese, S Bielekova, B Kadom, N Leist, TP Martin, R Frank, JA McFarland, HF AF Markovic-Plese, S Bielekova, B Kadom, N Leist, TP Martin, R Frank, JA McFarland, HF TI Longitudinal MRI study - The effects of azathioprine in MS patients refractory to interferon beta-1b SO NEUROLOGY LA English DT Article ID REMITTING MULTIPLE-SCLEROSIS; BRAIN AB An open-label study was performed to assess the effectiveness of oral azathioprine (AZA) on augmenting the response to interferon beta-1b (IFNbeta-1b) in patients with treatment-refractory relapsing-remitting MS. Six IFNbeta-1b-treated MS patients with continued disease activity were studied on IFNbeta-1b and AZA therapy for a median period of 15 months. A 69% reduction in the number of contrast-enhancing lesions was observed during the combination therapy (p = 0.002). C1 NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Lab Diagnost Radiol Res, NIH, Bethesda, MD 20892 USA. RP McFarland, HF (reprint author), NINDS, Neuroimmunol Branch, NIH, Bldg 10,Rm 5B-16,10 Ctr Dr, Bethesda, MD 20892 USA. NR 10 TC 22 Z9 22 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUN 10 PY 2003 VL 60 IS 11 BP 1849 EP 1851 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 688DT UT WOS:000183418400030 PM 12796549 ER PT J AU Vasselli, JR Shih, JH Iyengar, SR Maranchie, J Riss, J Worrell, R Torres-Cabala, C Tabios, R Mariotti, A Stearman, R Merino, M Walther, MM Simon, R Klausner, RD Linehan, WM AF Vasselli, JR Shih, JH Iyengar, SR Maranchie, J Riss, J Worrell, R Torres-Cabala, C Tabios, R Mariotti, A Stearman, R Merino, M Walther, MM Simon, R Klausner, RD Linehan, WM TI Predicting survival in patients with metastatic kidney cancer by gene-expression profiling in the primary tumor SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RENAL-CELL CARCINOMA; MESSENGER-RNA AMPLIFICATION; PATTERNS; IDENTIFICATION; IMMUNOTHERAPY; LYMPHOCYTES; ADHESION; GENOME AB To identify potential molecular determinants of tumor biology and possible clinical outcomes, global gene-expression patterns were analyzed in the primary tumors of patients with metastatic renal cell cancer by using cDNA microarrays. We used grossly dissected tumor masses that included tumor, blood vessels, connective tissue, and infiltrating immune cells to obtain a gene-expression "profile" from each primary tumor. Two patterns of gene expression were found within this uniformly staged patient population, which correlated with a significant difference in overall survival between the two patient groups. Subsets of genes most significantly associated with survival were defined, and vascular cell adhesion molecule-1 (VCAM-1) was the gene most predictive for survival. Therefore, despite the complex biological nature of metastatic cancer, basic clinical behavior as defined by survival may be determined by the gene-expression patterns expressed within the compilation of primary gross tumor cells. We conclude that survival in patients with metastatic renal cell cancer can be correlated with the expression of various genes based solely on the expression profile in the primary kidney tumor. C1 NCI, Canc Res Ctr, Urol Oncol Branch, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, Biometr Res Branch, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, Lab Biosyst & Canc, Bethesda, MD 20892 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Canc Res Ctr, Urol Oncol Branch, Bldg 10,Room 2B47, Bethesda, MD 20892 USA. EM uob@mail.nih.gov OI Maranchie, Jodi/0000-0002-8534-9468 NR 23 TC 120 Z9 124 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 10 PY 2003 VL 100 IS 12 BP 6958 EP 6963 DI 10.1073/pnas.11317454100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 689LC UT WOS:000183493500015 PM 12777628 ER PT J AU Gui, CY Dean, A AF Gui, CY Dean, A TI A major role for the TATA box in recruitment of chromatin modifying complexes to a globin gene promoter SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LOCUS-CONTROL REGION; RNA-POLYMERASE-II; TRANSCRIPTION FACTOR NF-E2; LEUCINE ZIPPER PROTEIN; HISTONE ACETYLATION; ORDERED RECRUITMENT; ERYTHROID-CELLS; IN-VIVO; MAMMALIAN-CELLS; SWI/SNF COMPLEX AB The developmentally regulated mammalian beta-globin genes are activated by a distant locus control region/enhancer. To understand the role of chromatin remodeling complexes in this activation, we used stably replicated chromatin templates, in which transcription activation of the human embryonic epsilon-globin gene depends on the tandem Maf-recognition elements (MAREs) within the beta-globin locus control region HS2 enhancer, to which the erythroid factor NF-E2 binds. The HS2 MAREs are required for nucleosome mobilization and histone hyperacetylation at the distant promoter. Nucleosome mobilization also requires the promoter TATA box, and is independent of histone hyperacetylation. In contrast, promoter hyperacetylation requires the promoter GATA-1, and CACC-factor activator motifs, as well as the TATA box. ChlP analysis reveals that NF-E2 is associated with the active epsilon-globin promoter, which lacks an NF-E2 binding sequence, in a TATA box and HS2/MARE-dependent fashion. NF-E2 association with the epsilon-globin promoter coincides with that of RNA polymerase II at both regulatory sites. The results emphasize MARE-TATA box interactions in the recruitment of complexes modifying promoter chromatin for transcription activation and imply close physical interaction between widely separated regulatory sequences mediated through these sites. C1 NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Dean, A (reprint author), NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. NR 63 TC 16 Z9 16 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 10 PY 2003 VL 100 IS 12 BP 7009 EP 7014 DI 10.1073/pnas.126499100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 689LC UT WOS:000183493500024 PM 12773626 ER PT J AU Hardikar, AA Marcus-Samuels, B Geras-Raaka, E Raaka, BM Gershengorn, MC AF Hardikar, AA Marcus-Samuels, B Geras-Raaka, E Raaka, BM Gershengorn, MC TI Human pancreatic precursor cells secrete FGF2 to stimulate clustering into hormone-expressing islet-like cell aggregates SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE migration; paracrine; aggregation; differentiation ID FIBROBLAST-GROWTH-FACTOR; DIFFERENTIATION; ORGANOGENESIS; SIGNALS; MORPHOGENESIS; ENDODERM; PROLIFERATION; MIGRATION; NOTOCHORD; RECEPTORS AB Development of the endocrine pancreas includes a series of early events wherein precursor cells cluster, that is migrate to form cell aggregates, which subsequently differentiate into islets of Langerhans. We show that PANC-1 cells, a human pancreatic cell line, differentiates into hormone-producing islet-like cell aggregates after exposure to a defined serum-free medium. These cells were used to provide the following evidence that fibroblast growth factor (FGF)2 is a paracrine chemoattractant during PANC-1 cell clustering: (i) FGF2 is secreted and remains bound to the extracellular matrix from where it may diffuse to form chemoattractive gradients; (it) a subset of cells expresses FGF receptors (FGFRs) -1, -2, -3, and -4; (iii) inhibition of FGFR tyrosine kinase inhibits cell clustering; and (iv) FGF2 neutralizing antibody inhibits clustering. In addition, adult human islet-derived precursor cells, which cluster and differentiate in a manner similar to PANC-1 cells, also secrete FGF2 and express FGFRs. We conclude that FGF2, acting as a paracrine chemoattractant, stimulates clustering of precursor cells, an early step leading to islet-like cell aggregate formation. Similar processes may occur during development of the islet of Langerhans in humans. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. RP Gershengorn, MC (reprint author), Bldg 50,Room 4135,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 36 TC 103 Z9 104 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 10 PY 2003 VL 100 IS 12 BP 7117 EP 7122 DI 10.1073/pnas.1232230100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 689LC UT WOS:000183493500042 PM 12799459 ER PT J AU Yu, DG Sawitzke, JA Ellis, H Court, DL AF Yu, DG Sawitzke, JA Ellis, H Court, DL TI Recombineering with overlapping single-stranded DNA oligonucleotides: Testing a recombination intermediate SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID BACTERIAL ARTIFICIAL CHROMOSOMES; ESCHERICHIA-COLI; BETA-PROTEIN; PHAGE-LAMBDA; HOMOLOGOUS RECOMBINATION; BACTERIOPHAGE-LAMBDA; RECA PROTEIN; COHESIVE ENDS; REPAIR; SYSTEM AB A phage A-based recombination system, Red, can be used for high-efficiency mutagenesis, repair, and engineering of chromosomal or episomal DNA in vivo in Escherichia coli. When long linear double-stranded DNA with short flanking homologies to their targets are used for the recombination, the lambda Exo, Beta, and Gam proteins are required. The current model is: (i) Gam inhibits the host RecBCD activity, thereby protecting the DNA substrate for recombination; (ii) Exo degrades from each DNA end in a 5'-->3' direction, creating double-stranded DNA with 3' single-stranded DNA tails; and (iii) Beta binds these 3' overhangs to protect and anneal them to complementary sequences. We have tested this model for Red recombination by using electroporation to introduce overlapping, complementary oligonucleotides that when annealed in vivo approximate the recombination intermediate that Exo should create. Using this technique we found Exo-independent recombination. Surprisingly, a similarly constructed substrate with 5' overhangs recombined more efficiently. This 5' overhang recombination required both Exo and Beta for high levels of recombination and the two oligonucleotides need to overlap by only 6 bp on their 3' ends. Results indicate that Exo may load Beta onto the 3' overhang it produces. In addition, multiple overlapping oligonucleotides were successfully used to generate recombinants in vivo, a technique that could prove useful for many genetic engineering procedures. C1 NCI, Ctr Canc Res, Gene Regulat & Chromosome Biol Lab, Ft Detrick, MD 21702 USA. RP Court, DL (reprint author), Lexicon Genet Inc, 4000 Res Forest Dr, The Woodlands, TX 77381 USA. NR 28 TC 53 Z9 59 U1 1 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 10 PY 2003 VL 100 IS 12 BP 7207 EP 7212 DI 10.1073/pnas.1232375100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 689LC UT WOS:000183493500057 PM 12771385 ER PT J AU Rajan, P Panchision, DM Newell, LE McKay, RDG AF Rajan, P Panchision, DM Newell, LE McKay, RDG TI BMPs signal alternately through a SMAD or FRAP-STAT pathway to regulate fate choice in CNS stem cells SO JOURNAL OF CELL BIOLOGY LA English DT Article DE bone morphogenetic protein; stem cell; SMAD; STAT; mammalian FRAP ID BONE MORPHOGENETIC PROTEIN; CENTRAL-NERVOUS-SYSTEM; NEURAL CREST; ASTROCYTIC DIFFERENTIATION; SERINE PHOSPHORYLATION; LINEAGE COMMITMENT; PROGENITOR CELLS; GROWTH-FACTOR; IN-VIVO; RECEPTORS AB The ability of stem cells to generate distinct fates is critical for the generation of cellular diversity during development. Central nervous system (CNS) stem cells respond to bone morphogenetic protein (BMP) 4 by differentiating into a wide variety of dorsal CNS and neural crest cell types. We show that distinct mechanisms are responsible for the generation of two of these cell types, smooth muscle and glia. Smooth muscle differentiation requires BMP-mediated Smad1/5/8 activation and predominates where local cell density is low. In contrast, glial differentiation predominates at high local densities in response to BMP4 and is specifically blocked by a dominant-negative mutant Stat3. Upon BMP4 treatment, the serine-threonine kinase FKBP12/rapamycin-associated protein (FRAP), mammalian target of rapamycin (mTOR), associates with Stat3 and facilitates STAT activation. Inhibition of FRAP prevents STAT activation and glial differentiation. Thus, glial differentiation by BMP4 occurs by a novel pathway mediated by FRAP and STAT proteins. These results suggest that a single ligand can regulate cell fate by activating distinct cytoplasmic signals. C1 NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP McKay, RDG (reprint author), 36 Convent Dr,MSC 4092, Bethesda, MD 20892 USA. NR 56 TC 149 Z9 154 U1 0 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD JUN 9 PY 2003 VL 161 IS 5 BP 911 EP 921 DI 10.1083/jcb.200211021 PG 11 WC Cell Biology SC Cell Biology GA 689QP UT WOS:000183504700008 PM 12796477 ER PT J AU Stone, JS Shang, JL Tomarev, S AF Stone, JS Shang, JL Tomarev, S TI Expression of proxl defines regions of the avian otocyst that give rise to sensory or neural cells SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Review DE prospero; transcription factor; neurogenesis; hair cell development; otocyst ID CHICKEN INNER-EAR; HOMEOBOX GENE PROX-1; GROWTH-FACTOR-ALPHA; MIND BOMB MUTANT; BASILAR PAPILLA; HAIR-CELLS; FATE SPECIFICATION; NEURONAL PRECURSORS; DROSOPHILA-PROSPERO; MAMMALIAN COCHLEA AB The simple primordium of the inner ear (otocyst) differentiates into many cell types, including sensory neurons and hair cells. We examined expression of the divergent homeobox transcription factor, cProx1, during otocyst development in chickens. Nuclear cProx1 protein is not evident in the otic placode but emerges in the otic cup by stage 12. At stage 16, cProx1-positive nuclei are scattered continuously throughout the neuroepithelium, from anteroventral to posteromedial. These labeled cells are neural precursors; they express BIII-tubulin and migrate to the cochleovestibular ganglion between stages 13 and 21. By stage 18, two areas develop a dense pattern of cProx1 expression in which every nucleus is labeled. These areas emerge at the anterior and posterior extremes of the band of scattered cProx1 expression and express the sensory markers cSerrate1 and Cath1 by stage 23. Four discrete patches of dense cProx1 expression appear by stage 23 that correspond to the future superior crista, lateral crista, saccular macula, and posterior crista, as confirmed by immunolabeling for hair cell antigen (HCA) by stage 29. The remaining sensory epithelia display a dense pattern of cProx1 expression and label for HCA by stage 29. In the basilar papilla, nuclear cProx1 expression is down-regulated in most hair cells by stage 37 and in many supporting cells by stage 40. Our findings show that regions of the otocyst that give rise to neurons or hair cells are distinguished by their relative density of cProx1-positive nuclei, and suggest a role for cProx1 in the genesis of these cell types. Published 2003 Wiley-Liss, Inc. C1 Univ Washington, Virginia Merrill Bloedel Hearing Res Ctr, Dept Otolaryngol Head & Neck Surg, Seattle, WA 98195 USA. NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Stone, JS (reprint author), Univ Washington, Sch Med, Dept Otolaryngol, Virginia Merrill Bloedel Hearing Res Ctr, CHDD CD 176,Box 357923, Seattle, WA 98195 USA. FU NIDCD NIH HHS [DC04661, DC02854, DC03696] NR 122 TC 30 Z9 32 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD JUN 9 PY 2003 VL 460 IS 4 BP 487 EP 502 DI 10.1002/cne.10662 PG 16 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 674HC UT WOS:000182630500004 PM 12717709 ER PT J AU Dayer, AG Ford, AA Cleaver, KM Yassaee, M Cameron, HA AF Dayer, AG Ford, AA Cleaver, KM Yassaee, M Cameron, HA TI Short-term and long-term survival of new neurons in the rat dentate gyrus SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE cell cycle; cell death; bromodeoxyuridine; hippocampus; adult neurogenesis development ID GENERATED GRANULE CELLS; ADULT NEUROGENESIS; HIPPOCAMPAL-FORMATION; REGION; DEATH; MICE AB New neurons continue to be generated in the dentate gyrus throughout adulthood. Previous studies have shown that a significant proportion of new granule cells labeled with the thymidine analogue bromodeoxyuridine (BrdU) are lost from the adult dentate gyrus within 2 weeks. How long this loss continues and the extent to which it represents cell death, as opposed to dilution of label, is unclear. To address these questions, adult rats were injected with BrdU, and BrdU labeling in the dentate gyrus was compared at several survival time points. Double labeling with BrdU and the cell cycle marker Ki-67 showed that BrdU is detectable for up to 4 days in some cells that continue to divide, indicating that any decrease in the number of BrdU-Iabeled cells after 4 days is likely to reflect cell death rather than BrdU dilution. Death of new cells in the granule cell layer occurred at a steady rate between 6 and 28 days after labeling, resulting in loss of 50% of BrdU-labeled cells over this 22-day period. New granule cells that survived this first month lived for at least 5 additional months. In contrast, 26% of the granule cells labeled with BrdU at the peak of dentate gyrus development on postnatal day (P) 6 died between 1 and 6 months after labeling. These findings suggest that granule cells born during adulthood that become integrated into circuits and survive to maturity are very stable and may permanently replace granule cells born during development. Published 2003 Wiley-Liss, Inc. C1 NIMH, Unit Neuroplast, Mood & Anxiety Disorders Program, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. RP Dayer, AG (reprint author), NIMH, Unit Neuroplast, Mood & Anxiety Disorders Program, Dept Hlth & Human Serv,NIH, Bldg 36-3D26 MSC 4027, Bethesda, MD 20892 USA. RI Cameron, Heather/E-6221-2011; OI Cameron, Heather/0000-0002-3245-5777; Winkel, Abigail/0000-0001-6149-5842; Dayer, Alexandre/0000-0002-4490-9780 NR 28 TC 379 Z9 394 U1 2 U2 10 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD JUN 9 PY 2003 VL 460 IS 4 BP 563 EP 572 DI 10.1002/cne.10675 PG 10 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 674HC UT WOS:000182630500009 PM 12717714 ER PT J AU Choi, DK Yoo, KW Hong, SK Rhee, M Sakaki, Y Kim, CH AF Choi, DK Yoo, KW Hong, SK Rhee, M Sakaki, Y Kim, CH TI Isolation and expression of Napor/CUG-BP2 in embryo development SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE RNA-binding protein; ELAV-Iike; Napor; neural differentiation; rhombomere 5; mind bomb mutant ID RNA-BINDING PROTEINS; RIGHT-VENTRICULAR DYSPLASIA; GENE-EXPRESSION; NERVOUS-SYSTEM; CELL-DEATH; ZEBRAFISH; REGULATORS; FAMILY; NAPOR; HUC AB The human neuroblastoma apoptosis-related RNA-binding protein NAPOR is an ELAV-like RNA-binding protein with three characteristic RNA recognition motifs (RRMs). We report here the cloning and characterization of a zebrafish Napor that has a high sequence homology to human NAPOR protein. Whole-mount in situ hybridization analysis revealed that zebrafish napor is dynamically expressed in early development. In addition to its maternal expression, napor transcripts were detected in adaxial mesoderm cells and lateral neural plate cells at early somite stages. By 10-somite stage, napor expression was restricted to the central nervous system, having a specific expression domain of rhombomere 5 in the hindbrain. In 24 hpf embryo, napor was expressed in subsets of differentiating neural cells in the forebrain and hindbrain as well as somitic muscle cells. The number of napor-expressing neural cells was greatly increased in the mind bomb mutant that has neurogenic phenotype resulting from deficits in the Notch signaling pathway. Furthermore, overexpression of napor by RNA microinjection resulted in severe defects in nervous system and gastrulation, suggesting the need for tight control of napor gene regulation during embryo development. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Chungnam Natl Univ, Dept Biol, Taejon 305764, South Korea. Cornell Univ, Dept Neurol & Neurosci, New York, NY 10021 USA. NICHD, Lab Mol Genet, NIH, Bethesda, MD 20892 USA. Univ Tokyo, Inst Med Sci, Ctr Human Genome, Tokyo 1088639, Japan. RP Kim, CH (reprint author), Chungnam Natl Univ, Dept Biol, Taejon 305764, South Korea. NR 28 TC 8 Z9 8 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 6 PY 2003 VL 305 IS 3 BP 448 EP 454 DI 10.1016/S0006-291X(03)00789-7 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 687BG UT WOS:000183355500002 PM 12763013 ER PT J AU Marlow, L Canet, RM Haugabook, SJ Hardy, JA Lahiri, DK Sambamurti, K AF Marlow, L Canet, RM Haugabook, SJ Hardy, JA Lahiri, DK Sambamurti, K TI APH1, PEN2, and Nicastrin increase A beta levels and gamma-secretase activity SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE amyloid; APH-1; APP; gamma-secretase; intramembrane proteolysis; Nicastrin; Notch; PEN-2; presenilin; regulated proteolysis; secretosome ID AMYLOID PRECURSOR PROTEIN; CALCIUM-BINDING PROTEIN; ALZHEIMERS-DISEASE; CAENORHABDITIS-ELEGANS; SEL-12 PRESENILIN; IN-VIVO; NOTCH; CLEAVAGE; EXPRESSION; INTERACTS AB A major component of the amyloid plaque core in Alzheimer's disease (AD) is the 40-42-residue amyloid beta peptide (Abeta). Mutations linked to AD such as those in presenilins 1 (PS1) and 2 (PS2) invariably increase the longer Abeta42 species that forms neurotoxic oligomers. It is believed that PS1/2 constitute the catalytic subunit of the gamma-secretase responsible for the final step in Abeta biogenesis. Recent genetic studies have identified a number of additional genes encoding APH1a, APH1b, PEN2, and Nicastrin proteins, which are part of the gamma-secretase complex with PS1. Further, knockout studies using RNAi showed that these components are essential for gamma-secretase activity. However, the nature Of gamma-secretase and how the aforementioned proteins regulate its activity are still incompletely understood. Here we present evidence that unlike PS1, overexpression of these proteins can increase the levels of Abeta, suggesting that these proteins are limiting for gamma-secretase activity. In addition, our studies also suggest that the presenilin partners regulate the relative levels of Abeta40 and Abeta42. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Med Univ S Carolina, Dept Physiol & Neurosci, Charleston, SC 29425 USA. Med Univ S Carolina, Ctr Aging, Charleston, SC 29425 USA. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Indiana Univ, Sch Med, Inst Psychiat Res, Dept Psychiat, Indianapolis, IN 46202 USA. RP Sambamurti, K (reprint author), Med Univ S Carolina, Dept Physiol & Neurosci, 173 Ashley Ave,Suite 403, Charleston, SC 29425 USA. RI Hardy, John/C-2451-2009 NR 45 TC 35 Z9 40 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 6 PY 2003 VL 305 IS 3 BP 502 EP 509 DI 10.1016/S0006-291X(03)00797-6 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 687BG UT WOS:000183355500010 PM 12763021 ER PT J AU Yokozeki, M Afanador, E Nishi, M Kaneko, K Shimokawa, H Yokote, K Deng, CX Tsuchida, K Sugino, H Moriyama, K AF Yokozeki, M Afanador, E Nishi, M Kaneko, K Shimokawa, H Yokote, K Deng, CX Tsuchida, K Sugino, H Moriyama, K TI Smad3 is required for enamel biomineralization SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Smad3; enamel; hypomineralization; tooth development ID DOMINANT AMELOGENESIS IMPERFECTA; NONSENSE MUTATION; TOOTH DEVELOPMENT; TGF-BETA; TARGETED DISRUPTION; MOUSE EMBRYO; EXPRESSION; DIFFERENTIATION; PROTEINASES; HOMEOSTASIS AB Smad3 is an intracellular signaling molecule that mediates the signal from transforming growth factor-beta (TGF-beta) and activin receptors. In this study, we reveal hypomineralized enamel in mice with the targeted deletion of the Smad3 gene. The Smad3 (-/-) mice had chalky white incisor enamel, while the enamel of the wild-type or Smad3 (+/-) mice was yellow-brown. Histological analysis of the undecalcified sections showed that the enamel thickness of the maxillary incisors in the Smad3 (-/-) mice was similar to that of the wild-type and Smad3 (+/-) mice while that the enamel of the maxillary molars in Smad3 (-/-) mice was disrupted in places. Microcomputed tomography (muCT) analysis revealed that the mineralization of the maxillary incisors and mandibular molars in the Smad3 (-/-) mice showed significant reduction in the degree of mineralization when compared to that of the wild-type and Smad3 mice. Scanning electron microscopic (SEM) analysis of the mandibular incisors revealed that the enamel surface of the Smad3 mice was irregular and disrupted in places and showed images similar to decalcified mature enamel. The histological analysis of the decalcified sections showed that distinct morphological changes in the ameloblasts at the secretory and maturational stages were not observed between the Smad3 (-/-) and Smad3 or wild-type mice, while the enamel matrix was observed in the decalcified sections of the mandibular molars in the Smad3 mice. These results suggested that Smad3 was required for enamel biomineralization, and TGF-beta and activin signaling might be critical for its process. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Univ Tokushima, Sch Dent, Dept Orthodont, Tokushima 7708504, Japan. Tokyo Med & Dent Univ, Grad Sch, Dept Hard Tissue Engn, Div Biomatrix,Bunkyo Ku, Tokyo 1138549, Japan. Chiba Univ, Sch Med, Dept Internal Med 2, Chiba 2600856, Japan. NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. Univ Tokushima, Inst Enzyme Res, Tokushima 7708503, Japan. RP Moriyama, K (reprint author), Univ Tokushima, Sch Dent, Dept Orthodont, 3-18-15 Kuramoto Cho, Tokushima 7708504, Japan. RI deng, chuxia/N-6713-2016 NR 35 TC 17 Z9 19 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 6 PY 2003 VL 305 IS 3 BP 684 EP 690 DI 10.1016/S0006-291X(03)00806-4 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 687BG UT WOS:000183355500037 PM 12763048 ER PT J AU Kuo, MR Morbidoni, HR Alland, D Sneddon, SF Gourlie, BB Staveski, MM Leonard, M Gregory, JS Janjigian, AD Yee, C Musser, JM Kreiswirth, B Iwamoto, H Perozzo, R Jacobs, WR Sacchettini, JC Fidock, DA AF Kuo, MR Morbidoni, HR Alland, D Sneddon, SF Gourlie, BB Staveski, MM Leonard, M Gregory, JS Janjigian, AD Yee, C Musser, JM Kreiswirth, B Iwamoto, H Perozzo, R Jacobs, WR Sacchettini, JC Fidock, DA TI Targeting tuberculosis and malaria through inhibition of enoyl reductase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CARRIER PROTEIN REDUCTASE; FATTY-ACID SYNTHESIS; POTENTIAL ANTIBACTERIAL AGENTS; MYCOBACTERIUM-TUBERCULOSIS; PLASMODIUM-FALCIPARUM; ESCHERICHIA-COLI; ACP REDUCTASE; ANTIBIOTIC THIOLACTOMYCIN; DIHYDROFOLATE-REDUCTASE; APICOMPLEXAN PARASITES AB Tuberculosis and malaria together result in an estimated 5 million deaths annually. The spread of multidrug resistance in the most pathogenic causative agents, Mycobacterium tuberculosis and Plasmodium falciparum, underscores the need to identify active compounds with novel inhibitory properties. Although genetically unrelated, both organisms use a type II fatty-acid synthase system. Enoyl acyl carrier protein reductase (ENR), a key type II enzyme, has been repeatedly validated as an effective antimicrobial target. Using high throughput inhibitor screens with a combinatorial library, we have identified two novel classes of compounds with activity against the M. tuberculosis and P. falciparum enzyme (referred to as InhA and PfENR, respectively). The crystal structure of InhA complexed with NAD(+) and one of the inhibitors was determined to elucidate the mode of binding. Structural analysis of InhA with the broad spectrum antimicrobial triclosan revealed a unique stoichiometry where the enzyme contained either a single triclosan molecule, in a configuration typical of other bacterial ENR: triclosan structures, or harbored two triclosan molecules bound to the active site. Significantly, these compounds do not require activation and are effective against wild-type and drug-resistant strains of M. tuberculosis and P. falciparum. Moreover, they provide broader chemical diversity and elucidate key elements of inhibitor binding to InhA for subsequent chemical optimization. C1 Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. Yeshiva Univ Albert Einstein Coll Med, Howard Hughes Med Inst, Bronx, NY 10461 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Div Infect Dis, Newark, NJ 07103 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Ctr Emerging Pathogens, Newark, NJ 07103 USA. Genzyme Corp, Genzyme Drug Discovery, Cambridge, MA 02139 USA. NIAID, Lab Human Bacterial Pathogenesis, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. Publ Hlth Res Inst, TB Ctr, New York, NY 10016 USA. RP Sacchettini, JC (reprint author), Texas A&M Univ, Dept Biochem & Biophys, Biochem & Biophys Bldg,Rm 221, College Stn, TX 77843 USA. OI Fidock, David/0000-0001-6753-8938 FU NIAID NIH HHS [AI43268] NR 46 TC 166 Z9 175 U1 2 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 JUN 6 PY 2003 VL 278 IS 23 BP 20851 EP 20859 DI 10.1074/jbc.M211968200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 684WY UT WOS:000183230500054 PM 12606558 ER PT J AU Peisajovich, SG Gallo, SA Blumenthal, R Shai, Y AF Peisajovich, SG Gallo, SA Blumenthal, R Shai, Y TI C-terminal octylation rescues an inactive T20 mutant - Implications for the mechanism of HIV/simian immunodeficiency virus-induced membrane fusion SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TYPE-1 ENVELOPE GLYCOPROTEIN; HIV-1 ENTRY; INFLUENZA HEMAGGLUTININ; 3(10)-HELICAL PEPTIDES; TRANSMEMBRANE PROTEIN; ACTIVE CONFORMATION; VIRAL FUSION; SIV GP41; ECTODOMAIN; INHIBITION AB T20, a synthetic peptide corresponding to a C-terminal segment of the envelope glycoprotein (gp41) of human and simian immunodeficiency viruses, is a potent inhibitor of viral infection. We report here that C-terminal octylation of simian immunodeficiency virus gp41-derived T20 induces a significant increase in its inhibitory potency. Furthermore, when C-terminally octylated, an otherwise inactive mutant in which the C-terminal residues GNWF were replaced by ANAA has potency similar to that of the wild type T20. This effect cannot be explained by a trivial inhibitory effect of the octyl group added to the peptides, because the N-terminally octylated peptides have the same activity as the non-octylated parent peptides. The effects caused by octylation on the oligomerization, secondary structure, and membrane-interaction properties of the peptides were investigated. Our results shed light on the mechanism of inhibition by T20 and provide experimental support for the existence of a pre-hairpin intermediate. C1 Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. NCI, Lab Expt & Computat Biol, NIH, Ft Detrick, MD 21702 USA. RP Shai, Y (reprint author), Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. RI Peisajovich, Sergio/C-6641-2011; OI Gallo, Stephen/0000-0001-6043-2153 NR 41 TC 46 Z9 48 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 6 PY 2003 VL 278 IS 23 BP 21012 EP 21017 DI 10.1074/jbc.M212773200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 684WY UT WOS:000183230500074 PM 12646555 ER PT J AU Chastain, PD Makhov, AM Nossal, NG Griffith, J AF Chastain, PD Makhov, AM Nossal, NG Griffith, J TI Architecture of the replication complex and DNA loops at the fork generated by the bacteriophage T4 proteins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LAGGING-STRAND SYNTHESIS; POLYMERASE-III HOLOENZYME; HELICASE ASSEMBLY PROTEIN; LEADING-STRAND; ESCHERICHIA-COLI; PURIFICATION; BINDING; VISUALIZATION; PROCESSIVITY; TEMPLATE AB Rolling circle replication has previously been reconstituted in vitro using M13 duplex circles containing preformed forks and the 10 purified T4 bacteriophage replication proteins. Leading and lagging strand synthesis in these reactions is coupled and the size of the Okazaki fragments produced is typical of those generated in T4 infections. In this study the structure of the DNAs and DNA-protein complexes engaged in these in vitro reactions has been examined by electron microscopy. Following deproteinization, circular duplex templates with linear tails as great as 100 kb are observed. The tails are fully duplex except for one to three single-stranded DNA segments close to the fork. This pattern reflects Okazaki fragments stopped at different stages in their synthesis. Examination of the DNA-protein complexes in these reactions reveals M13 duplex circles in which 64% contain a single large protein mass ( replication complex) and a linear duplex tail. In 56% of the replicating molecules with a tail there is at least one fully duplex loop at the replication complex resulting from the portion of the lagging strand engaged in Okazaki fragment synthesis folding back to the replisome. The single-stranded DNA segments at the fork bound by gene 32 and 59 proteins are not extended but rather appear organized into highly compact structures ("bobbins"). These bobbins constitute a major portion of the mass of the full replication complex. C1 Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. NIDDK, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. RP Griffith, J (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. FU NIGMS NIH HHS [GM31819] NR 40 TC 42 Z9 42 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 6 PY 2003 VL 278 IS 23 BP 21276 EP 21285 DI 10.1074/jbc.M301573200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 684WY UT WOS:000183230500106 PM 12649286 ER PT J AU Zanuy, D Nussinov, R AF Zanuy, D Nussinov, R TI The sequence dependence of fiber organization. A comparative molecular dynamics study of the islet amyloid polypeptide segments 22-27 and 22-29 SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE amyloid conformation; islet amyloid peptide; beta-sheet; molecular dynamics simulation; protein unfolding ID FIBRIL FORMATION; PEPTIDE; FIBRILLOGENESIS; IDENTIFICATION; AGGREGATION; HUNTINGTONS; OLIGOMERS; FRAGMENTS; DISEASE AB Amyloid fiber formation and the possible polymorphism of molecular arrangements depend on the polypeptide length and composition. Here, we seek the chemical clues underlying these processes. Our starting point is based on the experimental observation that some short peptide segments are able to develop fibers that are very similar to those of their original parent proteins. We focus our study on the NFGAILSS peptide, derived from the human islet amyloid polypeptide (residues 22-29). This peptide turned out to be a perfect example, illustrating the fact that the amyloid microscopic organization is highly complex, rather than simply involving hydrogen bond formation. Furthermore, obtaining a reliable molecular model has allowed us to analyze the differences between the amyloid structure we have obtained for this peptide and that obtained for the previously studied, two residues shorter, segment (residues 22-27, NFGAIL). This comparative study yields some clues about chemical events that govern the aggregation of proteins into oriented fibers, such as molecular packing between sheets and the degree of interaction specificity. We characterize the important role played by the hydrophobic and aromatic residues in the inter-sheet association and present new approaches toward the understanding of the nature of events that are likely to take place during fibril formation. These include analysis of interaction patterns derived from specific sheet-associated packing. Published by Elsevier Science Ltd. C1 NCI, SAIC Frederick Inc, Lab Expt & Computat Biol, Basic Res Program, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Fac Med, Dept Human Genet, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. NCI, Lab Expt & Computat Biol, Frederick, MD 21702 USA. RP Nussinov, R (reprint author), NCI, SAIC Frederick Inc, Lab Expt & Computat Biol, Basic Res Program, Bldg 469,Rm 151, Frederick, MD 21702 USA. RI Zanuy, David/G-3930-2014 OI Zanuy, David/0000-0001-7704-2178 FU PHS HHS [N01-C0-12400] NR 28 TC 76 Z9 78 U1 0 U2 15 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUN 6 PY 2003 VL 329 IS 3 BP 565 EP 584 DI 10.1016/S0022-2836(03)00491-1 PG 20 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 687DG UT WOS:000183360300011 PM 12767835 ER PT J AU Kimmel, AR Parent, CA AF Kimmel, AR Parent, CA TI The signal to move: D-discoideum go orienteering SO SCIENCE LA English DT Editorial Material ID DICTYOSTELIUM; CHEMOTAXIS; CELLS; SUPPRESSOR; GRADIENTS; MODEL AB Cells migrating directionally toward a chemoattractant source display a highly polarized cytoskeletal organization, with F-actin localized predominantly at the anterior and myosin II at the lateral and posterior regions. Dictyostelium discoideum has proven a useful system for elucidating signaling pathways that regulate this chemotactic response. During development, extracellular adenosine 3', 5' monophosphate (cAMP) functions as a primary signal to activate cell surface cAMP receptors (cARs). These receptors transduce different signals depending on whether or not they are coupled to heterotrimeric guanine nucleotide-binding proteins (G proteins) (see the STKE Connections Maps). Multiple G protein-stimulated pathways interact to establish polarity in chemotaxing D. discoideum cells by localizing F-actin at their leading edge and by regulating the phosphorylation state and assembly of myosin II. Many of the molecular interactions described are fundamental to the regulation of chemotaxis in other eukaryotic cells. C1 NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Parent, CA (reprint author), NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 22 TC 61 Z9 61 U1 0 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUN 6 PY 2003 VL 300 IS 5625 BP 1525 EP 1527 DI 10.1126/science.1085439 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 686QU UT WOS:000183333100037 PM 12791977 ER PT J AU Wikstrom, M Verkhovsky, MI Hummer, G AF Wikstrom, M Verkhovsky, MI Hummer, G TI Water-gated mechanism of proton translocation by cytochrome c oxidase SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS LA English DT Article DE electron transfer; proton pumping; proton-electron coupling; cell respiration ID HEME-COPPER OXIDASES; PARACOCCUS-DENITRIFICANS; RHODOBACTER-SPHAEROIDES; ESCHERICHIA-COLI; OXYGEN REDUCTION; SUBUNIT-I; PATHWAYS; SITE; SIMULATION; DYNAMICS AB Cytochrome c oxidase is essential for aerobic life as a membrane-bound energy transducer. O-2 reduction at the haem a(3)-Cu-B centre consumes electrons transferred via haem a from cytochrome c outside the membrane. Protons are taken up from the inside, both to form water and to be pumped across the membrane (M.K.F. Wikstrom, Nature 266 (1977) 271 [1]; M. Wikstrom, K. Krab, M. Saraste, Cytochrome Oxidase, A Synthesis, Academic Press, London, 1981 [2]). The resulting electrochemical proton gradient drives ATP synthesis (P. Mitchell, Chemiosmotic Coupling in Oxidative and Photosynthetic Phosphorylation, Glynn Research, Bodmin, UK, 1966 [3]). Here we present a molecular mechanism for proton pumping coupled to oxygen reduction that is based on the unique properties of water in hydrophobic cavities. An array of water molecules conducts protons from a conserved glutamic acid, either to the Delta-propionate of haem a(3) (pumping), or to haem a(3)-Cu-B (water formation). Switching between these pathways is controlled by the redox-state-dependent electric field between haem a and haem a(3)-Cu-B, which determines the water-dipole orientation, and therefore the proton transfer direction. Proton transfer via the propionate provides a gate to O-2 reduction. This pumping mechanism explains the unique arrangement of the metal cofactors in the structure. It is consistent with the large body of biochemical data, and is shown to be plausible by molecular dynamics simulations. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Univ Helsinki, Helsinki Bioenerget Grp, Inst Biotechnol, FI-00014 Helsinki, Finland. Univ Helsinki, Biocentrum Helsinki, FI-00014 Helsinki, Finland. NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Wikstrom, M (reprint author), Univ Helsinki, Helsinki Bioenerget Grp, Inst Biotechnol, PB 65,Viikinkaari 1, FI-00014 Helsinki, Finland. EM marten.wikstrom@helsinki.fi RI Wikstrom, Marten/A-4403-2008; Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 32 TC 210 Z9 211 U1 3 U2 23 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2728 EI 0006-3002 J9 BBA-BIOENERGETICS JI Biochim. Biophys. Acta-Bioenerg. PD JUN 5 PY 2003 VL 1604 IS 2 BP 61 EP 65 DI 10.1016/S0005-2728(03)00041-0 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 684TP UT WOS:000183222900002 PM 12765763 ER PT J AU Moolchan, ET Aung, AT Henningfield, JE AF Moolchan, ET Aung, AT Henningfield, JE TI Treatment of adolescent tobacco smokers: issues and opportunities for exposure reduction approaches SO DRUG AND ALCOHOL DEPENDENCE LA English DT Review DE adolescents; smoking; tobacco; exposure reduction; treatment; policy ID NICOTINE PATCH THERAPY; CIGARETTE-SMOKING; YOUNG-ADULTS; DEPRESSIVE SYMPTOMS; MONOAMINE-OXIDASE; MAJOR DEPRESSION; CLINICAL-TRIAL; CESSATION; DEPENDENCE; ANXIETY AB The cycle of tobacco dependence typically begins with the initiation of tobacco use during adolescence. Many teenagers try to quit smoking, fail and subsequently desire treatment for their tobacco dependence. Adolescents do not currently benefit from the same level of societal support for quit attempts as adults, and they may be less motivated for total cessation despite the short and long-term health consequences of smoking. Overall, the combination of low participation, high attrition and low complete cessation rates for adolescent smokers in treatment prompts the consideration of alternative treatment endpoints. It is likely that interactions among the processes of child and adolescent development, smoke exposure and trajectory influence patterns of tobacco use and treatment for tobacco dependence in adolescents. A rational framework is needed to integrate the study of these dynamic interactions to address tobacco dependence among youth from an exposure reduction, in addition to a cessation, perspective. This paper considers the issues and potential implications of tobacco exposure reduction therapy as an intermediate treatment goal for adolescent smokers who are dependent or dependence-prone, but for whom initial treatment interventions do not yield complete tobacco cessation. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved. C1 NIDA, NIH, Intramural Res Program, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. Pinney Associates, Bethesda, MD 20814 USA. RP Moolchan, ET (reprint author), Clin Pharmacol & Therapeut Res Branch, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 88 TC 18 Z9 18 U1 0 U2 5 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JUN 5 PY 2003 VL 70 IS 3 BP 223 EP 232 DI 10.1016/S0376-8716(03)00012-7 PG 10 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 690WC UT WOS:000183572600001 PM 12757960 ER PT J AU Hu, XJ Machius, M Yang, W AF Hu, XJ Machius, M Yang, W TI Monovalent cation dependence and preference of GHKL ATPases and kinases SO FEBS LETTERS LA English DT Article DE GHKL ATPase and kinase; monovalent cation; active site; catalysis ID HSP90 MOLECULAR CHAPERONE; RNA TERTIARY STRUCTURE; CRYSTAL-STRUCTURE; DNA GYRASE; ANTINEOPLASTIC AGENTS; ATP BINDING; PROTEIN; DOMAIN; FRAGMENT; REPAIR AB The GHKL phosphotransferase superfamily, characterized by four sequence motifs that form the ATP-binding site, consists of the ATPase domains of type II DNA topoisomerases, Hsp90, and MutL, and bacterial and mitochondrial protein kinases. In addition to a magnesium ion, which is essential for catalysis, a potassium ion bound adjacent to the triphosphate moiety of ATP in a rat mitochondrial protein kinase, BCK (branched-chain alpha-ketoacid dehydrogenase kinase), has been shown to be indispensable for nucleotide binding and hydrolysis. Using X-ray crystallographic, biochemical, and genetic analyses, we find that the monovalent cation-binding site is conserved in MutL, but both Na+ and K+ support the MutL ATPase activity. When Ala100 of MutL is substituted by proline, mimicking the K+-binding environment in BCK, the mutant MutL protein becomes exclusively dependent on Na+ for the ATPase activity. The coordination of this Na+ ion is identical to that of the K+ ion in BCK and involves four carbonyl oxygen atoms emanating from the hinges of the ATP lid and a non-bridging oxygen of the bound nucleotide. A similar monovalent cation-binding site is found in DNA gyrase with additional coordination by a serine side chain. The conserved and protein-specific monovalent cation-binding site is unique to the GHKL superfamily and probably essential for both ATPase and kinase activity. Dependence on different monovalent cations for catalysis may be exploited for future drug design specifically targeting each individual member of the GHKL superfamily. (C) 2003 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75390 USA. RP Yang, W (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RI Yang, Wei/D-4926-2011 OI Yang, Wei/0000-0002-3591-2195 NR 32 TC 27 Z9 29 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUN 5 PY 2003 VL 544 IS 1-3 BP 268 EP 273 DI 10.1016/S0014-5793(03)00519-2 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 687TR UT WOS:000183393500050 PM 12782329 ER PT J AU Poulev, A O'Neal, JM Logendra, S Pouleva, RB Timeva, V Garvey, AS Gleba, D Jenkins, IS Halpern, BT Kneer, R Cragg, GM Raskin, I AF Poulev, A O'Neal, JM Logendra, S Pouleva, RB Timeva, V Garvey, AS Gleba, D Jenkins, IS Halpern, BT Kneer, R Cragg, GM Raskin, I TI Elicitation, a new window into plant chemodiversity and phytochemical drug discovery SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID NATIONAL-CANCER-INSTITUTE; CELL-SUSPENSION CULTURES; ALKALOID BIOSYNTHESIS; CATHARANTHUS-ROSEUS; ROOT CULTURES; BIODIVERSITY; ACCUMULATION; FEASIBILITY; ELICITORS; INFECTION AB Plant extracts collected from the wild are important sources for drug discovery. However, these extracts suffer from a lack of reproducible bioactivity and chemical composition caused by the highly inducible, variable, and transitory nature of plant secondary metabolism. Here, we demonstrate that exposing roots of hydroponically grown plants to chemical elicitors selectively and reproducibly induced the production of bioactive compounds, dramatically increased the hit rate, and more than doubled the number of plant species showing in vitro activity against bacteria, fungi, or cancer. Elicitation performed under controlled conditions dramatically improves reliability and efficiency of plant extracts in drug discovery while preserving wild species and their habitats. C1 Rutgers State Univ, Cook Coll, Biotech Ctr, New Brunswick, NJ 08901 USA. Phytomed Inc, Dayton, NJ 08810 USA. NCI, Frederick Fairview Ctr, Frederick, MD 21702 USA. RP Raskin, I (reprint author), Rutgers State Univ, Cook Coll, Biotech Ctr, Foran Hall,59 Dudley Rd, New Brunswick, NJ 08901 USA. NR 30 TC 57 Z9 60 U1 2 U2 13 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 JUN 5 PY 2003 VL 46 IS 12 BP 2542 EP 2547 DI 10.1021/jm020359t PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 684RM UT WOS:000183220400029 PM 12773057 ER PT J AU Bottaro, DP Liotta, LA AF Bottaro, DP Liotta, LA TI Cancer - Out of air is not out of action SO NATURE LA English DT Editorial Material ID MET TYROSINE KINASE; C-MET; RECEPTOR; HGF/SF; MUTATIONS C1 NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Invas & Metastasis Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Bottaro, DP (reprint author), NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RI Bottaro, Donald/F-8550-2010 OI Bottaro, Donald/0000-0002-5057-5334 NR 14 TC 90 Z9 108 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 5 PY 2003 VL 423 IS 6940 BP 593 EP 595 DI 10.1038/423593a PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 686BT UT WOS:000183301200023 PM 12789320 ER PT J AU La Spada, AR Taylor, JP AF La Spada, AR Taylor, JP TI Polyglutamines placed into context SO NEURON LA English DT Review ID BULBAR MUSCULAR-ATROPHY; NUCLEAR-LOCALIZATION; ANDROGEN RECEPTOR; MOUSE MODEL; EXPRESSION; EXPANSIONS; PROTEINS; DISEASE AB Nine inherited neurodegenerative disorders result from polyglutamine expansions. Two recently published papers on spinocerebellar ataxia type 1, together with studies on spinobulbar muscular atrophy last year, indicate that host protein context is the key arbiter of polyglutamine disease protein toxicity. This insight may represent the most important development in the field since the recognition of nuclear inclusions or the propensity of polyglutamine to aggregate. Indeed, an intimate and inextricable relationship may exist between polyglutamine neurotoxicity and the normal interactions, domains, modifications, and functions of the respective disease proteins. C1 Univ Washington, Ctr Med, Dept Lab Med, Div Med Genet Med, Seattle, WA 98195 USA. Univ Washington, Ctr Med, Dept Lab Med, Div Neurogenet Neurol, Seattle, WA 98195 USA. NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP La Spada, AR (reprint author), Univ Washington, Ctr Med, Dept Lab Med, Div Med Genet Med, Seattle, WA 98195 USA. NR 19 TC 90 Z9 92 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JUN 5 PY 2003 VL 38 IS 5 BP 681 EP 684 DI 10.1016/S0896-6273(03)00328-3 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 687DU UT WOS:000183361400004 PM 12797953 ER PT J AU Schmidt, BL Gear, RW Levine, JD AF Schmidt, BL Gear, RW Levine, JD TI Response of neuropathic trigeminal pain to the combination of low-dose nalbuphine plus naloxone in humans SO NEUROSCIENCE LETTERS LA English DT Article DE kappa opioids; nerve injury; local anesthetic toxicity; opioid antagonism; anti-analgesia; dysesthesia ID PERIPHERAL COMPONENT; MONONEUROPATHIC RATS; ANTIANALGESIC ACTION; INVOLVEMENT; ANALGESIA; DYNORPHIN; AGONIST AB We report on the response of medically refractory neuropathic trigeminal pain in three patients to intravenous administration of a combination of the kappa-partial agonist opioid nalbuphine and the opioid antagonist naloxone. Each of the three patients had developed a painful peripheral neuropathy as a complication of chemical or mechanical injury to the trigeminal nerve. Each patient had been tried on a number of analgesics, including mu-opioids, and had not gained relief or was not able to tolerate side effects of the medications. Pain intensity was measured for 3 It following drug administration using a 10 cm visual analog scale. All three patients reported marked decrease in pain following administration of the nalbuphine and naloxone combination. These findings suggest a novel approach to the management for neuropathic pain. (C) 2003 Published by Elsevier Science Ireland Ltd. C1 Univ Calif San Francisco, Dept Oral & Maxillofacial Surg, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Div Neurosci, San Francisco, CA 94143 USA. Univ Calif San Francisco, NIH Pain Ctr, San Francisco, CA 94143 USA. RP Levine, JD (reprint author), Univ Calif San Francisco, Dept Oral & Maxillofacial Surg, C-522,Box 0440,521 Parnassus Ave, San Francisco, CA 94143 USA. OI Schmidt, Brian/0000-0002-2409-8984 FU NINR NIH HHS [NR03923] NR 11 TC 7 Z9 7 U1 1 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JUN 5 PY 2003 VL 343 IS 2 BP 144 EP 146 DI 10.1016/S0304-3940(03)00356-2 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 684XY UT WOS:000183232800018 PM 12759184 ER PT J AU Engel, S Martinez, H Shamoon, H Engel, H Dahms, W Mayer, L Pendegras, S Zegarra, H Miller, D Singerman, L Smith-Brewer, S Genuth, S Brillon, D Lackaye, M Heinemann, M Reppuci, V Lee, T Whitehouse, F Kruger, D Galpern, A Carey, JD Bergenstal, R Johnson, M Kendall, D Spencer, M Noller, D Morgan, K Etzwiler, D Jacobson, A Golden, E Sharuk, G Arrigg, P Baeser, R Ganda, O Rosenzweig, J Wolpert, H Economides, P Handy, O Rand, L Nathan, D Fritz, S Godine, J McKitrick, C Lou, P Service, FJ Ziegler, G Pach, J Lindsey, J Colwell, J Wood, D Mayfield, R Hermayer, K Szpiech, M Lyons, T Parker, J Farr, A Elsing, S Thompson, T Selby, J Bracey, M Molitch, M Schaefer, B Jampol, L Weinberg, D Lyon, A Strugula, Z Shankle, J Astlesford, P Kolterman, O Lorenzi, G Goldbaum, M Sivitz, W Bayless, M Zeither, R Weingeist, T Stone, E Boidt, HC Gehres, K Russell, S Counts, D Kowarski, A Ostrowski, D Donner, T Steidl, S Jones, B Herman, W Greene, D Martin, C Stevens, MJ Vine, AK Elner, S Bantle, J Rogness, B Olsen, T Steuer, E Goldstein, D Hitt, S Giangiacomo, J Hainsworth, D Schade, D Burge, M Canady, J Schluter, M Das, A Hornbeck, D Schwartz, S Bourne, PA Maschak-Carey, BJ Baker, L Braunstein, S Brucker, A Orchard, T Silvers, N Songer, T Doft, B Olson, S Bergren, RL Lobes, L Fineman, M Drash, A Malone, J Vaccaro-Kish, J Berger, C Gstalder, R Pavan, PR Morrison, A Dagogo-Jack, S Schussler, S Kitabchi, A Lambeth, H Murphy, MB Moser, S Meyer, D Iannacone, A Bryer-Ash, M Raskin, P Strowig, S Edwards, A Alappatt, J Wilson, C Park, S He, Y Zinman, B Barnie, A MacLean, S Devenyi, R Mandelcorn, M Brent, M Palmer, J Catton, S Kinyoun, J Van Ottingham, L Ginsberg, J Dupre, J Harth, J Canny, C Nicolle, D May, M Lorenz, R Lipps, J Survant, L Feman, S Tawansy, K Agarwal, A Adkins, T White, N Santiago, J Levandoski, L Boniuk, I Grand, G Thomas, M Burgess, D Joseph, D Blinder, K Shah, G Tamborlane, W Gatcomb, P Stoessel, K Taylor, K Dahms, B Trail, R Quin, J Lachin, J Cleary, P Kenny, D Backlund, J Diminick, L Determan, A Klump, K Hawkins, M Cowie, C Fradkin, J Siebert, C Eastman, R Davis, M Hubbard, L Geithman, P Kastorff, L Neider, M Badal, D Esser, B Miner, K Wabers, H Glander, K Joyce, J Robinson, N Hurtenbach, C Hannon, C Steffes, M Bucksa, J Chavers, B O'Leary, D Funk, L Polak, J Crow, R O'Donnell, C Gloeb, B Thomas, S Detrano, R Wong, N Fox, M Kim, L Oudiz, R Weir, G Clark, C D'Agostino, R Espeland, M Klein, B Manolio, T Rand, L Singer, D Stern, M Garvey, WT Lyons, TJ Jenkins, A Klein, R Lopes-Virella, M Virella, G Jaffa, AA Zheng, D Lackland, D McGee, D Mayfield, RK Brabham, M Boright, A Paterson, A Scherer, S Zinman, B Brunzell, J Hokanson, J Marcovina, S Purnell, J Sibley, S Deeb, S Edwards, K Nathan, D AF Engel, S Martinez, H Shamoon, H Engel, H Dahms, W Mayer, L Pendegras, S Zegarra, H Miller, D Singerman, L Smith-Brewer, S Genuth, S Brillon, D Lackaye, M Heinemann, M Reppuci, V Lee, T Whitehouse, F Kruger, D Galpern, A Carey, JD Bergenstal, R Johnson, M Kendall, D Spencer, M Noller, D Morgan, K Etzwiler, D Jacobson, A Golden, E Sharuk, G Arrigg, P Baeser, R Ganda, O Rosenzweig, J Wolpert, H Economides, P Handy, O Rand, L Nathan, D Fritz, S Godine, J McKitrick, C Lou, P Service, FJ Ziegler, G Pach, J Lindsey, J Colwell, J Wood, D Mayfield, R Hermayer, K Szpiech, M Lyons, T Parker, J Farr, A Elsing, S Thompson, T Selby, J Bracey, M Molitch, M Schaefer, B Jampol, L Weinberg, D Lyon, A Strugula, Z Shankle, J Astlesford, P Kolterman, O Lorenzi, G Goldbaum, M Sivitz, W Bayless, M Zeither, R Weingeist, T Stone, E Boidt, HC Gehres, K Russell, S Counts, D Kowarski, A Ostrowski, D Donner, T Steidl, S Jones, B Herman, W Greene, D Martin, C Stevens, MJ Vine, AK Elner, S Bantle, J Rogness, B Olsen, T Steuer, E Goldstein, D Hitt, S Giangiacomo, J Hainsworth, D Schade, D Burge, M Canady, J Schluter, M Das, A Hornbeck, D Schwartz, S Bourne, PA Maschak-Carey, BJ Baker, L Braunstein, S Brucker, A Orchard, T Silvers, N Songer, T Doft, B Olson, S Bergren, RL Lobes, L Fineman, M Drash, A Malone, J Vaccaro-Kish, J Berger, C Gstalder, R Pavan, PR Morrison, A Dagogo-Jack, S Schussler, S Kitabchi, A Lambeth, H Murphy, MB Moser, S Meyer, D Iannacone, A Bryer-Ash, M Raskin, P Strowig, S Edwards, A Alappatt, J Wilson, C Park, S He, Y Zinman, B Barnie, A MacLean, S Devenyi, R Mandelcorn, M Brent, M Palmer, J Catton, S Kinyoun, J Van Ottingham, L Ginsberg, J Dupre, J Harth, J Canny, C Nicolle, D May, M Lorenz, R Lipps, J Survant, L Feman, S Tawansy, K Agarwal, A Adkins, T White, N Santiago, J Levandoski, L Boniuk, I Grand, G Thomas, M Burgess, D Joseph, D Blinder, K Shah, G Tamborlane, W Gatcomb, P Stoessel, K Taylor, K Dahms, B Trail, R Quin, J Lachin, J Cleary, P Kenny, D Backlund, J Diminick, L Determan, A Klump, K Hawkins, M Cowie, C Fradkin, J Siebert, C Eastman, R Davis, M Hubbard, L Geithman, P Kastorff, L Neider, M Badal, D Esser, B Miner, K Wabers, H Glander, K Joyce, J Robinson, N Hurtenbach, C Hannon, C Steffes, M Bucksa, J Chavers, B O'Leary, D Funk, L Polak, J Crow, R O'Donnell, C Gloeb, B Thomas, S Detrano, R Wong, N Fox, M Kim, L Oudiz, R Weir, G Clark, C D'Agostino, R Espeland, M Klein, B Manolio, T Rand, L Singer, D Stern, M Garvey, WT Lyons, TJ Jenkins, A Klein, R Lopes-Virella, M Virella, G Jaffa, AA Zheng, D Lackland, D McGee, D Mayfield, RK Brabham, M Boright, A Paterson, A Scherer, S Zinman, B Brunzell, J Hokanson, J Marcovina, S Purnell, J Sibley, S Deeb, S Edwards, K Nathan, D CA Diabet Control Complications Trial TI Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID BLOOD-GLUCOSE CONTROL; INSULIN-RESISTANCE ATHEROSCLEROSIS; CORONARY-ARTERY-DISEASE; WALL THICKNESS; COMPLICATIONS TRIAL; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; RISK-FACTOR; PROGRESSION; ULTRASOUND AB BACKGROUND: Cardiovascular disease causes severe morbidity and mortality in type 1 diabetes, although the specific risk factors and whether chronic hyperglycemia has a role are unknown. We examined the progression of carotid intima-media thickness, a measure of atherosclerosis, in a population with type 1 diabetes. METHODS: As part of the Epidemiology of Diabetes Interventions and Complications (EDIC) study, the long-term follow-up of the Diabetes Control and Complications Trial (DCCT), 1229 patients with type 1 diabetes underwent B-mode ultrasonography of the internal and common carotid arteries in 1994-1996 and again in 1998-2000. We assessed the intima-media thickness in 611 subjects who had been randomly assigned to receive conventional diabetes treatment during the DCCT and in 618 who had been assigned to receive intensive diabetes treatment. RESULTS: At year 1 of the EDIC study, the carotid intima-media thickness was similar to that in an age- and sex-matched nondiabetic population. After six years, the intima-media thickness was significantly greater in the diabetic patients than in the controls. The mean progression of the intima-media thickness was significantly less in the group that had received intensive therapy during the DCCT than in the group that had received conventional therapy (progression of the intima-media thickness of the common carotid artery, 0.032 vs. 0.046 mm; P=0.01; and progression of the combined intima-media thickness of the common and internal carotid arteries, -0.155 vs. 0.007; P=0.02) after adjustment for other risk factors. Progression of carotid intima-media thickness was associated with age, and the EDIC base-line systolic blood pressure, smoking, the ratio of low-density lipoprotein to high-density lipoprotein cholesterol, and urinary albumin excretion rate and with the mean glycosylated hemoglobin value during the mean duration (6.5 years) of the DCCT. CONCLUSIONS: Intensive therapy during the DCCT resulted in decreased progression of intima-media thickness six years after the end of the trial. C1 DCCT EDIC Res Grp, Bethesda, MD 20892 USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Cornell Univ, Med Ctr, Ithaca, NY 14853 USA. Henry Ford Hlth Syst, Detroit, MI USA. Int Diabet Ctr, Minneapolis, MN USA. Joslin Diabet Ctr, Boston, MA 02215 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. Med Univ S Carolina, Mol Risk Factors Program Project, Charleston, SC 29425 USA. Northwestern Univ, Evanston, IL 60208 USA. Univ Calif San Diego, San Diego, CA 92103 USA. Univ Iowa, Iowa City, IA 52242 USA. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Univ Minnesota, Minneapolis, MN 55455 USA. Univ Missouri, Columbia, MO 65211 USA. Univ New Mexico, Albuquerque, NM 87131 USA. Univ Penn, Philadelphia, PA 19104 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Univ S Florida, Tampa, FL 33620 USA. Univ Tennessee, Knoxville, TN 37996 USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Univ Toronto, Toronto, ON, Canada. Univ Western Ontario, London, ON N6A 3K7, Canada. Vanderbilt Univ, Nashville, TN USA. Washington Univ, St Louis, MO USA. Yale Univ, Sch Med, New Haven, CT 06520 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. George Washington Univ, Ctr Biostat, Washington, DC 20052 USA. NIDDKD, Program Off, Bethesda, MD 20892 USA. Univ Wisconsin, Cent Fundus Photog Reading Ctr, Madison, WI 53706 USA. Univ Minnesota, Cent Biochem Lab, Minneapolis, MN 55455 USA. Tufts Univ New England Med Ctr, Cent Carotid Ultrasound Unit, Boston, MA 02111 USA. Univ Minnesota, Cent Electrocardiog Reading Unit, Minneapolis, MN 55455 USA. Harbor UCLA Res & Educ Int, Comp Tomog Reading Ctr, Torrance, CA USA. Hosp Sick Children, Genet Studies Grp, Toronto, ON M5G 1X8, Canada. Univ Washington, Lipoprot Distribut Obes Grp, Seattle, WA 98195 USA. RP Engel, S (reprint author), DCCT EDIC Res Grp, Box NDIC DCCT, Bethesda, MD 20892 USA. EM dnathan@partners.org RI Zinman, Bernard/E-7266-2013; Paterson, Andrew/A-4088-2011; OI Paterson, Andrew/0000-0002-9169-118X; orchard, trevor/0000-0001-9552-3215; Lachin, John/0000-0001-9838-2841 NR 48 TC 463 Z9 472 U1 2 U2 11 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 5 PY 2003 VL 348 IS 23 BP 2294 EP 2303 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 686AA UT WOS:000183296300004 ER PT J AU Hartge, P AF Hartge, P TI Genes, hormones, and pathways to breast cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID SURGICAL ADJUVANT BREAST; REPRODUCTIVE HISTORY; MUTATION CARRIERS; RISK; TAMOXIFEN; BRCA1; WOMEN; PREVENTION C1 NCI, Rockville, MD 20852 USA. RP Hartge, P (reprint author), NCI, Rockville, MD 20852 USA. NR 11 TC 7 Z9 7 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 5 PY 2003 VL 348 IS 23 BP 2352 EP 2354 DI 10.1056/NEJMe030065 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 686AA UT WOS:000183296300013 PM 12789001 ER PT J AU Nadareishvili, Z Hallenbeck, J AF Nadareishvili, Z Hallenbeck, J TI Neuronal regeneration after stroke SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID NEURAL STEM-CELLS; NEUROGENESIS C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. RP Nadareishvili, Z (reprint author), NINDS, Stroke Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 5 TC 21 Z9 22 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 5 PY 2003 VL 348 IS 23 BP 2355 EP 2356 DI 10.1056/NEJMcibr023192 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 686AA UT WOS:000183296300014 PM 12789002 ER PT J AU King, KE Ponnamperuma, RM Yamashita, T Tokino, T Lee, LA Young, MF Weinberg, WC AF King, KE Ponnamperuma, RM Yamashita, T Tokino, T Lee, LA Young, MF Weinberg, WC TI Delta Np63 alpha functions as both a positive and a negative transcriptional regulator and blocks in vitro differentiation of murine keratinocytes SO ONCOGENE LA English DT Article DE Delta Np63 alpha; p63; p53 homologues; keratinocytes; epidermal differentiation ID SQUAMOUS-CELL CARCINOMAS; P53 GENE DOSAGE; MALIGNANT PROGRESSION; P53-RELATED PROTEIN; SPONTANEOUS TUMORS; P63 EXPRESSION; CORE DOMAIN; P73; HOMOLOG; APOPTOSIS AB DeltaNp63 is overexpressed in squamous carcinomas where it is associated with proliferation and is believed to enhance cell growth by blocking p53-mediated transactivation. In normal epithelium, DeltaNp63alpha protein expression is abundant in basal cells and decreases with differentiation. To explore the biological consequences of DeltaNp63alpha overexpression in relation to squamous carcinogenesis, we evaluated its effect on normal squamous differentiation and p53 transactivation function in keratinocytes. Forced overexpression of DeltaNp63alpha in primary murine keratinocytes in vitro inhibits morphological differentiation induced by elevated extracellular [Ca2+], abrogates Ca2+-induced growth arrest, and blocks expression of maturation-specific proteins keratin 10 and filaggrin. This suggests that DeltaNp63 overexpression in squamous carcinomas may serve to maintain the basal cell phenotype and promote cell survival. DeltaNp63alpha blocks transactivation of p53 responsive reporter constructs mediated by endogenous or exogenous p53 at 17 h postinfection, as expected. However, at 41 h, when p53-mediated transactivation is diminished, DeltaNp63alpha: enhances transactivation of these reporter constructs by 2.2-12-fold over control. Maximal DeltaNp63alpha-induced transactivation requires intact p53 responsive elements, but is independent of cellular p53 status. This positive transcriptional function of DeltaNp63alpha appears to be cell-type specific, as it is not observed in primary dermal fibroblasts or Saos-2 cells. These findings support DeltaNp63alpha as a master regulator of keratinocyte differentiation, and suggest a novel function of this protein in the maintenance of epithelial homeostasis. C1 US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. Sapporo Med Univ, Sch Med, Sapporo, Hokkaido 0608556, Japan. Univ Colorado, Sch Med, Denver, CO 80262 USA. Denver Hlth Med Ctr, Denver, CO 80262 USA. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Weinberg, WC (reprint author), US FDA, Ctr Biol Evaluat & Res, 29 Lincoln Dr,HFM-564,Bldg 29B,Room 3NN04, Bethesda, MD 20892 USA. RI Weinberg, Wendy/A-8920-2009 NR 49 TC 103 Z9 108 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 5 PY 2003 VL 22 IS 23 BP 3635 EP 3644 DI 10.1038/sj.onc.1206536 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 687WD UT WOS:000183399200014 PM 12789272 ER PT J AU Masur, H Emanuel, E Lane, HC AF Masur, H Emanuel, E Lane, HC TI Severe acute respiratory syndrome - Providing care in the face of uncertainty SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 NIAID, Dept Crit Care Med, NIH, Bethesda, MD 20892 USA. NIAID, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Masur, H (reprint author), NIAID, Dept Crit Care Med, NIH, 10 Ctr Dr,Bldg 10,Room 7D43, Bethesda, MD 20892 USA. NR 17 TC 24 Z9 26 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 4 PY 2003 VL 289 IS 21 BP 2861 EP 2863 DI 10.1001/jama.289.21.JED30036 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 684KH UT WOS:000183205500036 PM 12734146 ER PT J AU Launer, LJ AF Launer, LJ TI Nonsteroidal anti-inflammatory drugs and Alzheimer disease - What's next? SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID ANTIINFLAMMATORY DRUGS; CYCLO-OXYGENASE-2 INHIBITORS; CONTROLLED TRIAL; DOUBLE-BLIND; INDOMETHACIN; ARTHRITIS; IBUPROFEN; NAPROXEN C1 NIA, Neuroepidemiol Sect, Lab Epidemiol Demog Biometry, Bethesda, MD 20892 USA. RP Launer, LJ (reprint author), NIA, Neuroepidemiol Sect, Lab Epidemiol Demog Biometry, Gateway Bldg,7201 Wisconsin Ave,Rm 3C-309, Bethesda, MD 20892 USA. NR 24 TC 21 Z9 22 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 4 PY 2003 VL 289 IS 21 BP 2865 EP 2867 DI 10.1001/jama.289.21.2865 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 684KH UT WOS:000183205500038 PM 12783919 ER PT J AU Tycko, R Ishii, Y AF Tycko, R Ishii, Y TI Constraints on supramolecular structure in amyloid fibrils from two-dimensional solid-state NMR spectroscopy with uniform isotopic labeling SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; PARALLEL BETA-SHEET; BETA-AMYLOID((10-35)); ANTIPARALLEL; ORGANIZATION; FRAGMENT; PEPTIDE; PROTEIN; MODEL C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Univ Illinois, Dept Chem, Chicago, IL 60607 USA. RP Tycko, R (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. RI Ishii, Yoshitaka/F-4558-2014 OI Ishii, Yoshitaka/0000-0002-7724-6469 NR 21 TC 88 Z9 90 U1 1 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUN 4 PY 2003 VL 125 IS 22 BP 6606 EP 6607 DI 10.1021/ja0342042 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 686GX UT WOS:000183314000004 PM 12769550 ER PT J AU Iwahara, J Anderson, DE Murphy, EC Clore, GM AF Iwahara, J Anderson, DE Murphy, EC Clore, GM TI EDTA-derivatized deoxythymidine as a tool for rapid determination of protein binding polarity to DNA by intermolecular paramagnetic relaxation enhancement SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; METAL-ION BINDING; NMR-SPECTROSCOPY; RESTRAINTS; COMPLEXES; OLIGONUCLEOTIDES; SEQUENCE; DUPLEX; SITE C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. RI Clore, G. Marius/A-3511-2008; OI Clore, G. Marius/0000-0003-3809-1027; Iwahara, Junji/0000-0003-4732-2173 NR 25 TC 58 Z9 59 U1 2 U2 18 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUN 4 PY 2003 VL 125 IS 22 BP 6634 EP 6635 DI 10.1021/ja034488q PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 686GX UT WOS:000183314000018 PM 12769564 ER PT J AU Liu, JE Robbins, DC Palmieri, V Bella, JN Roman, MJ Fabsitz, R Howard, BV Welty, TK Lee, ET Devereux, RB AF Liu, JE Robbins, DC Palmieri, V Bella, JN Roman, MJ Fabsitz, R Howard, BV Welty, TK Lee, ET Devereux, RB TI Association of albuminuria with systolic and diastolic left ventricular dysfunction in type 2 diabetes - The strong heart study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID PRESSURE-OVERLOAD HYPERTROPHY; AMERICAN-INDIANS; RISK-FACTORS; ECHOCARDIOGRAPHIC ASSESSMENT; CARDIOVASCULAR-DISEASE; ARTERIAL-HYPERTENSION; SHORTENING RELATIONS; MICROALBUMINURIA; GLYCOSAMINOGLYCANS; MORTALITY AB OBJECTIVES We sought to compare systolic and diastolic function in American Indians with diabetes mellitus (DM) based on albuminuria status. BACKGROUND Albuminuria has been shown to predict cardiovascular disease (CVD) in populations with DM. However, the mechanism of the association of albuminuria and CVD is unclear. METHODS We compared echo-derived indices of left ventricular (LV) systolic and diastolic function in three groups of American Indians with DM based on albuminuria status: I = no albuminuria (< 30 mg albumin/g creatinine); II = microalbuminuria (30 to 300 mg/g); and III macroalbuminuria (> 300 mg/g). RESULTS Group II and III were slightly older than Group I with no significant gender difference between groups. Systolic blood pressure increased and body mass index decreased from Group I to Group III. Left ventricular systolic function was lower in the groups with albuminuria with step-wise decreases in ejection fraction and stress-corrected midwall shortening (MWS) from Group I to Group III. Similar findings were noted in diastolic LV filling with lower mitral E/A ratios and longer deceleration times in groups with albuminuria. The proportion of participants with abnormal MWS and abnormal LV diastolic relaxation showed step-wise increases from no albuminuria to macroalbuminuria. In multivariate analysis, albuminuria status remained independently associated with both systolic and diastolic dysfunction after adjusting for age, gender, body mass index, systolic blood pressure, duration of diabetes, coronary artery disease, and LV mass. CONCLUSIONS Albuminuria is independently associated with LV systolic and diastolic dysfunction in type 2 DM; this may explain in part the relationship of albuminuria to increased cardiovascular (CV) events in the DM population. Screening for albuminuria identifies individuals with high CV risk and possible cardiac dysfunction. (C) 2003 by the American College of Cardiology Foundation. C1 New York Hosp, Cornell Med Ctr, Dept Med, New York, NY 10021 USA. New York Hosp, Cornell Med Ctr, Div Cardiol, New York, NY 10021 USA. NHLBI, Bethesda, MD 20892 USA. Medstar Res Inst, Washington, DC USA. Aberdeen Area Tribal Chairmens Hlth Board, Rapid City, SD USA. Univ Oklahoma, Hlth Sci Ctr, Sch Publ Hlth, Oklahoma City, OK USA. RP Liu, JE (reprint author), New York Presbyterian Hosp, Weill Cornell Med Ctr, Div Cardiol, Box 222,525 E 68th St, New York, NY 10021 USA. OI Palmieri, Vittorio/0000-0003-3732-524X FU NCRR NIH HHS [M10 RR 004734]; NHLBI NIH HHS [U01 HL 41642, U01 HL 41652, U01 HL 41654] NR 41 TC 69 Z9 79 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN 4 PY 2003 VL 41 IS 11 BP 2022 EP 2028 DI 10.1016/S0735-1097(03)00403-0 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 684QY UT WOS:000183219100019 PM 12798576 ER PT J AU Kraemer, KH AF Kraemer, KH TI NRAS hypermutability in familial melanoma with CDKN2A mutations - Cause and effect? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID DYSPLASTIC NEVUS SYNDROME; DNA-POLYMERASE-ETA; XERODERMA-PIGMENTOSUM; ULTRAVIOLET HYPERMUTABILITY; CELLS; IRRADIATION; PLASMID C1 NCI, Basic Res Labs, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kraemer, KH (reprint author), NCI, Basic Res Labs, Ctr Canc Res, Bldg 37,Rm 4002 MSC 4258, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 BC004517-31] NR 19 TC 3 Z9 3 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUN 4 PY 2003 VL 95 IS 11 BP 768 EP 769 PG 2 WC Oncology SC Oncology GA 686LP UT WOS:000183323500002 PM 12783922 ER PT J AU Bazzano, LA He, J Muntner, P Vupputuri, S Whelton, PK AF Bazzano, LA He, J Muntner, P Vupputuri, S Whelton, PK TI Relationship between cigarette smoking and novel risk factors for cardiovascular disease in the United States SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID C-REACTIVE PROTEIN; CORONARY-ARTERY DISEASE; APPARENTLY HEALTHY-MEN; PLASMA HOMOCYSTEINE; LIQUID-CHROMATOGRAPHY; HEART-DISEASE; INFLAMMATION; ASSOCIATION; FIBRINOGEN; SMOKERS AB Background: Few studies have examined the relationship between cigarette smoking and novel risk factors for cardiovascular disease in a general population or have included a biochemical marker of current smoking. Objective: To examine the relationship between cigarette smoking and serum C-reactive protein, fibrinogen, and homocysteine levels. Design: Cross-sectional study. Setting: The U.S. general population. Patients: 4187 current smokers, 4791 former smokers, and 8375 never-smokers 18 years of age or older who participated in the Third National Health and Nutrition Examination Survey conducted between 1988 and 1994. Measurements: serum C-reactive protein levels were categorized as detectable (2.2 to 9.9 mg/L) or clinically elevated (greater than or equal to10 mg/L), and fibrinogen and homocysteine levels were defined as elevated if in the 85th percentile or greater (11.1 mumol/L and 12.7 mmol/L, respectively). Results: After adjustment for traditional cardiovascular disease risk factors, cigarette smoking was related to elevated levels of C-reactive protein, fibrinogen, and homocysteine. Compared with never smoking cigarettes, self-reported current cigarette smoking was associated with a C-reactive protein level in the detectable (odds ratio, 1.66 [95% CI, 1.40 to 1.97]; P < 0.001) or clinically elevated (odds ratio, 1.98 [CI, 1.57 to 2.51]; P < 0.001) ranges, with elevated levels of fibrinogen (odds ratio, 2.15 [CI, 1.65 to 2.80]; P < 0.001) and homocysteine (odds ratio, 2.10 [CI, 1.62 to 2.74]; P < 0.001). There were positive and significant dose-response relationships between measures of cigarette smoking (cigarettes per day, pack-years, and serum cotinine levels) and elevated levels of novel risk factors. Conclusions: These findings suggest that inflammation and hyperhomocysteinemia may be important mechanisms by which smoking promotes atherosclerotic disease. C1 Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA 70112 USA. Tulane Univ, Sch Med, New Orleans, LA 70112 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RP He, J (reprint author), Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, 1430 Tulane Ave SL18, New Orleans, LA 70112 USA. FU NHLBI NIH HHS [R01 HL60300] NR 32 TC 188 Z9 198 U1 1 U2 5 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUN 3 PY 2003 VL 138 IS 11 BP 891 EP 897 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 686AB UT WOS:000183296400004 PM 12779299 ER PT J AU Wang, TJ Levy, D Benjamin, EJ Vasan, RS AF Wang, TJ Levy, D Benjamin, EJ Vasan, RS TI The epidemiology of "asymptomatic" left ventricular systolic dysfunction: Implications for screening SO ANNALS OF INTERNAL MEDICINE LA English DT Review ID BRAIN NATRIURETIC PEPTIDE; CONGESTIVE-HEART-FAILURE; IDIOPATHIC DILATED CARDIOMYOPATHY; CONVERTING ENZYME-INHIBITORS; MYOCARDIAL-INFARCTION; DIASTOLIC DYSFUNCTION; GENERAL-PRACTICE; PROGNOSTIC IMPLICATIONS; CARDIOVASCULAR HEALTH; CLINICAL IMPLICATIONS AB Congestive heart failure is a progressive disorder that is frequently preceded by asymptomatic left ventricular systolic dysfunction. We reviewed the epidemiology, diagnosis, and natural history of asymptomatic left ventricular systolic dysfunction and evaluated community-wide screening for this condition as a potential strategy to reduce the incidence of heart failure. Asymptomatic left ventricular systolic dysfunction has an estimated prevalence of 3% to 6%, and is at least as common in the community as systolic heart failure. Because it often occurs in the absence of known cardiovascular disease, this condition may go unrecognized and undertreated. In randomized trials, individuals with asymptomatic left ventricular systolic dysfunction have high rates of incident heart failure and death. However, little is known about the prognosis of individuals with this condition in the community, who have a substantially lower prevalence of myocardial infarction, have milder degrees of systolic dysfunction, and are older than patients enrolled in clinical trials. Current evidence is inadequate to support community-wide screening for asymptomatic left ventricular systolic dysfunction, either with echocardiography or with assays for natriuretic peptides. Given the increasing prevalence of heart failure, additional studies are needed to develop effective strategies to detect and optimally manage individuals with asymptomatic left ventricular dysfunction in the community. C1 Framingham Heart Dis Epidemiol Study, NHLBI, Framingham, MA 01702 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston Med Ctr, Boston, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. NHLBI, Bethesda, MD USA. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, NHLBI, 73 Mt Wayne Ave,Suite 2, Framingham, MA 01702 USA. OI Ramachandran, Vasan/0000-0001-7357-5970 FU NHLBI NIH HHS [1U01-HL-66582, K24 HL-04334-01A1, N01-HC-25195] NR 82 TC 114 Z9 117 U1 0 U2 1 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUN 3 PY 2003 VL 138 IS 11 BP 907 EP 916 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 686AB UT WOS:000183296400006 PM 12779301 ER PT J AU Nakayama, J Xiao, GP Noma, K Malikzay, A Bjerling, P Ekwall, K Kobayashi, R Grewal, SIS AF Nakayama, J Xiao, GP Noma, K Malikzay, A Bjerling, P Ekwall, K Kobayashi, R Grewal, SIS TI Alp13, an MRG family protein, is a component of fission yeast Clr6 histone deacetylase required for genomic integrity SO EMBO JOURNAL LA English DT Article DE chromosome segregation; Clr6; fission yeast; histone deacetylase; mitosis; S.pombe ID SCHIZOSACCHAROMYCES-POMBE; CHROMOSOME SEGREGATION; TRANSCRIPTIONAL REPRESSION; RETINOBLASTOMA PROTEIN; COMPLEX; CHROMATIN; IDENTIFICATION; ACETYLATION; INTERACTS; SIN3 AB The post-translational modifications of histones are key to the modulation of chromatin structure. Distinct patterns of modifications established by histone-modifying enzymes control diverse chromosomal processes. Here, we report the purification and molecular characterization of the fission yeast Clr6 histone deacetyl ase involved in higher order chromatin assembly. We show that a chromodomain protein Alp13, which belongs to the conserved MRG protein family linked to cellular senescence in humans, is associated with Clr6. In addition, Clr6 interacts with homologs of the mammalian transcriptional co-repressors Sin3, Pst1 and Pst2, and a WD40 repeat-containing protein, Prw1. Alp13, Pst2 and Prw1 form a stable complex with Clr6 in the nucleus. Deletion of any of these factors causes progressive loss of viability and sensitivity to DNA-damaging agents, and impairs condensation/resolution of chromosomes during mitosis. This is accompanied by hyperacetylation of histones and a reduction in histone H3 Ser10 phosphorylation, which correlates with chromosome condensation during mitosis. These results link the MRG family protein Alp13 to histone deacetylation, and suggest that Clr6 and its associated factors are essential for fundamental chromosomal events. C1 Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. Karolinska Inst, Novum, Dept Biosci, S-14157 Huddinge, Sweden. RP Grewal, SIS (reprint author), NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RI Nakayama, Jun-ichi/C-6003-2011 FU NIGMS NIH HHS [GM59772, R01 GM059772] NR 48 TC 49 Z9 55 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD JUN 2 PY 2003 VL 22 IS 11 BP 2776 EP 2787 DI 10.1093/emboj/cdg248 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 684YG UT WOS:000183233600023 PM 12773392 ER PT J AU Gonzalez-Espinosa, C Odom, S Olivera, A Hobson, JP Martinez, MEC Oliveira-dos-Santos, A Barra, L Spiegel, S Penninger, JM Rivera, J AF Gonzalez-Espinosa, C Odom, S Olivera, A Hobson, JP Martinez, MEC Oliveira-dos-Santos, A Barra, L Spiegel, S Penninger, JM Rivera, J TI Preferential signaling and induction of allergy-promoting lymphokines upon weak stimulation of the high affinity IgE receptor on mast cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE cytokines; Gab2; IgE; LAT; mast cells ID FC-EPSILON-RI; ACTIVATED PROTEIN-KINASE; GENE-EXPRESSION; CALCIUM MOBILIZATION; CO-STIMULATION; GROWTH-FACTOR; MAP KINASES; IFN-GAMMA; T-CELLS; LIGAND AB Mast cell degranulation and de novo cytokine production is a consequence of antigen-aggregation of the immunoglobulin E (IgE)-occupied high affinity receptor for IgE (FcepsilonPI). Herein, we report that lymphokines that promote allergic inflammation, like MCP-1, were potently induced at low antigen (Ag) concentrations or at low receptor occupancy with IgE whereas some that down-regulate this response, like interleukin (IL)-10, required high receptor occupancy. Weak stimulation of mast cells caused minimal degranulation whereas a half-maximal secretory response was observed for chemokines and, with the exception of TNF-alpha, a weaker cytokine secretory response was observed. The medium from weakly stimulated mast cells elicited a monocyte/macrophage chemotactic response similar to that observed at high receptor occupancy. Weak stimulation also favored the phosphorylation of Gab2 and p38MAPK, while LAT and ERK2 phosphorylation was induced by a stronger stimulus. Gab2-deficient mast cells were severely impaired in chemokine mRNA induction whereas LAT-deficient mast cells showed a more pronounced defect in cytokines. These findings demonstrate that perturbation of small numbers of IgE receptors on mast cells favors certain signals that contribute to a lymphokine response that can mediate allergic inflammation. C1 NIAMSD, Mol Inflammat Sect, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. CINVESTAV, Dept Pharmacol, Mexico City 14330, DF, Mexico. Virginia Commonwealth Univ, Dept Biochem, Richmond, VA 23298 USA. Austrian Acad Sci, Inst Mol Biotechnol, A-1030 Vienna, Austria. Univ Hlth Network, Ontario Canc Inst, Toronto, ON M5G 2C1, Canada. Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2C1, Canada. Univ Toronto, Dept Immunol, Toronto, ON M5G 2C1, Canada. RP NIAMS, NIH, Bldg 10,Room 9N228, Bethesda, MD 20892 USA. EM juan_rivera@nih.gov RI Penninger, Josef/I-6860-2013 OI Penninger, Josef/0000-0002-8194-3777 NR 56 TC 108 Z9 109 U1 2 U2 7 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD JUN 2 PY 2003 VL 197 IS 11 BP 1453 EP 1465 DI 10.1084/jem.20021806 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 687KT UT WOS:000183376300006 PM 12782712 ER PT J AU Sohn, HW Gu, H Pierce, SK AF Sohn, HW Gu, H Pierce, SK TI Cbl-b negatively regulates B cell antigen receptor signaling in mature B cells through ubiquitination of the tyrosine kinase Syk SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE B cells; antigen receptor; ubiquitination; tyrosine kinase; capping ID INOSITOL PHOSPHATASE SHIP; CROSS-LINKING; C-CBL; ACTIVATION; PROTEIN; DOMAIN; MICE; PHOSPHORYLATION; UBIQUITYLATION; VISUALIZATION AB Members of the Cbl family of molecular adaptors play key roles in regulating tyrosine kinase-dependent signaling in a variety of cellular systems. Here we provide evidence that in B cells Cbl-b functions as a negative regulator of B cell antigen receptor (BCR) signaling during the normal course of a response. In B cells from Cbl-b-deficient mice cross-linking the BCRs resulted in sustained phosphorylation of Igalpha, Syk, and phospholipase C (PLC)-gamma2, leading to prolonged Ca2+ mobilization, and increases in extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal protein kinase (JNK) phosphorylation and surface expression of the activation marker, CD69. Image analysis following BCR cross-linking showed sustained polarization of the BCRs into large signaling-active caps associated with phosphorylated Syk in Cbl-b-deficient B cells in contrast to the BCRs in Cbl-b-expressing B cells that rapidly proceeded to form small, condensed, signaling inactive caps. Significantly, prolonged phosphorylation of Syk correlated with reduced ubiquitination of Syk indicating that Cbl-b negatively regulates BCR signaling by targeting Syk for ubiquitination. C1 NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. NIAID, Immunol Lab, NIH, Rockville, MD 20852 USA. RP Pierce, SK (reprint author), NIAID, Immunogenet Lab, NIH, Twinbrook 2,12441 Parklawn Dr,Rm 200B,MSC 8180, Rockville, MD 20852 USA. NR 46 TC 81 Z9 88 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 JUN 2 PY 2003 VL 197 IS 11 BP 1511 EP 1524 DI 10.1084/jem.20021686 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 687KT UT WOS:000183376300011 PM 12771181 ER PT J AU Tycko, R AF Tycko, R TI Applications of solid state NMR to the structural characterization of amyloid fibrils: methods and results SO PROGRESS IN NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY LA English DT Review ID NUCLEAR-MAGNETIC-RESONANCE; MULTIPLE-QUANTUM NMR; ANGLE-SPINNING NMR; BETA-SHEET STRUCTURE; SHIFT CORRELATION SPECTROSCOPY; PROTEIN SECONDARY STRUCTURE; UNIFORMLY LABELED MOLECULE; C-13 CHEMICAL-SHIFTS; SYNCHROTRON X-RAY; ALZHEIMERS-DISEASE C1 NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDKD, Phys Chem Lab, NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. NR 134 TC 45 Z9 47 U1 3 U2 18 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0079-6565 J9 PROG NUCL MAG RES SP JI Prog. Nucl. Magn. Reson. Spectrosc. PD JUN 2 PY 2003 VL 42 IS 1-2 BP 53 EP 68 DI 10.1016/S0079-6565(03)00003-7 PG 16 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Chemistry; Physics; Spectroscopy GA 699DP UT WOS:000184040900003 ER PT J AU Kirihara, M Kawasaki, M Takuwa, T Kakuda, H Wakikawa, T Takeuchi, Y Kirk, KL AF Kirihara, M Kawasaki, M Takuwa, T Kakuda, H Wakikawa, T Takeuchi, Y Kirk, KL TI Efficient synthesis of (R)- and (S)-1-amino-2,2-difluorocyclopropanecarboxylic acid via lipase-catalyzed desymmetrization of prochiral precursors SO TETRAHEDRON-ASYMMETRY LA English DT Article ID 1-AMINOCYCLOPROPANE CARBOXYLIC-ACID; OLIGO-GEM-DIFLUOROCYCLOPROPANES; ORGANIC FLUORINE-COMPOUNDS; GLYCINE; NUCLEOPHILES AB The asymmetric syntheses of (+)-(R)-1-amino-2,2-difluorocyclopropane-1-carboxylic acid and its enantiomer have been accomplished. Key reactions in the synthetic design are lipase-catalyzed desymmetrization of a prochiral diol and a prochiral diacetate. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 Shizuoka Inst Sci & Technol, Dept Mat Sci, Shizuoka 4378555, Japan. Toyama Prefectural Univ, Fac Engn, Toyama 9390398, Japan. Toyama Med & Pharmaceut Univ, Fac Pharmaceut Sci, Toyama 9300194, Japan. Toyama Med & Pharmaceut Univ, Chem Lab, Toyama 9300194, Japan. NIH, Dept Hlth & Human Serv, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Kirihara, M (reprint author), Shizuoka Inst Sci & Technol, Dept Mat Sci, Toyosawa 2200-2, Shizuoka 4378555, Japan. EM kirihara@ms.sist.ac.jp NR 23 TC 28 Z9 28 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0957-4166 J9 TETRAHEDRON-ASYMMETR JI Tetrahedron: Asymmetry PD JUN 2 PY 2003 VL 14 IS 12 BP 1753 EP 1761 DI 10.1016/S0957-4166(03)00350-1 PG 9 WC Chemistry, Inorganic & Nuclear; Chemistry, Organic; Chemistry, Physical SC Chemistry GA 692VV UT WOS:000183681700024 ER PT J AU Purcell, RH Nguyen, H Shapiro, M Engle, RE Govindarajan, S Blackwelder, WC Wong, DC Prieels, JP Emerson, SU AF Purcell, RH Nguyen, H Shapiro, M Engle, RE Govindarajan, S Blackwelder, WC Wong, DC Prieels, JP Emerson, SU TI Pre-clinical immunogenicity and efficacy trial of a recombinant hepatitis E vaccine SO VACCINE LA English DT Article DE hepatitis E; vaccine; monkey ID E VIRUS; CYNOMOLGUS MONKEYS; INSECT CELLS; IDENTIFICATION; INFECTION; TRANSMISSION; ANTIBODIES; MACAQUES; PROTEIN AB We have demonstrated that recombinant hepatitis E vaccine suitable for clinical evaluation was highly immunogenic and efficacious in preventing hepatitis E and even infection in rhesus macaques following intravenous challenge with three different genotypes of hepatitis E virus (HEV). Two doses of vaccine were essential for optimal protection; the two-dose regimen was more important than the formulation of the vaccine for achieving efficacy. The titers of anti-HEV that were protective in this study were quantified against a World Health Organization (WHO) standard. This permits direct comparison of the results with other studies. The results of this pre-clinical trial of a candidate hepatitis E vaccine strongly suggest that it will be highly efficacious for preventing hepatitis E in the field trial of this vaccine that is currently in progress in Nepal. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Mol Hepatitis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Bioqual Inc, Rockville, MD 20850 USA. Liver Res & Educ Fdn Inc, Rancho Los Amigos Hosp, Downey, CA 90242 USA. Glaxo SmithKline, Rixensart, Belgium. RP Purcell, RH (reprint author), NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, 50 S Dr MSC 8009, Bethesda, MD 20892 USA. FU NIAID NIH HHS [AI-0035]; PHS HHS [N01-A0-02733] NR 25 TC 77 Z9 92 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUN 2 PY 2003 VL 21 IS 19-20 BP 2607 EP 2615 DI 10.1016/S0264-410X(03)00100-2 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 682PK UT WOS:000183100600052 PM 12744897 ER PT J AU Burke, TR Lee, K AF Burke, TR Lee, K TI Phosphotyrosyl mimetics in the development of signal transduction inhibitors SO ACCOUNTS OF CHEMICAL RESEARCH LA English DT Review ID SOLID-PHASE SYNTHESIS; TYROSINE KINASE INHIBITORS; SH2 DOMAIN BINDING; STRUCTURE-BASED DESIGN; PHOSPHATE-CONTAINING LIGANDS; ATP COMPETITIVE INHIBITORS; SRC HOMOLOGY-2 DOMAIN; O-PHOSPHOTYROSINE; 1,2,3-TRISUBSTITUTED CYCLOPROPANES; ENANTIOSELECTIVE SYNTHESIS AB Phosphotyrosyl (pTyr) residues play important roles in cellular signal transduction by facilitating recognition and binding necessary for critical protein-protein interactions, and for this reason pTyr motifs represent attractive starting points in the development of signaling antagonists. Although the pTyr phosphoryl moiety is central in these phenomena, its incorporation into signaling inhibitors is contraindicated due to enzymatic lability and limited bioavailabilty associated with phosphate esters. To address these limiations, an entire field of study has arisen devoted to the design and utilization of pTyr mimetics. This Account provides a perspective on the roles of pTyr residues in signal transduction and approaches to pTyr mimetic development. C1 NCI, Med Chem Lab, Canc Res Ctr, NIH, Frederick, MD 21701 USA. RP Burke, TR (reprint author), NCI, Med Chem Lab, Canc Res Ctr, NIH, Frederick, MD 21701 USA. RI Burke, Terrence/N-2601-2014 NR 83 TC 88 Z9 90 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0001-4842 J9 ACCOUNTS CHEM RES JI Accounts Chem. Res. PD JUN PY 2003 VL 36 IS 6 BP 426 EP 433 DI 10.1021/ar020127o PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA 692JF UT WOS:000183657400009 PM 12809529 ER PT J AU Marquez, VE Blumberg, PM AF Marquez, VE Blumberg, PM TI Synthetic diacylglycerols (DAG) and DAG-lactones as activators of protein kinase C (PK-C) SO ACCOUNTS OF CHEMICAL RESEARCH LA English DT Review ID CONFORMATIONALLY CONSTRAINED ANALOGS; PHORBOL ESTER BINDING; TUMOR PROMOTERS; ACYL CHAINS; LIGANDS; DELTA; AFFINITY; ISOZYMES; DOMAIN; LIPOPHILICITY AB The central role of protein kinase C (PK-C) in cellular signal transduction has established it as an important therapeutic target for cancer and other diseases. We have developed a series of 4,4disubstituted-gamma-butyrolactones, which contain a constrained glycerol backbone (DAG-lactones) and behave as potent and selective activating ligands of PK-C with affinities that approach those of the structurally complex natural product agonists, such as the phorbol esters. This Account traces the design and construction of these molecules. Initially, we examined the consequences of reducing the entropic penalty associated with the transformation of a DAG into a DAG-lactone. Then, using molecular modeling to extend insights arising from the newly solved crystal structure of a C1 domain complexed with phorbol ester, we incorporated amino acid-specific branched hydrophobic chains to provide a new generation of DAG-lactones that have the capacity to bind to PK-C with low nanomolar affinity. Depending on the specific pattern of hydrophobic substitution, some DAG-lactones are able to induce selective translocation of individual PK-C isozymes to different cellular compartments, and since the specific nature of these hydrophobic interactions influences biological outcome, some of these compounds exhibit cell-specific antitumor activity. The ability to direct specific PK-C isozyme translocation with sets of structurally simple, yet highly potent molecules provides a powerful tool for engineering a plethora of molecules with novel biological functions. C1 NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Marquez, VE (reprint author), NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. NR 35 TC 71 Z9 71 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0001-4842 J9 ACCOUNTS CHEM RES JI Accounts Chem. Res. PD JUN PY 2003 VL 36 IS 6 BP 434 EP 443 DI 10.1021/ar020124b PG 10 WC Chemistry, Multidisciplinary SC Chemistry GA 692JF UT WOS:000183657400010 PM 12809530 ER PT J AU Nash, TE AF Nash, TE TI Human case management and treatment of cysticercosis SO ACTA TROPICA LA English DT Article; Proceedings Paper CT International Workshop on Taenia Solium Cysticercosis/Taeniosis with Special Focus on Eastern and Southern Africa CY AUG 19-22, 2002 CL ARUSHA, TANZANIA SP Cysticercosis Working Grp Eastern & SO Africa DE cysticercosis; Taenia solium; treatment; cestode; tapeworm ID RURAL GUATEMALAN COMMUNITIES; TAENIA-SOLIUM CYSTICERCOSIS; DAY PRAZIQUANTEL THERAPY; DISAPPEARING CT LESIONS; HIGH-DOSE PRAZIQUANTEL; CEREBRAL CYSTICERCOSIS; ALBENDAZOLE THERAPY; SUBARACHNOID CYSTICERCI; PORCINE CYSTICERCOSIS; TOMOGRAPHIC LESIONS AB Disease manifestations due to neurocysticercosis vary markedly and depend upon the location, size and number of cysts as well as the viability or degeneration of cysts and presence, type and degree of host response. Accordingly, the clinical management for each patient should be individualized. Treatment modalities include: (1) larvicidal drugs such as albendazole or praziquantel in patients with viable cysts; (2) corticosteroids or other agents to suppress or prevent the host's immune response; (3) anti-seizure medication(s) to treat or prevent recurrent seizures; (4) surgical interventions; and (5) the use of supportive family, social or health agencies in impaired individuals. Although it is known that larvicidal treatment kills viable cysts that commonly resolve or calcify, the clinical benefit of this treatment in the most common presentations is unproven. However, medical treatment of giant subarachnoid cysts, large parenchymal cysts or orbital cysts causing mass effect has led to definite clinical improvement in uncontrolled trials. Whether there is faster radiological improvement and/or clinical benefit in the treatment of cysts showing signs of inflammation by magnetic resonance imaging (enhancement and/or edema) is like-wise controversial. There is no general understanding when or how to use corticosteroids to suppress natural or treatment-induced inflammation around cysts although their use when inflammation contributes or could be expected to cause undo morbidity or mortality is reasonable. Anti-seizure medication should usually be employed in patients with seizures or patients who may likely develop seizures. Surgical intervention is required to alleviate mass effect, remove some cysts causing obstruction of the ventricles, shunt placement for hydrocephalus, and sometimes for removal and/or decompression of large or critically located cysts before larvicidal treatment. (C) 2003 Elsevier Science B.V. All rights reserved. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 21043 USA. RP Nash, TE (reprint author), NIAID, Parasit Dis Lab, NIH, 9000 Rockville Pike,Bldg 4,Rm B1-06, Bethesda, MD 21043 USA. NR 63 TC 22 Z9 22 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0001-706X J9 ACTA TROP JI Acta Trop. PD JUN PY 2003 VL 87 IS 1 BP 61 EP 69 DI 10.1016/S0001-706X(03)00056-1 PG 9 WC Parasitology; Tropical Medicine SC Parasitology; Tropical Medicine GA 690XX UT WOS:000183576700009 PM 12781379 ER PT J AU Elkashef, A Vocci, F AF Elkashef, A Vocci, F TI Biological markers of cocaine addiction: implications for medications development SO ADDICTION BIOLOGY LA English DT Review ID SERUM PROLACTIN LEVELS; CEREBRAL BLOOD-FLOW; DEPENDENT PATIENTS; CRACK COCAINE; EYE-MOVEMENTS; INTRAVENOUS COCAINE; DOPAMINE-RECEPTORS; GENDER DIFFERENCES; EVOKED-POTENTIALS; POLYDRUG USERS AB The search for effective medications for cocaine addiction has been elusive. The failure to find such medications so far could be due to poor understanding of the underlying biology both in the premorbid condition and following the disease state of chronic cocaine use. Population heterogeneity could be a major factor in response to medications. In an attempt to highlight the issue of biomarkers we reviewed physiological, neuroendocrine and neuroimaging studies to identify specific biological changes/markers that could be used to characterize subgroups among chronic cocaine users. Merging the biology within medications studies of cocaine abusers could prove useful for targeting specific pharmacological agents to subgroups of patients, prediction of response to medication and relapse to use. C1 NIDA, Div Treatment Res & Dev, NIH, Bethesda, MD 20892 USA. RP Elkashef, A (reprint author), NIDA, Div Treatment Res & Dev, NIH, 6001 Execut Blvd,Room 4123,MSC 9551, Bethesda, MD 20892 USA. NR 69 TC 16 Z9 17 U1 2 U2 4 PU CARFAX PUBLISHING PI BASINGSTOKE PA RANKINE RD, BASINGSTOKE RG24 8PR, HANTS, ENGLAND SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD JUN PY 2003 VL 8 IS 2 BP 123 EP 139 DI 10.1080/1355621031000117356 PG 17 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 698JJ UT WOS:000183995100001 PM 12850771 ER PT J AU Ingman, K Salvadori, S Lazarus, L Korpi, ER Honkanen, A AF Ingman, K Salvadori, S Lazarus, L Korpi, ER Honkanen, A TI Selective delta-opioid receptor antagonist N,N(CH3)(2)-Dmt-Tic-OH does not reduce ethanol intake in alcohol-preferring AA rats SO ADDICTION BIOLOGY LA English DT Article ID AVOIDING ANA RATS; OPIATE RECEPTORS; WISTAR RATS; NALTREXONE; DRINKING; ADDICTION; NALTRINDOLE; PREFERENCE; BINDING; REWARD AB We studied the effect of a novel delta-opioid receptor antagonist N,N(CH3)(2)Dmt-Tic-OH (Me-2-Dmt-Tic-OH) on voluntary ethanol intake in an alcohol-preferring AA (Alko, Alcohol) rat line using a 4-hour limited access paradigm. Acute injections of Me-2-Dmt-Tic-OH (10 and 30 mg/kg, i.p.) did not reduce 1-hour or 4-hour ethanol intake. Subtype non-selective opioid receptor antagonist naltrexone [0.1 and 0.3 mg/kg, subcutaneously (s.c.)] significantly reduced 1-hour ethanol drinking but had no effect on 4-hour ethanol consumption. Locomotor stimulation induced by the delta-opioid receptor agonist Tyr-D-Pen-Gly-Phe-D-Pen (DPDPE; 15 mug, intracerebroventricularly) was significantly attenuated by Me-2-Dmt-Tic-OH (10 and 30 mg/kg, i.p.), which confirmed its efficacy as a delta-opioid receptor antagonist in rat brain. Our results support the idea that delta-opioid receptors do not mediate alcohol reward in AA rats. C1 Univ Turku, Dept Pharmacol & Clin Pharmacol, FIN-20520 Turku, Finland. Univ Ferrara, Dept Pharmaceut Sci & Biotechnol, I-44100 Ferrara, Italy. NIEHS, LCBRA, Res Triangle Pk, NC 27709 USA. RP Ingman, K (reprint author), Univ Turku, Dept Pharmacol & Clin Pharmacol, Itainen Pitkakatu 4, FIN-20520 Turku, Finland. NR 39 TC 12 Z9 15 U1 1 U2 1 PU CARFAX PUBLISHING PI BASINGSTOKE PA RANKINE RD, BASINGSTOKE RG24 8PR, HANTS, ENGLAND SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD JUN PY 2003 VL 8 IS 2 BP 173 EP 179 DI 10.1080/1355621031000117400 PG 7 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 698JJ UT WOS:000183995100006 PM 12850776 ER PT J AU Fagan, P Eisenberg, M Frazier, L Stoddard, AM Avrunin, JS Sorensen, G AF Fagan, P Eisenberg, M Frazier, L Stoddard, AM Avrunin, JS Sorensen, G TI Employed adolescents and beliefs about self-efficacy to avoid smoking SO ADDICTIVE BEHAVIORS LA English DT Article DE self-efficacy; social influences; smoking; nicotine dependence ID NICOTINE DEPENDENCE; CESSATION; SMOKERS; PROGRAMS; HEALTH AB This paper examines self-efficacy to avoid cigarette smoking and its association with smoking and quitting behavior, peer and worksite influences, nicotine dependence, and socio-dernographic variables among employed adolescents. A cross-sectional survey was used to collect data from employed adolescents ages 15-18 who worked in 10 participating grocery stores in Massachusetts. Eighty-three percent of workers (n = 379), completed the survey. Results from the multivariate model indicate that daily smokers were less confident in their ability to avoid smoking than those who smoked less frequently. As nicotine dependence increased, self-efficacy beliefs decreased. In addition, as friends' encouragement to quit increased, self-efficacy beliefs also increased. Work-related variables were not associated with self-efficacy beliefs among smokers. This study suggests that smoking frequency, nicotine dependence, and friends' encouragement to quit are associated with self-efficacy to avoid smoking. Researchers may tailor interventions for daily and less-than-daily smokers, build on peer networks that encourage quitting and help smokers resist pressures to smoke, and enhance strategies for coping with nicotine dependence. in high-risk situations. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. Univ Massachusetts, Amherst, MA 01003 USA. RP Fagan, P (reprint author), NCI, Div Canc Control & Populat Sci, Tobacco Control Res Branch, Execut Plaza N,Room 4042,6130 Ex Blvd,MSC 7337, Bethesda, MD 20892 USA. FU NINR NIH HHS [R01 NR04748] NR 27 TC 21 Z9 23 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 J9 ADDICT BEHAV JI Addict. Behav. PD JUN PY 2003 VL 28 IS 4 BP 613 EP 626 DI 10.1016/S0306-4603(02)00227-7 PG 14 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 678VX UT WOS:000182888300001 PM 12726779 ER PT J AU Brizioli, E Bernabei, R Grechi, F Masera, F Landi, F Bandinelli, S Cavazzini, C Gangemi, S Ferrucci, L AF Brizioli, E Bernabei, R Grechi, F Masera, F Landi, F Bandinelli, S Cavazzini, C Gangemi, S Ferrucci, L TI Nursing home case-mix instruments: Validation of the RUG-III system in Italy SO AGING CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE case-mix classification; long-term care; nursing home; older persons; reimbursement system; RUG-III system ID LONG-TERM-CARE; RESOURCE UTILIZATION GROUPS; DIAGNOSIS-RELATED GROUPS; CLASSIFICATION-SYSTEM; PAYMENT SYSTEM; QUALITY; FACILITIES AB Background and aims: The current Italian reimbursement system for long-term care does not adequately consider the great variability in the health and functional status of older persons who are admitted to long-term care institutions. Furthermore, no procedure is implemented to monitor the quality of care provided to older residents. We conducted this study to verify whether the RUG-III (Resource Utilization Groups-version III), a tool for assessing the case-mix of nursing home residents, which is widely used in the United States and in many European countries, can be effectively used in the Italian health care system. Methods: We administered an Italian version of the RUG-III to 1000 older residents of 11 intermediate- and long-term care institutions. We also collected objective information on the amount of care provided directly or indirectly to each resident by nurses, physical therapists, and other health professionals. Results: The RUG-III 44 group classification system explained 61 and 44% of the variance in rehabilitative and nursing wage-adjusted care time, respectively. Conclusions: Our findings provide strong evidence that the RUG-III classification, applied to Italian intermediate- and long-term care institutions, provides a robust estimate of the amount of nursing and rehabilitation resources consumed by older residents. (C)2003, Editrice Kurtis C1 NIA, Gerontol Res Ctr, Clin Res Branch, Longitudinal Studies Sect, Baltimore, MD 21224 USA. Healthcare Serv, Grp S Stefano, Potenza, MC, Italy. Univ Cattolica Sacro Cuore, Dept Geriatr, I-20123 Milan, Italy. Reg Hlth Agcy, Ancona, Italy. INRCA Geriatr Dept, Lab Clin Epidemiol, Florence, Italy. RP Ferrucci, L (reprint author), NIA, Gerontol Res Ctr, Clin Res Branch, Longitudinal Studies Sect, 5600 Nathan Shock Dr,Rm D6N, Baltimore, MD 21224 USA. NR 20 TC 5 Z9 5 U1 1 U2 3 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 1594-0667 J9 AGING CLIN EXP RES JI Aging Clin. Exp. Res. PD JUN PY 2003 VL 15 IS 3 BP 243 EP 253 PG 11 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 727DG UT WOS:000185640800008 PM 14582687 ER PT J AU Lyon, ME Trexler, C Akpan-Townsend, C Pao, M Selden, K Fletcher, J Addlestone, IC D'Angelo, LJ AF Lyon, ME Trexler, C Akpan-Townsend, C Pao, M Selden, K Fletcher, J Addlestone, IC D'Angelo, LJ TI A family group approach to increasing adherence to therapy in HIV-infected youths: Results of a pilot project SO AIDS PATIENT CARE AND STDS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIRETROVIRAL THERAPY; PROTEASE INHIBITORS; DRUG COMPLIANCE; CHILDREN; MEDICATION; ASTHMA; CARE; DETERMINANTS; MORTALITY AB This paper describes the development of a novel, pilot program in which a combined family group and peer approach were used to increase adherence to antiretroviral therapy in HIV-infected youths. Twenty-three HIV-positive youths, 15-22 years of age and 23 family members or "treatment buddies" participated in one of three 12-week programs. The intervention had six biweekly family and youth education sessions and six biweekly youth-only education sessions. Devices to increase adherence to antiretroviral therapy such as pill boxes, calendars, and watch alarms were introduced at youth-only sessions. Eighteen of the 23 youths completed a group. Ninety-one percent of youths self-reported increased adherence to medications after completion of a group. Four participants experienced a one-log reduction in viral loads to undetectable levels during the intervention. Two participants continued to decline antiretroviral medications at the end of the intervention and demonstrated no decrease in viral load. Participants tested five devices and rated the multiple alarm watch as the best aid for improving adherence to medication. Family/treatment buddies rated the overall program as highly helpful, citing social support as most valuable. An unanticipated benefit was an increase in other health behaviors, including medical and dental appointments, hepatitis B and influenza immunizations, and referrals to mental health and substance abuse treatment. C1 Childrens Natl Med Ctr, Dept Adolescent & Young Adult Med, Burgess Clin, Div Adolescent Young Adult Med, Washington, DC 20010 USA. NIMH, IRP OCD, Bethesda, MD 20892 USA. RP Lyon, ME (reprint author), Childrens Natl Med Ctr, Dept Adolescent & Young Adult Med, Burgess Clin, Div Adolescent Young Adult Med, 111 Michigan Ave NW, Washington, DC 20010 USA. OI Lyon, Maureen/0000-0002-0955-3969 NR 42 TC 49 Z9 49 U1 2 U2 8 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1087-2914 J9 AIDS PATIENT CARE ST JI Aids Patient Care STDS PD JUN PY 2003 VL 17 IS 6 BP 299 EP 308 DI 10.1089/108729103322108175 PG 10 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 698CX UT WOS:000183981000005 PM 12880493 ER PT J AU Purohit, V Russo, D Salin, M AF Purohit, V Russo, D Salin, M TI Role of iron in alcoholic liver disease: introduction and summary of the symposium SO ALCOHOL LA English DT Article; Proceedings Paper CT Symposium on Role of Iron in Alcoholic Liver Disease CY OCT, 2002 CL BETHESDA, MARYLAND DE iron; alcoholic liver disease (ALD); oxidative stress; hemochromatosis; iron chelator ID TOXICITY; INJURY; STORES AB The National Institute on Alcohol Abuse and Alcoholism and the Office of Dietary Supplements, National Institutes of Health, sponsored a symposium on the "Role of Iron in Alcoholic Liver Disease" at Bethesda, Maryland, USA, October 2002. Alcoholic liver disease is a major cause of illness and death in the United States. Oxidative stress plays a key role in the pathogenesis of alcoholic liver disease. Iron can induce oxidative stress by catalyzing the conversion of superoxide and hydrogen peroxide to more potent oxidants such as hydroxyl radicals, which can cause tissue injury by initiating lipid peroxidation and causing oxidation of proteins and nucleic acids. Increasing evidence supports the suggestion that iron plays a significant role in the pathogenesis of alcoholic liver disease by exacerbating oxidative stress. Understanding the underlying mechanisms by which iron participates in the initiation and development of alcoholic liver disease may help design strategies for the treatment and prevention of the disease. For this symposium, nine speakers were invited to address the following issues: (1) iron intake from foods and dietary supplements; (2) hepatic iron overload in alcoholic liver disease; (3) iron-dependent activation of nuclear factor-kappa B (NF-kappaB) in Kupffer cells; (4) iron and cytochrome P450 2131 (CYP2E1)-dependent oxidative stress and liver toxicity; (5) iron-induced oxidative stress in alcoholic hepatic fibrogenesis; (6) hemochromatosis and alcoholic liver disease; (7) iron as a co-morbid factor in nonhemochromatotic liver diseases; (8) iron and liver cancer; and (9) iron chelators and iron toxicity. On the basis of these presentations, it is concluded that heavy alcohol intake can result in increased accumulation of iron in the liver, in both hepatocytes and Kupffer cells. Iron-induced oxidative stress may promote the severity of alcoholic liver disease by (1) inducing NF-kappaB activation and subsequently increasing transcription of proinflammatory cytokines in Kupffer cells; (2) exacerbating CYP2E1-induced oxidative stress, especially in hepatocytes, through production of more toxic hydroxyl radicals; (3) stimulating hepatic stellate cells to produce excess amount of collagen and other matrix proteins that can lead to fibrosis; and (4) causing DNA damage and mutations that promote the development of liver cancer. Dietary iron supplements may further exacerbate the severity of alcoholic liver disease by increasing the magnitude of oxidative stress. We hope that the studies presented will stimulate further research in this exciting area. (C) 2003 Elsevier Inc. All rights reserved. C1 NIAAA, Biomed Res Branch, Div Basic Res, NIH, Bethesda, MD 20892 USA. RP Purohit, V (reprint author), NIAAA, Biomed Res Branch, Div Basic Res, NIH, 6000 Execut Blvd,Suite 402, Bethesda, MD 20892 USA. NR 10 TC 28 Z9 30 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0741-8329 J9 ALCOHOL JI Alcohol PD JUN PY 2003 VL 30 IS 2 BP 93 EP 97 DI 10.1016/S0741-8329(03)00132-0 PG 5 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA 721PR UT WOS:000185325200002 PM 12957291 ER PT J AU Swanson, CA AF Swanson, CA TI Iron intake and regulation: implications for iron deficiency and iron overload SO ALCOHOL LA English DT Article; Proceedings Paper CT Symposium on Role of Iron in Alcoholic Liver Disease CY OCT, 2002 CL BETHESDA, MARYLAND DE iron intake; iron homeostasis; iron deficiency; iron excess; supplementation ID HEART-STUDY COHORT; HEREDITARY HEMOCHROMATOSIS; CAUSAL RELATIONSHIP; STORES; ABSORPTION; PREVALENCE; RISK; MEN; INHIBITION; ANEMIA AB Although iron deficiency anemia is the most common nutritional deficiency worldwide and in the United States, the health effects of iron overload merit increased attention. In the United States, public health interventions such as fortification and enrichment of foods with iron were undertaken to reduce the prevalence of iron deficiency anemia and improve health. These measures, along with iron supplementation, remain controversial, because additional exposure to dietary iron places some segments of the population at increased risk of iron excess. The health consequences of unmistakable iron excess are exemplified by hemochromatosis, an iron storage disease associated with liver damage further exacerbated by alcohol consumption. Progressive liver damage associated with this condition is generally attributed to increased oxidative stress. In otherwise healthy individuals, more modest levels of iron storage may occur if iron is provided by supplements or otherwise added to the food supply. Increased iron intake and storage have been linked to a variety of chronic diseases. The associations are not firmly established but are of considerable public health importance. (C) 2003 Elsevier Inc. All rights reserved. C1 NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Swanson, CA (reprint author), NIH, Off Dietary Supplements, 6100 Execut Blvd,Room 3B01,MSC 7517, Bethesda, MD 20892 USA. NR 32 TC 36 Z9 37 U1 2 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0741-8329 J9 ALCOHOL JI Alcohol PD JUN PY 2003 VL 30 IS 2 BP 99 EP 102 DI 10.1016/S0741-8329(03)00103-4 PG 4 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA 721PR UT WOS:000185325200003 PM 12957292 ER PT J AU Rouault, TA AF Rouault, TA TI Hepatic iron overload in alcoholic liver disease: why does it occur and what is its role in pathogenesis? SO ALCOHOL LA English DT Article; Proceedings Paper CT Symposium on Role of Iron in Alcoholic Liver Disease CY OCT, 2002 CL BETHESDA, MARYLAND DE alcohol; iron; cirrhosis; IRP1; transferrin receptor; ferritin; oxidative stress ID REGULATORY PROTEIN-2; OXIDATIVE STRESS; ETHANOL-CONSUMPTION; BINDING PROTEIN; SULFUR CLUSTERS; DIETARY IRON; METABOLISM; DEGRADATION; GENE; TRANSFERRIN AB Iron overload is frequently observed in alcoholic liver disease. However, it is not known why hepatic iron accumulation occurs or how it contributes to disease progression. In this review, information about the role of iron in the pathophysiology of liver disease is reviewed and discussed. (C) 2003 Elsevier Inc. All rights reserved. C1 NICHHD, Sect Human Iron Metab, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), NICHHD, Sect Human Iron Metab, Cell Biol & Metab Branch, NIH, Bldg 18,Room 101, Bethesda, MD 20892 USA. NR 37 TC 26 Z9 27 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0741-8329 J9 ALCOHOL JI Alcohol PD JUN PY 2003 VL 30 IS 2 BP 103 EP 106 DI 10.1016/S0741-8329(03)00102-2 PG 4 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA 721PR UT WOS:000185325200004 PM 12957293 ER PT J AU Rajagopalan, S Mohler, E Lederman, RJ Saucedo, J Mendelsohn, FO Olin, J Blebea, J Goldman, C Trachtenberg, JD Pressler, M Rasmussen, H Annex, BH Hirsch, AT AF Rajagopalan, S Mohler, E Lederman, RJ Saucedo, J Mendelsohn, FO Olin, J Blebea, J Goldman, C Trachtenberg, JD Pressler, M Rasmussen, H Annex, BH Hirsch, AT TI Regional angiogenesis with vascular endothelial growth factor (VEGF) in peripheral arterial disease: Design of the RAVE trial SO AMERICAN HEART JOURNAL LA English DT Article ID INTRAMUSCULAR GENE-TRANSFER; THERAPEUTIC ANGIOGENESIS; INTERMITTENT CLAUDICATION; CLINICAL-TRIALS; VECTOR AB Background Patients with intermittent claudication caused by infrainguinal atherosclerosis have limited pharmacologic options "Therapeutic angiogenesis" is a novel treatment approach that seeks to improve perfusion of ischemic limbs by the induction of collateral vessel formation. This trial is a phase 2 randomized double-blind placebo-controlled proof of concept trial that will use an intramuscular adenoviral gene transfer approach of vascular endothelial growth factor, 12 1 isoform (Ad(GV)VEGF(121.10)) to patients with severe IC caused by infrainguinal disease. Methods This is a phase 2, double-blind, randomized, placebo-controlled, dose-finding, multicenter study. Patients with severe intermittent claudication caused by infrainguinal atherosclerosis predominantly involving the superficial femoral artery confirmed with imaging studies that meet inclusion criteria will be stratified on the basis of the presence or absence of diabetes mellitus and randomized in a 1 :1 :1 fashion to low dose (4 x 10(9) particle units); high dose (4 x 10(10) particle units), or placebo arms (35-36 patients per group). Subjects are required to have exercise-limiting IC in the index extremity during 2 qualifying exercise treadmill tests, with peak walking times between 1 and 10 minutes. A single dose of Ad(GV)VEGF(121.10) will be administered as 20 intramuscular injections throughout the area of the lower limb requiring collateralization. Results The primary efficacy parameter for the Regional Angiogenesis With Vascular Endothelial Growth Factor (RAVE) trial is the change in peak walking time at 12 weeks compared with baseline. The sample size is expected to provide an 80% power to detect a difference of 1.5 minutes between any of the 2 treatment groups and the placebo group. Secondary efficacy parameters include claudication onset time, hemodynamic effects of therapy assessed with ankle-brachial index, assessment of physical impairment, and health-related quality of life as measured with the Walking Impairment Questionnaire and SF-36 Health Survey. All randomized patients will also be evaluated for safety. C1 Univ Michigan Hlth Syst, Dept Internal Med, Div Cardiol, Sect Vasc Med, Ann Arbor, MI USA. Univ Penn, Med Ctr, Philadelphia Heart Inst, Philadelphia, PA 19104 USA. NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. Univ Arkansas, Dept Cardiol, Little Rock, AR 72204 USA. Baptist Med Ctr Princeton, Dept Cardiol, Birmingham, AL USA. Inst Heart & Vasc, Morristown, NJ USA. Penn State Univ, Milton S Hershey Med Ctr, Dept Vasc Surg, Hershey, PA 17033 USA. Watson Clin LLP, Lakeland, FL USA. Decatur Mem Hosp, Decatur, IL USA. Pfizer Global Res & Dev, Ann Arbor, MI USA. GenVec, Gaithersburg, MD USA. Duke Univ, Dept Med, Div Cardiol, Durham, NC USA. Durham Vet Affairs Med Ctr, Durham, NC USA. Univ Minnesota, Sch Med, Div Cardiovasc, Minnesota Vasc Dis Ctr,Vasc Med Program, Minneapolis, MN 55455 USA. RP Rajagopalan, S (reprint author), Univ Michigan Hlth Syst, Womens Hosp L3119, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. OI lederman, robert/0000-0003-1202-6673 NR 21 TC 42 Z9 45 U1 0 U2 3 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD JUN PY 2003 VL 145 IS 6 BP 1114 EP 1118 DI 10.1016/S0002-8703(03)00102-9 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 690NW UT WOS:000183556100029 PM 12796772 ER PT J AU Schaffer, WL Galloway, JM Roman, MJ Palmieri, V Liu, JE Lee, ET Best, LG Fabsitz, RR Howard, BV Devereux, RB AF Schaffer, WL Galloway, JM Roman, MJ Palmieri, V Liu, JE Lee, ET Best, LG Fabsitz, RR Howard, BV Devereux, RB TI Prevalence and correlates of rheumatic heart disease in American Indians (The Strong Heart Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CARDIOVASCULAR-DISEASE; REGURGITATION C1 Cornell Med Ctr, New York, NY USA. Univ Arizona, Tucson, AZ 85721 USA. Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. Missouri Breaks Ind Res, Timber Lake, SD USA. NHLBI, Bethesda, MD 20892 USA. Medstar Res Inst, Washington, DC USA. RP Devereux, RB (reprint author), New York Presbyterian Hosp, Div Cardiol, Box 222,525 E 68th St, New York, NY 10021 USA. OI Palmieri, Vittorio/0000-0003-3732-524X FU NCRR NIH HHS [M10 RR 004734]; NHLBI NIH HHS [U01 HL 41642, U01 HL 41654, U01 HL 41652] NR 20 TC 8 Z9 8 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUN 1 PY 2003 VL 91 IS 11 BP 1379 EP 1382 DI 10.1016/S0002-9149(03)00338-2 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 685EE UT WOS:000183247200024 PM 12767442 ER PT J AU Yanovski, JA AF Yanovski, JA TI Rapid weight gain during infancy as a predictor of adult obesity SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Editorial Material ID BODY-MASS; CHILDHOOD; GROWTH; ASSOCIATION; OVERWEIGHT; CHILDREN; COHORT C1 NICHHD, Dev Endocrinol Branch, Unit Growth & Obes, NIH, Bethesda, MD 20892 USA. RP Yanovski, JA (reprint author), NICHHD, Dev Endocrinol Branch, Unit Growth & Obes, NIH, 10 Ctr Dr MSC 1862,Bldg 10,Room 10N262, Bethesda, MD 20892 USA. NR 12 TC 5 Z9 6 U1 0 U2 1 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUN PY 2003 VL 77 IS 6 BP 1350 EP 1351 PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 682GY UT WOS:000183084400003 PM 12791608 ER PT J AU Newby, P Muller, D Hallfrisch, J Qiao, N Andres, R Tucker, KL AF Newby, P Muller, D Hallfrisch, J Qiao, N Andres, R Tucker, KL TI Dietary patterns and changes in body mass index and waist circumference in adults SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE dietary patterns; cluster analysis; obesity; body composition; diet assessment; BMI; waist circumference ID CORONARY HEART-DISEASE; FOOD EATING PATTERNS; CLUSTER-ANALYSIS; RISK-FACTORS; LIFE-STYLE; FAT INTAKE; CARDIOVASCULAR-DISEASE; ENERGY DENSITY; BRITISH ADULTS; MEN BORN AB Background: Obesity has increased > 20% in the past decade in the United States, and more than one-half of US adults are overweight or obese. Objective: Our objective was to further elucidate the nutritional etiology of changes in body mass index (BMI; in kg/m(2)) and waist circumference by dietary intake pattern. We hypothesized that a healthy dietary pattern would lead to smaller changes in BMI and waist circumference than would other dietary patterns. Design: Subjects were 459 healthy men and women participating in the ongoing Baltimore Longitudinal Study of Aging. Diet was assessed with the use of 7-d dietary records, from which 41 food groups were created and entered into a cluster analysis. Results: Five dietary patterns were derived (healthy, white bread, alcohol, sweets, and meat and potatoes). The mean annual change in BMI was 0.30 +/- 0.06 for subjects in the meat-and-potatoes cluster and 0.05 +/- 0.06 for those in the healthy cluster (P < 0.01). The mean annual change in waist circumference was more than 3 times as great for subjects in the white-bread cluster (1.32 +/- 0.29 cm) as for those in the healthy cluster (0.43 +/- 0.27 cm) (P < 0.05). Conclusions: Consuming a diet high in fruit, vegetables, reduced-fat dairy, and whole grains and low in red and processed meat, fast food, and soda was associated with smaller gains in BMI and waist circumference. Because foods are not consumed in isolation, dietary pattern research based on natural eating behavior may be useful in understanding dietary causes of obesity and in helping individuals trying to control their weight. C1 Tufts Univ, USDA, Jean Mayer Human Nutr Res Ctr Aging, Boston, MA 02111 USA. NIA, NIH, Baltimore, MD 21224 USA. RP Tucker, KL (reprint author), Tufts Univ, USDA, Jean Mayer Human Nutr Res Ctr Aging, 711 Washington St,9th Floor, Boston, MA 02111 USA. RI Tucker, Katherine/A-4545-2010; OI Tucker, Katherine/0000-0001-7640-662X NR 67 TC 263 Z9 271 U1 7 U2 44 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUN PY 2003 VL 77 IS 6 BP 1417 EP 1425 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 682GY UT WOS:000183084400013 PM 12791618 ER PT J AU Mills, JL Von Kohorn, I Conley, MR Zeller, JA Cox, C Williamson, RE Dufour, DR AF Mills, JL Von Kohorn, I Conley, MR Zeller, JA Cox, C Williamson, RE Dufour, DR TI Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE pernicious anemia; vitamin B-12; cobalamin; folate; folic acid; vitamin B-12 deficiency; masking of pernicious anemia ID COBALAMIN DEFICIENCY; ELDERLY POPULATION; FOLATE; PREVALENCE AB Background: In some patients with vitamin B-12 deficiency mistakenly treated with folio acid, anemia resolved but neurologic complications became worse (masking). Fortification of enriched cereal grains with folio acid has raised concerns that people who consume large quantities of cereal grains, particularly the elderly, may be at increased risk of masking. It is unclear, however, what proportion of people with low vitamin B-12 concentrations do not have anemia and whether the proportion is increasing. Objective: We investigated whether fortification has increased the proportion of patients with low vitamin B-12 but without anemia. Design: We reviewed the laboratory results of every patient for whom a vitamin B-12 concentration was measured at the Veterans Affairs Medical Center in Washington, DC, between 1992 and 2000. Those with a low vitamin B-12 concentration (<258 pmol/L) had their hematocrits and mean cell volumes checked. The proportion without anemia was examined by year before, during, and after folio acid fortification began. Results: There were 1573 subjects with a low vitamin B-12 concentration. The proportion without anemia did not increase significantly from the prefortification period (39.2%) to the period of optional fortification (45.5%) and the postfortification period (37.6%). These findings did not change when the analysis was limited to patients aged >60 y or when a more conservative definition of low vitamin B-12 (<150 pmol/L) was used. Conclusions: Despite evidence that folio acid exposure has increased dramatically since food fortification began, this population showed no evidence of an increase in low vitamin B-12 concentrations without anemia. If confirmed, these results would indicate that food fortification has not caused a major increase in masking of vitamin B-12 deficiency. C1 NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Vet Affairs Med Ctr, Pathol & Lab Med Serv, Washington, DC 20422 USA. Vet Affairs Med Ctr, Informat Resource Management Serv, Washington, DC 20422 USA. RP Mills, JL (reprint author), NICHD, Pediat Epidemiol Sect, Div Epidemiol Stat & Prevent Res, DHHS,NIH, 6100 Bldg,Room 7B03, Bethesda, MD 20892 USA. NR 14 TC 83 Z9 87 U1 0 U2 3 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUN PY 2003 VL 77 IS 6 BP 1474 EP 1477 PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 682GY UT WOS:000183084400021 PM 12791626 ER PT J AU van Wijngaarden, E Stewart, PA Olshan, AF Savitz, DA Bunin, GR AF van Wijngaarden, E Stewart, PA Olshan, AF Savitz, DA Bunin, GR TI Parental occupational exposure to pesticides and childhood brain cancer SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE brain neoplasms; case-control studies; child; occupational exposure; pesticides ID RISK-FACTORS; RETROSPECTIVE ASSESSMENT; PROXY RESPONDENTS; YOUNG-CHILDREN; TUMORS; INTERVIEW AB The authors examined the risk of childhood brain cancer in relation to parental exposure to classes of pesticides among 154 children diagnosed with astrocytoma and 158 children diagnosed with primitive neuroectodermal tumors (PNET) in the United States and Canada between 1986 and 1989. Controls were selected by random digit dialing and were individually matched to cases by race, age, and geographic area. Each job in the fathers' work history and the usual occupation of mothers were assigned a probability, intensity, and frequency of exposure to insecticides, herbicides, and agricultural and nonagricultural fungicides. Elevated risks of astrocytoma were found for paternal exposure (ever vs. never) to all four classes of pesticides (odds ratio (OR) = 1.4-1.6). An increased risk of PNET was observed for only herbicides (OR = 1.5). For mothers, odds ratios for astrocytoma were elevated for insecticides, herbicides, and nonagricultural fungicides (OR = 1.3-1.6) but not agricultural fungicides (OR = 1.0). No indication was found of an increased risk for PNET. There was little indication for an association with cumulative and average parental exposure. Most risk estimates were around unity, and exposure-response patterns were absent. Overall, it seems unlikely that parental exposure to pesticides plays an important role in the etiology of childhood brain cancer. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP van Wijngaarden, E (reprint author), Appl Epidemiol Inc, POB 2424, Amherst, MA 01004 USA. NR 34 TC 32 Z9 33 U1 1 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2003 VL 157 IS 11 BP 989 EP 997 DI 10.1093/aje/kwg082 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 688EP UT WOS:000183420800007 PM 12777362 ER PT J AU Agelli, M Porter, K McQuillan, G Kington, R AF Agelli, M Porter, K McQuillan, G Kington, R TI Consent to participation in medical research: Ethnical and age differences SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 11-14, 2003 CL ATLANTA, GEORGIA SP Soc Epidemiol Res C1 NIH, Bethesda, MD 20892 USA. Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2003 VL 157 IS 11 SU S MA 370 BP S93 EP S93 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 687PJ UT WOS:000183385400364 ER PT J AU Althuis, M Gao, YT Rashid, A Deng, J Wang, BS Shen, MC Sakoda, L Brinton, LA Fraumeni, JF Hsing, AW AF Althuis, M Gao, YT Rashid, A Deng, J Wang, BS Shen, MC Sakoda, L Brinton, LA Fraumeni, JF Hsing, AW TI Hormonal factors and biliary tract cancer risk among women. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 11-14, 2003 CL ATLANTA, GEORGIA SP Soc Epidemiol Res C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2003 VL 157 IS 11 SU S MA 34 BP S9 EP S9 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 687PJ UT WOS:000183385400036 ER PT J AU Cooper, GS Campbell, R Dooley, MA Gilkeson, GS Treadwell, EL AF Cooper, GS Campbell, R Dooley, MA Gilkeson, GS Treadwell, EL TI Prevalence of disability among lupus patients and controls. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 11-14, 2003 CL ATLANTA, GEORGIA SP Soc Epidemiol Res C1 NIEHS, Durham, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2003 VL 157 IS 11 SU S MA 325 BP S82 EP S82 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 687PJ UT WOS:000183385400318 ER PT J AU Harville, E Wilcox, A Lie, R Vindenes, H Aabyholm, E AF Harville, E Wilcox, A Lie, R Vindenes, H Aabyholm, E TI Cleft palate in the Norwegian population, 1967-1998. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 11-14, 2003 CL ATLANTA, GEORGIA SP Soc Epidemiol Res C1 NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2003 VL 157 IS 11 SU S MA 128 BP S32 EP S32 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 687PJ UT WOS:000183385400126 ER PT J AU Harville, E Wilcox, A Lie, R Vindenes, H Aabyholm, F AF Harville, E Wilcox, A Lie, R Vindenes, H Aabyholm, F TI Cleft lip in Norway, 1967-1998. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 11-14, 2003 CL ATLANTA, GEORGIA SP Soc Epidemiol Res C1 NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2003 VL 157 IS 11 SU S MA 27 BP S7 EP S7 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 687PJ UT WOS:000183385400027 ER PT J AU Herrell, R Merikangas, K AF Herrell, R Merikangas, K TI Is the inverse association between migraine and alcohol abuse/dependence attributable to a common diathesis? SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 11-14, 2003 CL ATLANTA, GEORGIA SP Soc Epidemiol Res C1 NIMH, DHHS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2003 VL 157 IS 11 SU S MA 125 BP S32 EP S32 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 687PJ UT WOS:000183385400123 ER PT J AU Mattison, D AF Mattison, D TI Sex matters: "Gender" differences in toxicology. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 11-14, 2003 CL ATLANTA, GEORGIA SP Soc Epidemiol Res C1 NICHD, NIH, Bethesda, MD 20892 USA. RI Mattison, Donald/C-2015-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2003 VL 157 IS 11 SU S MA 277 BP S70 EP S70 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 687PJ UT WOS:000183385400270 ER PT J AU Michaud, DS Willett, WC Rimm, EB Giovannucci, E AF Michaud, DS Willett, WC Rimm, EB Giovannucci, E TI Peptic ulcer disease and the risk of bladder cancer in men. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 11-14, 2003 CL ATLANTA, GEORGIA SP Soc Epidemiol Res C1 NCI, Bethesda, MD 20892 USA. RI Michaud, Dominique/I-5231-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2003 VL 157 IS 11 SU S MA 47 BP S12 EP S12 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 687PJ UT WOS:000183385400047 ER PT J AU Oleksyk, TK Shrestha, S O'Brien, SJ Goldfarb, LG Smith, MW AF Oleksyk, TK Shrestha, S O'Brien, SJ Goldfarb, LG Smith, MW TI Associations of the inflammatory gene polymorpirsms and the Viliuisk Encephalomyelitis syndrome. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 11-14, 2003 CL ATLANTA, GEORGIA SP Soc Epidemiol Res C1 NCI, NIH, Frederick, MD 21701 USA. RI Smith, Michael/B-5341-2012; Taras, Oleksyk/J-8805-2013 OI Taras, Oleksyk/0000-0002-8148-3918 NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2003 VL 157 IS 11 SU S MA 166 BP S42 EP S42 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 687PJ UT WOS:000183385400164 ER PT J AU Parks, C Hudson, L Cooper, G Pandey, J AF Parks, C Hudson, L Cooper, G Pandey, J TI Epstein-Barr virus seroprevalence in systemic lupus erythematosus: Interaction with cytotoxic T lymphocyte antigen-4 genotypes. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 11-14, 2003 CL ATLANTA, GEORGIA SP Soc Epidemiol Res C1 NIEHS, Durham, NC USA. MUSC, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2003 VL 157 IS 11 SU S MA 195 BP S49 EP S49 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 687PJ UT WOS:000183385400189 ER PT J AU Rajaraman, P De Roos, A Stewart, P Linet, M Inskip, P AF Rajaraman, P De Roos, A Stewart, P Linet, M Inskip, P TI Occupational risk factors for meningiomas and acoustic neuromas in the United States. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 11-14, 2003 CL ATLANTA, GEORGIA SP Soc Epidemiol Res C1 NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2003 VL 157 IS 11 SU S MA 320 BP S80 EP S80 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 687PJ UT WOS:000183385400313 ER PT J AU Sakoda, L Gao, YT Rashid, A Deng, J Shen, MC Han, TQ Wang, BS Althuis, M Fraumeni, JF Hsing, AW AF Sakoda, L Gao, YT Rashid, A Deng, J Shen, MC Han, TQ Wang, BS Althuis, M Fraumeni, JF Hsing, AW TI Obesity and risk of biliary tract cancers SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 11-14, 2003 CL ATLANTA, GEORGIA SP Soc Epidemiol Res C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2003 VL 157 IS 11 SU S MA 251 BP S63 EP S63 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 687PJ UT WOS:000183385400243 ER PT J AU Saraiya, M Hall, HI Thompson, T Hartman, A Glanz, K Rimer, B Rose, D AF Saraiya, M Hall, HI Thompson, T Hartman, A Glanz, K Rimer, B Rose, D TI Utilization of examination for skin cancer among US adults from 1992,1998, and 2000 national health interview surveys. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 11-14, 2003 CL ATLANTA, GEORGIA SP Soc Epidemiol Res C1 Ctr Dis Control & Prevent, NCI, Natl Ctr Hlth Stat, Atlanta, GA 30341 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2003 VL 157 IS 11 SU S MA 56 BP S14 EP S14 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 687PJ UT WOS:000183385400057 ER PT J AU Schisterman, EF Liu, A AF Schisterman, EF Liu, A TI Comparison of diagnostic accuracy of biomarkers with pooled assessments SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 11-14, 2003 CL ATLANTA, GEORGIA SP Soc Epidemiol Res C1 NICHD, DESPER, NIH, DHHS, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2003 VL 157 IS 11 SU S MA 237 BP S60 EP S60 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 687PJ UT WOS:000183385400230 ER PT J AU Stancil, TR Li, C Hyman, JJ Drury, TF Reid, BC Reichman, ME AF Stancil, TR Li, C Hyman, JJ Drury, TF Reid, BC Reichman, ME TI Dental insurance and clinical dental exam outcomes in NHANES III. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 11-14, 2003 CL ATLANTA, GEORGIA SP Soc Epidemiol Res C1 NIDCR, NIH, Rockville, MD 20850 USA. NGIT Hlth Solut & Serv, Rockville, MD 20850 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2003 VL 157 IS 11 SU S MA 180 BP S45 EP S45 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 687PJ UT WOS:000183385400175 ER PT J AU Whitcomb, BW Schisterman, EF Buck, GM Weiner, JM Greizerstein, H Kostyniak, PJ AF Whitcomb, BW Schisterman, EF Buck, GM Weiner, JM Greizerstein, H Kostyniak, PJ TI Relative concentrations of organochlorine pesticides and polychlorinated biphenyls in adipose tissue and serum of women of reproductive age. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 11-14, 2003 CL ATLANTA, GEORGIA SP Soc Epidemiol Res C1 NICHD, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2003 VL 157 IS 11 SU S MA 25 BP S7 EP S7 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 687PJ UT WOS:000183385400026 ER PT J AU Williams-Brown, S Singh, GK AF Williams-Brown, S Singh, GK TI Community social organization and cancer incidence and mortality in the United States, 1993-2000. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 11-14, 2003 CL ATLANTA, GEORGIA SP Soc Epidemiol Res C1 NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2003 VL 157 IS 11 SU S MA L5 BP S105 EP S105 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 687PJ UT WOS:000183385400411 ER PT J AU Mahady, GB Pendland, SL Chadwick, LR AF Mahady, GB Pendland, SL Chadwick, LR TI Resveratrol and red wine extracts inhibit the growth of CagA plus strains of Helicobacter pylori in vitro SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Letter ID RISK C1 Univ Illinois, NIH, Coll Pharm,Dept Pharm Practice, Ctr Bot Dietary Supplements Res, Chicago, IL 60612 USA. RP Mahady, GB (reprint author), Univ Illinois, NIH, Coll Pharm,Dept Pharm Practice, Ctr Bot Dietary Supplements Res, MC 877,Room 122,833 S Wood St, Chicago, IL 60612 USA. FU NCCIH NIH HHS [AT00412-02, R21 AT000412-02] NR 6 TC 48 Z9 49 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD JUN PY 2003 VL 98 IS 6 BP 1440 EP 1441 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 691PV UT WOS:000183615400036 PM 12818294 ER PT J AU Fogli, A Rodriguez, D Eymard-Pierre, E Bouhour, F Labauge, P Meaney, BF Zeesman, S Kaneski, CR Schiffmann, R Boespflug-Tanguy, O AF Fogli, A Rodriguez, D Eymard-Pierre, E Bouhour, F Labauge, P Meaney, BF Zeesman, S Kaneski, CR Schiffmann, R Boespflug-Tanguy, O TI Ovarian failure related to eukaryotic initiation factor 2B mutations SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID VANISHING WHITE-MATTER; NERVOUS-SYSTEM HYPOMYELINATION; CHILDHOOD ATAXIA; FACTOR EIF2B; LEUKOENCEPHALOPATHY; LEUKODYSTROPHY; DYSGENESIS; IDENTIFICATION; APOPTOSIS; PHENOTYPE AB Ovarian failure (OF) at age <40 years occurs in &SIM;1% of all women. Other than karyotype abnormalities, very few genes are known to be associated with this ovarian dysfunction. We studied eight patients who presented with premature OF and white-matter abnormalities on magnetic resonance imaging. Neurological signs may be absent or present after OR In seven patients, we report for the first time mutations in three of the five EIF2B genes (EIF2B2, -4, and -5) that were recently shown to cause childhood ataxia with central nervous system hypomyelination/vanishing white-matter disease leukodystrophy. The correlation we observed between the age at onset of the neurological deterioration and the severity of OF suggests a common pathophysiological pathway. C1 Fac Med, INSERM, UMR 384, F-63001 Clermont Ferrand, France. Hop A Trousseau, Serv Neuropediat, INSERM, U546, Paris, France. Hop Pierre Wertheimer, Lyon, France. Ctr Hosp Univ, Dept Neurol, Nimes, France. McMaster Univ, Dept Pediat, Hamilton, ON, Canada. Hamilton Hlth Sci, Hamilton Reg Lab Med Program, Hamilton, ON, Canada. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Boespflug-Tanguy, O (reprint author), Fac Med, INSERM, UMR 384, 28 Pl Henri Dunant,BP 38, F-63001 Clermont Ferrand, France. OI Kaneski, Christine/0000-0003-1453-2502 NR 28 TC 93 Z9 99 U1 0 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUN PY 2003 VL 72 IS 6 BP 1544 EP 1550 DI 10.1086/375404 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 685QV UT WOS:000183275500017 PM 12707859 ER PT J AU Messing, K Punnett, L Bond, M Alexanderson, K Pyle, J Zahm, S Wegman, D Stock, SR de Grosbois, S AF Messing, K Punnett, L Bond, M Alexanderson, K Pyle, J Zahm, S Wegman, D Stock, SR de Grosbois, S TI Be the fairest of them all: Challenges and recommendations for the treatment of gender in occupational health research SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Review DE gender; sex; women; men; research methodology; epidemiology; ergonomics; confounding; effect modification; gender-based analysis ID CORONARY HEART-DISEASE; CARPAL-TUNNEL SYNDROME; SICKNESS ABSENCE; JOB STRAIN; WORKERS-COMPENSATION; INDUSTRY DATA; MUSCULOSKELETAL DISORDERS; FAMILY RESPONSIBILITIES; DEATH CERTIFICATES; WORKING-CONDITIONS AB Background Both women's and men's occupational health problems merit scientific attention. Researchers need to consider the effect of gender on how occupational health issues are experienced, expressed, defined, and addressed. More serious consideration of gender-related factors will help identify risk factors for both women and men. Methods The authors, who come from a number of disciplines (ergonomics, epidemiology, public health, social medicine, community psychology, economics, sociology) pooled their critiques in order to arrive at the most common and significant problems faced by occupational health researchers who wish to consider gender appropriately. Results This paper describes some ways that gender can be and has been handled in studies of occupational health, as well as some of the consequences. The paper also suggests specific research practices that avoid errors. Obstacles to gender-sensitive practices are considered. Conclusions Although gender-sensitive practices may be difficult to operationalize in some cases, they enrich the scientific quality of research and should lead to better data and ultimately to well-targeted prevention programs. (C) 2003 Wiley-Liss, Inc. C1 Univ Quebec, CINBIOSE, Dept Biol Sci, Montreal, PQ H3C 3P8, Canada. Univ Massachusetts, Dept Work Environm, Lowell, MA USA. Univ Massachusetts, Kerr Ergon Inst, Lowell, MA USA. Univ Massachusetts, Dept Psychol, Ctr Women & Work, Lowell, MA USA. Linkoping Univ, Fac Hlth Sci, Dept Hlth & Soc, Div Social Med & Publ Hlth, Linkoping, Sweden. Univ Massachusetts, Dept Reg Econ & Social Dev, Lowell, MA USA. NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. Montreal Dept Publ Hlth, Montreal, PQ, Canada. RP Messing, K (reprint author), Univ Quebec, CINBIOSE, Dept Biol Sci, CP 8888 Succ Ctr Ville, Montreal, PQ H3C 3P8, Canada. RI Alexanderson, Kristina/J-3429-2013; OI Alexanderson, Kristina/0000-0002-9313-3413 NR 156 TC 147 Z9 152 U1 1 U2 22 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD JUN PY 2003 VL 43 IS 6 BP 618 EP 629 DI 10.1002/ajim.10225 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 682GF UT WOS:000183082800007 PM 12768612 ER PT J AU Trespalacios, FC Taylor, AJ Agodoa, LY Bakris, GL Abbott, KC AF Trespalacios, FC Taylor, AJ Agodoa, LY Bakris, GL Abbott, KC TI Heart failure as a cause for hospitalization in chronic dialysis patients SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE blood pressure; angiotensin-converting enzyme (ACE) inhibitors; beta-blockers; aspirin; hemodialysis (HD); peritoneal dialysis (PD); United States Renal Data System (USRDS); heart failure (HF); coronary heart disease (CHD); blood pressure; pulse pressure ID STAGE RENAL-DISEASE; ACUTE CORONARY SYNDROMES; VENTRICULAR SYSTOLIC FUNCTION; ACUTE MYOCARDIAL-INFARCTION; UNITED-STATES; RISK-FACTORS; HEMODIALYSIS-PATIENTS; CARDIOVASCULAR EVENTS; CALCIUM-CHANNEL; PULSE PRESSURE AB Background: Risk factors for heart failure (HF) have not been reported previously in a nationally representative sample of dialysis patients. Methods: We conducted a historic cohort study of 1,995 patients enrolled in the US Renal Data System Dialysis Morbidity and Mortality Study Wave 2 who were Medicare eligible at the study start and were followed up until December 31, 1999, or receipt of a renal transplant. Cox regression analysis was used to model associations with time to first hospitalization for both recurrent and de novo HF (International Classification of Diseases, Ninth Revision code 428.x), defined as patients with and without a history of HF, respectively. Results The incidence density of HF was 71/1,000 person-years. Angiotensin-converting enzyme inhibitors and beta-blockers were each used in less than 25% of patients with a known history of HF. A history of coronary heart disease was associated with an increased total risk for HF, as were hemodialysis (versus peritoneal dialysis), aspirin use, and a history of diabetes. However, hemodialysis and aspirin use were the only factors associated with both de novo and recurrent HE Widened pulse pressure was associated with de novo HF. The mortality rate after HF was 83% at 3 years (adjusted hazard ratio for mortality, 2.10; 95% confidence interval, 1.80 to 2.45; P < 0.0001). Conclusion: In chronic dialysis patients, hemodialysis and aspirin use were associated with increased risk for both total and de novo HF. Hospitalized HF was associated with a significantly increased risk for death. C1 Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. Walter Reed Army Med Ctr, Serv Cardiol, Washington, DC 20307 USA. Madigan Army Med Ctr, Serv Nephrol, Ft Lewis, WA USA. NIDDKD, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. RP Abbott, KC (reprint author), Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. OI Abbott, Kevin/0000-0003-2111-7112 NR 44 TC 83 Z9 85 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUN PY 2003 VL 41 IS 6 BP 1267 EP 1277 DI 10.1016/S0272-6386(03)00359-7 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 685JJ UT WOS:000183259000021 PM 12776280 ER PT J AU Moore, DF Ye, F Schiffmann, R Butman, JA AF Moore, DF Ye, F Schiffmann, R Butman, JA TI Increased signal intensity in the pulvinar on T1-weighted images: A pathognomonic MR imaging sign of Fabry disease SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article AB BACKGROUND AND PURPOSE: Fabry disease is a multisystem X-linked disorder characterized clinically by angiokeratoma, corneal and lenticular abnormalities, acroparesthesia, and renal and cardiac dysfunction and stroke. We sought to describe novel neuroimaging characteristics of Fabry disease. METHODS: Neuroradiologic records of 104 hemizygous patients with Fabry disease evaluated between 1994 and 2002 were reviewed. In total, 94 MR studies consisting of T1- and T2-weighted images were examined for the presence of hyperintensity on the T1-weighted images. Additional CT, gradient-echo (T2*-weighted), and fat-suppression MR studies were reviewed to characterize further the T1 abnormality in selected patients. In some patients, cerebral blood flow (CBF) was quantified by using arterial spin tagging (AST). RESULTS: Overall, 22 patients (similar to23%) demonstrated pulvinar hyperintensity on T1-weighted images; the frequency increased with age to over 30% by age 50 years. Susceptibility-weighted T2* studies demonstrated a low-signal-intensity abnormality in the pulvinar in the more severe cases, whereas CT demonstrated the pulvinar to be mineralized. CT attenuation corresponded with an increasing signal intensity on T1-weighted images. Posterior circulation CBF was found to be elevated on individual AST studies, especially in the thalamus. CONCLUSION: Hyperintensity in the pulvinar on T1-weighted images is a common finding in Fabry disease, likely reflecting the presence of calcification. Although other minreralizing abnormalities may result in calcification of deep gray nuclei, exclusive involvement of the pulvinar may be distinctively characteristic to Fabry disease. Increased CBF in the posterior circulation, particularly the thalamus, suggests that the dystrophic calcification is secondary to cerebral hyperperfusion and selective vulnerability of the pulvinar and adjacent thalamic nuclei. The finding of isolated pulvinar hyperintensity on T1-weighted images should suggest Fabry disease, particularly when seen in conjunction with other nonspecific neuroradiologic manifestations of the disease. C1 NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. NIMH, Funct MRI Facil, Intramural Res Program, NIH, Bethesda, MD 20892 USA. NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. RP Schiffmann, R (reprint author), NINDS, Dev & Metab Neurol Branch, NIH, Bldg 10,Rm 3D03,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Butman, John/A-2694-2008; OI Butman, John/0000-0002-1547-9195 NR 19 TC 86 Z9 94 U1 1 U2 5 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD JUN-JUL PY 2003 VL 24 IS 6 BP 1096 EP 1101 PG 6 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 691TB UT WOS:000183620600012 PM 12812932 ER PT J AU Solomon, D AF Solomon, D CA ALTS Grp TI Results of a randomized trial on the management of cytology interpretations of atypical squamous cells of undetermined significance SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE atypical squamous cells of undetermined significance; human papillomavirus; cervix; clinical management; randomized clinical trial; cytology; colposcopy ID ASCUS-LSIL TRIAGE; HUMAN-PAPILLOMAVIRUS; BETHESDA SYSTEM; PAPANICOLAOU SMEARS; CERVICAL CYTOLOGY; WOMEN; ABNORMALITIES; GUIDELINES; STRATEGIES; NEOPLASIA AB OBJECTIVE: This study was undertaken to compare alternative strategies for the initial management of a cytologic diagnosis of atypical squamous cells of undetermined significance (ASCUS). STUDY DESIGN: A total of 3488 women with a community-based ASCUS interpretation were randomly assigned to immediate colposcopy, triage that was based on enrollment HPV DNA testing and liquid-based cytology at a colposcopy referral threshold of high-grade squamous intraepithelial lesion (HSIL), or conservative management based on repeat cytology at a referral threshold of HSIL. All arms included 2 years of semiannual follow-up and colposcopy at exit. Loop electrosurgical excision procedure was offered to women with histologic diagnoses of cervical intraepithelial neoplasia (CIN) grade 2 or 3 at any visit or persistent CIN grade 1 at exit. The study end point was 2-year cumulative diagnosis of CIN grade 3. RESULTS: The 2-year cumulative diagnosis of CIN grade 3 was 8% to 9% in all study arms. The immediate colposcopy strategy yielded 53.6% sensitivity for cumulative cases of CIN grade 3 diagnosed over 2 years. The human papillomavirus (HPV) triage strategy referred 55.6% of women and detected 72.3% of cumulative cases of CIN grade 3. A conservative management strategy of repeat cytology at the HSIL threshold referred 12.3% of women while detecting 54.6% of cumulative CIN grade 3. To compare triage tests, we re-estimated the performance of HPV and cytology in successfully referring women with underlying CIN grade 3 (ie, ignoring the insensitivity we discovered in colposcopically directed biopsies). A single enrollment HPV test identified 92.4% of the women diagnosed with CIN grade 3. Serial cytology, even at an ASCUS threshold, would have required two visits to achieve similar sensitivity (95.4%) and would have referred 67.1% to colposcopy. CONCLUSION: HPV triage is at least as sensitive as immediate colposcopy for detecting CIN grade 3 and refers about half as many women to colposcopy. Follow-up that used repeat cytology is sensitive at an ASCUS referral threshold but requires two follow-up visits and ultimately more colposcopic examinations than HPV triage. C1 NCI, Breast & Gynecol Canc Res Grp, Div Canc Prevent, NIH,DHHS, Rockville, MD 20852 USA. RP Solomon, D (reprint author), NCI, Breast & Gynecol Canc Res Grp, Div Canc Prevent, NIH,DHHS, Execut Pl N,Room 2123, Rockville, MD 20852 USA. NR 22 TC 383 Z9 394 U1 0 U2 5 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JUN PY 2003 VL 188 IS 6 BP 1383 EP 1392 DI 10.1067/mob.2003.457 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 694QC UT WOS:000183784600002 ER PT J AU Guido, R Schiffman, M Solomon, D Burke, L AF Guido, R Schiffman, M Solomon, D Burke, L CA ALTS Grp TI Postcolposcopy management strategies for women referred with low-grade squamous intraepithelial lesions or human papillomavirus DNA-positive atypical squamous cells of undetermined significance: A two-year prospective study SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE cervical intraepithelial neoplasia grade 1; cervix; clinical management; colposcopy; cytology; human papillomavirus ID RANDOMIZED TRIAL AB OBJECTIVE: This study was undertaken to compare postcolposcopy management strategies for women referred for low-grade squamous intraepithelial lesions (LSIL) or oncogenic human papillomavirus (HPV) DNA-positive atypical squamous cells of undetermined significance (ASCUS), with cervical intraepithelial neoplasia (CIN) grade 1 or less found at initial colposcopy. STUDY DESIGN: A 2-year prospective follow-up of 1539 women was designed to assess the percentage sensitivity of different postcolposcopy management strategies to detect subsequent CIN grade 2 or 3 and percentage referral to repeat colposcopy. RESULTS: HPV testing at 12 months was sensitive (92.2%) for detection of CIN grade 2 or 3 with a referral rate to repeat colposcopy of 55.0%. Repeat semiannual cytology with referral to colposcopy at an ASCUS threshold demonstrated similar sensitivity (88.0%) but with a higher rate of referral to colposcopy (63.6%). Combining cytology and HPV testing did not increase sensitivity and hurt specificity. Baseline viral load and colposcopic impression were not helpful. CONCLUSION: The most efficient test for identifying women with CIN grade 2 or 3 after colposcopy might be an HPV test alone at 12 months. C1 NCI, Breast & Gynecol Canc Res Grp, Div Canc Prevent, NIH,DHHS, Bethesda, MD USA. NIH, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Rockville, MD 20852 USA. Univ Pittsburgh, Magee Womens Hosp, Hlth Care Syst, Pittsburgh, PA 15260 USA. Beth Israel Deaconess Med Ctr Hosp, Boston, MA USA. RP Solomon, D (reprint author), NCI, Breast & Gynecol Canc Res Grp, Div Canc Prevent, NIH,DHHS, Execut Pl N,Room 2130,6130 Execut Blvd, Rockville, MD 20852 USA. FU NCI NIH HHS [CA-55157, CA-55154, CA-55159, CA-55153, CA-55105, CA-55156, CA-55155, CA-55158] NR 10 TC 117 Z9 121 U1 1 U2 6 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JUN PY 2003 VL 188 IS 6 BP 1401 EP 1405 DI 10.1067/mob.2003.456 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 694QC UT WOS:000183784600004 PM 12824969 ER PT J AU Cox, JT Schiffman, M Solomon, D AF Cox, JT Schiffman, M Solomon, D CA ALTS Grp TI Prospective follow-up suggests similar risk of subsequent cervical intraepithelial neoplasia grade 2 or 3 among women with cervical intraepithelial neoplasia grade 1 or negative colposcopy and directed biopsy SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE atypical squamous cells of undetermined significance; low-grade squamous intraepithelial lesions; cervical intraepithelial neoplasia; human papillomavirus; clinical treatment; colposcopy ID ATYPICAL SQUAMOUS-CELLS; ASCUS-LSIL TRIAGE; UNDETERMINED SIGNIFICANCE; RANDOMIZED TRIAL; NATURAL-HISTORY; LESION TRIAGE; PUNCH BIOPSY; MANAGEMENT; DIAGNOSIS; EXCISION AB OBJECTIVE: The purpose of this study was to determine the risk of cumulative cervical intraepithelial neoplasia (CIN) grade 2 or 3 according to initial colposcopy and directed biopsy results among women with low-grade squamous intraepithelial lesions (LSIL) or human papillomavirus (HPV) DNA positive atypical squamous cells of undetermined significance (ASCUS). STUDY DESIGN: A 2-year follow-up of 897 cases of LSIL and 1193 cases of HPV DNA positive ASCUS from the ASCUS/LSIL Triage Study was used to simulate American Society for Colposcopy and Cervical Pathology Consensus Conference recommendations. Women with CIN grade 1 or less were followed up for 2 years by semiannual cytologic examination, with universal exit colposcopy. The clinical end point was a cumulative clinical center histologic diagnosis of CIN grade 2 or 3. RESULTS: The cumulative risk of CIN grade 2 or 3 was equivalent for LSIL (27.6%) and HPV positive ASCUS (26.7%). After excluding the women with a diagnosis of CIN grade 2 or 3 at initial colposcopy and directed biopsy (17.9%), the remaining women were at nearly identical risk for subsequent CIN grade 2 or 3 regardless of initial colposcopy result (completely negative colposcopy-11.3%; negative colposcopically directed biopsy-11.7%; and CIN grade 1 biopsy-13.0%). CONCLUSION: LSIL and HPV positive ASCUS are clinically equivalent. Initial colposcopic detection of obviously prevalent CIN grade 2 or 3 reduces risk. However, for the remaining women who have CIN grade 1 or less on colposcopy and directed biopsy, the risk for subsequent CIN grade 2 or 3 (whether missed, prevalent, or truly incident) is approximately 12% over 2 years. This risk does not vary meaningfully by initial distinction of histologic CIN grade 1 from negative colposcopy and biopsy. C1 NCI, Breast & Gynecol Canc Res Grp, Div Canc Prevent, NIH,DHHS, Rockville, MD 20852 USA. Univ Calif Santa Barbara, Santa Barbara, CA 93106 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Solomon, D (reprint author), NCI, Breast & Gynecol Canc Res Grp, Div Canc Prevent, NIH,DHHS, Execut Plaza N,Room 2123, Rockville, MD 20852 USA. FU NCI NIH HHS [CA-55105, CA-55153, CA-55154, CA-55155, CA-55156, CA-55157, CA-55158, CA-55159] NR 24 TC 190 Z9 202 U1 1 U2 4 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JUN PY 2003 VL 188 IS 6 BP 1406 EP 1412 DI 10.1067/mob.2003461 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 694QC UT WOS:000183784600005 PM 12824970 ER PT J AU Khadeer, MA Tang, ZH Tenenhouse, HS Eiden, MV Murer, H Hernando, N Weinman, EJ Chellaiah, MA Gupta, A AF Khadeer, MA Tang, ZH Tenenhouse, HS Eiden, MV Murer, H Hernando, N Weinman, EJ Chellaiah, MA Gupta, A TI Na+-dependent phosphate transporters in the murine osteoclast: cellular distribution and protein interactions SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE phosphate transport; osteoclasts; Npt2a; NHERF-1; PiT-1 ID APE LEUKEMIA-VIRUS; RETROVIRUS RECEPTOR; COTRANSPORTER; EXPRESSION; GENE; IDENTIFICATION; DOMAINS; FAMILY; GLVR-1; NPT2 AB We previously demonstrated that inhibition of Na-dependent phosphate (P-i) transport in osteoclasts led to reduced ATP levels and diminished bone resorption. These findings suggested that Na/P-i cotransporters in the osteoclast plasma membrane provide P-i for ATP synthesis and that the osteoclast may utilize part of the P-i released from bone resorption for this purpose. The present study was undertaken to define the cellular localization of Na/P-i cotransporters in the mouse osteoclast and to identify the proteins with which they interact. Using glutathione S-transferase (GST) fusion constructs, we demonstrate that the type IIa Na/P-i cotransporter (Npt2a) in osteoclast lysates interacts with the Na/H exchanger regulatory factor, NHERF-1, a PDZ protein that is essential for the regulation of various membrane transporters. In addition, NHERF-1 in osteoclast lysates interacts with Npt2a in spite of deletion of a putative PDZ-binding domain within the carboxy terminus of Npt2a. In contrast, deletion of the carboxy-terminal TRL amino acid motif of Npt2a significantly reduced its interaction with NHERF-1 in kidney lysates. Studies in osteoclasts transfected with green fluorescent protein-Npt2a constructs indicated that Npt2a colocalizes with NHERF-1 and actin at or near the plasma membrane of the osteoclast and associates with ezrin, a linker protein associated with the actin cytoskeleton, likely via NHERF-1. Furthermore, we demonstrate by RT/PCR of osteoclast RNA and in situ hybridization that the type III Na/P-i cotransporter, PiT-1, is also expressed in mouse osteoclasts. To examine the cellular distribution of PiT-1, we infected mouse osteoclasts with a retroviral vector encoding PiT-1 fused to an epitope tag. PiT-1 colocalizes with actin and is present on the basolateral membrane of the polarized osteoclast, similar to that previously reported for Npt2a. Taken together, our data suggest that association of Npt2a with NHERF-1, ezrin, and actin, and of PiT-1 with actin, may be responsible for membrane sorting and regulation of these Na/P-i cotransporters in the osteoclast. C1 Univ Baltimore, Dept Oral & Craniofacial Biol Sci, Baltimore, MD 21201 USA. McGill Univ, Dept Pediat, Montreal Childrens Hosp, Inst Res, Montreal, PQ H3Z 2Z3, Canada. McGill Univ, Dept Human Genet, Montreal Childrens Hosp, Inst Res, Montreal, PQ H3Z 2Z3, Canada. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. Univ Zurich Irchel, Inst Physiol, CH-8057 Zurich, Switzerland. Univ Maryland, Dept Med, Baltimore, MD 21201 USA. RP Gupta, A (reprint author), Univ Baltimore, Dept Oral & Craniofacial Biol Sci, 666 W Baltimore St, Baltimore, MD 21201 USA. FU NIAMS NIH HHS [AR-44706, AR-46292]; NIDDK NIH HHS [DK-55881] NR 31 TC 27 Z9 28 U1 1 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD JUN PY 2003 VL 284 IS 6 BP C1633 EP C1644 DI 10.1152/ajpcell.00580.2002 PG 12 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 675DP UT WOS:000182678000033 PM 12606316 ER PT J AU Egan, JM Meneilly, GS Elahi, D AF Egan, JM Meneilly, GS Elahi, D TI Effects of 1-mo bolus subcutaneous administration of exendin-4 in type 2 diabetes SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE insulinotropic effect; glucose disposal; glucagon; C-peptide; hemoglobin A(1C) ID GLUCAGON-LIKE PEPTIDE-1; DEPENDENT INSULINOTROPIC POLYPEPTIDE; ENERGY-INTAKE; BETA-CELL; PROMOTES SATIETY; ZUCKER RATS; FOOD-INTAKE; 7-36 AMIDE; IN-VITRO; GLUCOSE AB A gut insulinotropic peptide, glucagon-like peptide-1 (GLP-1), when given continuously subcutaneously, has been shown to be an effective agent to treat type 2 diabetes. Because of inactivation by dipeptidyl peptidase IV ( DPP IV), it has a very short half-life (90-120 s), hence the need for continuous administration. Exendin-4 is an agonist of the GLP-1 receptor. It is not a substrate for DPP IV, and we previously demonstrated that intravenous administration has potent insulinotropic properties in type 2 diabetic volunteers. We evaluated the efficacy of bolus subcutaneous exendin-4 in insulin-naive type 2 diabetic volunteers. Ten patients aged 44-72 yr with mean fasting glucose levels of 11.4 +/- 0.9 mmol/l were enrolled, and daily or twice-daily bolus subcutaneous exendin-4 was self-administered for 1 mo. Glycosylated hemoglobin, multiple daily capillary blood glucose, beta-cell sensitivity to glucose, and peripheral tissue sensitivity to insulin were compared before and after treatment. The greatest decline in capillary blood glucose was seen before bed, with a drop from 15.5 to 9.2 mmol/l (P < 0.0001). Glycosylated hemoglobin improved significantly with treatment, from 9.1 to 8.3% (P = 0.009). β-Cell sensitivity to glucose was improved, as assessed by C-peptide levels during a hyperglycemic clamp. No significant adverse effects were noted or reported. Our data suggest that, even with this short duration of therapy, exendin-4 treatment had a significant effect on glucose homeostasis. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Geriatr Res Lab, Boston, MA 02114 USA. Univ British Columbia, Dept Med, Vancouver, BC V6T 2B5, Canada. NIA, Diabet Sect, NIH, Baltimore, MD 21224 USA. RP Elahi, D (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Geriatr Res Lab, GRB SB 0015,55 Fruit St, Boston, MA 02114 USA. FU NCRR NIH HHS [M01-RR-02719] NR 29 TC 60 Z9 63 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD JUN PY 2003 VL 284 IS 6 BP E1072 EP E1079 DI 10.1152/ajpendo.00315.2002 PG 8 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 675NA UT WOS:000182700400003 PM 12475750 ER PT J AU Song, S Oka, T AF Song, S Oka, T TI Regulation of type II deiodinase expression by EGF and glucocorticoid in HC11 mouse mammary epithelium SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE type II iodothyronine deiodinase; HC11 cells; mammary gland; epithelial growth factor; promoter activity ID MESSENGER-RIBONUCLEIC-ACID; RAT BROWN ADIPOCYTES; IODOTHYRONINE DEIODINASE; GROWTH-FACTORS; THYROID-HORMONES; BETA-CASEIN; GLAND; GENE; LACTATION; THYROXINE AB Thyroid hormones are important for mammary gland growth and development. The iodothyronine deiodinases play a key role in thyroid hormone metabolism. We have showed that type II 5'-deiodinase (5'D2) activity and mRNA are present in the mouse mammary gland and that their levels are reduced in the lactating gland. To investigate the regulatory mechanism of mouse 5'D2 gene (mdio2) expression in mammary epithelium, we employed the HC11 cell line, which is derived from mouse mammary epithelial cells and retains the ability to express differentiated function. HC11 cells were treated with combinations of insulin, glucocorticoid (GC, dexamethasone), prolactin, and epidermal growth factor (EGF), and 5'D2 activity and the D2-to-GAPDH mRNA ratio were measured by I-125(-) release from I-125- labeled thyroxine and semiquantitative RT-PCR, respectively. EGF increased both 5'D2 activity and mRNA levels about twofold. GC reduced both 5'D2 activity and mRNA in a dose-dependent manner, and their levels were decreased to approximately one-tenth and one-fifth, respectively, of control levels. These data demonstrated that mdio2 expression in HC11 cells is upregulated by EGF mainly at the pretranslational level and downregulated by GC at both pre- and posttranslational levels. Furthermore, we showed that GC reduced the promoter activity of the 627-bp 5'-upstream region of the mdio2/luciferase chimeric reporter gene, suggesting that GC exerts its effect, at least in part, at the transcriptional level. C1 NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RP Oka, T (reprint author), NIDDKD, Lab Genet & Physiol, NIH, Bldg 8,Rm 118,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 37 TC 11 Z9 12 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD JUN PY 2003 VL 284 IS 6 BP E1119 EP E1124 DI 10.1152/ajpendo.00571.2002 PG 6 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 675NA UT WOS:000182700400009 PM 12582014 ER PT J AU Stefan, N Stumvoll, M Bogardus, C Tataranni, PA AF Stefan, N Stumvoll, M Bogardus, C Tataranni, PA TI Elevated plasma nonesterified fatty acids are associated with deterioration of acute insulin response in IGT but not NGT SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE beta-cell; insulin secretion; insulin sensitivity; diabetes; oral and intravenous glucose tolerance tests; normal glucose tolerance; impaired glucose tolerance ID DEPENDENT DIABETES-MELLITUS; X-RAY ABSORPTIOMETRY; SECRETORY DYSFUNCTION; PIMA-INDIANS; PATHOGENESIS; RESISTANCE; LIPOTOXICITY; INFUSION; HUMANS; NIDDM AB High concentrations of nonesterified fatty acids ( NEFA) are a risk factor for developing type 2 diabetes in Pima Indians. In vitro and in vivo, chronic elevation of NEFA decreases glucose-stimulated insulin secretion. We hypothesized that high fasting plasma NEFA would increase the risk of type 2 diabetes by inducing a worsening of glucose-stimulated insulin secretion in Pima Indians. To test this hypothesis, fasting plasma NEFA concentrations, body composition, insulin action (M), acute insulin response ( AIR, 25-g IVGTT), and glucose tolerance (75-g OGTT) were measured in 151 Pima Indians [ 107 normal glucose tolerant (NGT), 44 impaired glucose tolerant (IGT)] at the initial visit. These subjects, participants in ongoing studies of the pathogenesis of obesity and type 2 diabetes, had follow-up measurements of body composition, glucose tolerance, M, and AIR. In NGT individuals, cross-sectionally, high fasting plasma NEFA concentrations at the initial visit were negatively associated with AIR after adjustment for age, sex, percent body fat, and M (P = 0.03). Longitudinally, high fasting plasma NEFA concentrations at the initial visit were not associated with change in AIR. In individuals with IGT, cross-sectionally, high fasting plasma NEFA concentrations at the initial visit were not associated with AIR. Longitudinally, high fasting plasma NEFA concentrations at the initial visit were associated with a decrease in AIR before (P < 0.0001) and after adjustment for sex, age at follow-up, time of follow-up, change in percent body fat and insulin sensitivity, and AIR at the initial visit (P = 0.0006). In conclusion, findings in people with NGT indicate that fasting plasma NEFA concentrations are not a primary etiologic factor for β-cell failure. However, in subjects who have progressed to a state of IGT, chronically elevated NEFA seem to have a deleterious effect on insulin-secretory capacity. C1 NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. RP Stefan, N (reprint author), NIDDKD, Clin Diabet & Nutr Sect, NIH, 4212 N 16th St Rm 5-41, Phoenix, AZ 85016 USA. OI Stefan, Norbert/0000-0002-2186-9595 NR 32 TC 21 Z9 26 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD JUN PY 2003 VL 284 IS 6 BP E1156 EP E1161 DI 10.1152/ajpendo.00427.2002 PG 6 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 675NA UT WOS:000182700400014 PM 12582008 ER PT J AU Ernst, M Kimes, AS London, ED Matochik, JA Eldreth, D Tata, S Contoreggi, C Leff, M Bolla, K AF Ernst, M Kimes, AS London, ED Matochik, JA Eldreth, D Tata, S Contoreggi, C Leff, M Bolla, K TI Neural substrates of decision making in adults with attention deficit hyperactivity disorder SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT 40th Annual Meeting of the American-College-of-Neuropsychopharmacology CY DEC 09-14, 2001 CL WAIKALOLA, HAWAII SP Amer Coll Neuropsychopharmacol ID ANTERIOR CINGULATE CORTEX; PREFRONTAL CORTEX; DEFICIT/HYPERACTIVITY DISORDER; RESPONSE COST; NORMAL-CHILDREN; REWARD; ADHD; SCALE; PET; REINFORCEMENT AB Objective: The characteristics of attention deficit hyperactivity disorder (ADHD) include abnormalities in reward responsivity that may interfere with decision making. The study examined reward responsivity in ADHD by comparing the neural correlates of decision making in adults with childhood-onset ADHD and in healthy adults. Method: The neural correlates of performance on a decision-making task and a control task were compared in 10 adults with ADHD and 12 age-matched healthy volunteers by using [O-15]H2O positron emission tomography. The decision-making task tested the ability to weigh short-term rewards against long-term losses. The control task matched all components of the decision-making task except for the decision-making process and related contingency. Results: The ventral and dorsolateral prefrontal cortex and the insula were activated during performance of the decision-making task in both the ADHD and healthy groups; however, activation in the ADHD group was less extended and did not involve other regions, such as anterior cingulate and hippocampus, that subserve emotion/memory processes. Direct comparison of data from the ADHD subjects and the healthy volunteers suggested that the healthy subjects engaged the hippocampal and insular regions more than did the ADHD subjects and that the ADHD subjects recruited the caudal part of the right anterior cingulate more than did the healthy subjects. Conclusions: The findings suggest that the neural circuits engaged during decision making differ in subjects with ADHD and healthy comparison subjects. This difference may explain observed deficits in motivated behaviors in ADHD. A better understanding of the nature of these deficits could ultimately be applied to refine treatment strategies for ADHD. C1 NIMH, MAP, Intramural Res Program, Bethesda, MD 20892 USA. NIDA, Intramural Res Program, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD USA. Univ Calif Los Angeles, Inst Neuropsychiat, Los Angeles, CA USA. RP Ernst, M (reprint author), NIMH, MAP, Intramural Res Program, 15K N Dr,Room 118,MSC 2670, Bethesda, MD 20892 USA. FU NCRR NIH HHS [RR-02719]; NIDA NIH HHS [DA-11426] NR 45 TC 153 Z9 158 U1 1 U2 16 PU AMER PSYCHIATRIC PRESS, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUN PY 2003 VL 160 IS 6 BP 1061 EP 1070 DI 10.1176/appi.ajp.160.6.1061 PG 10 WC Psychiatry SC Psychiatry GA 685BK UT WOS:000183240800008 PM 12777263 ER PT J AU McClure, EB Pope, K Hoberman, AJ Pine, DS Leibenluft, E AF McClure, EB Pope, K Hoberman, AJ Pine, DS Leibenluft, E TI Facial expression recognition in adolescents with mood and anxiety disorders SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID CHILDREN; SCHIZOPHRENIA; COMMUNICATION AB Objective: The authors examined facial expression recognition in adolescents with mood and anxiety disorders. Method: Standard facial emotion identification tests were given to youth with bipolar disorder (N = 11) or DSM-IV anxiety disorders (N = 10) and a group of healthy comparison subjects (N = 25). Method: Standard facial emotion identification tests were given to youth with bipolar disorder (N = 11) or DSM-IV anxiety disorders (N = 10) and a group of healthy comparison subjects (N = 25). Results: Relative to the anxiety disorder and healthy comparison groups, the subjects with bipolar disorder made more emotion recognition errors when presented with faces of children. Unlike the anxious and comparison subjects, bipolar disorder youth were prone to misidentify faces as angry. No differences in emotion recognition errors were seen when the adolescents were presented with adult faces. Conclusions: A bias to misinterpret the facial expressions of peers as angry may characterize youth with bipolar disorder but not youth with anxiety disorders. This bias may relate to social impairment in youth with bipolar disorder. C1 NIMH, MAP, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP McClure, EB (reprint author), NIMH, MAP, Dept Hlth & Human Serv, NIH, 15K N Dr,MSC 2670, Bethesda, MD 20892 USA. NR 14 TC 109 Z9 111 U1 1 U2 9 PU AMER PSYCHIATRIC PRESS, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUN PY 2003 VL 160 IS 6 BP 1172 EP 1174 DI 10.1176/appi.ajp.160.6.1172 PG 3 WC Psychiatry SC Psychiatry GA 685BK UT WOS:000183240800023 PM 12777278 ER PT J AU Morens, DM AF Morens, DM TI Characterizing a "New" disease: Epizootic and epidemic anthrax, 1769-1780 SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article AB In 1876, Robert Koch established anthrax as the first disease linked to a microbial agent. But Koch's efforts had followed more than 150 years of scientific progress in characterizing anthrax as a specific human and veterinary disease. Focusing on France and the period between 1769 and 1780, this brief review examines noteworthy early events in the characterization of anthrax. It suggests that some "new" diseases like anthrax might be "discovered" not only by luck, brilliance, or new technologies, but by clinical/epidemiological "puzzle-fitting," which can assemble a cohesive picture of a seemingly specific disease entity. If such processes have operated over 2 or more centuries, studying them may yield clues about desirable interactions between epidemiology/public health and experimental science in the characterization of new diseases. C1 NIAID, NIH, Bethesda, MD 20892 USA. Univ Hawaii, Sch Med, Honolulu, HI 96822 USA. RP Morens, DM (reprint author), NIAID, NIH, 6610 Rockledge Dr,Room 4097, Bethesda, MD 20892 USA. NR 44 TC 11 Z9 11 U1 0 U2 3 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUN PY 2003 VL 93 IS 6 BP 886 EP 893 DI 10.2105/AJPH.93.6.886 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 685ZJ UT WOS:000183294800013 PM 12773345 ER PT J AU Brown, TM Fee, E AF Brown, TM Fee, E TI Alfred C. Kinsey: A pioneer of sex research SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Biographical-Item C1 Univ Rochester, Dept Hist, Rochester, NY 14627 USA. Univ Rochester, Dept Community & Prevent Med, Rochester, NY 14627 USA. Natl Lib Med, Hist Med Div, NIH, Bethesda, MD USA. RP Brown, TM (reprint author), Univ Rochester, Dept Hist, 601 Elmwood Ave, Rochester, NY 14627 USA. NR 4 TC 2 Z9 2 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUN PY 2003 VL 93 IS 6 BP 896 EP 897 DI 10.2105/AJPH.93.6.896 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 685ZJ UT WOS:000183294800015 PM 12773347 ER PT J AU Fee, E Brown, TM Laylor, J AF Fee, E Brown, TM Laylor, J TI One size does not fit all in the transgender community SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 Natl Lib Med, Off director, NIH, Bethesda, MD USA. Univ Rochester, Dept Hist, Rochester, NY USA. Univ Rochester, Dept Community & Prevent Med, Rochester, NY USA. RP Fee, E (reprint author), Bldg 38,Room 1E21,8600 Rockville Pike, Bethesda, MD 20894 USA. NR 5 TC 6 Z9 6 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUN PY 2003 VL 93 IS 6 BP 899 EP 900 DI 10.2105/AJPH.93.6.899 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 685ZJ UT WOS:000183294800016 PM 12773348 ER PT J AU Chesney, MA Koblin, BA Barresi, PJ Husnik, MJ Celum, CL Colfax, G Mayer, K McKirnan, D Judson, FN Huang, YJ Coates, TJ AF Chesney, MA Koblin, BA Barresi, PJ Husnik, MJ Celum, CL Colfax, G Mayer, K McKirnan, D Judson, FN Huang, YJ Coates, TJ CA EXPLORE Study Team TI An individually tailored intervention for HIV prevention: Baseline data from the EXPLORE study SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID SEXUAL RISK BEHAVIOR; GAY MEN; BISEXUAL MEN; YOUNG MEN; NEGOTIATED SAFETY; HOMOSEXUAL MEN; DETERMINANTS; INFORMATION; MOTIVATION; PREVALENCE AB Objectives. We describe the intervention tested in EXPLORE, an HIV prevention trial aimed at men who have sex with men (MSM), and test the empirical basis of the individually tailored intervention. Methods. Data on participants! self-efficacy, communication skills, social norms, and enjoyment of unprotected anal intercourse were examined in relation to sexual risk. Combinations of these factors, together with alcohol use and noninjection drug use, were also examined. Results. The individual factors examined were associated with sexual risk behavior. The cohort was shown to be heterogeneous in regard to the presence of combinations of these risk-related factors. Conclusions. Baseline data from the EXPLORE study support the efficacy of the individually tailored intervention used. C1 NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. Univ Calif San Francisco, Sch Med, San Francisco, CA USA. New York Blood Ctr, New York, NY 10021 USA. Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98104 USA. Univ Washington, Sch Med, Seattle, WA USA. San Francisco Dept Publ Hlth, San Francisco, CA USA. Fenway Community Hlth Ctr, Boston, MA USA. Howard Brown Hlth Ctr, Chicago, IL USA. Denver Publ Hlth, Denver, CO USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. RP Chesney, MA (reprint author), NIH, Natl Ctr Complementary & Alternat Med, 31 Ctr Dr,2B11, Bethesda, MD 20892 USA. FU NIAID NIH HHS [U01 AI48016, 5 U01 AI46749-03, U01 AI046749, U01 AI047981, U01 AI047995, U01 AI048016, U01 AI048040, U01 AI47981-04, U01 AI47995, U01 AI48040] NR 43 TC 94 Z9 97 U1 4 U2 6 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUN PY 2003 VL 93 IS 6 BP 933 EP 938 DI 10.2105/AJPH.93.6.933 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 685ZJ UT WOS:000183294800026 PM 12773358 ER PT J AU Carey, MA Germolec, DR Bradbury, JA Gooch, RA Moorman, MP Flake, GP Langenbach, R Zeldin, DC AF Carey, MA Germolec, DR Bradbury, JA Gooch, RA Moorman, MP Flake, GP Langenbach, R Zeldin, DC TI Accentuated T helper type 2 airway response after allergen challenge in cyclooxygenase-1(-/-) but not cyclooxygenase-2(-/-) mice SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE cyclooxygenase; Th2 cytokine; ovalbumin ID ACTIVATION-REGULATED CHEMOKINE; BRONCHIAL EPITHELIAL-CELLS; SYNTHASE-DEFICIENT MICE; ADHESION MOLECULE-1; E-SELECTIN; IN-VITRO; EXPRESSION; INFLAMMATION; LUNG; EOTAXIN AB Acute pharmacologic inhibition of cyclooxygenase (COX)-1 or -2 during allergen sensitization and exposure leads to enhanced T helper type 2 (Th2) airway responses. COX-1 and -2 play functionally distinct roles in lymphocyte development, and consequently, genetic deficiency of either enzyme, as opposed to acute pharmacologic inhibition, may modulate Th2-mediated allergic airway disease differently. An ovalbumin-induced mouse model of allergic airway disease was used. The immunophenotype of bronchoalveolar lavage lymphocytes was assessed by flow cytometry, bronchoalveolar lavage cytokines, and chemokines were measured by enzyme-linked immunosorbent assay, adhesion molecule expression was assessed by immunoblotting in combination with immunohistochemistry, and bronchoconstriction was assessed by whole body plethysmography. The airways of COX-1(-/-) mice contained increased numbers of CD4(+) and CD8(+) T cells, exaggerated levels of the Th2 cytokines interleukin-4, -5, and -13, and increased levels of eotaxin and thymus- and activation-regulated chemokine. Allergen-induced bronchoconstriction was also increased in COX-1(-/-) mice. Vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 levels were increased in lungs of both COX-1(-/-) and COX-2(-/-) mice relative to wild type. These data suggest that genetic deficiency of COX-1 but not COX-2 modulates T cell recruitment, Th2 cytokine secretion, and lung function in the allergic airway. C1 NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Zeldin, DC (reprint author), NIEHS, Div Intramural Res, NIH, 111 TW Alexander Dr,Bldg 101, Res Triangle Pk, NC 27709 USA. NR 46 TC 41 Z9 41 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUN 1 PY 2003 VL 167 IS 11 BP 1509 EP 1515 DI 10.1164/rccm.200211-1383OC PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 682EL UT WOS:000183078300012 PM 12626351 ER PT J AU Wyatt, SB Williams, DR Calvin, R Henderson, FC Walker, ER Winters, K AF Wyatt, SB Williams, DR Calvin, R Henderson, FC Walker, ER Winters, K TI Racism and cardiovascular disease in African Americans SO AMERICAN JOURNAL OF THE MEDICAL SCIENCES LA English DT Review DE race; racism; stress; discrimination; cardiovascular disease; hypertension; behavioral risk factors; ethnicity; Jackson Heart Study ID CORONARY HEART-DISEASE; BLOOD-PRESSURE; RISK-FACTORS; HEALTH-CARE; SOCIOECONOMIC-STATUS; MENTAL-HEALTH; UNITED-STATES; CHLAMYDIA-PNEUMONIAE; PSYCHOLOGICAL STRESS; ETHNIC-DIFFERENCES AB This article provides an overview of the evidence on the ways racism can affect the disproportionate rates of cardiovascular disease (CVD) in African Americans. it describes the significant health disparities in CVD for blacks and whites and suggests that racial disparities should be understood within the context of persistent inequities in societal institutions and relations. Evidence and potential pathways for exploring effects of 3 levels of racism on cardiovascular health risk factors and outcomes are reviewed. First, institutional racism can lead to limited opportunities for socioeconomic mobility, differential access to goods and resources, and poor living conditions that can adversely affect cardiovascular health. Second perceived/personally mediated racism acts as a stressor and can induce psychophysiological reactions that negatively affect cardiovascular health. Third, in race-conscious societies, such as the United States, the negative self-evaluations of accepting negative cultural stereotypes as true (internalized racism) can have deleterious effects on cardiovascular health. Few population-based studies have examined the relationship between racism and CVD. The findings, though suggestive of a positive association, are neither consistent nor clear. The research agenda of the Jackson Heart Study in addressing the role of racism in CVD is presented. C1 Univ Mississippi, Med Ctr, Sch Nursing, Jackson, MS 39216 USA. Univ Mississippi, Med Ctr, Sch Med, Jackson, MS 39216 USA. Univ Michigan, Dept Sociol, Ann Arbor, MI 48109 USA. Univ Michigan, Inst Social Res, Survey Res Ctr, Ann Arbor, MI 48109 USA. Alcorn State Univ, Sch Nursing, Natchez, MS USA. NHLBI, Jackson Heart Study, Jackson, MS USA. RP Wyatt, SB (reprint author), Univ Mississippi, Med Ctr, Sch Nursing, 2500 N State St, Jackson, MS 39216 USA. FU NHLBI NIH HHS [N01-HC9571] NR 157 TC 98 Z9 99 U1 3 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-9629 J9 AM J MED SCI JI Am. J. Med. Sci. PD JUN PY 2003 VL 325 IS 6 BP 315 EP 331 DI 10.1097/00000441-200306000-00003 PG 17 WC Medicine, General & Internal SC General & Internal Medicine GA 689RJ UT WOS:000183506500003 PM 12811228 ER PT J AU Kirk, AD AF Kirk, AD TI Less is more: Maintenance minimization as a step toward tolerance SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Editorial Material ID TRANSPLANTATION TOLERANCE; MONOTHERAPY C1 NIDDKD, Transplantat Sect, Transplantat & Autoimmun Branch, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Kirk, AD (reprint author), NIDDKD, Transplantat Sect, Transplantat & Autoimmun Branch, NIH,US Dept HHS, Bethesda, MD 20892 USA. RI Kirk, Allan/B-6905-2012 NR 12 TC 7 Z9 7 U1 0 U2 0 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JUN PY 2003 VL 3 IS 6 BP 643 EP 645 DI 10.1034/j.1600-6143.2003.00138.x PG 3 WC Surgery; Transplantation SC Surgery; Transplantation GA 693NN UT WOS:000183723800003 PM 12780554 ER PT J AU Orvisky, E Stubblefield, B Long, RT Martin, BM Sidransky, E Krasnewich, D AF Orvisky, E Stubblefield, B Long, RT Martin, BM Sidransky, E Krasnewich, D TI Phosphomannomutase activity in congenital disorders of glycosylation type Ia determined by direct analysis of the interconversion of mannose-1-phosphate to mannose-6-phosphate by high-pH anion-exchange chromatography with pulsed amperometric detection SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE phosphomannomutase activity; congenital disorders of glycosylation; HPAEC-PAD mannose-1-phosphate ID DEFICIENT GLYCOPROTEIN SYNDROME; COAGULATION ABNORMALITIES; CDG-IA; BIOSYNTHESIS; TRANSFERRIN; SERUM; PMM2; ACID AB Congenital disorders of glycosylation (CDG) are a group of multisystemic disorders resulting from defects in the synthesis and processing of N-linked oligosaccharides. The most common form, CDG type Ia (CDG-Ia), results from a deficiency of the enzyme phosphomannomutase (PMM). PMM converts mannose 6-phosphate (man-6-P) to mannose-1-phosphate (man-1-P), which is required for the synthesis of GDP-mannose, a substrate for dolichol-linked oligosaccharide synthesis. The traditional assay for PMM, a coupled enzyme system based on the reduction of NADP(+) to NADPH using man-1-P as a substrate, has limitations in accuracy and reproducibility. Therefore, a moresensitive, direct test for PMM activity, based on the detection of the conversion of man-1-P to man-6-P by high-pH anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD), was developed. Using this assay, the activity of PMM was markedly deficient in fibroblasts and lymphoblasts from 23 patients with CDG-Ia (range 0-15.3% of control, average 4.9 +/- 4.7%) and also decreased in seven obligate heterozygotes (range 33.0-72.0% of control, average 52.2 +/- 14.7%). Unlike the spectrophotometric method, there was no overlap in PMM activity among patients, obligate heterozygotes, or controls. Thus, the PMM assay based on HPAEC-PAD has increased utility in the clinical setting, and can be used, together with transferrin isoelectric focusing, to diagnose patients with CDG-Ia and to identify heterozygotes when clinically indicated. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NIMH, Clin Neurosci Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Sidransky, E (reprint author), Sect Mol Neurogenet, 49 Convent Dr,MSC 4405,49-B1EE16, Bethesda, MD 20892 USA. NR 28 TC 7 Z9 8 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD JUN 1 PY 2003 VL 317 IS 1 BP 12 EP 18 DI 10.1016/S0003-2697(03)00109-X PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 679WE UT WOS:000182944300002 PM 12729595 ER PT J AU Gelderblom, H Baker, SD Zhao, M Verweij, J Sparreboom, A AF Gelderblom, H Baker, SD Zhao, M Verweij, J Sparreboom, A TI Distribution of paclitaxel in plasma and cerebrospinal fluid SO ANTI-CANCER DRUGS LA English DT Article; Proceedings Paper CT 43rd Annual Meeting of the American-Association-for-Cancer-Research CY APR 06-10, 2002 CL SAN FRANCISCO, CALIFORNIA SP Amer Assoc Canc Res DE cerebrospinal fluid; Cremophor EL; mass spectrometry; paclitaxel; pharmacokinetics ID LIQUID-CHROMATOGRAPHY; UNBOUND PACLITAXEL; CREMOPHOR EL; VEHICLE AB Our objective was to assess the distribution of paclitaxel in plasma and cerebrospinal fluid (CSF) in a cancer patient, and evaluate the role of the formulation vehicle Cremophor EL (CrEL) in drug distribution. Analysis of paclitaxel concentrations in CSF was performed using a triple-quadrupole mass spectrometric assay with electrospray ionization. Total and unbound paclitaxel levels in plasma were measured by liquid chromatography and equilibrium dialysis, respectively, and CrEL concentrations were determined by a colorimetric dye-binding microassay. Clinical samples were obtained from a 54-year-old female with breast cancer receiving a weekly regimen of paclitaxel (dose 60 mg/m(2)). The disposition of total paclitaxel in plasma was characterized by a bi-exponential elimination (terminal half-life 9.17 h) and a total clearance of 19.4l/h/m(2). The fraction of unbound paclitaxel in plasma ranged from 7.6 to 12.4% (unbound drug CL 176 l/h/m(2)). The plasma clearance of CrEL was 0.332 l/h/m(2), whereas CrEL levels were undetectable in CSF (below 0.5 mul/ml). Concentrations of paclitaxel in CSF (range 45.5-162 pg/ml) and unbound CSF:unbound plasma concentration ratios (range 0.093-9.53%) progressively increased up to 24 h, with a mean unbound drug fraction in CSF of 84 +/- 3.6% (range 81-88%). These findings indicate that there is substantial distribution of paclitaxel to CSF. Since the fraction of unbound paclitaxel is different between plasma and CSF, measurement of unbound paclitaxel is required to accurately assess the extent of drug penetration. (C) 2003 Lippincott Williams Wilkins. C1 Dr Daniel Den Hoed Canc Ctr, Dept Med Oncol, Rotterdam, Netherlands. Johns Hopkins Univ Hosp, Div Expt Therapeut, Sidney Kimmel Comp Canc Ctr, Baltimore, MD USA. RP Sparreboom, A (reprint author), NCI, Med Oncol Clin Res Unit, 9000 Rockville Pike,Bldg 10, Room 5A01, Bethesda, MD 20892 USA. RI Sparreboom, Alex/B-3247-2008 NR 16 TC 6 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4973 J9 ANTI-CANCER DRUG JI Anti-Cancer Drugs PD JUN PY 2003 VL 14 IS 5 BP 365 EP 368 DI 10.1097/01.cad.0000070483.94284.87 PG 4 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 688YN UT WOS:000183465000007 PM 12782943 ER PT J AU Narita, M Murata, T Shimizu, K Sugiyama, T Nakagawa, T Manganiello, VC Tagawa, T AF Narita, M Murata, T Shimizu, K Sugiyama, T Nakagawa, T Manganiello, VC Tagawa, T TI Phosphodiesterase 4 in osteoblastic osteosarcoma cells as a potential target for growth inhibition SO ANTI-CANCER DRUGS LA English DT Article DE osteoblastic osteosarcoma; phosphodiesterase ID CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES; DIFFERENTIATION; PROLIFERATION; LINE; MICE AB Reverse transcription-polymerise chain reaction (RT-PCR) analysis revealed that HOSM-1 cells, an osteosarcoma cell line established from human mandible, expressed mRNA for osteoblastic markers, such as alkaline phosphatase, osteonectin, osteocalcin and parathyroid hormone receptor, thus exhibiting an osteoblastic phenotype. We have investigated a possible role of cyclic nucleotide phosphodiesterases (PDEs) in osteosarcoma cells. RT-PCR analysis revealed that HOSM-1 cells expressed mRNA for PDE4A, 413 and 4C. In addition, rolipram, a specific inhibitor of PDE4, inhibited HOSM-1 cell proliferation. The finding that PDE4 is involved in proliferation of osteosarcoma cells suggests the possibility that PDE4 may be a new target for antitumor therapy. (C) 2003 Lippincott Williams Wilkins. C1 Mie Univ, Fac Med, Dept Oral & Maxillofacial Surg, Tsu, Mie 5148507, Japan. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD USA. RP Narita, M (reprint author), Mie Univ, Fac Med, Dept Oral & Maxillofacial Surg, 2-174 Edobashi, Tsu, Mie 5148507, Japan. NR 26 TC 9 Z9 9 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4973 J9 ANTI-CANCER DRUG JI Anti-Cancer Drugs PD JUN PY 2003 VL 14 IS 5 BP 377 EP 381 DI 10.1097/01.cad.0000070484.94284.49 PG 5 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 688YN UT WOS:000183465000009 PM 12782945 ER PT J AU DiCenzo, R Forrest, A Squires, KE Hammer, SM Fischl, MA Wu, HL Cha, R Morse, GD AF DiCenzo, R Forrest, A Squires, KE Hammer, SM Fischl, MA Wu, HL Cha, R Morse, GD CA Adult AIDS Clin Trials Grp Protoco TI Indinavir, efavirenz, and abacavir pharmacokinetics in human immunodeficiency virus-infected subjects SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID REVERSE-TRANSCRIPTASE INHIBITOR; SINGLE-DOSE PHARMACOKINETICS; HIV-1-INFECTED PATIENTS; PLASMA-LEVELS; DOUBLE-BLIND; COMBINATION; THERAPY; 1592U89; ADULTS; ZIDOVUDINE AB Adult AIDS Clinical Trials Group (AACTG) Protocol 886 examined the dispositions of indinavir, efavirenz, and abacavir in human immunodeficiency virus-infected subjects who received indinavir at 1,000 mg every 8 h (q8h) and efavirenz at 600 mg q24h or indinavir at 1,200 mg and efavirenz at 300 mg q12h with or without abacavir 300 at mg q12h. Thirty-six subjects participated. The median minimum concentration in plasma (C-min) for indinavir administered at 1,200 mg q12h was 88.1 nM (interquartile range [IR], 61.7 to 116.5 nM), whereas the median C-min for indinavir administered at 1,000 mg q8h was 139.3 nM (IR, 68.8 to 308.7 nM) (P = 0.19). Compared to the minimum C-min range for wild-type virus (80 to 120 ng/ml) estimated by the AACTG Adult Pharmacology Committee, the C-min for indinavir administered at 1,200 mg q12h (54 ng/ml) is inadequate. The apparent oral clearance (CL/F) (P = 0.28), apparent volume of distribution at steady state (V-ss/F) (P = 0.25), and half-life (t(1/2)) (P = 0.80) of indinavir did not differ between regimens. The levels of efavirenz exposure were similar between regimens. For efavirenz administered at 600 mg q24h and 300 mg q12h, the median maximum concentrations in plasma (C(max)s) were 8,968 nM (111, 5,784 to 11,768 nM) and 8,317 nM (6,587 to 10,239 nM), respectively (P = 0.66), and the C(min)s were 4,289 nM (IR, 2,462 to 5,904 nM) and 4,757 nM (IR, 3,088 to 6,644 nM), respectively (P = 0.29). Efavirenz pharmacokinetic parameters such as CL/F (P = 0.62), V-ss/F (P = 0.33), and t(1/2) (P = 0.37) were similar regardless of the dosing regimen. The median C-max, C-min, CL/F, V-ss/F, and t(1/2) for abacavir were 6,852 nM (IR, 5,702 to 7,532), 21.0 nM (IR, 21.0 to 87.5), 43.7 liters/h (IR, 37.9 to 55.2), 153.9 liters (IR, 79.6 to 164.4), and 2.0 h (IR, 1.8 to 2.8), respectively. In summary, when indinavir was given with efavirenz, the trough concentration of indinavir after administration of 1,200 mg q12h was inadequate. Abacavir did not influence the pharmacokinetics or exposure parameters of either indinavir or efavirenz. The levels of efavirenz exposure were similar in subjects receiving efavirenz q12h or q24h. C1 SUNY Buffalo, Sch Pharm & Pharmaceut Sci, AACTG Pharmacol Support Lab, Buffalo, NY 14260 USA. Univ So Calif, Los Angeles, CA USA. Columbia Univ, New York, NY USA. Univ Miami, Miami, FL 33152 USA. Harvard Univ, Boston, MA 02115 USA. NIAID, Bethesda, MD 20892 USA. RP Morse, GD (reprint author), SUNY Buffalo, Sch Pharm & Pharmaceut Sci, AACTG Pharmacol Support Lab, 317 Hochstetter Hall, Buffalo, NY 14260 USA. FU NCI NIH HHS [200PC006] NR 26 TC 16 Z9 18 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JUN PY 2003 VL 47 IS 6 BP 1929 EP 1935 DI 10.1128/AAC.47.6.1929-1935.2003 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 684BD UT WOS:000183184800022 PM 12760869 ER PT J AU Thomas, DD Miranda, KM Colton, CA Citrin, D Espey, MG Wink, DA AF Thomas, DD Miranda, KM Colton, CA Citrin, D Espey, MG Wink, DA TI Heme proteins and nitric oxide (NO): The neglected, eloquent chemistry in NO redox signaling and regulation SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Review ID SOLUBLE GUANYLATE-CYCLASE; MITOCHONDRIAL PERMEABILITY TRANSITION; CYTOCHROME-C RELEASE; HYDROXY-L-ARGININE; REACTIVE NITROGEN; CARBON-MONOXIDE; RELAXING FACTOR; NITROXYL ANION; BOVINE LUNG; RYANODINE RECEPTORS AB The role of nitric oxide (NO) in cellular physiology and signaling has been an important aspect in biomedical science over the last decade. As NO is a small uncharged radical, the chemistry of NO within the redox environment of the cell dictates the majority of its biological effects. The mechanisms that have received the most attention from a biological perspective involve reactions with oxygen and superoxide, despite the rich literature of metal-NO chemistry. However, NO and its related species participate in important chemistry with metalloproteins. In addition to the well known direct interactions of NO with heme proteins such as soluble guanylate cyclase and oxyhemoglobin, there is much important, but often underappreciated, chemistry between other nitrogen oxides and heme/metal proteins. Here the basic chemistry of nitrosylation and the interactions of NO and other nitrogen oxides with metal-oxo species such as found in peroxidases and monoxygenases are discussed. C1 NCI, Radiat Biol Branch, Tumor Biol Sect, NIH, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Div Neurol, Durham, NC 27710 USA. RP NCI, Radiat Biol Branch, Tumor Biol Sect, NIH, Bldg 10,Room B3-B69, Bethesda, MD 20892 USA. RI Miranda, Katrina/B-7823-2009 NR 102 TC 52 Z9 55 U1 0 U2 7 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD JUN PY 2003 VL 5 IS 3 BP 307 EP 317 DI 10.1089/152308603322110887 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 697PV UT WOS:000183953200007 PM 12880485 ER PT J AU Devadas, K Zhou, P Tewari, D Notkins, AL AF Devadas, K Zhou, P Tewari, D Notkins, AL TI Inhibition of HIV-1 replication by the combined action of anti-gp41 single chain antibody and IL-16 SO ANTIVIRAL RESEARCH LA English DT Article DE HIV-1; IL-16; anti-gp41; single-chain antibody ID TYPE-1 REPLICATION; GENE-TRANSFER; T-CELLS; LYMPHOCYTES; INTRABODIES; INFECTION; RESISTANT; CDNA; P17 AB HIV-1 replication is inhibited in T cells transfected with an anti-gp41 single chain antibody (ScFv) or IL-16. These two molecules target totally different events in the HIV-1 replication cycle. The present study shows that HIV-1 replication is inhibited to a substantially greater extent and for a longer duration in cells transfected with both anti-gp41 and IL-16 than with either molecule alone. It is concluded that anti-gp41 and IL-16 act in a synergistic fashion to inhibit HIV-1 replication. Published by Elsevier Science B.V. C1 NIDCR, Oral Immun & Infect Branch, Expt Med Sect, NIH, Bethesda, MD 20892 USA. RP Devadas, K (reprint author), NIDCR, Oral Immun & Infect Branch, Expt Med Sect, NIH, Bldg 30,Room 121,30 Convent Dr,MSC 4322, Bethesda, MD 20892 USA. NR 13 TC 1 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD JUN PY 2003 VL 59 IS 1 BP 67 EP 70 DI 10.1016/S0166-3542(03)00032-9 PG 4 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 700HK UT WOS:000184106400009 PM 12834863 ER PT J AU Ambrose, Z Miller, CJ Compton, L Hughes, SH Lifson, JD KewalRamani, VN AF Ambrose, Z Miller, CJ Compton, L Hughes, SH Lifson, JD KewalRamani, VN TI Viral resistance against a candidate HIV microbicide SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 12th International HIV Drug Resistance Workshop CY JUN 10-14, 2003 CL Los Cabos, MEXICO C1 NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. Calif Reg Primate Res Ctr, Davis, CA USA. NCI, AIDS Vaccine Program, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD JUN PY 2003 VL 8 IS 3 MA 27 BP U38 EP U38 PG 1 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 955YK UT WOS:000231265900039 ER PT J AU Boyer, PL Imamichi, T Sarafianos, SG Arnold, E Hughes, SH AF Boyer, PL Imamichi, T Sarafianos, SG Arnold, E Hughes, SH TI The Delta 67 complex of mutations enhances the ability of HIV-1 reverse transcriptase to excise zidovudine, stavudine and PMPA from blocked primers SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 12th International HIV Drug Resistance Workshop CY JUN 10-14, 2003 CL Los Cabos, MEXICO C1 NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. SAIC Frederick Inc, Clin Serv Program, Frederick, MD USA. Rutgers State Univ, Dept Chem, Piscataway, NJ USA. Ctr Adv Biotechnol & Med, Piscataway, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD JUN PY 2003 VL 8 IS 3 MA 30 BP U42 EP U42 PG 1 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 955YK UT WOS:000231265900042 ER PT J AU Grossman, Z Grossman, Z Hunt, PW Deeks, SG AF Grossman, Z Grossman, Z Hunt, PW Deeks, SG TI Distinct patterns of the virological and immunological response to antiretroviral therapy interpreted in terms of the dynamics of immune activation and HIV transmission SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 12th International HIV Drug Resistance Workshop CY JUN 10-14, 2003 CL Los Cabos, MEXICO C1 NIH, Bethesda, MD 20892 USA. Tel Aviv Univ, IL-69978 Tel Aviv, Israel. MOH, PHL, Natl HIV Reference Lab, Tel Hashomer, Israel. Univ Calif San Francisco, San Francisco Gen Hosp, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD JUN PY 2003 VL 8 IS 3 MA 57 BP U63 EP U64 PG 2 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 955YK UT WOS:000231265900069 ER PT J AU Halvas, E Aldrovandi, G Balfe, JP Beck, I Boltz, V Frenkel, L Hazelwood, J Johnson, V Kearney, M Kovacs, A Kuritzkes, D Metzner, K Nissley, D Nowicki, M Ziermann, R Zhao, Y Jennings, C Bremer, J Brambilla, D Mellors, J AF Halvas, E Aldrovandi, G Balfe, JP Beck, I Boltz, V Frenkel, L Hazelwood, J Johnson, V Kearney, M Kovacs, A Kuritzkes, D Metzner, K Nissley, D Nowicki, M Ziermann, R Zhao, Y Jennings, C Bremer, J Brambilla, D Mellors, J TI Updated, blinded, multicentre comparison of the sensitivity of different technologies to detect and quantify a minor drug-resistant HIV-1 variant SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 12th International HIV Drug Resistance Workshop CY JUN 10-14, 2003 CL Los Cabos, MEXICO C1 Univ Pittsburgh, Pittsburgh, PA USA. Univ Alabama, Birmingham, AL USA. Birmingham VA Med Hosp, Birmingham, AL USA. Columbia Univ, New York, NY USA. Univ Washington, Seattle, WA 98195 USA. NCI, Frederick, MD 21701 USA. Univ So Calif, Los Angeles, CA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Univ Erlangen Nurnberg, Erlangen, Germany. Bayer Hlth Care Diagnost, Emeryville, CA USA. Childrens Mem Hosp, Chicago, IL 60614 USA. Rush Med Coll, Chicago, IL 60612 USA. New England Res Inst, Watertown, MA 02172 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD JUN PY 2003 VL 8 IS 3 MA 92 BP U91 EP U92 PG 2 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 955YK UT WOS:000231265900104 ER PT J AU Kearney, M Palmer, S Maldarelli, F Bixby, C Bazmi, H Rock, D Falloon, J Davey, R Dewar, R Metcalf, J Mellors, J Coffin, J AF Kearney, M Palmer, S Maldarelli, F Bixby, C Bazmi, H Rock, D Falloon, J Davey, R Dewar, R Metcalf, J Mellors, J Coffin, J TI Comparison of single-genome sequencing with standard genotype analysis for detection of HIV-1 drug resistance mutations SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 12th International HIV Drug Resistance Workshop CY JUN 10-14, 2003 CL Los Cabos, MEXICO C1 NCI, HIV Drug Resistance Program, NIH, Bethesda, MD 20892 USA. NIAID, CCMD Clin, NIH, Bethesda, MD USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD USA. Univ Pittsburgh, Div Infect Dis, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD JUN PY 2003 VL 8 IS 3 MA 86 BP U87 EP U88 PG 2 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 955YK UT WOS:000231265900098 ER PT J AU Maldarelli, F Palmer, S Kearney, M Falloon, J Davey, RT Powers, A Vogel, S Pau, A Dewar, R Metcalf, JA Mellors, J Coffin, J AF Maldarelli, F Palmer, S Kearney, M Falloon, J Davey, RT Powers, A Vogel, S Pau, A Dewar, R Metcalf, JA Mellors, J Coffin, J TI Short duration, single drug discontinuation to assess the activity of individual drugs in patients failing antiretroviral therapy SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 12th International HIV Drug Resistance Workshop CY JUN 10-14, 2003 CL Los Cabos, MEXICO C1 NCI, HIV Drug Resistance Program, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Div Infect Dis, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD JUN PY 2003 VL 8 IS 3 MA 133 BP U129 EP U129 PG 1 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 955YK UT WOS:000231265900145 ER PT J AU Mellors, J Palmer, S Nissley, D Kearney, M Halvas, E Bixby, C Demeter, L Eshleman, S Bennett, K Hart, S Vaida, F Wantman, M Coffin, J Hammer, S AF Mellors, J Palmer, S Nissley, D Kearney, M Halvas, E Bixby, C Demeter, L Eshleman, S Bennett, K Hart, S Vaida, F Wantman, M Coffin, J Hammer, S CA ACTG 398 Study Team TI Low frequency non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant variants contribute to failure of efavirenz-containing regimens in NNRTI-experienced patients with negative standard genotypes for NNRTI mutations SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 12th International HIV Drug Resistance Workshop CY JUN 10-14, 2003 CL Los Cabos, MEXICO C1 Univ Pittsburgh, Pittsburgh, PA USA. NCI, Drug Resistance Program, Frederick, MD 21701 USA. SAIC, Frederick, MD USA. Univ Rochester, Rochester, NY USA. Johns Hopkins Univ, Baltimore, MD USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Frontier Sci, Amherst, NY USA. Columbia Univ, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD JUN PY 2003 VL 8 IS 3 MA 134 BP U129 EP U130 PG 2 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 955YK UT WOS:000231265900146 ER PT J AU Nissley, DV Halvas, E Garfinkel, D Mellors, J Strathern, J AF Nissley, DV Halvas, E Garfinkel, D Mellors, J Strathern, J TI Detection of rare drug-resistant HIV-1 reverse transcriptase variants using a sensitive phenotypic assay SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 12th International HIV Drug Resistance Workshop CY JUN 10-14, 2003 CL Los Cabos, MEXICO C1 SAIC Frederick, Frederick, MD USA. Univ Pittsburgh, Pittsburgh, PA USA. NCI, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD JUN PY 2003 VL 8 IS 3 MA 93 BP U92 EP U93 PG 2 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 955YK UT WOS:000231265900105 ER PT J AU Palmer, S Kearney, M Boltz, V Maldarelli, F Achaz, G Mellors, J Daar, E Coffin, J AF Palmer, S Kearney, M Boltz, V Maldarelli, F Achaz, G Mellors, J Daar, E Coffin, J TI Population genetics in HIV-1 super-infection SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 12th International HIV Drug Resistance Workshop CY JUN 10-14, 2003 CL Los Cabos, MEXICO C1 NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21701 USA. Univ Pittsburgh, Div Infect Dis, Pittsburgh, PA USA. Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA. Univ Calif Los Angeles, Sch Med, Harbor UCLA Med Ctr, Torrance, CA 90509 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD JUN PY 2003 VL 8 IS 3 MA 62 BP U67 EP U68 PG 2 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 955YK UT WOS:000231265900074 ER PT J AU Simon, V Padte, N Driver, I Wang, NC DiMascio, M Markowitz, M AF Simon, V Padte, N Driver, I Wang, NC DiMascio, M Markowitz, M TI Influence of gag and pol regions on replication efficiency of a multidrug-resistant HIV-1 variant: a systematic assessment SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 12th International HIV Drug Resistance Workshop CY JUN 10-14, 2003 CL Los Cabos, MEXICO C1 Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10021 USA. NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD JUN PY 2003 VL 8 IS 3 MA 77 BP U78 EP U78 PG 1 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 955YK UT WOS:000231265900089 ER PT J AU Wiegand, A Maldarelli, F Palmer, S Polis, M Falloon, J Mican, J Davey, R Rock, D Liu, S Planta, A Shen, J Burke, R Metcalf, JA Mellors, J Coffin, J AF Wiegand, A Maldarelli, F Palmer, S Polis, M Falloon, J Mican, J Davey, R Rock, D Liu, S Planta, A Shen, J Burke, R Metcalf, JA Mellors, J Coffin, J TI Stable, persistent viraemia in patients with plasma HIV-1 RNA suppressed to less than 75 copies/ml on potent antiretroviral therapy SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 12th International HIV Drug Resistance Workshop CY JUN 10-14, 2003 CL Los Cabos, MEXICO C1 NCI, HIV Drug Resistance Program, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Div Infect Dis, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD JUN PY 2003 VL 8 IS 3 MA 60 BP U66 EP U66 PG 1 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 955YK UT WOS:000231265900072 ER PT J AU Hammond, MEH Barker, P Taube, S Gutman, S AF Hammond, MEH Barker, P Taube, S Gutman, S TI Standard reference material for Her2 testing - Report of a National Institute of Standards and Technology-sponsored Consensus Workshop SO APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY LA English DT Article DE Her2; manufactured materials; immunohistochemistry; cancer drug tests ID IN-SITU HYBRIDIZATION; BREAST-CANCER; IMMUNOHISTOCHEMICAL ASSAY; HER-2/NEU; CARCINOMA AB A workshop was sponsored by the National Institute of Standards and Technology, the Cancer Diagnosis Program of the National Cancer Institute, the Food and Drug Administration, and the College of American Pathologists to address the need for a reference material for Her2 gene protein testing. It was agreed that such a standard was desirable and necessary to ensure the reliability of Her2 testing to qualify patients for trastuzumab therapy. Two standards consisting of well characterized cell lines will be produced, 1 that will be a National Institute of Standards and Technology-certifiable standard, and 1 that will be a commercially developed standard for use in all Her2 testing. It was also agreed that all Her2 testing must be performed on samples fixed only in 10% buffered formalin, as specified in the Food and Drug Administration-approved testing methods. Participants agreed to plan strategies to educate pathologists, clinicians, and laboratories about the need and use of such a standard. A National Committee for Clinical Laboratory Standards guideline for the use of the standard reference material will be created to facilitate this process. C1 Latter Day St Hosp, Dept Pathol, Salt Lake City, UT 84143 USA. Univ Utah, Sch Med, Salt Lake City, UT USA. Natl Inst Stand & Technol, Gaithersburg, MD 20899 USA. NCI, Div Canc Treatment & Diagnosis, Canc Diagnosis Program, Rockville, MD USA. US FDA, Div Clin Lab Devices, Rockville, MD 20857 USA. RP Hammond, MEH (reprint author), Latter Day St Hosp, Dept Pathol, 8th Ave & C St, Salt Lake City, UT 84143 USA. NR 14 TC 25 Z9 29 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-3345 J9 APPL IMMUNOHISTO M M JI Appl. Immunohistochem. PD JUN PY 2003 VL 11 IS 2 BP 103 EP 106 PG 4 WC Anatomy & Morphology; Medical Laboratory Technology; Pathology SC Anatomy & Morphology; Medical Laboratory Technology; Pathology GA 687FX UT WOS:000183366700001 PM 12777990 ER PT J AU Gannot, I Garashi, A Gannot, G Chernomordik, V Gandjbakhche, A AF Gannot, I Garashi, A Gannot, G Chernomordik, V Gandjbakhche, A TI In vivo quantitative three-dimensional localization of tumor labeled with exogenous specific fluorescence markers SO APPLIED OPTICS LA English DT Article; Proceedings Paper CT Biomedical Topical Meeting of the Optical-Society-of-America CY 2002 CL MIAMI BEACH, FL SP Optl Soc Amer ID TURBID MEDIA; RECONSTRUCTION; SPECTROSCOPY; TISSUE; MEDICINE; MODEL AB We introduce a diffused optical detection system based on the administration of a fluorophore-antibody conjugate to diseased tissue. The conjugate interacts with the antigens expressed by the diseased tissue, resulting in fluorescent labeling of the antigen. By combining an optical detection system with a reconstruction algorithm developed on the basis of the random-walk model, we were able to determine the position of the fluorophore (and, thus, of the diseased cells) in the tissue. We present three-dimensional reconstructions of the location of a fluorophore (FITC-fluorescein isothiocyanate) in the tongues of mice. Measurements were performed with the fluorophore embedded at various simulated depths. The simulations were performed with agarose-based gel slabs applied to the tongue as tissuelike phantoms. Reconstructed fluorophore locations agree well with the actual values. (C) 2003 Optical Society of America. C1 Tel Aviv Univ, Fac Engn, Dept Biomed Engn, IL-69978 Tel Aviv, Israel. NCI, NIH, Bethesda, MD 20892 USA. NICHHD, Bethesda, MD 20892 USA. RP Tel Aviv Univ, Fac Engn, Dept Biomed Engn, IL-69978 Tel Aviv, Israel. EM gannot@eng.tau.ac.il; avital@eng.tau.ac.il; gannotg@pop.nci.nih.gov; vchern@helix.nih.gov; amir@helix.nih.gov NR 24 TC 22 Z9 22 U1 0 U2 0 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1559-128X EI 2155-3165 J9 APPL OPTICS JI Appl. Optics PD JUN 1 PY 2003 VL 42 IS 16 BP 3073 EP 3080 DI 10.1364/AO.42.003073 PG 8 WC Optics SC Optics GA 685HL UT WOS:000183256600026 PM 12790459 ER PT J AU Blumberg, HP Leung, HC Skudlarski, P Lacadie, CM Fredericks, CA Harris, BC Charney, DS Gore, JC Krystal, JH Peterson, BS AF Blumberg, HP Leung, HC Skudlarski, P Lacadie, CM Fredericks, CA Harris, BC Charney, DS Gore, JC Krystal, JH Peterson, BS TI A functional magnetic resonance imaging study of bipolar disorder - State- and trait-related dysfunction in ventral prefrontal cortices SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 56th Annual Meeting of the Society-of-Biological-Psychiatry CY MAY 03-05, 2001 CL NEW ORLEANS, LOUISIANA SP Soc Biol Psychiat ID ANTERIOR CINGULATE CORTEX; CEREBRAL BLOOD-FLOW; STROOP TASK-PERFORMANCE; MAJOR DEPRESSION; MOOD DISORDERS; ORBITOFRONTAL CORTEX; BRAIN ACTIVATION; FRONTAL-LOBE; SELECTIVE ATTENTION; INTERFERENCE TASK AB Background: Abnormalities in prefrontal and anterior cingulate cortices are implicated in disturbances of attention, cognition, and impulse regulation in bipolar disorder. Acute episodes have been associated with dysfunction in these brain regions, and more enduring trait-related dysfunction has been implicated by volumetric and cellular abnormalities in these regions. The relative contributions of prefrontal regions to state and trait disturbances in bipolar disorder, however, have not been defined. We sought to characterize state- and trait-related functional impairment in frontal systems in bipolar disorder. Methods: Thirty-six individuals with bipolar disorder 1 (11 with elevated, 10 with depressed, and 15 with euthymic mood states) and 20 healthy control subjects matched for handedness and sex participated in an event-related functional magnetic resonance imaging study of the color-word Stroop to determine mean percentage of regional task-related signal change. Results: Signal increased during the Stroop task similarly across diagnostic groups in a distribution that included dorsal anterior cingulate and prefrontal cortices, consistent with previously reported activations in this task. Signal changes associated with specific mood states in bipolar disorder were detected in ventral prefrontal cortex, with a blunted increase in signal on the right side in the elevated mood group (P=.005) and an exaggerated increase in signal on the left side in the depressed group (P=.02) compared with the euthymic group. Patients (vs healthy controls) demonstrated blunted activation in a spatially distinct, rostral region of left ventral prefrontal cortex that was independent of mood state (P<.005). Conclusions: Bipolar disorder is associated with a trait abnormality in left ventral prefrontal cortex. Additional ventral prefrontal abnormalities may be associated with specific acute mood states. The hemispheric laterality of the abnormality and the directions of signal change may relate to the valence of the mood episode. C1 Vet Affairs Connecticut Healthcare Syst, Dept Psychiat 116A, West Haven, CT 06516 USA. Yale Univ, Dept Psychiat, Sch Med, New Haven, CT 06520 USA. Yale Univ, Dept Diagnost Radiol, Sch Med, New Haven, CT 06520 USA. SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. NIMH, Mood Anxiety Disorders Res Program, Bethesda, MD 20892 USA. Vanderbilt Univ, Ctr Med, Dept Radiol, Nashville, TN 37232 USA. Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, Dept Psychiat, New York, NY 10032 USA. RP Blumberg, HP (reprint author), Vet Affairs Connecticut Healthcare Syst, Dept Psychiat 116A, 950 Campbell Ave, West Haven, CT 06516 USA. FU NIAAA NIH HHS [K02AA 00261-01]; NIMH NIH HHS [MH01232, MH59139] NR 76 TC 318 Z9 322 U1 3 U2 13 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD JUN PY 2003 VL 60 IS 6 BP 601 EP 609 DI 10.1001/archpsyc.60.6.601 PG 9 WC Psychiatry SC Psychiatry GA 688GB UT WOS:000183424900007 PM 12796223 ER PT J AU Berman, JJ AF Berman, JJ TI Concept-match medical data scrubbing - How pathology text can be used in research SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID CONFIDENTIALITY AB Context.-In the normal course of activity, pathologists create and archive immense data sets of scientifically valuable information. Researchers need pathology-based data sets, annotated with clinical information and linked to archived tissues, to discover and validate new diagnostic tests and therapies. Pathology records can be used for research purposes (without obtaining informed patient consent for each use of each record), provided the data are rendered harmless. Large data sets can be made harmless through 3 computational steps: (1) deidentification, the removal or modification of data fields that can be used to identify a patient (name, social security number, etc); (2) rendering the data ambiguous, ensuring that every data record in a public data set has a nonunique set of characterizing data; and (3) data scrubbing, the removal or transformation of words in free text that can be used to identify persons or that contain information that is incriminating or otherwise private. This article addresses the problem of data scrubbing. Objective.-To design and implement a general algorithm that scrubs pathology free text, removing all identifying or private information. Methods.-The Concept-Match algorithm steps through confidential text. When a medical term matching a standard nomenclature term is encountered, the term is replaced by a nomenclature code and a synonym for the original term. When a high-frequency "stop" word, such as a, an, the, or for, is encountered, it is left in place. When any other word is encountered, it is blocked and replaced by asterisks. This produces a scrubbed text. An open-source implementation of the algorithm is freely available. Results-The Concept-Match scrub method transformed pathology free text into scrubbed output that preserved the sense of the original sentences, while it blocked terms that did not match terms found in the Unified Medical Language System (UMLS). The scrubbed product is safe, in the restricted sense that the output retains only standard medical terms. The software implementation scrubbed more than half a million surgical pathology report phrases in less than an hour. Conclusions.-Computerized scrubbing can render the textual portion of a pathology report harmless for research purposes. Scrubbing and deidentification methods allow pathologists to create and use large pathology databases to conduct medical research. C1 NCI, Canc Diag Program, DCTD, NIH, Rockville, MD 20892 USA. RP Berman, JJ (reprint author), NCI, Canc Diag Program, DCTD, NIH, EPN Room 6028,6130 Execut Blvd, Rockville, MD 20892 USA. NR 19 TC 36 Z9 37 U1 0 U2 3 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD JUN PY 2003 VL 127 IS 6 BP 680 EP 686 PG 7 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 682HD UT WOS:000183084900004 PM 12741890 ER PT J AU Moolchan, ET Berlin, I Robinson, ML Cadet, JL AF Moolchan, ET Berlin, I Robinson, ML Cadet, JL TI Characteristics of African American teenage smokers who request cessation treatment - Implications for addressing health disparities SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID NICOTINE PATCH THERAPY; SERUM COTININE LEVELS; ADOLESCENT SMOKERS; TOLERANCE QUESTIONNAIRE; ETHNIC-DIFFERENCES; PLASMA COTININE; FAGERSTROM TEST; WHITE SMOKERS; SMOKING; BLACK AB Background: Ethnoracial disparities in both tobacco-related mortality and treatment outcome for smoking cessation have been reported among adults, but there is a dearth of information on ethnoracial differences among adolescent smokers. Objective: To compare smoking-related characteristics in African American and non-African American teen-aged applicants for a smoking cessation trial. Participants, Design, and Setting: Four hundred thirty-two teenaged smokers (mean [SD] age, 15.6 [1.5] years; 61.8%, female; 31.9%, African American) responded via telephone to various media advertisements. Self-reported sociodemographic, smoking-related, and clinical data were obtained to determine preeligibility for trial participation. Main Outcome Measures: The number of cigarettes smoked per day, Fagerstrom Test for Nicotine Dependence (FTND) score, motivation to quit, self-reported health problems, and medication use. Results: Compared with non-African Americans, African Americans had lower FTND scores (mean [SD] score, 5.31 [2.24] vs 6.18 [2.18]; P < .01), and smoked fewer cigarettes per day (mean [SD] number of cigarettes, 12.6 [8.3] vs 15.4 [7.5] cigarettes/d; P < .04). The FTND scores were similar in both groups when adjusted for the number of cigarettes smoked per day. African American and non-African American teenagers reported similar motivation to quit (mean [SD] score, 8.64 [1.68] vs 8.53 [1.59], respectively). No difference was found in frequency of physical health problems (eg, asthma), diagnosed psychiatric conditions, or prescribed psychiatric medication although fewer African American teenaged smokers took medication for physical problems (21.2% vs 36.7%). Conclusions: Cessation treatment interventions designed for African American youths should include lower FTND-defined levels, or the use of other instruments that do not focus on the number of cigarettes smoked per day. Our findings also highlight the importance of ethnocultural issues in treatment research that aims to address health disparities. C1 NIDA, Intramural Res Program, Teen Tobacco Addict Treatment Res Clin, Clin Pharmacol & Therapeut Res Branch,NIH, Baltimore, MD 21224 USA. Pitie Salpetriere Med Sch, Dept Pharmacol, Paris, France. RP Moolchan, ET (reprint author), NIDA, Intramural Res Program, Teen Tobacco Addict Treatment Res Clin, Clin Pharmacol & Therapeut Res Branch,NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 45 TC 20 Z9 20 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD JUN PY 2003 VL 157 IS 6 BP 533 EP 538 DI 10.1001/archpedi.157.6.533 PG 6 WC Pediatrics SC Pediatrics GA 688AB UT WOS:000183408900005 PM 12796232 ER PT J AU Joyce, C Freeman, L Brewer, HB Santamarina-Fojo, S AF Joyce, C Freeman, L Brewer, HB Santamarina-Fojo, S TI Study of ABCA1 function in transgenic mice SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE high-density lipoproteins; apolipoprotein B-containing lipoproteins; atherosclerosis; cholesterol efflux; aortic atherosclerosis; ABC transporters ID ATP-BINDING CASSETTE; DENSITY-LIPOPROTEIN DEFICIENCY; REVERSE CHOLESTEROL TRANSPORT; APOLIPOPROTEIN-E GENE; TANGIER-DISEASE; CELLULAR CHOLESTEROL; MESSENGER-RNA; EFFLUX; MACROPHAGES; ATHEROSCLEROSIS AB The ATP-binding cassette transporter A1 (ABCA1), identified in 1999 as the gene defective in Tangier disease, promotes efflux of cellular cholesterol from macrophages and other peripheral tissues to apolipoprotein acceptors. These ABCA1-mediated processes are anticipated to have antiatherogenic properties, prompting the development of pharmacological agents that increase ABCA1 gene expression as well as the establishment of ABCA1-transgenic mouse lines. Preliminary studies of ABCA1-Tg mice seem to validate the selection of this transporter as a therapeutic target for the treatment of low HDL syndromes and cardiovascular disease but have also raised new questions regarding the function of ABCA1. In particular, the relative contribution of hepatic and peripheral ABCA1 to plasma HDL levels and to reverse cholesterol transport, as well as the potential role of ABCA1 in modulating the plasma concentrations of the apolipoprotein B-containing lipoproteins and protecting against atherosclerosis, seem to be promising areas of investigation. The present review summarizes the most recent studies and discusses insights provided by these transgenic mouse models. C1 NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. RP Joyce, C (reprint author), NHLBI, Mol Dis Branch, NIH, Bldg 10,Room 7N115, Bethesda, MD 20892 USA. NR 53 TC 73 Z9 79 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD JUN PY 2003 VL 23 IS 6 BP 965 EP 971 DI 10.1161/01.ATV.0000055194.85073.FF PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 690BR UT WOS:000183527900008 PM 12615681 ER PT J AU Zhu, JH Quyyumi, AA Wu, HS Csako, G Rott, D Zalles-Ganley, A Ogunmakinwa, J Halcox, J Epstein, SE AF Zhu, JH Quyyumi, AA Wu, HS Csako, G Rott, D Zalles-Ganley, A Ogunmakinwa, J Halcox, J Epstein, SE TI Increased serum levels of heat shock protein 70 are associated with low risk of coronary artery disease SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE coronary artery disease; heat shock protein; antibodies; protective effect ID HEAT-SHOCK PROTEINS; SYSTEMIC LUPUS-ERYTHEMATOSUS; TRANSGENIC MICE; CAROTID ATHEROSCLEROSIS; CARDIOVASCULAR-DISEASE; STRESS; PROTECTION; ISCHEMIA; INJURY; HSP70 AB Objective-Previous studies suggest that heat shock protein (HSP) 60 has a contributory role in atherosclerosis development. We examined whether circulating HSP70 protein and anti-HSP70 antibodies are associated with coronary artery disease (CAD). Methods and Results-Blood samples from 421 patients (62% men, mean age 57 years) evaluated for CAD by coronary angiography were tested. Serum HSP70 was detectable in 67% of study subjects with levels ranging from 0.2 to 27.1 ng/mL (mean, 1.08; median, 0.5). HSP70 levels were higher in non-CAD patients than CAD patients (median, 0.72 versus 0.34; P = 0.0006). Individuals with HSP70 levels above the median (0.5 ng/mL) had half the risk of CAD than individuals with levels below the median (adjusted odds ratio, 0.52; 95% confidence limit, 0.32 to 0.86). The association of high HSP70 levels with low CAD risk was independent of traditional CAD risk factors (P = 0.011). Disease severity (number of diseased vessels) was also inversely associated with HSP70 protein levels (P = 0.010). The adjusted odds ratio of having multivessel disease for patients with high HSP70 protein levels was 0.54 (95% confidence limit, 0.36 to 0.81). In contrast, no association between anti-HSP70 IgG seropositivity and the prevalence of CAD was found (P = 0.916). Conclusions-These data provide the first evidence that high levels of human HSP70 are associated with the low CAD risk, probably through its multiple protective effects on a cell's response to stress. C1 Washington Hosp Ctr, MedStar Res Inst, Cardiovasc Res Inst, Washington, DC 20010 USA. Emory Univ Hosp, Div Cardiol, Atlanta, GA 30322 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. RP Zhu, JH (reprint author), Washington Hosp Ctr, MedStar Res Inst, Cardiovasc Res Inst, Washington, DC 20010 USA. EM jianhui.zhu@med.star.net OI Halcox, Julian/0000-0001-6926-2947 NR 29 TC 115 Z9 124 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD JUN PY 2003 VL 23 IS 6 BP 1055 EP 1059 DI 10.1161/01.ATV.0000074899.60898.FD PG 5 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 690BR UT WOS:000183527900021 PM 12730089 ER PT J AU Andriamanalijaona, R Felisaz, N Kim, SJ King-Jones, K Lehmann, M Pujol, JP Boumediene, K AF Andriamanalijaona, R Felisaz, N Kim, SJ King-Jones, K Lehmann, M Pujol, JP Boumediene, K TI Mediation of interleukin-1 beta-induced transforming growth factor beta 1 expression by activator protein 4 transcription factor in primary cultures of bovine articular chondrocytes - Possible cooperation with activator protein 1 SO ARTHRITIS AND RHEUMATISM LA English DT Article ID OSTEO-ARTHRITIS; RECEPTOR EXPRESSION; ENHANCER BINDING; MYC-HOMOLOGY; DNA-BINDING; TGF-BETA; IN-VIVO; CARTILAGE; REGION; GENE AB Objective. Interleukin-1 (IL-1) and transforming growth factor beta1 (TGFbeta1) play major roles in osteoarticular diseases, exerting opposite effects on both the catabolism and anabolism of cartilage matrix. Previous findings suggest that IL-1 and TGFbeta1 could function in a feedback interaction. However, the effect exerted by IL-1 on expression of TGFbeta by articular chondrocytes is, so far, poorly understood. The present study was carried out to determine the influence of IL-1beta on the expression of TGFbeta1 by bovine articular chondrocytes (BACs) in primary culture. Methods. BAC primary cultures were treated with IL-1beta, and TGFbeta1 messenger RNA (mRNA) steady-state levels and protein expression were measured by real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Transient transfection of TGFbeta1 gene promoter constructs was performed to delineate the DNA sequences that mediate the IL-1beta effect. Electrophoretic mobility shift assays (EMSAs) and supershift analysis were used to characterize the transcription factors binding to these sequences. Results. Cultured BACs responded to IL-1beta exposure by exhibiting an increase of TGFbeta1 expression at both the mRNA and protein levels. The effect was found to be mediated by a major 80-bp sequence located between -732 and -652 upstream of the transcription initiation site. EMSA and supershift analysis revealed that the transcription factors activator protein 4 (AP-4) and AP-1 specifically bound to the -720/-696 part of this sequence under IL-1beta treatment. Overexpression of AP-4 in the BAC cultures resulted in stimulation of the transcriptional activity of the -732/+11 TGFbeta1 promoter construct through the same. IL-1beta-responsive element. Conclusion. IL-1beta induces an increase of TGFbeta1 in articular chondrocytes through activation of AP-4 and AP-1 binding to the TGFbeta1 gene promoter. These findings may help us understand the role of IL-1beta in the disease process. Notwithstanding its deleterious effect on cartilage, IL-1 could initiate the repair response displayed by injured cartilage in the early stages of osteoarthritis through its ability to enhance TGFbeta1 expression by local chondrocytes. C1 Fac Med, Lab Connect Tissue Biochem, F-14032 Caen, France. NCI, Bethesda, MD 20892 USA. Free Univ Berlin, Inst Genet, D-1000 Berlin, Germany. RP Pujol, JP (reprint author), Fac Med, Lab Connect Tissue Biochem, F-14032 Caen, France. OI BOUMEDIENE, Karim/0000-0001-6517-8318 NR 47 TC 30 Z9 30 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD JUN PY 2003 VL 48 IS 6 BP 1569 EP 1581 DI 10.1002/art.11020 PG 13 WC Rheumatology SC Rheumatology GA 688AQ UT WOS:000183410300016 PM 12794825 ER PT J AU Hull, KM Kastner, DL AF Hull, KM Kastner, DL TI Emerging clinical spectrum of tumor necrosis factor receptor-associated periodic syndrome: comment on the articles by Hull et al and Dode et al - Reply SO ARTHRITIS AND RHEUMATISM LA English DT Letter ID TNF RECEPTOR; MUTATIONS; FAMILY C1 NIAMSD, NIH, Bethesda, MD 20892 USA. RP Hull, KM (reprint author), NIAMSD, NIH, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD JUN PY 2003 VL 48 IS 6 BP 1769 EP 1770 DI 10.1002/art.11147 PG 2 WC Rheumatology SC Rheumatology GA 688AQ UT WOS:000183410300044 ER PT J AU Johnson-Thompson, M AF Johnson-Thompson, M TI Walter Schlesinger SO ASM NEWS LA English DT Biographical-Item C1 Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC USA. RP Johnson-Thompson, M (reprint author), Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0044-7897 J9 ASM NEWS JI ASM News PD JUN PY 2003 VL 69 IS 6 BP 306 EP 306 PG 1 WC Microbiology SC Microbiology GA 757HU UT WOS:000187557600014 ER PT J AU Chanock, RM Stollar, V AF Chanock, RM Stollar, V TI Walter Schlesinger SO ASM NEWS LA English DT Biographical-Item C1 NIAID, NIH, Bethesda, MD 20892 USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Piscataway, NJ 08854 USA. RP Chanock, RM (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0044-7897 J9 ASM NEWS JI ASM News PD JUN PY 2003 VL 69 IS 6 BP 307 EP 307 PG 1 WC Microbiology SC Microbiology GA 757HU UT WOS:000187557600015 ER PT J AU Hampton, RR AF Hampton, RR TI Metacognition as evidence for explicit representation in nonhumans SO BEHAVIORAL AND BRAIN SCIENCES LA English DT Editorial Material AB Metacognition is either direct, as when information is recalled before making a confidence judgment, or indirect, as when the probability of successful future retrieval is determined inferentially. Direct metacognition may require an explicit mental representation as its object and can only be demonstrated under specific experimental circumstances. Other forms of metacognition can be based on publicly observable stimuli rather than introspection. C1 NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. RP Hampton, RR (reprint author), NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. EM robert@ln.nimh.nih.gov NR 5 TC 4 Z9 4 U1 1 U2 4 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 0140-525X J9 BEHAV BRAIN SCI JI Behav. Brain Sci. PD JUN PY 2003 VL 26 IS 3 BP 346 EP + PG 7 WC Psychology, Biological; Behavioral Sciences; Neurosciences SC Psychology; Behavioral Sciences; Neurosciences & Neurology GA 836TX UT WOS:000222579800032 ER PT J AU Kafkafi, N Lipkind, D Benjamini, Y Mayo, CL Elmer, GI Golani, I AF Kafkafi, N Lipkind, D Benjamini, Y Mayo, CL Elmer, GI Golani, I TI SEE locomotor behavior test discriminates C57BL/6J and DBA/2J mouse inbred strains across laboratories and protocol conditions SO BEHAVIORAL NEUROSCIENCE LA English DT Article ID RAT EXPLORATORY-BEHAVIOR; FALSE DISCOVERY RATE; LOW RESPONDERS; MICE; COCAINE; PHENOTYPE; STANDARDIZATION; CHARACTERIZE; GENE; RECOMMENDATIONS AB Conventional tests of behavioral phenotyping frequently have difficulties differentiating certain genotypes and replicating these differences across laboratories and protocol conditions. This study explores the hypothesis that automated tests can be designed to quantify ethologically relevant behavior patterns that more readily characterize heritable and replicable phenotypes. It used SEE (Strategy for the Exploration of Exploration) to phenotype the locomotor behavior of the C57BL/6 and DBA/2 mouse inbred strains across 3 laboratories. The 2 genotypes differed in 15 different measures of behavior, none of which had a significant genotype-laboratory interaction. Within the same laboratory, most of these differences were replicated in additional experiments despite the test photoperiod phase being changed and saline being injected. Results suggest that well-designed tests may considerably enhance replicability across laboratories. C1 Univ Maryland, Sch Med, Dept Psychiat, Maryland Psychiat Res Ctr, Baltimore, MD 21224 USA. Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD USA. Tel Aviv Univ, Dept Stat, IL-69978 Tel Aviv, Israel. RP Kafkafi, N (reprint author), Univ Maryland, Sch Med, Dept Psychiat, Maryland Psychiat Res Ctr, POB 21247, Baltimore, MD 21224 USA. RI Benjamini, Yoav/C-4219-2008 FU NINDS NIH HHS [1 R01 NS4023] NR 54 TC 44 Z9 45 U1 0 U2 0 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7044 J9 BEHAV NEUROSCI JI Behav. Neurosci. PD JUN PY 2003 VL 117 IS 3 BP 464 EP 477 DI 10.1037/0735-7044.117.3.464 PG 14 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 682CQ UT WOS:000183073600006 PM 12802875 ER PT J AU Catez, F Lim, JH Hock, R Postnikov, YV Bustin, M AF Catez, F Lim, JH Hock, R Postnikov, YV Bustin, M TI HMGN dynamics and chromatin function SO BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE LA English DT Article; Proceedings Paper CT 24th International West Coast Chromatin and Chromosomes Conference CY DEC 12-21, 2002 CL PACIFIC GROVE, CALIFORNIA SP Sangamo Biosci, Biochem & Cell Biol DE HMG; nuclear proteins; chromatin; HMGN ID CHROMOSOMAL-PROTEIN HMG-17; RNA-POLYMERASE-II; NUCLEOSOMAL BINDING DOMAIN; MOBILITY GROUP PROTEINS; LIVING HUMAN-CELLS; HISTONE H1; TRANSCRIPTIONAL ACTIVITY; SPLICING FACTORS; MITOTIC PHOSPHORYLATION; RAPID EXCHANGE AB Recent studies indicate that most nuclear proteins, including histone HI and HMG are highly mobile and their interaction with chromatin is transient. These findings suggest that the structure of chromatin is dynamic and the protein composition at any particular chromatin site is not fixed. Here we discuss how the dynamic behavior of the nucleosome binding HMGN proteins affects the structure and function of chromatin. The high intranuclear mobility of HMGN insures adequate supply of protein throughout the nucleus and serves to target these proteins to their binding sites. Transient interactions of the proteins with nucleosomes destabilize the higher order chromatin, enhance the access to nucleosomal DNA, and impart flexibility to the chromatin fiber. While roaming the nucleus, the HMGN proteins encounter binding partners and form metastable multiprotein complexes, which modulate their chromatin interactions. Studies with HMGN proteins underscore the important role of protein dynamics in chromatin function. C1 NCI, Prot Sect, Lab Metab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. Bioctr, Dept Cell & Dev Biol, D-97074 Wurzburg, Germany. RP Bustin, M (reprint author), NCI, Prot Sect, Lab Metab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RI Bustin, Michael/G-6155-2015 NR 71 TC 23 Z9 23 U1 0 U2 2 PU NATL RESEARCH COUNCIL CANADA PI OTTAWA PA RESEARCH JOURNALS, MONTREAL RD, OTTAWA, ONTARIO K1A 0R6, CANADA SN 0829-8211 J9 BIOCHEM CELL BIOL JI Biochem. Cell Biol. PD JUN PY 2003 VL 81 IS 3 BP 113 EP 122 DI 10.1139/003-040 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 704CC UT WOS:000184319300003 PM 12897844 ER PT J AU Pilch, DR Sedelnikova, OA Redon, C Celeste, A Nussenzweig, A Bonner, WM AF Pilch, DR Sedelnikova, OA Redon, C Celeste, A Nussenzweig, A Bonner, WM TI Characteristics of gamma-H2AX foci at DNA double strand breaks sites SO BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE LA English DT Article; Proceedings Paper CT 24th International West Coast Chromatin and Chromosomes Conference CY DEC 12-21, 2002 CL PACIFIC GROVE, CALIFORNIA SP Sangamo Biosci, Biochem & Cell Biol ID HISTONE H2AX; IONIZING-RADIATION; GENOMIC INSTABILITY; CORE HISTONE; DAMAGE; CHROMATIN; RELEVANCE; MACROH2A; CELLS AB Phosphorylated H2AX (gamma-H2AX) is essential to the efficient recognition and (or) repair of DNA double strand breaks (DSBs), and many molecules, often thousands, of H2AX become rapidly phosphorylated at the site of each nascent DSB. An antibody to gamma-H2AX reveals that this highly amplified process generates nuclear foci. The phosphorylation site is a serine four residues from the C-terminus which has been evolutionarily conserved in organisms from giardia intestinalis to humans. Mice and yeast lacking the conserved serine residue demonstrate a variety of defects in DNA DSB processing. H2AX(Delta/Delta) mice are smaller, sensitive to ionizing radiation, defective in class switch recombination and spermatogenesis while cells from the mice demonstrate substantially increased numbers of genomic defects. gamma-H2AX foci formation is a sensitive biological dosimeter and presents new and exciting opportunities to understand important biological processes, human diseases, and individual variations in radiation sensitivity. These potentialities demonstrate the importance of understanding the parameters and functions of gamma-H2AX formation. C1 NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Bonner, WM (reprint author), NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. NR 26 TC 285 Z9 295 U1 1 U2 18 PU NATL RESEARCH COUNCIL CANADA PI OTTAWA PA RESEARCH JOURNALS, MONTREAL RD, OTTAWA, ONTARIO K1A 0R6, CANADA SN 0829-8211 J9 BIOCHEM CELL BIOL JI Biochem. Cell Biol. PD JUN PY 2003 VL 81 IS 3 BP 123 EP 129 DI 10.1139/003-042 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 704CC UT WOS:000184319300004 PM 12897845 ER PT J AU Leibenluft, E Charney, DS Pine, DS AF Leibenluft, E Charney, DS Pine, DS TI Researching the pathophysiology of pediatric bipolar disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article; Proceedings Paper CT Conference on Pediatric Bipolar Disorder CY MAR, 2002 CL BOSTON, MASSACHUSETTS DE child; bipolar disorder; attention; emotion; mania ID DEFICIT HYPERACTIVITY DISORDER; FRONTAL BRAIN ASYMMETRY; EMISSION COMPUTED-TOMOGRAPHY; MANIC-DEPRESSIVE ILLNESS; ANTERIOR CINGULATE; AFFECTIVE STYLE; LIFE EVENTS; FUNCTIONAL NEUROANATOMY; ORBITOFRONTAL CORTEX; BIOLOGICAL SUBSTRATE AB We suggest that the core feature of bipolar disorder (BPD) is marked state fluctuations. The pathophysiology of switches into depressed, irritable, and extreme positive valence states requires study, with the latter deserving particular focus because it represents a pathognomonic feature of BPD in both adults and children. Hypotheses regarding the pathophysiology of pediatric BPD must account for these marked state fluctuations as well as for specific developmental aspects of the illness. These developmental aspects include marked irritability (in addition to euphoria and depression) and very rapid cycles, along with high rates of attention-deficit/hyperactivity disorder. We review research on neural mechanisms underlying positive valence states and state regulation, focusing on those data relevant to BPD and to development. Researchers are beginning to explore the response of manic patients and control subjects to positive affective stimuli, and considerable research in both nonhuman primates and humans has focused on the cortico-limbic-striatal circuits mediating responses to rewarding stimuli. In control subjects, positive affect affects cognition, and data indicate that prefrontal electroencephalogram asymmetry may differ between control subjects with consistently positive affect and those with more negative affect; however, this latter generalization may not apply to adolescents. With regard to the pathophysiology of state switching in pediatric BPD, data in control subjects indicating that attention regulation plays a role in emotion regulation may be germane. In addition, research detailing physiologic and psychological responses to negative emotional stimuli in bipolar patients and control subjects may increase our understanding of the mechanisms underlying both irritability and rapid cycling seen in children with BPD. Potential foci for research on the pathophysiology of pediatric BPD include reactivity to standardized positive and negative emotional stimuli, and the interaction between emotion regulation and attentional processes. (C) 2003 Society of Biological Psychiatry. C1 NIMH, Mood & Anxiety Program, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Leibenluft, E (reprint author), NIMH, Mood & Anxiety Program, Dept Hlth & Human Serv, NIH, Bldg 10,Room 4N-208,10 Ctr Dr,MSC 1255, Bethesda, MD 20892 USA. NR 113 TC 73 Z9 75 U1 9 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 1 PY 2003 VL 53 IS 11 BP 1009 EP 1020 DI 10.1016/S0006-3223(03)00069-6 PG 12 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 686UT UT WOS:000183339900011 PM 12788246 ER PT J AU Sachs, GS Thase, ME Otto, MW Bauer, M Miklowitz, D Wisniewski, SR Lavori, P Lebowitz, B Rudorfer, M Frank, E Nierenberg, AA Fava, M Bowden, C Ketter, T Marangell, L Calabrese, J Kupfer, D Rosenbaum, JF AF Sachs, GS Thase, ME Otto, MW Bauer, M Miklowitz, D Wisniewski, SR Lavori, P Lebowitz, B Rudorfer, M Frank, E Nierenberg, AA Fava, M Bowden, C Ketter, T Marangell, L Calabrese, J Kupfer, D Rosenbaum, JF TI Rationale, design, and methods of the systematic treatment enhancement program for bipolar disorder (STEP-BD) SO BIOLOGICAL PSYCHIATRY LA English DT Article; Proceedings Paper CT Conference on Pediatric Bipolar Disorder CY MAR, 2002 CL BOSTON, MASSACHUSETTS DE bipolar disorder; effectiveness research; bipolar depression; relapse prevention ID RATING-SCALE; DEPRESSION; LITHIUM; ILLNESS; PROPHYLAXIS; COMORBIDITY; PREDICTORS; STRATEGIES; INVENTORY; SUICIDE AB The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was conceived in response to a National Institute of Mental Health initiative seeking a public health intervention model that could generate externally valid answers to treatment effectiveness questions related to bipolar disorder. STEP-BD, like all effectiveness research, faces many design challenges, including how to do the following: recruit a representative sample of patients for studies of readily available treatments; implement a common intervention strategy across diverse settings; determine outcomes for patients in multiple phases of illness; make provisions for testing as yet undetermined new treatments; integrate adjunctive psychosocial interventions; and avoid biases due to subject drop-out and last-observation-carried-forward data analyses. To meet these challenges, STEP-BD uses a hybrid design to collect longitudinal data as patients make transitions between naturalistic studies and randomized clinical trials. Bipolar patients of every subtype with age greater than or equal to 15 years are accessioned into a study registry. All patients receive a systematic assessment battery at entry and are treated by a psychiatrist (trained to deliver care and measure outcomes in patients with bipolar disorder) using a series of model practice procedures consistent with expert recommendations. At every follow-up visit, treating psychiatrist completes a standardized assessment and assigns an operationalized clinical status based on DSM-IV criteria. Patients have independent evaluations at regular intervals throughout the study and remain under the, care of the same treating psychiatrist while making transitions between randomized care studies and the standard care treatment pathways. This article reviews the methodology used for the selection and certification of the clinical treatment centers, training study personnel, the general approach to clinical management, and the sequential treatment strategies offered in the STEP-BD standard and randomized care pathways for bipolar depression and relapse prevention. (C) 2003 Society of Biological Psychiatry. C1 Harvard Univ, Partners Bipolar Treatment Ctr, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. Harvard Univ, Dept Psychiat, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. Univ Pittsburgh, Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. Brown Univ, Dept Psychiat, Providence, RI 02912 USA. Univ Colorado, Dept Psychiat, Boulder, CO 80309 USA. Stanford Univ, Sch Med, Dept Psychiat, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. NIMH, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, Dept Psychiat, San Antonio, TX USA. Baylor Coll Med, Dept Psychiat, Houston, TX 77030 USA. Case Western Reserve Univ, Dept Psychiat, Cleveland, OH 44106 USA. RP Sachs, GS (reprint author), Harvard Univ, Partners Bipolar Treatment Ctr, Massachusetts Gen Hosp, Sch Med, 50 Stanford St,5th Floor, Boston, MA 02114 USA. OI Wisniewski, Stephen/0000-0002-3877-9860 FU NIMH NIH HHS [N01MH80001] NR 50 TC 338 Z9 341 U1 4 U2 17 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 1 PY 2003 VL 53 IS 11 BP 1028 EP 1042 DI 10.1016/S0006-3223(03)00165-3 PG 15 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 686UT UT WOS:000183339900013 PM 12788248 ER PT J AU Gallardo-Williams, MT Maronpot, RR Turner, CH Johnson, CS Harris, MW Jayo, MJ Chapin, RE AF Gallardo-Williams, MT Maronpot, RR Turner, CH Johnson, CS Harris, MW Jayo, MJ Chapin, RE TI Effects of boric acid supplementation on bone histomorphometry, metabolism, and biomechanical properties in aged female F-344 rats SO BIOLOGICAL TRACE ELEMENT RESEARCH LA English DT Article DE bone mineral density; bone strength; boron; 17 beta-estradiol; ovariectomy; osteocalcin ID DIETARY BORON SUPPLEMENTATION; MECHANICAL-PROPERTIES; POSTMENOPAUSAL WOMEN; ESTROGEN; DISPOSITION; ANDROGEN; BALANCE; ANIMALS; HORMONE; HUMANS AB Postmenopausal women may benefit from dietary interventions in order to increase bone strength and prevent fractures. Dietary boron (B) may be beneficial for optimal calcium metabolism and, as a consequence, optimal bone metabolism. The present study evaluated the effects of boron, in the form of boric acid, with or without 17beta-estradiol (E-2) supplementation (via subcutaneous implant), in ovariectomized (OVX) aged 13-mo-old F-344 rats. Boric acid was administered by gavage at a subtoxic dose (8.7 mg B/kg/d) for 40 d. Results indicate that serum level of minerals as well as osteocalcin (a marker of bone resorption) are dependent to a greater extent on the hormonal status of the animals than on boron supplementation. Boron treatment increased the E-2-induced elevation of urinary calcium and magnesium. Bone mineral density (BMD) of the L5 vertebra and proximal femur was highest in the E-2-treated groups; no increase in BMD was conferred by boron treatment. By histomorphometry of the proximal tibial metaphysis, osteoblastic, osteoid, and eroded surfaces were significantly suppressed by E-2 treatment, but not by boron treatment. In biomechanical testing of femur and vertebra, neither E-2 nor boron treatment significantly increased bone strength. At the levels given, boron alone provided no protection against OVX-induced osteopenia. In addition, combination therapy (B+E-2) provided no additional benefits over those of 17beta-estradiol treatment alone in this aged rat model. C1 NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. Indiana Univ, Dept Orthopaed Surg, Indianapolis, IN 46204 USA. Pathol Associates Inc, Advance, NC USA. RP Gallardo-Williams, MT (reprint author), NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. OI Chapin, Robert/0000-0002-5997-1261 NR 28 TC 18 Z9 21 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0163-4984 J9 BIOL TRACE ELEM RES JI Biol. Trace Elem. Res. PD SUM PY 2003 VL 93 IS 1-3 BP 155 EP 169 DI 10.1385/BTER:93:1-3:155 PG 15 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 699XQ UT WOS:000184082600016 PM 12835499 ER PT J AU Brown, PR Miki, K Harper, DB Eddy, EA AF Brown, PR Miki, K Harper, DB Eddy, EA TI A-kinase anchoring protein 4 binding proteins in the fibrous sheath of the sperm flagellum SO BIOLOGY OF REPRODUCTION LA English DT Article DE gamete biology; gametogenesis; sperm; spermatogenesis; testis ID MOUSE SPERMATOGENIC CELLS; II REGULATORY SUBUNIT; GLUTATHIONE-S-TRANSFERASE; TYROSINE PHOSPHORYLATION; LOCALIZATION; HEXOKINASE; DOMAIN; TESTIS; GENE; IDENTIFICATION AB The fibrous sheath is a unique cytoskeletal structure located in the principal piece of the sperm flagellum and is constructed of two longitudinal columns connected by closely spaced circumferential ribs. Cyclic AMP-dependent protein kinases are secured within specific cytoplasmic domains by A-kinase anchoring proteins (AKAPs), and the most abundant protein in the fibrous sheath is AKAP4. Several other fibrous sheath proteins have been identified, but how the fibrous sheath assembles is not understood. Yeast two-hybrid assays and deletion mutagenesis were used to identify AKAP4-binding proteins and to map the binding regions on AKAP4 and on the proteins identified. We found that AKAP4 binds AKAP3 and two novel spermatogenic cell-specific proteins, fibrous Sheath Interacting Proteins 1 and 2 (FSIP1, FSIP2). Transcription of Akap4, Akap3, and Fsip1 begins in early spermatid development, whereas transcription of Fsip2 begins in late spermatocyte development. AKAP3 is synthesized in round spermatids and incorporated into the fibrous sheath concurrently with formation of the rib precursors. However, AKAP4 is synthesized and incorporated into the nascent fibrous sheath late in spermatid development. The AKAP4 precursor is processed in the flagellum and only the mature form of AKAP4 appears to bind AKAP3. These results suggest that AKAP3 is involved in organizing the basic structure of the fibrous sheath, whereas AKAP4 has a major role in completing fibrous sheath assembly. C1 NIEHS, LRDT, Gamete Biol Sect, Lab Reprod & Dev Toxicol,NIH, Res Triangle Pk, NC 27709 USA. RP Eddy, EA (reprint author), NIEHS, LRDT, Gamete Biol Sect, Lab Reprod & Dev Toxicol,NIH, C4-01,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 48 TC 81 Z9 95 U1 0 U2 2 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD JUN PY 2003 VL 68 IS 6 BP 2241 EP 2248 DI 10.1095/biolreprod.102.013466 PG 8 WC Reproductive Biology SC Reproductive Biology GA 683CN UT WOS:000183130000036 PM 12606363 ER PT J AU Seth, P Husain, MM Gupta, P Schoneboom, BA Grieder, FB Mani, H Maheshwari, RK AF Seth, P Husain, MM Gupta, P Schoneboom, BA Grieder, FB Mani, H Maheshwari, RK TI Early onset of virus infection and up-regulation of cytokines in mice treated with cadmium and manganese SO BIOMETALS LA English DT Article DE encephalomyocarditis virus; infection; Semliki forest virus; Venezuelan Equine Encephalitis virus; virus ID RECEPTOR ANTAGONIST IL-1RA; SEMLIKI-FOREST-VIRUS; BLOOD-BRAIN-BARRIER; HEAVY-METALS; ENCEPHALOMYOCARDITIS VIRUS; VIRAL-INFECTION; SYSTEM; IMMUNOTOXICOLOGY; PERMEABILITY; REPLICATION AB A substantial database indicates that a large number of environmental pollutants, chemicals and therapeutic agents to which organisms are exposed cause immunotoxicity. The suppression of immune functions may cause increased susceptibility of the host to a variety of microbial pathogens potentially resulting in a life-threatening state. Evaluation of the immunotoxic potential of chemical xenobiotics is of great concern and, therefore, we have investigated the impact of exposure of inorganic metals, specifically cadmium (Cd) and manganese (Mn) on Encephalomyocarditis virus (EMCV), Semliki Forest virus (SFV), and Venezuelan Equine Encephalitis virus (VEEV) infection. Pretreatment with a single, oral dose of Cd or Mn increased the susceptibility of mice to a sub-lethal infection of these viruses as observed by increased severity of symptoms and mortality compared to untreated controls. An early onset of virus infection was found in brains of Cd and Mn treated animals. Histopathological observations of the brain indicate evidence of inflammation and greater tissue pathology in Cd- or Mn-exposed mice compared to control animals. Meningitis and vascular congestion was seen in virus infected mice in all the metal treated groups, and further, the perivascular inflammation appeared earlier in treated mice compared to control. Encephalitis was maximum in Cd pretreated mice. Widespread environmental contamination of metals and the potential for their exposure and subsequent infection of humans or animals is indicative that further studies of these and all other metals are important to understand the effect of environmental pollution on human health. C1 USUHS, Dept Pathol, Ctr Combat Casualty Care & Life Sustainment Res, Bethesda, MD 20814 USA. Ind Toxicol Res Ctr, Lucknow 226001, Uttar Pradesh, India. USUHS, Neurosci Program, Bethesda, MD 20814 USA. NIH, Natl Ctr Res Resources, Bethesda, MD 20892 USA. Armed Forces Med Coll, Pune, Maharashtra, India. RP Maheshwari, RK (reprint author), USUHS, Dept Pathol, Ctr Combat Casualty Care & Life Sustainment Res, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. NR 34 TC 15 Z9 16 U1 0 U2 2 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0966-0844 J9 BIOMETALS JI Biometals PD JUN PY 2003 VL 16 IS 2 BP 359 EP 368 DI 10.1023/A:1020682716212 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 603FY UT WOS:000178549300013 PM 12572694 ER PT J AU Dunson, DB AF Dunson, DB TI Bayesian inference on order-constrained parameters in generalized linear models SO BIOMETRICS LA English DT Article DE Bayes factor; categorical covariates; constrained estimation; Gibbs sampling; isotonic regression; monotonicity; simple ordering; trend test ID ISOTONIC REGRESSION; RESTRICTIONS; FERTILITY; BIOASSAY AB In biomedical studies, there is often interest in assessing the association between one or more ordered categorical predictors and an outcome variable, adjusting for covariates. For a k-level predictor, one typically uses either a k-1 degree of freedom (df) test or a single df trend test, which requires scores for the different levels of the predictor. In the absence of knowledge of a parametric form for the response function, one can incorporate monotonicity constraints to improve the efficiency of tests of association. This article proposes a general Bayesian approach for inference on order-constrained parameters in generalized linear models. Instead of choosing a prior distribution with support on the constrained space, which can result in major computational difficulties, we propose to map draws from an unconstrained posterior density using an isotonic regression transformation. This approach allows flat regions over which increases in the level of a predictor have no effect. Bayes factors for assessing ordered trends can be computed based on the output from a Gibbs sampling algorithm. Results from a simulation study are presented and the approach is applied to data from a time-to-pregnancy study. C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. RP Dunson, DB (reprint author), NIEHS, Biostat Branch, POB 12233,MD A3-03, Res Triangle Pk, NC 27709 USA. NR 23 TC 28 Z9 28 U1 0 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0006-341X J9 BIOMETRICS JI Biometrics PD JUN PY 2003 VL 59 IS 2 BP 286 EP 295 DI 10.1111/1541-0420.00035 PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 693TU UT WOS:000183735100009 PM 12926713 ER PT J AU Dunson, DB Watson, M Taylor, JA AF Dunson, DB Watson, M Taylor, JA TI Bayesian latent variable models for median regression on multiple outcomes SO BIOMETRICS LA English DT Article DE comet assay; factor analysis; measurement error; multivariate response; repeated measures; semiparametric; single-cell electrophoresis; substitution likelihood ID RESIDUAL ANALYSIS; BINARY AB Often a response of interest cannot be measured directly and it is necessary to rely on multiple surrogates, which can be assumed to be conditionally independent given the latent response and observed covariates. Latent response models typically assume that residual densities are Gaussian. This article proposes a Bayesian median regression modeling approach, which avoids parametric assumptions about residual densities by relying on an approximation based on quantiles. To accommodate within-subject dependency, the quantile response categories of the surrogate outcomes are related to underlying normal variables, which depend on a latent normal response. This underlying Gaussian covariance structure simplifies interpretation and model fitting, without restricting the marginal densities of the surrogate outcomes. A Markov chain Monte Carlo algorithm is proposed for posterior computation, and the methods are applied to single-cell electrophoresis (comet assay) data from a genetic toxicology study. C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Dunson, DB (reprint author), NIEHS, Biostat Branch, POB 12233,MD A3-03, Res Triangle Pk, NC 27709 USA. OI taylor, jack/0000-0001-5303-6398 NR 22 TC 19 Z9 19 U1 0 U2 4 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0006-341X J9 BIOMETRICS JI Biometrics PD JUN PY 2003 VL 59 IS 2 BP 296 EP 304 PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 693TU UT WOS:000183735100010 PM 12926714 ER PT J AU Follmann, D Proschan, M Leifer, E AF Follmann, D Proschan, M Leifer, E TI Multiple outputation: Inference for complex clustered data by averaging analyses from independent data SO BIOMETRICS LA English DT Article DE bootstrap; generalized estimating equations; generalized linear mixed models; multiple imputation; resampling; within-cluster resampling ID LONGITUDINAL DATA; MODELS AB This article applies a simple method for settings where one has clustered data, but statistical methods are only available for independent data. We assume the statistical method provides us with a normally distributed estimate, I and an estimate of its variance (σ) over cap (2). We randomly select a data point from each cluster and apply our statistical method to this independent data. We repeat this multiple times, and use the average of the associated (θ) over cap 's as our estimate. An estimate of the variance is given by the average of the (σ) over cap (2)'s minus the sample variance of the (θ) over cap 's. We call this procedure multiple outputation, as all "excess" data within each cluster is thrown out multiple times. Hoffman, Sen, and Weinberg (2001, Biometrika 88, 1121-1134) introduced this approach for generalized linear models when the cluster size is related to outcome. In this article, we demonstrate the broad applicability of the approach. Applications to angular data, p-values, vector parameters, Bayesian inference, genetics data, and random cluster sizes are discussed. In addition, asymptotic normality of estimates based on all possible outputations, as well as a finite number of outputations, is proven given weak conditions. Multiple outputation provides a simple and broadly applicable method for analyzing clustered data. It is especially suited to settings where methods for clustered data are impractical, but can also be applied generally as a quick and simple tool. C1 NIAID, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, Bethesda, MD USA. RP Follmann, D (reprint author), NIAID, 6700B Rockledge Dr MSC 7609, Bethesda, MD 20892 USA. NR 14 TC 54 Z9 54 U1 0 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0006-341X J9 BIOMETRICS JI Biometrics PD JUN PY 2003 VL 59 IS 2 BP 420 EP 429 DI 10.1111/1541-0420.00049 PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 693TU UT WOS:000183735100023 PM 12926727 ER PT J AU Svitel, J Balbo, A Mariuzza, RA Gonzales, NR Schuck, P AF Svitel, J Balbo, A Mariuzza, RA Gonzales, NR Schuck, P TI Combined affinity and rate constant distributions of ligand populations from experimental surface binding kinetics and equilibria SO BIOPHYSICAL JOURNAL LA English DT Article ID PLASMON RESONANCE BIOSENSOR; BIOMOLECULAR INTERACTION ANALYSIS; ADSORPTION ENERGY-DISTRIBUTION; PROTEIN-PROTEIN INTERACTIONS; SIZE-DISTRIBUTION ANALYSIS; MAXIMUM-ENTROPY ANALYSIS; INTEGRAL-EQUATIONS; MASS-TRANSPORT; DISPLACEMENT-REACTIONS; OPTICAL BIOSENSORS AB The present article considers the influence of heterogeneity in a mobile analyte or in an immobilized ligand population on the surface binding kinetics and equilibrium isotherms. We describe strategies for solving the inverse problem of calculating two-dimensional distributions of rate and affinity constants from experimental data on surface binding kinetics, such as obtained from optical biosensors. Although the characterization of a heterogeneous population of analytes binding to uniform surface sites may be possible under suitable experimental conditions, computational difficulties currently limit this approach. In contrast, the case of uniform analytes binding to heterogeneous populations of surface sites is computationally feasible, and can be combined with Tikhonov-Phillips and maximum entropy regularization techniques that provide the simplest distribution that is consistent with the data. The properties of this ligand distribution analysis are explored with several experimental and simulated data sets. The resulting two-dimensional rate and affinity constant distributions can describe well experimental kinetic traces measured with optical biosensors. The use of kinetic surface binding data can give significantly higher resolution than affinity distributions from the binding isotherms alone. The shape and the level of detail of the calculated distributions depend on the experimental conditions, such as contact times and the concentration range of the analyte. Despite the flexibility introduced by considering surface site distributions, the impostor application of this model to surface binding data from transport limited binding processes or from analyte distributions can be identified by large residuals, if a sufficient range of analyte concentrations and contact times are used. The distribution analysis can provide a rational interpretation of complex experimental surface binding kinetics, and provides an analytical tool for probing the homogeneity of the populations of immobilized protein. C1 NIH, ORS, Div Bioengn & Phys Sci, Off Director, Bethesda, MD 20892 USA. Univ Maryland, Inst Biotechnol, Ctr Adv Res Biotechnol, Rockville, MD USA. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Schuck, P (reprint author), NIH, ORS, Div Bioengn & Phys Sci, Off Director, Bldg 13,Rm 3N17,13 S Dr, Bethesda, MD 20892 USA. EM pschuck@helix.nih.gov OI Schuck, Peter/0000-0002-8859-6966 NR 91 TC 63 Z9 64 U1 0 U2 10 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 JUN PY 2003 VL 84 IS 6 BP 4062 EP 4077 PG 16 WC Biophysics SC Biophysics GA 683CL UT WOS:000183129800050 PM 12770910 ER PT J AU Meimberg, H Thalhammer, S Brachmann, A Muller, B Eichacker, LA Heckl, WM Heubl, G AF Meimberg, H Thalhammer, S Brachmann, A Muller, B Eichacker, LA Heckl, WM Heubl, G TI Selection of chloroplasts by laser microbeam microdissection for single-chloroplast PCR SO BIOTECHNIQUES LA English DT Article ID MEDIATED MANIPULATION; OPTICAL TWEEZERS; DNA; MICROMANIPULATION; AMPLIFICATION; CELLS; SEQUENCES; REGIONS; GENOME; GENES AB Laser microbeam microdissection and laser pressure catapulting offer the possibility of separating cell compartments, thus allowing for contamination-free analysis. Using these methods, we were able to select single chloroplasts of Nicotiana tabacum. Starting from homogenized leaf material, chloroplasts were purified by differential centrifugation and applied directly onto a poly-ethylene-naphthalate membrane that was mounted on a microscope slide. Single chloroplasts were dissected under microscopic control and catapulted into a PCR tube. Subsequent PCR of a spacer region between the trnT and trnF genes verified the successful amplification of DNA from a single chloroplast. The advantage of this method compared to the use of capillaries or optical tweezers is that one is able to prepare high numbers of samples in a short time. C1 Univ Munich, Beriech Biodiversitatsforsch Systemat Bot, D-80638 Munich, Germany. NIH, Bethesda, MD 20892 USA. RP Meimberg, H (reprint author), Univ Munich, Beriech Biodiversitatsforsch Systemat Bot, Menzinger Str 67, D-80638 Munich, Germany. RI Thalhammer, Stefan/C-1031-2011; Brachmann, Andreas/I-2241-2013 OI Brachmann, Andreas/0000-0001-7980-8173 NR 26 TC 19 Z9 19 U1 1 U2 4 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD JUN PY 2003 VL 34 IS 6 BP 1238 EP 1243 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 688JB UT WOS:000183429700018 PM 12813891 ER PT J AU Lorenz, MGO Cortes, LM Lorenz, JJ Liu, ET AF Lorenz, MGO Cortes, LM Lorenz, JJ Liu, ET TI Strategy for the design of custom cDNA microarrays SO BIOTECHNIQUES LA English DT Article ID GENE-EXPRESSION AB DNA microarrays are valuable but expensive tools for expression profiling of cells, tissues, and organs. The design of custom microarrays leads to cost reduction without necessarily compromising their biological value. Here we present a strategy for designing custom cDNA microarrays and constructed a microarray for mouse immunology research (ImmunoChip(TM)). The strategy used interrogates expressed sequence tag databases available in the public domain but overcomes many of the problems encountered. Immunologically relevant clusters were selected based on the expression of expressed sequence tags in relevant libraries. Selected clusters were organized in modules, and the best representative clones were identified. When tested, this microarray was found to have minimal clone identity errors or phage contamination and identified molecular signatures of lymphoid cell lines. Our proposed design of custom microarrays avoids probe redundancy, allows the organization of the chip to optimize chip production, and reduces microarray production costs. The strategy described is also useful for the design of oligonucleotide microarrays. C1 NCI, Gaithersburg, MD USA. Univ Calgary, Calgary, AB, Canada. NINDS, Bethesda, MD 20892 USA. Natl Univ Singapore, Genome Inst Singapore, Singapore 117548, Singapore. RP Lorenz, MGO (reprint author), USN, Med Res Ctr, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. EM lorenzm@nmrc.nav.mil RI Liu, Edison/C-4141-2008 NR 4 TC 4 Z9 6 U1 0 U2 0 PU BIOTECHNIQUES OFFICE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD JUN PY 2003 VL 34 IS 6 BP 1264 EP + PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 688JB UT WOS:000183429700022 PM 12813895 ER PT J AU Zarate, CA Quiroz, JA AF Zarate, CA Quiroz, JA TI Combination treatment in bipolar disorder: a review of controlled trials SO BIPOLAR DISORDERS LA English DT Review DE bipolar depression; combination treatment; controlled studies; maintenance; mania; treatment ID PLACEBO-CONTROLLED TRIAL; TERM LITHIUM TREATMENT; DOUBLE-BLIND; MOOD STABILIZER; ACUTE MANIA; PSYCHOTROPIC MEDICATIONS; CARBONATE; EFFICACY; CARBAMAZEPINE; VALPROATE AB Objectives: Monotherapy is often inadequate and combination drug regimens have become the norm for the treatment of bipolar disorder. Virtually all classes of psychotropic drugs have been used in bipolar disorder in combination for a variety of indications. This article reviews the available published data from controlled, blinded studies regarding combination treatments in the different treatment phases of bipolar disorder. Methods: Articles for this review were obtained from a search of the Medline database (1966-2002), using the following keywords and phrases: add-on, antipsychotic, anticonvulsant, antidepressant, combination treatment, lithium, neuroleptic, and polypharmacy. The search was augmented by data presented at scientific meetings. Data included in this article were only from controlled studies that evaluated combinations of two or more agents. Results: For acute mania, the most useful combination treatments as determined by controlled studies, appear to be an antipsychotic drug with a mood-stabilizer. The combination of lithium and valproate, even though widely used for acute mania, is lacking in controlled data. For acute bipolar depression, the controlled combination studies reviewed fail to show clear advantages in efficacy of an antidepressant with a mood-stabilizer versus two stabilizers or a mood-stabilizer alone. Large, controlled, randomized, long-term studies with modern antidepressants are not available. Controlled combination studies of mood-stabilizers suggest gains in efficacy over monotherapy in the long-term treatment of bipolar disorder. Conclusions: Controlled combination studies in bipolar disorder are uncommon. Increased attention should be given to study combination treatments in all phases of bipolar illness to determine the most efficacious and safest combinations. C1 NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Zarate, CA (reprint author), NIMH, Mood & Anxiety Disorders Program, 9000 Rockville Pike,Bldg 10,Room 3S250, Bethesda, MD 20892 USA. NR 48 TC 42 Z9 43 U1 1 U2 2 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2003 VL 5 IS 3 BP 217 EP 225 DI 10.1034/j.1399-5618.2003.00034.x PG 9 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 683NZ UT WOS:000183156800007 PM 12780875 ER PT J AU Ciciotte, SL Gwynn, B Moriyama, K Huizing, M Gahl, WA Bonifacino, JS Peters, LL AF Ciciotte, SL Gwynn, B Moriyama, K Huizing, M Gahl, WA Bonifacino, JS Peters, LL TI Cappuccino, a mouse model of Hermansky-Pudlak syndrome, encodes a novel protein that is part of the pallidin-muted complex (BLOC-1) SO BLOOD LA English DT Article; Proceedings Paper CT 44th Annual Meeting of the American-Society-of-Hematology CY DEC 06-10, 2002 CL PHILADELPHIA, PENNSYLVANIA SP Amer Soc Hematol ID STORAGE-POOL DEFICIENCY; PALE EAR EP; VESICLE FORMATION; GENE; MUTATION; HOMOLOG; ADAPTER; DEFECTS; MICE; MELANOSOMES AB Hermansky-Pudlak syndrome (HIPS) is a disorder of organelle biogenesis affecting 3 related organelles-melanosomes, platelet dense bodies, and lysosomes. Four genes causing HIPS in humans (HPS1-HPS4) are known, and at least 15 nonallelic mutations cause HPS in the mouse. Where their functions are known, the HPS-associated proteins are involved in, some aspect of intracellular vesicular trafficking, that is, protein sorting and vesicle docking and fusion. Biochemical and genetic evidence indicates that the HPS-associated genes encode components of at least distinct protein complexes: the adaptor complex AP-3; the HPS1/HPS4 complex; and BLOC-1 (bio-genesis of lysosome-related organelles complex-1), consisting of the proteins encoded at mouse HPS loci, pallid(pa) and muted (mu), and at least 3 other unidentified proteins. Here, we report the cloning of the mouse HIPS mutation cappuccino, (cno). We show that the wild-type cno gene encodes a novel, ubiquitously expressed cytoplasmic protein that coassembles With pallidin and the muted protein in the BLOC-1 complex. Further, we identify a frameshift mutation in mutant cno/cno mice. The C-terminal 81 amino acids are replaced with 72 different amino acids in the mutant CNO protein, and its ability to interact in BLOC-1 is abolished. We performed mutation screening of patients with HP and failed to identify any CNO defects. Notably, although defects in components of the HPS1/HPS4 and the AP-3 complexes are associated with HIPS in humans, no defects in the known components of BLOC-1 have been identified in 142 patients with HIPS screened to date, suggesting that BLOC-1 function may be critical in humans. (C) 2003 by The American Society of Hematology. C1 Jackson Lab, Bar Harbor, ME 04609 USA. NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Peters, LL (reprint author), Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. OI Bonifacino, Juan S./0000-0002-5673-6370 FU NCI NIH HHS [CA34196]; NCRR NIH HHS [RR01183]; NHLBI NIH HHS [HL55321, R01 HL055321] NR 40 TC 51 Z9 55 U1 1 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 1 PY 2003 VL 101 IS 11 BP 4402 EP 4407 DI 10.1182/blood-2003-01-0020 PG 6 WC Hematology SC Hematology GA 682CJ UT WOS:000183072800034 PM 12576321 ER PT J AU McFarland, HI Hansal, SA Morris, DI McVicar, DW Love, PE Rosenberg, AS AF McFarland, HI Hansal, SA Morris, DI McVicar, DW Love, PE Rosenberg, AS TI Signaling, through MHC in transgenic mice generates a population of memory phenotype cytolytic cells that lack TCR SO BLOOD LA English DT Article ID NAIVE T-CELLS; CLASS-I MHC; ZETA-CHAIN; ANTIGEN RECEPTOR; LYMPHOCYTES-T; CUTTING EDGE; HEMATOPOIETIC-CELLS; PRECURSOR CELLS; GAMMA-CHAIN; TUMOR-CELLS AB We constructed a chimeric molecule, composed of the T-cell receptor (TCR)-zeta chain fused to the extracellular domains of a prototypical allogeneic major histocompatibility complex (MHC) class I molecule, D-d, to assess whether such a construct could affect Dd allospecific responses in vitro and in vivo. To generate cytotoxic T lymphocytes (CTLs) expressing the construct, D-d-zeta was targeted to lymphocyte populations in transgenic mice by placing its expression under control of the CD2 promoter. In response to ligation of D-d, lymphocytes from transgenic mice expressing high levels of D-d-zeta are activated to proliferate and kill cells binding to Dd, despite the near total loss of CD8(+) T cells in these mice. Thus, the D-d-zeta cytolytic cell was found not to be a conventional CD8(+) CTL, but rather an unusual T lineage cell (CD3(-)CD5(+)Thy1.1(+)) that lacked alphabeta or gammadelta TCRs, as well as CD4 and CD8 coreceptors, but expressed surface markers strikingly similar to memory CTLs, including CD44, Ly-6C, and CD122. These cells originate in the thymus and potently veto responses to D-d in vitro. Lacking TCRs, these veto cells are unlikely to mediate graft-versus-host disease (GVHD) and thus may be useful as a cellular therapy for therapeutic deletion of alloreactive T cells in the settings of graft rejection and GVHD. (C) 2003 by The American Society of Hematology. C1 US FDA, Ctr Biol Evaluat & Res, Div Therapeut Prot, Bethesda, MD 20014 USA. NCI, Expt Immunol Lab, Div Basic Sci, NIH, Frederick, MD 21701 USA. NICHHD, Lab Mammalian Gene & Dev, NIH, Bethesda, MD 20892 USA. RP McFarland, HI (reprint author), 29A-2B12,8800 Rockville Pike, Bethesda, MD 20892 USA. RI McVicar, Daniel/G-1970-2015; McFarland, Hugh/K-1503-2016 OI McFarland, Hugh/0000-0002-3322-038X NR 62 TC 5 Z9 5 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 1 PY 2003 VL 101 IS 11 BP 4520 EP 4528 DI 10.1182/blood-2002-10-3265 PG 9 WC Hematology SC Hematology GA 682CJ UT WOS:000183072800052 PM 12586613 ER PT J AU Pineault, N Buske, C Feuring-Buske, M Abramovich, C Rosten, P Hogge, DE Aplan, PD Humphries, RK AF Pineault, N Buske, C Feuring-Buske, M Abramovich, C Rosten, P Hogge, DE Aplan, PD Humphries, RK TI Induction of acute myeloid leukemia in mice by the human leukemia-specific fusion gene NUP98-HOXD13 in concert with Meis1 SO BLOOD LA English DT Article ID ACUTE MYELOGENOUS LEUKEMIA; HEMATOPOIETIC-CELLS CAUSES; BONE-MARROW CELLS; HOMEOBOX GENES; HOX PROTEINS; DNA-BINDING; DIFFERENTIAL EXPRESSION; HOMEODOMAIN PROTEINS; NUCLEOPORIN NUP98; IN-VITRO AB HOX genes, notably members of the HOXA cluster, and HOX cofactors have increasingly been linked to human leukemia. Intriguingly, HOXD13, a member of the HOXD cluster not normally expressed in hematopoietic cells, was recently identified as a partner of NUP98 in a t(2;11) translocation associated with t-AML/MDS. We have now tested directly the leukemogenic potential of the NUP98-HOXD13t(2; 11) fusion gene in the murine hematopoletic model. NUP98-HOXD13 strongly promoted growth and impaired differentiation of early hematopoietic progenitor cells in vitro; this effect was dependent on the NUP98 portion and an intact HOXD13 homeodomain. Expression of the NUP98-HOXD13 fusion gene in vivo resulted in a partial impairment of lymphopolesis but did not induce evident hematologic disease until late after transplantation (more than 5 months), when some mice developed a myeloproliferative-like disease. In contrast, mice transplanted with bone marrow (BM) cells cotransduced with NUP98-HOXD13 and the HOX cofactor Meis1 rapidly developed lethal and transplantable acute myeloid leukemia (AML), with a median disease onset of 75 days. In summary, this study demonstrates that NUP98-HOXD13 can be directly implicated in the molecular process leading to leukemic transformation, and it supports a model in which the transforming properties of NUP98-HOXD13 are mediated through HOX-dependent pathways. (C) 2003 by The American Society of Hematology. C1 British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada. Natl Canc Inst, Div Clin Sci, Gaithersburg, MD USA. Univ British Columbia, Dept Med, Vancouver, BC V5Z 1M9, Canada. RP Humphries, RK (reprint author), British Columbia Canc Agcy, Terry Fox Lab, 601 W 10th Ave, Vancouver, BC V5Z 1L3, Canada. RI Aplan, Peter/K-9064-2016; OI Humphries, Richard/0000-0003-0540-7005 FU NIDDK NIH HHS [DK48642] NR 54 TC 96 Z9 97 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 1 PY 2003 VL 101 IS 11 BP 4529 EP 4538 DI 10.1128/blood-2002-08-2484 PG 10 WC Hematology SC Hematology GA 682CJ UT WOS:000183072800053 PM 12543865 ER PT J AU Sanchez-Izquierdo, D Buchonnet, G Siebert, R Gascoyne, RD Climent, J Karran, L Marin, M Blesa, D Horsman, D Rosenwald, A Staudt, LM Albertson, DG Du, MQ Ye, HT Marynen, P Garcia-Conde, J Pinkel, D Dyer, MJS Martinez-Climent, JA AF Sanchez-Izquierdo, D Buchonnet, G Siebert, R Gascoyne, RD Climent, J Karran, L Marin, M Blesa, D Horsman, D Rosenwald, A Staudt, LM Albertson, DG Du, MQ Ye, HT Marynen, P Garcia-Conde, J Pinkel, D Dyer, MJS Martinez-Climent, JA TI MALT1 is deregulated by both chromosomal translocation and amplification in B-cell non-Hodgkin lymphoma SO BLOOD LA English DT Article ID MARGINAL-ZONE LYMPHOMA; COMPARATIVE GENOMIC HYBRIDIZATION; CHRONIC LYMPHOCYTIC-LEUKEMIA; LEVEL DNA AMPLIFICATIONS; CENTRAL-NERVOUS-SYSTEM; NF-KAPPA-B; FOLLICULAR LYMPHOMA; LOW-GRADE; BCL10 EXPRESSION; BCL-2 GENE AB The MALT1 gene was identified through its involvement in t(11;18)(q21;q21), seen in 30% of cases of mucosa-associated, lymphoid tissue (MALT) lymphoma. Here, we show that deregulated MALT1 expression may occur in B-cell non-Hodgkin lymphoma (B-NHL) of various histologic subtypes either through translocation to the immunoglobulin heavy chain (IGH) locus or by genomic amplification, First, 2 cases, one case of MALT lymphoma and another of aggressive marginal zone lymphoma (MZL) with t(14;1 8)(q32;q21), cytogenetically identical to the translocation involving BCL2 Were shown by fluorescence in situ hybridization (FISH) to involve MALT1, which lies about 5 Mb centromeric of BCL2. Molecular cloning of both by long-distance inverse polymerase chain reaction showed breakpoints lying 1 to 2 kilobase (kb) centromeric of the first 5' MALT1 exon; both cases showed MALT1 overexpression at either RNA or protein levels. Second, we examined the structure and gene expression profile of genomic amplifications involving 18q21 in a panel of 40 B-NHL cell lines using comparative genomic hybridization to microarrays (array CGH) and gene expression profiling techniques. Using array CGH, 2 peaks of genomic amplification were observed one centered around BCL2 and the other around MALT1. Of the 3 cell lines with MALT1 Amplification, 2 showed MALT1 overexpression as assessed by gene profiling, quantitative reverse transcription-polymerase chain re action (QRT-PCR), and Western blotting. To determine if comparable events occurred in primary MALT and splenic MZL tumors, 40 cases were analyzed by FISH or QRT-PCR; genomic amplification and MALT1 overexpression were seen in 2 cases. Together, these data implicate MALT1 as a dominant oncogene that may play a role in the pathogenesis of B-NHL. (C) 2003 by The American Society of Hematology. C1 Univ Leicester, MRC, Toxicol Unit, Dept Haematol, Leicester LE1 9HN, Leics, England. Univ Valencia, Hosp Clin, Dept Hematol & Med Oncol, E-46003 Valencia, Spain. Univ Hosp, Inst Human Genet, Kiel, Germany. British Columbia Canc Agcy, Dept Pathol, Vancouver, BC V5Z 4E6, Canada. NCI, Metab Branch, Bethesda, MD 20892 USA. Univ Calif San Francisco, Inst Res, San Francisco, CA 94143 USA. UCL, Dept Histopathol, London, England. Katholieke Univ Leuven, Inst Biotechnol, Ctr Human Genet Flanders Interuniv, Louvain, Belgium. RP Dyer, MJS (reprint author), Univ Leicester, MRC, Toxicol Unit, Dept Haematol, Hodgkin Bldg,POB 138,Lancaster Rd, Leicester LE1 9HN, Leics, England. EM mjsd1@leicester.ac.uk; martinez_jos@gva.es RI Siebert, Reiner/A-8049-2010; Martinez-Climent, Jose/I-9199-2012; Dyer, Martin/F-2691-2014 OI Martinez-Climent, Jose/0000-0002-7938-3950; Dyer, Martin/0000-0002-5033-2236 FU NCI NIH HHS [U01-CA84967-1] NR 53 TC 137 Z9 144 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 1 PY 2003 VL 101 IS 11 BP 4539 EP 4546 DI 10.1182/blood-2002-10-3236 PG 8 WC Hematology SC Hematology GA 682CJ UT WOS:000183072800054 PM 12560219 ER PT J AU Nasr, R Rosenwald, A El-Sabban, ME Arnulf, B Zalloua, P Lepelletier, Y Bex, F Hermine, O Staudt, L de The, H Bazarbachi, A AF Nasr, R Rosenwald, A El-Sabban, ME Arnulf, B Zalloua, P Lepelletier, Y Bex, F Hermine, O Staudt, L de The, H Bazarbachi, A TI Arsenic/interferon specifically reverses 2 distinct gene networks critical for the survival of HILV-1-infected leukemic cells SO BLOOD LA English DT Article ID NF-KAPPA-B; VIRUS TYPE-I; ARSENIC TRIOXIDE; TAX PROTEIN; RECEPTOR-ALPHA; HTLV-I; PROMYELOCYTIC LEUKEMIA; PROTEOLYTIC ACTIVITY; TRANSFORMED-CELLS; IMMUNE-RESPONSE AB Adult T-cell leukemia (ATL) is a severe chemotherapy-resistant malignancy associated with prolonged infection by the human T cell-lymphotropic virus 1 (HTLV-1) retrovirus. Although the Tax viral transactivator is clearly an oncogene, the role of its continuous expression in the maintenance of the transformed phenotype is controversial. Because arsenic trioxide (As) and interferon alpha (IFN) synergize to induce cell cycle arrest and apoptopis of ATL cells both ex vivo and in vitro, we investigated the effects of As alone and As/IFN combination on gene networks in HTLV-1-infected leukemic cells. The As/IFN combination reduced Tax expression and, accordingly, reversed the Tax-induced constitutive nuclear factor kappaB (NF-kappaB) activation. Using DNA microarray analyses, we demonstrated that As rapidly and selectively blocks the transcription of NF-kappaB-dependent genes in HTLV-1-infected cells only. Reversal of NF-kappaB activation by As alone resulted from dramatic stabilization of IkappaB-alpha and IkappaB-epsilon, independently of IkappaB kinase (IKK) activity modulation or Tax degradation. In contrast, only the As/IFN combination induced late and massive down-regulation of cell cycle-regulated genes, concomitantly with Tax degradation by the proteasome and cell death induction, indicating the importance of continuous Tax expression for ATL cell survival. These 2 successive events likely account for. the potent and specific effects, of the As/IFN combination in ATL. (C) 2003 by The American Society of Hematology. C1 Amer Univ Beirut, Dept Internal Med, Beirut, Lebanon. Amer Univ Beirut, Dept Biochem, Beirut, Lebanon. Amer Univ Beirut, Dept Human Morphol, Beirut, Lebanon. NCI, Canc Res Ctr, Metab Branch, NIH, Bethesda, MD 20892 USA. Hop Necker Enfants Malad, CNRS, URA 1461, Paris, France. Hop Necker Enfants Malad, Dept Hematol, Paris, France. Chron Care Ctr, Baabda, Lebanon. Free Univ Brussels, Dept Mol Biol, Brussels, Belgium. CNRS, UPR 9051, Lab Associe Comite Paris Ligue Contre Canc, Paris, France. RP Bazarbachi, A (reprint author), Amer Univ Beirut, Dept Internal Med, POB 113-6044, Beirut, Lebanon. NR 41 TC 68 Z9 71 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 1 PY 2003 VL 101 IS 11 BP 4576 EP 4582 DI 10.1182/blood-2002-09-2986 PG 7 WC Hematology SC Hematology GA 682CJ UT WOS:000183072800059 PM 12560223 ER PT J AU Sturzebecher, S Wandinger, KP Rosenwald, A Sathyamoorthy, M Tzou, A Mattar, P Frank, JA Staudt, L Martin, R McFarland, HF AF Sturzebecher, S Wandinger, KP Rosenwald, A Sathyamoorthy, M Tzou, A Mattar, P Frank, JA Staudt, L Martin, R McFarland, HF TI Expression profiling identifies responder and non-responder phenotypes to interferon-beta in multiple sclerosis SO BRAIN LA English DT Article DE cDNA microarrays; expression profile; interferon-beta; multiple sclerosis ID GENE-EXPRESSION; DISEASE PROGRESSION; LESIONS; ALPHA; RELEVANCE; RECEPTOR; CELLS; MS AB Autoimmune diseases such as multiple sclerosis are characterized by complex genetic traits and pathomechanisms that translate into clinical heterogeneity. This wide heterogeneity of multiple sclerosis as well as different biological responses to immunomodulatory drugs can be expected to contribute to differential treatment responses. Strategies that dissect the relationship between the treatment response and the biological characteristics in individual patients are valuable not only as a clinical tool, but also in leading to a better understanding of the disease. Here we address the in vitro and ex vivo RNA expression profile under one approved therapy of multiple sclerosis, interferon-beta (IFN-beta, Betaseron), by cDNA microarrays and demonstrate that non-responder and responder phenotypes to IFN-beta as assessed by longitudinal gadolinium-enhanced MRI scans and clinical disease activity differ in their ex vivo gene expression profile. These findings will help to better elucidate the mechanism of action of IFN-beta in relation to different disease patterns and eventually lead to optimized therapy. C1 NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. NIH, Lab Diagnost Radiol Res, Ctr Clin, Bethesda, MD USA. Schering AG, SBU Therapeut, D-1000 Berlin, Germany. RP Martin, R (reprint author), NINDS, Neuroimmunol Branch, NIH, Bldg 10,Room 5B-16,10 Ctr DR MSC 1400, Bethesda, MD 20892 USA. NR 33 TC 133 Z9 137 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD JUN PY 2003 VL 126 BP 1419 EP 1429 DI 10.1093/brain/awg147 PN 6 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 682MD UT WOS:000183095000015 PM 12764062 ER PT J AU Erickson, K Schulkin, J AF Erickson, K Schulkin, J TI Facial expressions of emotion: A cognitive neuroscience perspective SO BRAIN AND COGNITION LA English DT Review ID HUMAN AMYGDALA; PRESCHOOL-CHILDREN; 6-MONTH-OLD INFANTS; GUSTATORY STIMULI; RATTUS-NORVEGICUS; SODIUM DEPLETION; TEMPORAL CORTEX; BASIC EMOTIONS; RECOGNITION; RESPONSES AB Facial expressions are one example of emotional behavior that illustrate the importance of emotions to both basic survival and social interaction. Basic facial responses to stimuli such as sweet and bitter taste are important for species fitness and governed by simple rules. Even at this basic level, facial responses have communicative value to other species members. During evolution simple facial responses were extended for use in more complex nonverbal communications; the responses are labile. The perception and production of facial expressions are cognitive processes and numerous subcortical and cortical areas contribute to these operations. We suggest that no specific emotion center exists over and above cognitive systems in the brain, and that emotion should not be divorced from cognition. (C) 2003 Published by Elsevier Science (USA). C1 Georgetown Univ, Dept Physiol & Biophys, Washington, DC 20007 USA. NIMH, Mood & Anxiety Disorder Program, NIH, Bethesda, MD USA. RP Schulkin, J (reprint author), Georgetown Univ, Dept Physiol & Biophys, Washington, DC 20007 USA. NR 109 TC 37 Z9 38 U1 11 U2 38 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0278-2626 J9 BRAIN COGNITION JI Brain Cogn. PD JUN PY 2003 VL 52 IS 1 BP 52 EP 60 DI 10.1016/S0278-2626(03)00008-3 PG 9 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 693TT UT WOS:000183735000007 PM 12812804 ER PT J AU Hagemann, D Waldstein, SR Thayer, JF AF Hagemann, D Waldstein, SR Thayer, JF TI Central and autonomic nervous system integration in emotion SO BRAIN AND COGNITION LA English DT Article DE autonomic nervous system; central nervous system; dynamical models; emotion; hemispheric lateralization; inhibitory control ID SKIN-CONDUCTANCE RESPONSES; BILATERAL AMYGDALA DAMAGE; LATERAL BRAIN-FUNCTION; HEART-RATE RESPONSES; HEMISPHERE ASYMMETRY; AROUSAL; DISSOCIATION; REACTIVITY; STIMULI; FILMS AB Emotions involve physiological responses that are regulated by the brain. The present paper reviews the empirical literature on central nervous system (CNS) and autonomic nervous system (ANS) concomitants of emotional states, with a focus on studies that simultaneously assessed CNS and ANS activity. The reviewed data support two primary conclusions: (1) numerous cortical and subcortical regions show co-occurring activity with ANS responses in emotion, and (2) there may be reversed asymmetries on cortical and subcortical levels with respect to CNS/ANS interrelations. These observations are interpreted in terms of a model of neurovisceral integration in emotion, and directions for future research are presented. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NIA, Lab Personal & Cognit, NIH, Gerontol Res Ctr, Baltimore, MD 21224 USA. Univ Maryland Baltimore Cty, Dept Psychol, Baltimore, MD 21250 USA. Univ Maryland Baltimore Cty, Sch Med, Dept Med, Div Gerontol, Baltimore, MD 21201 USA. Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Baltimore, MD 21201 USA. RP Hagemann, D (reprint author), Univ Trier, Fachbereich Psychol 1, Univ Ring 15, D-54286 Trier, Germany. NR 82 TC 72 Z9 76 U1 2 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0278-2626 J9 BRAIN COGNITION JI Brain Cogn. PD JUN PY 2003 VL 52 IS 1 BP 79 EP 87 DI 10.1016/S0278-2626(03)00011-3 PG 9 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 693TT UT WOS:000183735000010 PM 12812807 ER PT J AU Dang, NH Aytac, U Sato, K O'Brien, S Melenhorst, J Morimoto, C Barrett, AJ Molldrem, JJ AF Dang, NH Aytac, U Sato, K O'Brien, S Melenhorst, J Morimoto, C Barrett, AJ Molldrem, JJ TI T-large granular lymphocyte lymphoproliferative disorder: expression of CD26 as a marker of clinically aggressive disease and characterization of marrow inhibition SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE CD26; T-LGL; CFU-GM; cytopenia; T-cell activation ID DIPEPTIDYL-PEPTIDASE-IV; CELL ACTIVATION ANTIGEN; NON-HODGKINS-LYMPHOMAS; PERIPHERAL-BLOOD; MONOCLONAL-ANTIBODY; 1F7 CD26; MYELODYSPLASTIC SYNDROME; RHEUMATOID-ARTHRITIS; MULTIPLE-SCLEROSIS; SURFACE-MOLECULE AB T-large granular lymphocyte lymphoproliferative disorder (T-LGL LPD) is an indolent disease characterized by prolonged cytopenia and the presence of circulating large granular lymphocytes in the patient's peripheral blood. Although the disease is commonly thought of as indolent, most patients eventually require therapy because of recurrent infections secondary to neutropenia as well as a need for frequent blood product transfusions. CD26 is a 110-kDa surface glycoprotein with an essential role in T-cell function, including being a marker of T-cell activation and a mediator of T-cell activating signals. In this study, we evaluated CD26 expression in T-LGL patients and correlate CD26 expression with clinical behaviour. In addition, we examined the potential mechanism of cytopenia that is associated with this disorder. Our findings suggest that CD26 is a marker of aggressive T-LGL LPD and that CD26-related signalling may be aberrant in T-LGL LPD. Furthermore, inhibition of granulocyte-macrophage colony-forming units may be mediated by CD8(+) cells of T-LGL LPD patients and is major histocompatibility complex class I-restricted. C1 Univ Texas, MD Anderson Canc Ctr, Dept Blood & Marrow Transplantat, Sect Transplantat Immunol, Houston, TX 77030 USA. NHLBI, Hematol Branch, Bethesda, MD 20892 USA. Univ Tokyo, Inst Med Sci, Tokyo, Japan. RP Molldrem, JJ (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Blood & Marrow Transplantat, Sect Transplantat Immunol, 1515 Holcombe Blvd,Box 448, Houston, TX 77030 USA. FU NCI NIH HHS [CA 49639, CA 85843, CA 81247] NR 39 TC 28 Z9 28 U1 1 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD JUN PY 2003 VL 121 IS 6 BP 857 EP 865 DI 10.1046/j.1365-2141.2003.04365.x PG 9 WC Hematology SC Hematology GA 686DK UT WOS:000183305700005 PM 12786796 ER PT J AU Goldin, LR Ishibe, N Sgambati, M Marti, GE Fontaine, L Lee, MP Kelley, JM Scherpbier, T Buetow, KH Caporaso, NE AF Goldin, LR Ishibe, N Sgambati, M Marti, GE Fontaine, L Lee, MP Kelley, JM Scherpbier, T Buetow, KH Caporaso, NE TI A genome scan of 18 families with chronic lymphocytic leukaemia SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE chronic lymphocytic leukaemia; genetics; family studies; linkage mapping; candidate genes ID LINKAGE ANALYSIS; LOD SCORES; GENETIC DISSECTION; COMPLEX TRAITS; ATM MUTATIONS; LEUKEMIA; CANCER; ANTICIPATION; GUIDELINES AB Chronic lymphocytic leukaemia (CLL) accounts for about 30% of all leukaemias and is most prevalent in older individuals. Significant familial aggregation has been demonstrated but the mode of inheritance is unknown. Recurrent cytogenetic abnormalities are frequently found in CLL tumour cells but no susceptibility genes have been confirmed. We have collected clinical data and biospecimens on families ascertained for having at least two living patients with CLL. The current study included DNA samples from 94 individuals (38 affected patients) in 18 families. We have carried out a genome scan using the ABI 28-panel medium density linkage mapping set (average spacing of 10 cM and average heterozygosity of 80%). Genotypes for 359 markers were scored. Multipoint limit of detection (lod) scores were calculated, assuming both dominant and recessive inheritance and allowing for increased penetrance with age and genetic heterogeneity. Non-parametric linkage scores were also calculated. Lod scores of 1.0 or greater were found on regions of chromosomes 1, 3, 6, 12, 13 and 17, but none of these loci achieved statistical significance. Four of these six regions (6q, 13q, 12 and 17p) coincide with areas where cytogenetic abnormalities are frequently observed in CLL tumour cells and are, therefore, strong candidate regions for containing germ line changes. C1 NCI, Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Div Cell & Gene Therapies, Flow & Image Cytometry Sect, Bethesda, MD USA. NCI, Lab Populat Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Goldin, LR (reprint author), NCI, Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Room 7008,MSC 7236, Bethesda, MD 20892 USA. NR 34 TC 42 Z9 42 U1 1 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD JUN PY 2003 VL 121 IS 6 BP 866 EP 873 DI 10.1046/j.1365-2141.2003.04372.x PG 8 WC Hematology SC Hematology GA 686DK UT WOS:000183305700006 PM 12786797 ER PT J AU Ringden, O Barrett, AJ Zhang, MJ Loberiza, FR Bolwell, BJ Cairo, MS Gale, RP Hale, GA Litzow, MR Martino, R Russell, JA Tiberghien, P Urbano-Ispizua, A Horowitz, MM AF Ringden, O Barrett, AJ Zhang, MJ Loberiza, FR Bolwell, BJ Cairo, MS Gale, RP Hale, GA Litzow, MR Martino, R Russell, JA Tiberghien, P Urbano-Ispizua, A Horowitz, MM TI Decreased treatment failure in recipients of HLA-identical bone marrow or peripheral blood stem cell transplants with high CD34 cell doses SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE CD34; allogeneic; transplantation; leukaemia; graft type ID VERSUS-HOST-DISEASE; ALLOGENEIC TRANSPLANTATION; HEMATOLOGICAL MALIGNANCIES; UNRELATED DONORS; MYELOGENOUS LEUKEMIA; HIGH-RISK; GRAFT; SURVIVAL; SIBLINGS; RELAPSE AB We studied the association between CD34 cell dose and transplant outcomes in 359 bone marrow (BM) and 511 peripheral blood stem cell (PBSC) transplant recipients from human leucocyte antigen (HLA)-identical siblings, reported to the International Bone Marrow Transplant Registry (IBMTR). Transplants for leukaemia were performed between 1995 and 1998. Patients were divided into those receiving below or above the median CD34(+) dose, for BM (3 x 10(6) /kg) and PBSC (6 x 10(6) /kg) grafts respectively. Cox proportional hazards regression was used to adjust for baseline patient-, disease- and transplant-related characteristics. Analysis of the BM recipients showed that high CD34 cell dose was associated with lower transplant-related mortality [relative risk (RR) = 0.60, P = 0.033] and treatment failure (inverse of leukaemia-free survival, RR = 0.69, P = 0.032). Among PBSC recipients, high CD34 dose was associated with faster recovery of neutrophils to > 0.5 x 10(9) /l (RR = 1.38, P < 0.001) and platelets to > 20 x 10(9) /l (RR = 1.34, P = 0.003), lower risk of relapse (RR = 0.62, P = 0.029) and treatment failure (RR = 0.74, P = 0.03). We conclude that higher CD34 cell doses decrease treatment failure in recipients of HLA-identical sibling BM and PBSC transplants. C1 Med Coll Wisconsin, Ctr Stat,Hlth Policy Inst, Int Bone Marrow Transplant Registry, Graft Versus Host Dis Graft Versus Leukaemia Work, Milwaukee, WI 53226 USA. Huddinge Univ Hosp, S-14186 Huddinge, Sweden. NHLBI, NIH, Bethesda, MD 20892 USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Columbia Univ, New York, NY USA. Ctr Adv Studies Leukaemia, Los Angeles, CA USA. St Jude Childrens Res Hosp, Memphis, TN 38105 USA. Mayo Clin, Rochester, MN USA. Hosp Santa Creu & Sant Pau, E-08025 Barcelona, Spain. Tom Baker Canc Clin, Calgary, AB, Canada. Estab Transfus Sangine Franche Comte, Besancon, France. Hosp Clin Barcelona, Barcelona, Spain. RP Horowitz, MM (reprint author), Med Coll Wisconsin, Ctr Stat,Hlth Policy Inst, Int Bone Marrow Transplant Registry, Graft Versus Host Dis Graft Versus Leukaemia Work, 8701 Watertown Plank Rd,POB 26509, Milwaukee, WI 53226 USA. EM olov.ringden@hs.se; marymh@mcw.edu FU NCI NIH HHS [CP 21161, U24 CA 76518] NR 29 TC 47 Z9 49 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD JUN PY 2003 VL 121 IS 6 BP 874 EP 885 DI 10.1046/j.1365-2141.2003.04364.x PG 12 WC Hematology SC Hematology GA 686DK UT WOS:000183305700007 PM 12786798 ER PT J AU Chu, KC Lamar, CA Freeman, HP AF Chu, KC Lamar, CA Freeman, HP TI Racial disparities in breast carcinoma survival rates - Separating factors that affect diagnosis from factors that affect treatment SO CANCER LA English DT Article DE breast carcinoma; estrogen receptor; stage distribution; stage specific survival; health disparities ID WHITE WOMEN; CANCER SURVIVAL; AFRICAN-AMERICAN; FOLLOW-UP; RACE; BLACK; STAGE; MAMMOGRAPHY; ETHNICITY; TRENDS AB BACKGROUND. Black females have lower breast carcinoma survival rates compared with white females. One possible reason is that black females have more, advanced-stage breast disease. Another factor may be racial differences in the utilization of cancer treatments. METHODS. The authors determined racial differences in 6-year stage specific survival rates, adjusting for age and treatments (using estrogen receptor [ER] status), to determine whether there were racial differences in treatment. Racial differences in the stage distributions of breast disease were used to examine the impact of racial factors on breast carcinoma diagnosis. RESULTS. For all breast carcinoma cases, the stage specific 6-year survival rates, in general, were significantly lower for black females for all stages combined and for Stages I-III in every age group. However, examination by different treatments, as measured by ER status, revealed some different results. Only black women younger than age 50 years with ER-positive tumors and women younger than age 65 years with ER-negative tumors had significantly lower stage-specific survival rates. In addition, the stage distribution analyses showed that black females of every age group had less Stage I breast disease. CONCLUSIONS. For younger black women (younger than age 50 years), there was evidence of racial differences in treatment for both women with ER-positive tumors and women with ER-negative tumors, as indicated by their lower stage-specific survival rates. In contrast, for black females age 65 years or older with ER-positive or ER-negative tumors, the lack of a significant difference in the stage-specific survival rate suggests that Medicare may help to alleviate racial disparities in cancer treatment. Furthermore, racial differences in the stage distributions indicated the need for earlier diagnosis for black females of every age. Published 2003 by the American Cancer Society. C1 NCI, Ctr Reduce Canc Hlth Dispar, Bethesda, MD 20892 USA. RP Chu, KC (reprint author), NCI, Ctr Reduce Canc Hlth Dispar, Bldg 6116,Execut Blvd,Room 6029,9009 Rockville Pi, Bethesda, MD 20892 USA. NR 40 TC 94 Z9 98 U1 3 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JUN 1 PY 2003 VL 97 IS 11 BP 2853 EP 2860 DI 10.1002/cncr.11411 PG 8 WC Oncology SC Oncology GA 681DR UT WOS:000183022100020 PM 12767100 ER PT J AU Swain, SM Whaley, FS Ewer, MS AF Swain, SM Whaley, FS Ewer, MS TI Congestive heart failure in patients treated with doxorubicin - A retrospective analysis of three trials SO CANCER LA English DT Article DE congestive heart failure (CHIF); doxorubicin; cardiotoxicity; radionuclide angiocardiography; breast carcinoma; nonsmall cell lung carcinoma; chemotherapy; dexrazoxane ID ADVANCED BREAST-CANCER; CARDIAC TROPONIN-T; RADIONUCLIDE ANGIOCARDIOGRAPHY; CONTAINING THERAPY; CARDIOTOXICITY; ADRIAMYCIN; REDUCTION; CARDIOPROTECTION; CARDIOMYOPATHY; DEXRAZOXANE AB BACKGROUND. Doxorubicin is a highly effective and widely used cytotoxic agent with application that is limited by cardiotoxicity related to the cumulative dose of the drug. A large-scale study that retrospectively evaluated the cardiotoxicity of doxorubicin reported that an estimated 7% of patients developed doxorubicin-related congestive heart failure (CHF) after a cumulative dose of 550 mg/m(2). To assess whether this estimate is reflective of the incidence in the broader clinical oncology setting, the authors evaluated data from three prospective studies to determine both the incidence of doxorubicin-related CHF and the accumulated dose of doxorubicin at which CHF occurs. METHODS. A group of 630 patients who were randomized to a doxorubicin-plus-placebo arm of three Phase III studies, two studies in patients with breast carcinoma and one study in patients with small cell lung carcinoma, were included in the analysis. RESULTS. Thirty-two of 630 patients had a diagnosis of CHF. Analysis indicated that an estimated cumulative 26% of patients would experience doxorubicin-related CHF at a cumulative dose of 550 mg/m(2). Age appeared to be an important risk factor for doxorubicin-related CHF after a cumulative dose of 400 mg/m(2), With older patients (age > 65 years) showing a greater incidence of CHF compared with younger patients (age less than or equal to 65 years). In addition, > 50% of the patients who experienced doxorubicin-related CHF had a reduction < 30% in left ventricular ejection fraction (LVEF) while they were on study. CONCLUSIONS. Doxorubicin-related CHF occurs with greater frequency and at a lower cumulative dose than previously reported. These findings further indicate that LVEF is not an accurate predictor of CHF in patients who receive doxorubicin. (C) 2003 American Cancer Society. C1 NIH, Dept Hlth & Human Serv, Gaithersburg, MD 20899 USA. Univ Texas, MD Anderson Canc Ctr, Dept Cardiol, Houston, TX USA. Univ Texas, MD Anderson Canc Ctr, Dept Med Affairs, Houston, TX USA. Pharmacia & Upjohn Inc, Global State & Programming, Kalamazoo, MI 49001 USA. RP Swain, SM (reprint author), NIH, Dept Hlth & Human Serv, 8901 Wisconsin Ave,Bldg 8,Room 5101, Gaithersburg, MD 20899 USA. OI Swain, Sandra/0000-0002-1320-3830 NR 24 TC 643 Z9 697 U1 3 U2 28 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JUN 1 PY 2003 VL 97 IS 11 BP 2869 EP 2879 DI 10.1002/cncr.11407 PG 11 WC Oncology SC Oncology GA 681DR UT WOS:000183022100022 PM 12767102 ER PT J AU Netzel-Arnett, S Hooper, JD Szabo, R Madison, EL Quigley, JP Bugge, TH Antalis, AM AF Netzel-Arnett, S Hooper, JD Szabo, R Madison, EL Quigley, JP Bugge, TH Antalis, AM TI Membrane anchored serine proteases: A rapidly expanding group of cell surface proteolytic enzymes with potential roles in cancer SO CANCER AND METASTASIS REVIEWS LA English DT Review DE serine protease; cancer; transmembrane; GPI anchor; TTSP; membrane ID AUTOSOMAL RECESSIVE DEAFNESS; TRYPSIN-LIKE PROTEASE; OVARIAN TUMOR-CELLS; HUMAN BREAST-CANCER; PROATRIAL NATRIURETIC PEPTIDE; BENIGN PROSTATIC HYPERPLASIA; TISSUE-SPECIFIC EXPRESSION; MATRIX-DEGRADING PROTEASE; RECEPTOR-RELATED PROTEIN; TESTICULAR GERM-CELLS AB Dysregulated proteolysis is a hallmark of cancer. Malignant cells require a range of proteolytic activities to enable growth, survival, and expansion. Serine proteases of the S1 or trypsin-like family have well recognized roles in the maintenance of normal homeostasis as well as in the pathology of diseases such as cancer. Recently a rapidly expanding subgroup of S1 proteases has been recognized that are directly anchored to plasma membranes. These membrane anchored serine proteases are anchored either via a carboxy-terminal transmembrane domain (Type I), a carboxy terminal hydrophobic region that functions as a signal for membrane attachment via a glycosyl-phosphatidylinositol linkage (GPI-anchored), or via an amino terminal proximal transmembrane domain (Type II or TTSP). The TTSPs also encode multiple domains in their stem regions that may function in regulatory interactions. The serine protease catalytic domains of these enzymes show high homology but also possess features indicating unique substrate specificities. It is likely that the membrane anchored serine proteases have evolved to perform complex functions in the regulation of cellular signaling events at the plasma membrane and within the extracellular matrix. Disruption or mutation of several of the genes encoding these proteases are associated with disease. Many of the membrane anchored serine proteases show restricted tissue distribution in normal cells, but their expression is widely dysregulated during tumor growth and progression. Diagnostic or therapeutic targeting of the membrane anchored serine proteases has potential as promising new approaches for the treatment of cancer and other diseases. C1 Amer Red Cross, Jerome H Holland Lab Biol Sci, Vasc Biol Dept, Rockville, MD 20855 USA. Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92093 USA. NIDCR, Proteases & Tissue Remodeling Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. Corvas Int, Dept Biol Mol, San Diego, CA 92121 USA. RP Antalis, AM (reprint author), Amer Red Cross, Jerome H Holland Lab Biol Sci, Vasc Biol Dept, 15601 Crabbs Branch Way, Rockville, MD 20855 USA. EM antalist@usa.redcross.org RI Hooper, John/B-4153-2011; Hooper, John/C-1481-2016 OI Hooper, John/0000-0003-1054-8486 NR 146 TC 197 Z9 209 U1 1 U2 17 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-7659 J9 CANCER METAST REV JI Cancer Metastasis Rev. PD JUN-SEP PY 2003 VL 22 IS 2-3 BP 237 EP 258 PG 22 WC Oncology SC Oncology GA 662ZH UT WOS:000181979500009 PM 12784999 ER PT J AU Blend, MJ Stastny, JJ Swanson, SM Brechbiel, MW AF Blend, MJ Stastny, JJ Swanson, SM Brechbiel, MW TI Labeling anti-HER2/neu monoclonal antibodies with In-111 and Y-90 using a bifunctional DTPA chelating agent SO CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS LA English DT Article DE radiolabeled Herceptin (R); In-111; Y-90-labeled anti-HER2/neu antibodies ID HUMAN-BREAST-CANCER; AMPLIFICATION; STABILITY; ONCOGENE; LIGAND; GENE AB The goal of this investigation was to develop stable radioimmunoconjugates (RICs) of anti-HER2/neu monoclonal antibodies (MoAbs) for imaging and therapy in an animal model bearing human breast tumor xenografts that express normal (MCF-7 cells) and increased amounts of HER2/neu receptors (HCC-1954, BT-474, SKBR-3 cells) on their cell surface membranes. Pharmacy-grade Herceptin, a murine anti-HER2/neu MoAb, and nonspecific mouse IgG protein were conjugated with the recently developed DTPA linker known as CHX-A"-DTPA. These immunoconjugates were labeled with (InCl3)-In-111 and (YCl3)-Y-90. Using a molar excess of 10:1 CHX-A"-DTPA to immunoglobulin, average specific activities of 1.87 muCi In-111/mug RIC and 2.71 muCi(90)Y/mug RIC were obtained. The purity of RICs was 96%+ for In-111 and 99%+ for Y-90. Stability in human plasma at 37degreesC for both RICs ranged from 98% at 24 h to 85% at 96 h. Binding capacity of the RICs was tested with human cancer cell lines MCF-7, HCC-1954, BT-474, and SKBR3. Using In-111-labeled nonspecific IgG protein as a control, In-111-Herceptin(R) RIC was found to bind to MCF-7 cells with a ratio of 2.5:1 and to SKBR-3 cells with a ratio of 85:1 after 3 h of incubation. In-111-anti-HER2/neu RIC bound to MCF-7 cells with a ratio of 6:1 and to SKBR-3 cells with a ratio of 115:1 after 3 h of incubation. 9 Y-anti-HER2/neu RIC bound 10-times greater to BT-474 cells than to MCF-7 cells. Thus, these MoAbs can be labeled with In-111 and Y-90 using the CHX-A"-DTPA linker. The resulting RICs (In-111- and Y-90-anti HER2/neu antibodies) are stable and bind significantly to HER2 overexpressing tumor cell lines. C1 Univ Illinois, Coll Med, Dept Radiol, Nucl Med Sect, Chicago, IL USA. Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, Chicago, IL USA. NCI, ROB, NIH, Bethesda, MD 20892 USA. RP Blend, MJ (reprint author), Univ Illinois Hosp, 1740 W Taylor St, Chicago, IL 60607 USA. NR 13 TC 31 Z9 38 U1 0 U2 4 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1084-9785 J9 CANCER BIOTHER RADIO JI Cancer Biother. Radiopharm. PD JUN PY 2003 VL 18 IS 3 BP 355 EP 363 DI 10.1089/108497803322285107 PG 9 WC Oncology; Medicine, Research & Experimental; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Research & Experimental Medicine; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging GA 705AK UT WOS:000184373900005 PM 12954122 ER PT J AU Tangrea, JA Albert, PS Lanza, E Woodson, K Corle, D Hasson, M Burt, R Caan, B Paskett, E Iber, F Kikendall, JW Lance, P Shike, M Weissfeld, J Schatzkin, A AF Tangrea, JA Albert, PS Lanza, E Woodson, K Corle, D Hasson, M Burt, R Caan, B Paskett, E Iber, F Kikendall, JW Lance, P Shike, M Weissfeld, J Schatzkin, A CA Polyp Prevention Study Grp TI Non-steroidal anti-inflammatory drug use is associated with reduction in recurrence of advanced and non-advanced colorectal adenomas (United States) SO CANCER CAUSES & CONTROL LA English DT Article DE adenomas; non-steroidal anti-inflammatory drugs; prospective; risk ID LONG-TERM USERS; REDUCED RISK; TUMOR-GROWTH; LARGE-BOWEL; ASPIRIN USE; RECTAL ADENOMAS; CANCER; SULINDAC; POLYPOSIS; INHIBITION AB Objective: To prospectively examine the association between non-steroidal anti-inflammatory drugs (NSAIDs) use (including dose and dosage schedule) and the recurrence of colorectal adenomas among individuals who were diagnosed with an adenoma at entry into a clinical trial. Methods: For this analysis, participants who completed the full follow-up (n = 1905) for the Polyp Prevention Trial (PPT) were evaluated. Information on current use and dose of NSAIDs and other drugs was obtained at baseline and at each subsequent study visit over the duration of the trial. The study endpoint was the recurrence of colorectal adenomas in the 3 years between the 1-year trial colonoscopy (T1) and the end of the trial colonoscopy (T4). Results: There was a significant reduction in overall adenoma recurrence among NSAIDs users (odds ratio [OR] = 0.77; 95% confidence interval [CI]: 0.63-0.95), with the greatest effect seen in advanced polyps (OR = 0.51; CI: 0.33-0.79). Among aspirin users, we observed a significant dose response for overall adenoma recurrence, with a 40% reduction in the OR association (OR = 0.56; 95% CI: 0.31-0.99) among those taking more than 325 mg per day. Conclusion: This prospective study provides further evidence that NSAIDs may play an important role in the chemoprevention of recurrent colorectal adenomas, even those with advanced features. C1 NCI, Ctr Canc Res, Canc Prevent Studies Branch, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Biometry Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. Westat Corp, Rockville, MD USA. Univ Utah, Salt Lake City, UT USA. Kaiser Fdn Res Inst, Oakland, CA USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. Vet Affairs Med Ctr, Vet Affairs Edward Hines Jr Hosp, Hines, IL USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. SUNY Buffalo, Sch Med & Biomed Sci, Buffalo, NY 14260 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Pittsburgh, Pittsburgh, PA USA. NCI, Nutrit Epidemiol Branch, Div Epidemiol & Genet, Bethesda, MD 20892 USA. RP Tangrea, JA (reprint author), NCI, Ctr Canc Res, Canc Prevent Studies Branch, Suite 321,6006 Execut Blvd, Bethesda, MD 20892 USA. RI Lance, Peter/I-2196-2014 OI Lance, Peter/0000-0003-2944-1881 NR 39 TC 50 Z9 54 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JUN PY 2003 VL 14 IS 5 BP 403 EP 411 DI 10.1023/A:1024990617158 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 705VU UT WOS:000184417300001 PM 12946034 ER PT J AU Lohrum, MAE Ludwig, RL Kubbutat, MHG Hanlon, M Vousden, KH AF Lohrum, MAE Ludwig, RL Kubbutat, MHG Hanlon, M Vousden, KH TI Regulation of HDM2 activity by the ribosomal protein L11 SO CANCER CELL LA English DT Article ID TUMOR-SUPPRESSOR P53; RING-FINGER DOMAIN; CELL-CYCLE ARREST; DNA-DAMAGE; NUCLEOLAR-LOCALIZATION; NUCLEAR EXPORT; ONCOPROTEIN MDM2; FEEDBACK LOOP; ACTINOMYCIN-D; HELA CELLS AB The HDM2 protein plays an important role in regulating the stability and function of the p53 tumor suppressor protein. In this report, we show that the ribosomal protein L11 can interact with HDM2 and inhibit HDM2 function, thus leading to the stabilization and activation of p53. The inhibition of HDM2 activity by L11 shows some similarity to the previously described activity of ARF, and expression of either ARF or H 1 can induce a p53 response. Enhancement of the interaction between endogenous L11 and HDM2 following treatment of cells with low levels of actinomycin-D suggests that the HDM2/L11 interaction represents a novel pathway for p53 stabilization in response to perturbations in ribosome biogenesis. C1 NCI, Frederick Canc Res & Dev Ctr, Regulat Cell Growth Lab, Frederick, MD 21702 USA. RP Vousden, KH (reprint author), NCI, Frederick Canc Res & Dev Ctr, Regulat Cell Growth Lab, Frederick, MD 21702 USA. NR 74 TC 391 Z9 400 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD JUN PY 2003 VL 3 IS 6 BP 577 EP 587 DI 10.1016/S1535-6108(03)00134-X PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 694TN UT WOS:000183790600010 PM 12842086 ER PT J AU Gravitt, PE Burk, RD Lorincz, A Herrero, R Hildesheim, A Sherman, ME Bratti, MC Rodriguez, AC Helzlsouer, KJ Schiffman, M AF Gravitt, PE Burk, RD Lorincz, A Herrero, R Hildesheim, A Sherman, ME Bratti, MC Rodriguez, AC Helzlsouer, KJ Schiffman, M TI A comparison between real-time polymerase chain reaction and hybrid capture 2 for human papillomavirus DNA quantitation SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SQUAMOUS INTRAEPITHELIAL LESIONS; UNDETERMINED SIGNIFICANCE; CERVICAL DISEASE; VIRAL LOAD; WOMEN; GRADE; PCR; TYPE-16; HPV-16; CANCER AB Studies investigating human papillomavirus (HPV) viral load as a risk factor in the development of squamous intraepithelial lesions (SILs) and cancer have often yielded conflicting results. These studies used a variety of HPV viral quantitation assays [including the commercially available hybrid capture 2 (HC 2) assay], which differ in their ability to account for differences in cervical cell collection, linear dynamic range of viral load quantitation, and determination of type-specific versus cumulative viral load measures. HPV-16 and HPV-18 viral quantitation using real-time PCR assays were performed to determine whether type-specific viral load measurements that adjust for specimen cellularity result in a different association between viral load and prevalent SH, and cancer, compared with HC 2 quantitation (which does not adjust for cellularity or multiple infections). In general, HPV-16 viral load as measured by real-time PCR increased linearly with increasing grade of SIL while HPV-18 measured using similar techniques increased through low-grade SIL (LSIL), with HPV-18 viral load among high-grade SIL and cancers near the level of cytologically normal women. HC 2 viral load, using the clinical 1.0 pg/ml cut point, differentiated cytologically normal women from women with any level of cytological abnormality (normal versus greater than or equal toLSIL) but did not change as lesion severity increased. There was no evidence for plateau of HC 2 at high copy numbers, nor was significant variability in total specimen cellularity observed. However, cumulative viral load measurements by HC 2, in the presence of multiple coinfections, overestimated type-specific viral load. Multiple infections were more common among women with no (32%) or LSIL (51%) [versus 23% in high-grade SIL/cancer], partially explaining the lack of a dose response using a cumulative HC2 viral load measure. The nonrandom distribution of multiple infections by case-control status and the apparent differential effect of viral load by genotype warrant caution when using HC 2 measurements to infer viral load associations with SIL and cancer. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. Digene Diagnost, Gaithersburg, MD USA. Proyecto Epidemiol Guanacaste, Guanacaste, Costa Rica. RP Gravitt, PE (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 22 TC 96 Z9 98 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2003 VL 12 IS 6 BP 477 EP 484 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 692PZ UT WOS:000183670600001 PM 12814990 ER PT J AU Kellerman, LC Valeyrie, L Fernandez, N Opolon, P Sabourin, JC Maubec, E Le Roy, P Kane, A Legrand, A Abina, MA Descamps, V Haddada, H AF Kellerman, LC Valeyrie, L Fernandez, N Opolon, P Sabourin, JC Maubec, E Le Roy, P Kane, A Legrand, A Abina, MA Descamps, V Haddada, H TI Regression of AK7 malignant mesothelioma established in immunocompetent mice following intratumoral gene transfer of interferon gamma SO CANCER GENE THERAPY LA English DT Article DE malignant mesothelioma; TGF-beta; gene transfer; recombinant adenovirus; IFN-gamma; apoptosis; tumor regression ID GROWTH-FACTOR-BETA; THYMIDINE KINASE GENE; CELL-LINES; PLEURAL MESOTHELIOMA; MESSENGER-RNAS; TGF-BETA; T-CELLS; INTERLEUKIN-6; THERAPY; CANCER AB Malignant mesothelioma ( MM) is a lethal tumor linked with a prior exposure to asbestos in which limited progress has been made so far using conventional therapies. MM is an example of a "nonimmunogenic'' tumor characterized by a fibrous stroma and an absence of infiltrating T lymphocytes. High levels of transforming growth factor-beta (TGF-beta) produced by mesothelioma cells have been related to the immune tolerance towards the tumor. In order to evaluate the effect of local delivery of cytokines such as interferon gamma (IFN-gamma) by gene transfer, we characterized and used a murine model, AK7, which appeared very similar to human mesothelioma. AK7 cells expressed low levels of major histocompatibility class I and class II antigens and secreted high levels of latent TGF-beta. The TGF-beta pathway in AK7 cells is operative but inefficient because endogenous TGF-beta is predominantly inactive. Treatment of pre-established AK7 tumors by direct intratumoral injection of an adenovirus vector expressing murine IFN-gamma, Ad. mIFN-gamma, led to significant tumor regression. Peripheral tumor infiltration by CD4+ and CD8+ T lymphocytes in the treated tumors appeared to be because of the induction of an immune response. Tumor relapse was observed, which could be due to local TGF-beta secretion by remaining tumor cells. C1 Inst Gustave Roussy, F-94805 Villejuif, France. Transgene SA, Strasbourg, France. Brown Univ, Dept Pathol & Lab Med, Providence, RI 02912 USA. Univ Montreal, Dept Microbiol & Immunol, Montreal, PQ H3C 3J7, Canada. Hop Bichat, F-75877 Paris, France. RP Haddada, H (reprint author), VRC NIH, Bldg 40, Bethesda, MD 20892 USA. NR 42 TC 9 Z9 9 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD JUN PY 2003 VL 10 IS 6 BP 481 EP 490 DI 10.1038/sj.cgt.7700594 PG 10 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 686AW UT WOS:000183299100007 ER PT J AU Daoud, SS Munson, PJ Reinhold, W Young, L Prabhu, VV Yu, QA LaRose, J Kohn, KW Weinstein, JN Pommier, Y AF Daoud, SS Munson, PJ Reinhold, W Young, L Prabhu, VV Yu, QA LaRose, J Kohn, KW Weinstein, JN Pommier, Y TI Impact of p53 knockout and topotecan treatment on gene expression profiles in human colon carcinoma cells: A pharmacogenomic study SO CANCER RESEARCH LA English DT Article ID MOLECULAR PHARMACOLOGY; TOPOISOMERASE-I; TARGET GENES; S100A4 MTS1; CANCER; METASTASIS; PROTEIN; GROWTH; CALCIUM; PHOSPHORYLATION AB To uncover transcriptional stress responses related to p53, we used cDNA microarrays (National Cancer Institute Oncochips comprising 6500 different genes) to characterize the gene expression profiles of wild-type p53 HCT-116 cells and an isogenic p53 knockout counterpart after treatment with topotecan, a specific topoisomerase I inhibitor. The use of the p53 knockout cells had the advantage over p53-overexpressing systems in that p53 activation is mediated physiologically. RNA was extracted after low (0.1 muM)- and high (1 muM)-dose topotecan at multiple time points within the first 6 h of treatment. To facilitate simultaneous study of the p53 status and pharmacological effects on gene expression, we developed a novel "cross-referenced network" experimental design and used multiple linear least squares fitting to optimize estimates of relative transcript levels in the network of experimental conditions. Approximately 10% of the transcripts were up- or down-regulated in response to topotecan in the p53+/+ cells, whereas only 1% of the transcripts changed in the p53-/- cells, indicating that p53 has a broad effect on the transcriptional response to this stress. Individual transcripts and their relationships were analyzed using clustered image maps and by a novel two-dimensional analysis/visualization, gene expression map, in which each gene expression level is represented as a function of both the genotypic/phenotypic difference (i.e., p53 status) and the treatment effect (i.e., of topotecan dose and time of exposure). Overall, drug-induced p53 activation was associated with a coherent genetic program leading to cell cycle arrest and apoptosis. We identified novel p53-induced and DNA damage-induced genes (the proapoptotic SIVA gene and a set of transforming growth factor beta-related genes). Genes induced independently of p53 included the antiapoptotic cFLIP gene and known stress genes related to the mitogen-activated protein kinase pathway and the Fos/Jun pathway. Genes that were negatively regulated by p53 included members of the antiapoptotic protein chaperone heat shock protein 70 family. Finally, among the p53-dependent genes whose expression was independent of drug treatment was S100A4, a small Ca2+-binding protein that has recently been implicated in p53 binding and regulation. The new experimental design and gene expression map analysis introduced here are applicable to a wide range of studies that encompass both treatment effects and genotypic or phenotypic differences. C1 Washington State Univ, Dept Pharmaceut Sci, Canc Prevent & Res Ctr, Pullman, WA 99164 USA. NCI, Math & Stat Comp Lab, Ctr Informat Technol, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Daoud, SS (reprint author), Washington State Univ, Dept Pharmaceut Sci, Canc Prevent & Res Ctr, 259 Wegner Hall, Pullman, WA 99164 USA. NR 33 TC 59 Z9 62 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 1 PY 2003 VL 63 IS 11 BP 2782 EP 2793 PG 12 WC Oncology SC Oncology GA 686WD UT WOS:000183343200013 PM 12782583 ER PT J AU Rybak, SM Sanovich, E Hollingshead, MG Borgel, SD Newton, DL Melillo, G Kong, DH Kaur, G Sausville, EA AF Rybak, SM Sanovich, E Hollingshead, MG Borgel, SD Newton, DL Melillo, G Kong, DH Kaur, G Sausville, EA TI "Vasocrine" formation of tumor cell-lined vascular spaces: Implications for rational design of antiangiogenic therapies SO CANCER RESEARCH LA English DT Article ID INFLAMMATORY BREAST-CANCER; BLOOD-VESSELS; VASCULOGENIC MIMICRY; ENDOTHELIAL-CELLS; GROWTH-FACTORS; IN-VITRO; ANGIOGENESIS; VIVO AB Here we report that B16F10 murine melanoma cells mimic endothelial cell behavior and the angiogenic process in vitro and in vivo. Cord formation in vitro by tumor cells is stimulated by hypoxia and vascular endothelial growth factor (VEGF) and inhibited by antibodies against VEGF and the VEGF KDR receptor (VEGF receptor 2). We define regulation of tumor cell-derived vascular space formation by these vasoactive compounds as "vasocrine" stimulation. ICRF 159 (Razoxane; NSC 129943) prevents tumor cell but not endothelial cell cord formation in vitro, and the antiangiogenic drug TNP-470 (NSC 642492) inhibits endothelial but not tumor cell cord formation in vitro. Both drugs inhibit formation of blood-filled vascular spaces in vivo. These results bear on the anticipated action of ICRF 159 in human clinical trials and novel strategies for targeting tumor blood supplies. C1 NCI, Frederick Canc Res & Dev Ctr, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp, Frederick, MD 21702 USA. RP Sausville, EA (reprint author), NCI, Dev Therapeut Program, Execut Plaza N,Room 8018,6130 Execut Blvd, Rockville, MD 20852 USA. FU PHS HHS [N01-C0-56000] NR 33 TC 38 Z9 39 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 JUN 1 PY 2003 VL 63 IS 11 BP 2812 EP 2819 PG 8 WC Oncology SC Oncology GA 686WD UT WOS:000183343200016 PM 12782586 ER PT J AU Lapointe, R Bellemare-Pelletier, A Housseau, F Thibodeau, J Hwu, P AF Lapointe, R Bellemare-Pelletier, A Housseau, F Thibodeau, J Hwu, P TI CD40-stimulated B lymphocytes pulsed with tumor antigens are effective antigen-presenting cells that can generate specific T cells SO CANCER RESEARCH LA English DT Article ID CLASS-II MOLECULES; HLA-DO; DENDRITIC CELLS; IN-VITRO; MHC; PEPTIDE; DM; LIGAND; CD40; CHAIN AB Although they are considered as antigen-presenting cells, the role of antigen-unspecific B lymphocytes in antigen presentation and T-lymphocyte stimulation remains controversial. In this paper, we tested the capacity of normal human peripheral activated B cells to stimulate T cells using melanoma antigens or melanoma cell lysates. B lymphocytes activated through CD40 ligation and then pulsed with tumor antigens efficiently processed and presented MHC class II-restricted peptides to specific CD4(+) T-cell clones. This suggests that CD40-activated B cells have the functional and molecular competence to present MHC class II epitopes when pulsed with exogenous antigens, thereby making them a relevant source of antigen-presenting cells to generate T cells. To test this hypothesis, CD40-activated B cells were pulsed with a lysate prepared from melanoma cells and used to stimulate peripheral autologous T cells. Interestingly, T cells specific to melanoma antigens were generated. Additional analysis of these T-cell clones revealed that they recognized MHC class II-restricted epitopes from tyrosinase, a known melanoma tumor antigen. The efficient antigen presentation by antigen-unspecific activated B cells was correlated with a down-regulation in the expression of HLA-DO, a B cell-specific protein known to interfere with HLA-DM function. Because HLA-DM is important in MHC class II peptide loading, the observed decrease in HLA-DO may partially explain the enhanced antigen presentation after B-cell activation. Results globally suggest that when they are properly activated, antigen-unspecific B-lymphocytes can present exogenous antigens by MHC class II molecules and stimulate peripheral antigen-specific T cells. Antigen presentation by activated B cells could be exploited for immunotherapy by allowing the in vitro generation of T cells specific against antigens expressed by tumors or viruses. C1 NCI, NIH, Bethesda, MD 20892 USA. Univ Montreal, Dept Microbiol & Immunol, Lab Immunol Mol, Montreal, PQ H3C 3J7, Canada. RP Hwu, P (reprint author), NCI, NIH, Bldg 10,Room 2B42,10 Ctr Dr, Bethesda, MD 20892 USA. NR 37 TC 119 Z9 128 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 1 PY 2003 VL 63 IS 11 BP 2836 EP 2843 PG 8 WC Oncology SC Oncology GA 686WD UT WOS:000183343200019 PM 12782589 ER PT J AU Musio, A Montagna, C Zambroni, D Indino, E Barbieri, O Citti, L Villa, A Ried, T Vezzoni, P AF Musio, A Montagna, C Zambroni, D Indino, E Barbieri, O Citti, L Villa, A Ried, T Vezzoni, P TI Inhibition of BUB1 results in genomic instability and anchorage-independent growth of normal human fibroblasts SO CANCER RESEARCH LA English DT Article ID CHINESE-HAMSTER CELLS; CHROMOSOMAL-ABERRATIONS; HAMMERHEAD RIBOZYMES; GENETIC INSTABILITY; COLORECTAL CANCERS; LIFE-SPAN; ANEUPLOIDY; TELOMERASE; MUTATIONS; APOPTOSIS AB The relative contribution of aneuploidy and gene mutations to human tumorigenesis is not yet known. Studies in mice have demonstrated that even single point mutations in oncogenes and tumor suppressor genes can dramatically increase tumor frequency. However, models to evaluate the definitive role of aneuploidy and genomic instability are not yet available. Human fibroblast cells have long been used as a tool for investigating proliferation, senescence, immortalization, and tumorigenesis, all processes that are strongly interrelated. We have now used antisense and ribozyme-mediated temporary inhibition of BUB1 to study the consequences of mitotic checkpoint failure on the development of aneuploidy. The analysis of cell colonies selected by soft agar growth showed evidence of chromosome instability and delayed senescence, without being tumorigenic in nude mice. Our data suggest that chromosomal instability and aneuploidy are early changes that precede tumorigenicity in the multistep process leading to neoplastic transformation. C1 CNR, Ist Tecnol Biol, I-20090 Segrate, Milan, Italy. NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Osped Poliambulanza, Ctr Ric Parco Sci E Menni, I-25100 Brescia, Italy. Ist Zooprofilattico Sperimentale Reg Lazio & Tosc, Dipartimento Firenze, I-50010 Florence, Italy. Univ Genoa, Dipartimento Oncol Biol & Genet, IST, I-16132 Genoa, Italy. CNR, Ist Fisiol Clin, I-56124 Pisa, Italy. RP Musio, A (reprint author), CNR, Ist Tecnol Biol, Via Fratelli Cervi 93, I-20090 Segrate, Milan, Italy. RI Barbieri, Ottavia/E-8768-2011; OI Villa, Anna/0000-0003-4428-9013 NR 42 TC 47 Z9 48 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 JUN 1 PY 2003 VL 63 IS 11 BP 2855 EP 2863 PG 9 WC Oncology SC Oncology GA 686WD UT WOS:000183343200021 PM 12782591 ER PT J AU Sriuranpong, V Park, JI Amornphimoltham, P Patel, V Nelkin, BD Gutkind, JS AF Sriuranpong, V Park, JI Amornphimoltham, P Patel, V Nelkin, BD Gutkind, JS TI Epidermal growth factor receptor-independent constitutive activation of STAT3 in head and neck squamous cell carcinoma is mediated by the autocrine/paracrine stimulation of the interleukin 6/gp130 cytokine system SO CANCER RESEARCH LA English DT Article ID PERIPHERAL-BLOOD CELLS; BREAST-CANCER CELLS; SERINE PHOSPHORYLATION; TYROSINE PHOSPHORYLATION; TRANSCRIPTION FACTORS; MAXIMAL ACTIVATION; EXPRESSION; LINES; APOPTOSIS; KINASE AB The aberrant growth of head and neck squamous cell carcinoma (HNSCC) is often associated with the constitutive activation of signal-transducer-and-activator-of-transcription-3 (STAT3), which is believeed to result from the persistent stimulation of EGF receptors that are highly expressed in squamous cell carcinoma (SCC) cells. To investigate he mechanism underlying STAT3 deregulation in HNSCC, we examined the interplay of the STAT3 and epidermal growth factor receptor (EGFR) signaling pathways using a panel of HNSCC cell lines. Although STAT3 was active in most HNSCC cell lines, only 3 of 10 HNSCC cell lines were moderately to strongly positive for activated EGFR. Even in the EGFR-positive cell lines, STAT3 activation was not dependent on EGFR activation, as STAT3 tyrosine phosphorylation levels persisted after treatment with AG1478, a chemical inhibitor of EGFR activity. Furthermore, we found that conditioned medium harvested from HNSCC cells could induce STAT3 tyrosine phosphorylation in immortalized keratinocytes regardless of the status of EGFR signaling. In contrast, blocking the cytokine gp130 coreceptor abolished STAT3 tyrosine phosphorylation in HNSCC cells and that induced by the conditioned medium. Immunodepletion studies suggested interleukin 6 (IL6) as the major autocrine/paracrine factor for STAT3 activation, which coincided with high levels of secretion of IL6 into the culture medium by these cancer cells. Treatment with a specific inhibitor of Janus kinase, AG490, in HNSCC cells led to a reduction of active STAT3 and caused significant growth retardation and apoptosis. Thus, constitutive activation of STAT3 in HNSCC may use an autocrine/paracrine-activating loop mediated by IL6 and other cytokines acting through the gp130 receptor family, which may confer both proliferative and survival potential in this malignancy. C1 Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Ctr Oncol, Baltimore, MD 21231 USA. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Bldg 30,Room 211, Bethesda, MD 20892 USA. RI Gutkind, J. Silvio/A-1053-2009 NR 51 TC 168 Z9 174 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 1 PY 2003 VL 63 IS 11 BP 2948 EP 2956 PG 9 WC Oncology SC Oncology GA 686WD UT WOS:000183343200032 PM 12782602 ER PT J AU Pompeia, C Lima, T Curi, R AF Pompeia, C Lima, T Curi, R TI Arachidonic acid cytotoxicity: can arachidonic acid be a physiological mediator of cell death? SO CELL BIOCHEMISTRY AND FUNCTION LA English DT Review DE arachidonic acid; apoptosis; necrosis; oxidative stress; eicosanoids; inflammation; cytotoxicity ID POLYUNSATURATED FATTY-ACIDS; TUMOR-NECROSIS-FACTOR; MITOCHONDRIAL PERMEABILITY TRANSITION; CYTOSOLIC PHOSPHOLIPASE A(2); HL-60 CELLS; IN-VITRO; HISTONE DEACETYLASE; OXIDATIVE STRESS; NADPH OXIDASE; CYTOCHROME-C AB Arachidonic acid is a polyunsaturated fatty acid that mediates inflammation and the functioning of several organs and systems either directly or upon its conversion into eicosanoids. However, arachidonic acid is found to be cytotoxic in vitro at concentrations that overlap physiological ones. It is tempting therefore to speculate that arachidonic acid may be a physiological inducer of apoptosis and that such cytotoxic action may be another of its roles in vivo. Nevertheless its pro-inflammatory and oxidative stress-inducing features are characteristic of necrosis and pathological conditions. We hereby review the cytotoxic action of arachidonic acid, indicate the possible pathways that lead to cell death and contemplate the cytotoxic role of arachidonic acid in vivo. Copyright (C) 2003 John Wiley Sons, Ltd. C1 Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. Univ Sao Paulo, Lab Cell Physiol, Dept Physiol & Biophys, Inst Biomed Sci, BR-05508 Sao Paulo, SP, Brazil. RP Pompeia, C (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, Bldg 50,Rm 4240,50 South Dr, Bethesda, MD 20892 USA. NR 59 TC 60 Z9 61 U1 0 U2 3 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0263-6484 J9 CELL BIOCHEM FUNCT JI Cell Biochem. Funct. PD JUN PY 2003 VL 21 IS 2 BP 97 EP 104 DI 10.1002/cbf.1012 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 679ZK UT WOS:000182951700001 PM 12736897 ER PT J AU Katsetos, CD Herman, MM Mork, SJ AF Katsetos, CD Herman, MM Mork, SJ TI Class III beta-tubulin in human development and cancer SO CELL MOTILITY AND THE CYTOSKELETON LA English DT Review DE class III beta-tubulin; cell distribution; neurons; glia; development; cancer ID MICROTUBULE-ASSOCIATED PROTEIN-2; PROSTATE CARCINOMA-CELLS; ORGAN-CULTURE SYSTEM; IMMUNOHISTOCHEMICAL CHARACTERIZATION; COMPARATIVE IMMUNOBLOT; MONOCLONAL-ANTIBODY; PRECURSOR CELLS; ALPHA-TUBULIN; MOUSE-BRAIN; IN-VITRO AB The differential cellular expression of class III beta-tubulin isotype (betaIII) is reviewed in the context of human embryological development and neoplasia. As compared to somatic organs and tissues, betaIII is abundant in the central and peripheral nervous systems (CNS and PNS) where it is prominently expressed during fetal and postnatal development. As exemplified in cecebellar and sympathoadrenal neurogenesis, the distribution of betaIII is neuron-associated, exhibiting distinct temporospatial gradients according to the regional neuroepithelia of origin. However, transient expression of this protein is also present in the subventricular zones of the CNS comprising putative neuronal- and/or glial precursor cells, as well as in Kulchitsky neuroendocrine cells of the fetal respiratory epithelium. This temporally restricted, potentially non-neuronal expression may have implications in the identification of presumptive neurons derived from embryonic stem cells. In adult tissues, the distribution of betaIII is almost exclusively neuron-specific. Altered patterns of expression are noted in cancer. In "embryonal" and "adult-type" neuronal tumors of the CNS and PNS, betaIII is associated with neuronal differentiation and decreased cell proliferation. In contrast, the presence of betaIII in gliomas and lung cancer is associated with an ascending histological grade of malignancy. Thus, betaIII expression in neuronal tumors is differentiation-dependent, while in non-neuronal tumors it is aberrant and/or represents "dedifferentiation" associated with the acquisition of progenitor-like phenotypic properties. Increased expression in various epithelial cancer cell lines is associated with chemoresistance to taxanes. Because betaIII is present in subpopulations of neoplastic, but not in normal differentiated glial or somatic epithelial cells, the elucidation of mechanisms responsible for the altered expression of this isotype may provide insights into the role of the microtubule cytoskeleton in tumorigenesis and tumor progression. (C) 2003 Wiley-Liss, Inc. C1 Univ Bergen, Gade Inst, Dept Pathol, Haukeland Hosp, Bergen, Norway. NIMH, Neuropathol Sect, Clin Brain Disorders Branch, IRP,NIH, Bethesda, MD 20892 USA. St Christophers Hosp Children, Res Labs, Neurol Sect, Dept Pathol & Lab Med, Philadelphia, PA 19134 USA. Drexel Univ, Coll Med, Dept Pediat, Neurol Sect, Philadelphia, PA USA. RP Katsetos, CD (reprint author), St Christophers Hosp Children, Res Labs, Neurol Sect, Dept Pathol & Lab Med, Erie Ave & Front St, Philadelphia, PA 19134 USA. NR 116 TC 153 Z9 159 U1 2 U2 10 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0886-1544 J9 CELL MOTIL CYTOSKEL JI Cell Motil. Cytoskeleton PD JUN PY 2003 VL 55 IS 2 BP 77 EP 96 DI 10.1002/cm.10116 PG 20 WC Cell Biology SC Cell Biology GA 684UF UT WOS:000183224400001 PM 12740870 ER PT J AU Creveling, CR AF Creveling, CR TI Honoring John William Daly - Foreword SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Biographical-Item C1 NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Creveling, CR (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD JUN PY 2003 VL 23 IS 3 BP 285 EP 287 DI 10.1023/A:1023628318904 PG 3 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 675DW UT WOS:000182678600001 ER PT J AU Shi, D Padgett, WL Daly, JW AF Shi, D Padgett, WL Daly, JW TI Caffeine analogs: Effects on ryanodine-sensitive calcium-release channels and GABA(A) receptors SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article DE caffeine; xanthines; diazepam; ryanodine; GABA receptors; calcium-release channels ID RAT-BRAIN MEMBRANES; MUSCLE SARCOPLASMIC-RETICULUM; ADENOSINE RECEPTORS; BENZODIAZEPINE RECEPTORS; BINDING-SITES; STRUCTURAL ALTERATIONS; INTRACELLULAR CALCIUM; CELLS; PHOSPHODIESTERASE; ANTAGONIST AB 1. Caffeine at 0.3-10 mM enhanced the binding of [H-3] ryanodine to calcium-release channels of rabbit muscle sarcoplasmic reticulum. A variety of other xanthines were as efficacious as caffeine or nearly so, but none appeared markedly more potent. 2. Caffeine at 1 mM markedly inhibited binding of [H-3] diazepam to GABA(A) receptors in rat cerebral cortical membranes. 3. Other xanthines also inhibited binding with certain dimethylpropargylxanthines being nearly fivefold more potent than caffeine. 4. Caffeine at 1 mM stimulated binding of [S-35] TBPS to GABAA receptors as did certain other xanthines. 5. The dimethylpropargylxanthines had little effect. 1,3-Dipropy1-8-cyclopentylxanthine at 100 1 muM had no effect on [H-3] diazepam binding, but markedly inhibited [S-35] TBPS binding. 6. Structure-activity relationships for xanthines do differ for calcium-release channels and and for different sites on GABA(A) receptors, but no highly selective lead compounds were identified. C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Daly, JW (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bldg 8,Room 1A17, Bethesda, MD 20892 USA. NR 56 TC 18 Z9 22 U1 0 U2 8 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD JUN PY 2003 VL 23 IS 3 BP 331 EP 347 DI 10.1023/A:1023688604792 PG 17 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 675DW UT WOS:000182678600006 PM 12825831 ER PT J AU Kim, SG Gao, ZG Soltysiak, KA Chang, TS Brodie, C Jacobson, KA AF Kim, SG Gao, ZG Soltysiak, KA Chang, TS Brodie, C Jacobson, KA TI P2Y(6) nucleotide receptor activates PKC to protect 1321N1 astrocytoma cells against tumor necrosis factor-induced apoptosis SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article DE nucleotide; pyrimidines; agonist; cell death; protein kinase; phospholipase C ID NF-KAPPA-B; ARTERY ENDOTHELIAL-CELLS; SMOOTH-MUSCLE CELLS; GROWTH-FACTOR-I; FACTOR-ALPHA; KINASE-C; SIGNAL-TRANSDUCTION; MEDIATED APOPTOSIS; EXTRACELLULAR ATP; DNA-SYNTHESIS AB 1. We recently reported that the activation by UDP of rat P2Y(6) nucleotide receptors expressed in 1321N1 astrocytoma cells protected them from TNFalpha-induced apoptosis by suppressing activation of caspase 3 and 8. This study aims to characterize the involvement of intracellular signaling pathways, including kinases, involved in the antiapoptotic effect of UDP. 2. Cell death was induced in 1321N1 astrocytoma cells permanently expressing the rat P2Y(6) receptor by exposure to TNFalpha in the presence of cycloheximide. The apoptotic fraction was analyzed using flow cytometry. 3. The activation of P2Y(6) receptors by UDP both protected the astrocytes from TNF-alpha induced apoptosis and activated protein kinase C ( PKC) isotypes. The phorbol ester PMA also activated PKC and protected the cells from TNFalpha-induced cell death. The alpha- and epsilon-isotypes of PKC were both activated in a persistent fashion upon 5-min exposure to either UDP ( 10 muM) or the phorbol ester PMA ( 100 nM). The PKCzeta isotype was markedly activated upon UDP treatment. 4. The addition of PKC inhibitors, GF109203X or Go6976, partially antagonized the protective effect of UDP and reduced the UDP-induced phosphorylation of extracellular signal-regulated protein kinases ( Erk). The inhibitors of Erk, PD98,059 or U0126, antagonized UDP-induced protection. 5. The antiapoptotic protein, Akt, was not affected by P2Y(6) receptor activation. Incubation of the astrocytes with calcium modifiers, BAPTA-AM or dantrolene, did not affect the UDP-induced protection from apoptosis. 6. The addition of phospholipase C ( PLC) inhibitors, D609 or U73122, partially antagonized both UDP-induced protection and PKC activation. C1 NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Lab Cell Signaling, NCI, NIH, Bethesda, MD 20892 USA. Bar Ilan Univ, Dept Life Sci, Ramat Gan, Israel. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Room B1A-19, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031116-20] NR 59 TC 29 Z9 29 U1 0 U2 1 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD JUN PY 2003 VL 23 IS 3 BP 401 EP 418 DI 10.1023/A:1023696806609 PG 18 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 675DW UT WOS:000182678600010 PM 12825835 ER PT J AU Fedorova, IM Jacobson, MA Basile, A Jacobson, KA AF Fedorova, IM Jacobson, MA Basile, A Jacobson, KA TI Behavioral characterization of mice lacking the A(3) adenosine receptor: Sensitivity to hypoxic neurodegeneration SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article DE adenosine receptor; neurodegeneration; knockout mice; analgesia; depression ID DELAYED NEURONAL DEATH; TARGETED DELETION; A(1) RECEPTOR; MOUSE HEART; KNOCK-OUT; IB-MECA; CELLS; ACTIVATION; LIGANDS; RELEASE AB 1. The potential neuroprotective actions of the A(3) adenosine receptor (A(3)AR) were investigated using mice with functional deletions of the A(3)AR (A(3)AR(-/-)) in behavioral assessments of analgesia, locomotion, tests predictive of depression and anxiety, and the effects of mild hypoxia on cognition and neuronal survival. 2. Untreated A(3)AR(-/-) mice were tested in standard behavioral paradigms, including activity in the open field, performance in the hot-plate, tail-flick, tail-suspension, and swim tests, and in the elevated plus maze. In addition, mice were exposed repeatedly to a hypoxic environment containing carbon monoxide (CO). The cognitive effects of this treatment were assessed using the contextual fear conditioning test. After testing, the density of pyramidal neurons in the CA1, 2, and 3 subfields of the hippocampus was determined using standard histological and morphometric techniques. 3. A(3)AR(-/-) mice showed increased locomotion in the open field test, elevated plus maze (number of arm entries) and light/dark box (number of transitions). However, they spent more time immobile in two different tests of antidepressant activity (Swim and tail suspension tests). A(3)AR(-/-) mice also showed evidence of decreased nociception in the hotplate, but not tail-flick tests. Further, A(3)AR(-/-) mice were more vulnerable to hippocampal pyramidal neuron damage following episodes of carbon monoxide (CO)-induced hypoxia. One week after exposure to CO a moderate loss of pyramidal neurons was observed in all hippocampal subfields of both wild-type (A(3)AR(+/+)) and A(3)AR(-/-) mice. However, the extent of neuronal death in the CA2-3 subfields was less pronounced in A(3)AR(+/+) than A(3)AR(+/+) mice. This neuronal loss was accompanied by a decline in cognitive function as determined using contextual fear conditioning. These histological and cognitive changes were reproduced in wild-type mice by repeatedly administering the A(3)AR-selective antagonist MRS 1523 (5-propyl-2-ethyl-4-propyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate 1 mg/kg i.p.). 4. These results indicate that pharmacologic or genetic suppression of A(3)AR function enhances some aspects of motor function and suppresses pain processing at supraspinal levels, while acting as a depressant in tests predictive of antidepressant action. Consistent with previous reports of the neuroprotective actions of A(3)AR agonists, A(3)AR(-/-) mice show an increase in neurodegeneration in response to repeated episodes of hypoxia. C1 NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD USA. Merck Res Labs, Dept Neurosci, W Point, PA USA. RP Basile, A (reprint author), Alkermes Inc, Biol Res, 88 Sidney St, Cambridge, MA 02139 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031117-20] NR 37 TC 60 Z9 62 U1 2 U2 3 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD JUN PY 2003 VL 23 IS 3 BP 431 EP 447 DI 10.1023/A:1023601007518 PG 17 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 675DW UT WOS:000182678600012 PM 12825837 ER PT J AU Johnson, BM Qiu, SX Zhang, SD Zhang, FG Burdette, JE Yu, LN Bolton, JL van Breemen, RB AF Johnson, BM Qiu, SX Zhang, SD Zhang, FG Burdette, JE Yu, LN Bolton, JL van Breemen, RB TI Identification of novel electrophilic metabolites of Piper methysticum Forst. (Kava) SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID EXTRACT; BIOACTIVATION; KAVALACTONES; PYRONES; SAFROLE; RATS AB Dietary supplements containing Piper methysticum Forst. (kava) have been implicated in multiple cases of liver injury in humans, including 10 recently reviewed cases in which patients required liver transplantation following the usage of kava-containing products (Centers for Disease Control and Prevention, reprinted. (2003) J. Am. Med. Assoc. 289, 36-37). To investigate a possible mechanism(s) of kava-induced hepatotoxicity, an extract of kava was incubated in vitro with hepatic microsomes, NADPH, and GSH. Electrophilic intermediates that were generated via metabolic activation were trapped as GSH conjugates and removed from the protein mixture using ultrafiltration. Positive ion electrospray LC-MS/MS with precursor ion scanning was used for the selective detection of GSH conjugates, and LC-MSn product ion scanning was used to elucidate their structures. Using this in vitro MS-based screening assay, two novel electrophilic metabolites of kava, 11,12-dihydroxy-7,8-dihydrokavain-o-quinone and 11,12-dihydroxykavain-o-quinone, were identified. Mercapturic acids of these quinoid species were not detected in the urine of a human volunteer following ingestion of a dietary supplement that contained kava; instead, the corresponding catechols were metabolized extensively to glucuronic acid and sulfate conjugates. These observations indicate that quinoid metabolites, under most circumstances, are probably not formed in substantial quantities following the ingestion of moderate doses of kava. However, the formation of electrophilic quinoid metabolites by hepatic microsomes in vitro suggests that such metabolites might contribute to hepatotoxicity in humans when metabolic pathways are altered (e.g., because of a drug interaction, genetic difference in enzyme expression, etc.) or if conjugation pathways become saturated. C1 Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, Chicago, IL 60612 USA. Univ Illinois, Coll Pharm, NIH, Ctr Bot Dietary Supplements Res, Chicago, IL 60612 USA. Herbstand Inc, Chesterfield, MO 63017 USA. RP van Breemen, RB (reprint author), Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, 8363 S Wood St, Chicago, IL 60612 USA. FU NCCIH NIH HHS [P50 AT00155] NR 27 TC 49 Z9 50 U1 1 U2 7 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 JUN PY 2003 VL 16 IS 6 BP 733 EP 740 DI 10.1021/tx020113r PG 8 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 692QU UT WOS:000183672400008 PM 12807356 ER PT J AU Cuajungco, MP Ando, Y Axelrod, FB Biaggioni, I Goldstein, DS Guttmacher, AE Gwinn-Hardy, K Hahn, MK Hilz, MJ Jacob, G Jens, J Kennedy, WR Liggett, SB O'Connor, DT Peltzer, SR Robertson, D Rubin, BY Scudder, Q Smith, LJ Sonenshein, GE Svejstrup, JQ Xu, Y Slaugenhaupt, SA AF Cuajungco, MP Ando, Y Axelrod, FB Biaggioni, I Goldstein, DS Guttmacher, AE Gwinn-Hardy, K Hahn, MK Hilz, MJ Jacob, G Jens, J Kennedy, WR Liggett, SB O'Connor, DT Peltzer, SR Robertson, D Rubin, BY Scudder, Q Smith, LJ Sonenshein, GE Svejstrup, JQ Xu, Y Slaugenhaupt, SA TI Hereditary dysautonomias: current knowledge and collaborations for the future SO CLINICAL AUTONOMIC RESEARCH LA English DT Review DE autonomic nervous system; catecholamine; neuropathy; amyloidosis ID FAMILIAL AMYLOIDOTIC POLYNEUROPATHY; INHIBITORY PEPTIDE CATESTATIN; NOREPINEPHRINE-TRANSPORTER DEFICIENCY; IDIOPATHIC ORTHOSTATIC INTOLERANCE; POLYMERASE-II HOLOENZYME; RENIN-ANGIOTENSIN SYSTEM; MOUSE IKBKAP GENE/; B KINASE COMPLEX; CATECHOLAMINE RELEASE; PARKINSON-DISEASE AB The hereditary dysautonomias (H-Dys) are a large group of disorders that affect the autonomic nervous system. Research in the field of H-Dys is very challenging, because the disorders involve interdisciplinary, integrative, and "mind-body" connections. Recently, medical scientists, NIH/NINDS representatives, and several patient support groups gathered for the first time in order to discuss recent findings and future directions in the H-Dys field. The H-Dys workshop was instrumental in promoting interactions between basic science and clinical investigators. It also allowed attendees to have an opportunity to meet each other, understand the similarities between the various forms of dysautonomia, and experience the unique perspective offered by patients and their families. Future advances in H-Dys research will depend on a novel multi-system approach by investigators from different medical disciplines, and it is hoped that towards a common goal, novel "bench-to-bedside" therapeutics will be developed to improve the lives of, or even cure, patients suffering from dysautonomic syndromes. C1 Massachusetts Gen Hosp, Dept Neurol, Mol Neurogenet Unit, Charlestown, MA USA. Kumamoto Univ, Sch Med, Dept Lab Med, Kumamoto 860, Japan. NYU, Sch Med, Dept Pediat, New York, NY USA. NYU, Sch Med, Dept Neurol, New York, NY USA. Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA. NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD USA. Natl Human Genome Res Inst, NIH, Bethesda, MD USA. NINDS, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Ctr Med, Ctr Mol Neurosci, Dept Pharmacol, Nashville, TN 37232 USA. Univ Erlangen Nurnberg, Dept Neurol, D-8520 Erlangen, Germany. Rambam Med Ctr, Jacob Recanati Autonom Dysfunct Ctr, Haifa, Israel. Humboldt Univ, Franz Volhard Clin Res Ctr, Berlin, Germany. Univ Minnesota, Dept Neurol, Minneapolis, MN 55455 USA. Univ Cincinnati, Div Pulm & Crit Care Med, Dept Internal Med, Cincinnati, OH USA. Univ Calif San Diego, Dept Nephrol, San Diego, CA 92103 USA. Familial Dysautonomia Hope Fdn, Newton, NC USA. Vanderbilt Univ, Med Ctr, Clin Res Ctr, Nashville, TN USA. Fordham Univ, Dept Biol Sci, Bronx, NY 10458 USA. RP Slaugenhaupt, SA (reprint author), Harvard Inst Human Genet, 77 Ave Louis Pasteur HIM Bldg,Rm 422, Boston, MA 02115 USA. RI Gwinn, Katrina/C-2508-2009; Cuajungco, Math/B-2647-2008; liggett, stephen/E-7453-2012; OI Cuajungco, Math/0000-0003-0749-9564; Svejstrup, Jesper/0000-0003-4964-6147 NR 123 TC 0 Z9 0 U1 0 U2 1 PU DR DIETRICH STEINKOPFF VERLAG PI DARMSTADT PA PO BOX 10 04 62, D-64204 DARMSTADT, GERMANY SN 0959-9851 J9 CLIN AUTON RES JI Clin. Auton. Res. PD JUN PY 2003 VL 13 IS 3 BP 180 EP 195 DI 10.1007/s10286-003-0098-2 PG 16 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 701CT UT WOS:000184151000005 PM 12822040 ER PT J AU Borden, EC Baker, LH Bell, RS Bramwell, V Demetri, GD Eisenberg, BL Fletcher, CDM Fletcher, JA Ladanyi, M Meltzer, P O'Sullivan, B Parkinson, DR Pisters, PWT Saxman, S Singer, S Sundaram, M van Oosterom, AT Verweij, J Waalen, J Weiss, SW Brennan, MF AF Borden, EC Baker, LH Bell, RS Bramwell, V Demetri, GD Eisenberg, BL Fletcher, CDM Fletcher, JA Ladanyi, M Meltzer, P O'Sullivan, B Parkinson, DR Pisters, PWT Saxman, S Singer, S Sundaram, M van Oosterom, AT Verweij, J Waalen, J Weiss, SW Brennan, MF TI Soft tissue sarcomas of adults: State of the translational science SO CLINICAL CANCER RESEARCH LA English DT Article; Proceedings Paper CT State of the Science Conference CY FEB 04-06, 2002 CL BETHESDA, MARYLAND ID GASTROINTESTINAL STROMAL TUMORS; POSITRON-EMISSION-TOMOGRAPHY; DOXORUBICIN PLUS IFOSFAMIDE; FUSION TRANSCRIPT STRUCTURE; ELECTRON-BEAM RADIOTHERAPY; KINASE INHIBITOR STI571; ABL TYROSINE KINASE; RADIATION-THERAPY; SYNOVIAL SARCOMA; GENE-EXPRESSION AB Sarcomas-like leukemias, which are also mesodermal malignancies-carry biological significance disproportionate to their clinical frequency. Identification of mutations and translocations associated with these tumors has illuminated aberrant signaling pathways that cause these diseases, determine their behavior, and are therapeutic targets. Activated receptor-associated tyrosine kinase c-kit, mutated in most gastrointestinal stromal tumors, has proven a clinically effective target for enzyme inhibition. A translocation involving a single gene family, consisting of EWS and related genes, has been identified in five different sarcomas, and its chimeric protein products could prove similarly amenable to inhibitors. Resolution of the histopathological complexity is being aided by data from molecular and chromosomal characterization. Improvements in imaging, definition of prognostic factors, and surgical and radiotherapeutic treatment have resulted in improved local control. Continued progress will depend on further adapting the rapidly evolving technologies of genomics and proteomics. It will also depend upon accurate histopathological diagnosis based on validated reagents and consistent methodologies applied to adequate tissue samples derived from patients with complete clinical data. Finally, multicenter, coordinated trials, such as those that occurred with assessment of imatinib mesylate in metastatic gastrointestinal stromal tumors, will assure the most rapid reductions in morbidity and mortality. C1 Cleveland Clin Fdn, Ctr Canc Drug Discovery & Dev, Cleveland, OH 44195 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. London Reg Canc Ctr, London, ON N6A 4L6, Canada. Dana Farber Canc Inst, Boston, MA 02115 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NHGRI, Bethesda, MD 20892 USA. Novartis Pharmaceut, E Hanover, NJ USA. NCI, Bethesda, MD 20892 USA. Mayo Clin, Rochester, MN USA. Univ Ziekenhuizen Gasthuisberg, Louvain, Belgium. Erasmus Univ, Med Ctr, Rotterdam, Netherlands. Scripps Res Inst, La Jolla, CA USA. Emory Univ, Atlanta, GA 30322 USA. RP Borden, EC (reprint author), Cleveland Clin Fdn, Ctr Canc Drug Discovery & Dev, 9500 Euclid Ave,Room 40, Cleveland, OH 44195 USA. NR 129 TC 170 Z9 177 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN PY 2003 VL 9 IS 6 BP 1941 EP 1956 PG 16 WC Oncology SC Oncology GA 687PP UT WOS:000183386000001 PM 12796356 ER PT J AU Gruszecki, AC Hortin, G Lam, J Kahler, D Smith, D Vines, J Lancaster, L Daly, TM Robinson, CA Hardy, RW AF Gruszecki, AC Hortin, G Lam, J Kahler, D Smith, D Vines, J Lancaster, L Daly, TM Robinson, CA Hardy, RW TI Utilization, reliability, and clinical impact of point-of-care testing during critical care transport: Six years of experience SO CLINICAL CHEMISTRY LA English DT Letter ID BLOOD ANALYZER C1 Univ Alabama, Dept Pathol, Birmingham, AL 35233 USA. Univ Alabama, Dept Med, Birmingham, AL 35233 USA. Univ Alabama, Dept Pathol, Birmingham, AL 35233 USA. Univ Alabama, Dept Surg, Birmingham, AL 35233 USA. Univ Alabama, Gene Therapy Ctr, Birmingham, AL 35233 USA. Univ Alabama, Dept Crit Care Transport, Birmingham, AL 35233 USA. NIH, Dept Lab Med, Bethesda, MD 20892 USA. RP Hardy, RW (reprint author), Univ Alabama, Dept Pathol & Lab Med, WP230,619 S 19th St, Birmingham, AL 35233 USA. NR 12 TC 2 Z9 2 U1 0 U2 1 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2003 VL 49 IS 6 BP 1017 EP 1019 DI 10.1373/49.6.1017 PN 1 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 682JJ UT WOS:000183088100042 PM 12766018 ER PT J AU Cecco, SA Rehak, NN AF Cecco, SA Rehak, NN TI Effect of hematocrit and oxygen tension on SureStep Pro glucose results. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-Clinical-Chemiatry CY JUL 20-24, 2003 CL PHILADELPHIA, PENNSYLVANIA C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2003 VL 49 IS 6 SU S BP A149 EP A149 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 682JP UT WOS:000183088700479 ER PT J AU Demeritt, D Chan, Y Remaley, AT AF Demeritt, D Chan, Y Remaley, AT TI Evaluation of a new fully automated rapid bio-intact (1-84) PTH assay for the intraoperative monitoring of parathyroidectomy surgery. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-Clinical-Chemiatry CY JUL 20-24, 2003 CL PHILADELPHIA, PENNSYLVANIA C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2003 VL 49 IS 6 SU S BP A50 EP A50 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 682JP UT WOS:000183088700157 ER PT J AU Hortin, L Meilinger, B Cohan, D Csako, G AF Hortin, L Meilinger, B Cohan, D Csako, G TI Mass spectrometry of peptides and proteins in biological specimens. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Association-for-Clinical-Chemiatry CY JUL 20-24, 2003 CL PHILADELPHIA, PENNSYLVANIA C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2003 VL 49 IS 6 SU S BP A111 EP A112 PN 2 PG 2 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 682JP UT WOS:000183088700355 ER PT J AU Ahmed, ZM Riazuddin, S Riazuddin, S Wilcox, ER AF Ahmed, ZM Riazuddin, S Riazuddin, S Wilcox, ER TI The molecular genetics of Usher syndrome SO CLINICAL GENETICS LA English DT Review DE deafness; retinitis pigmentosa; Usher syndrome; vestibular dysfunction ID SYNDROME TYPE-I; MYOSIN-VIIA GENE; SYNDROME-TYPE-IIA; SYNDROME TYPE 1D; NONSYNDROMIC RECESSIVE DEAFNESS; SYNDROME TYPE 1F; SYNDROME TYPE 1C; HEARING-LOSS; SENSORINEURAL DEAFNESS; RETINITIS-PIGMENTOSA AB Association of sensorineural deafness and progressive retinitis pigmentosa with and without a vestibular abnormality is the hallmark of Usher syndrome and involves at least 12 loci among three different clinical subtypes. Genes identified for the more commonly inherited loci are USH2A (encoding usherin), MYO7A (encoding myosin VIIa), CDH23 (encoding cadherin 23), PCDH15 (encoding protocadherin 15), USH1C (encoding harmonin), USH3A (encoding clarin 1), and USH1G (encoding SANS). Transcripts from all these genes are found in many tissues/cell types other than the inner ear and retina, but all are uniquely critical for retinal and cochlear cell function. Many of these protein products have been demonstrated to have direct interactions with each other and perform an essential role in stereocilia homeostasis. C1 NIDCD, Genet Mol Lab, Sect Human Genet, NIH, Rockville, MD 20850 USA. Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. RP Wilcox, ER (reprint author), NIDCD, Genet Mol Lab, Sect Human Genet, NIH, 5 Res Court,2A-19 Rockville, Rockville, MD 20850 USA. NR 110 TC 101 Z9 105 U1 1 U2 13 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD JUN PY 2003 VL 63 IS 6 BP 431 EP 444 DI 10.1034/j.1399-0004.2003.00109.x PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 685TC UT WOS:000183278500001 PM 12786748 ER PT J AU de Serres, FJ Blanco, I Fernandez-Bustillo, E AF de Serres, FJ Blanco, I Fernandez-Bustillo, E TI Genetic epidemiology of alpha-1 antitrypsin deficiency in southern Europe: France, Italy, Portugal and Spain SO CLINICAL GENETICS LA English DT Article DE alpha-1 antitrypsin deficiency; alpha-1 protease inhibitor; alpha-1 protease; genetic epidemiology; Pi phenotypes; Pi subtypes; population genetics ID HETEROZYGOUS ALPHA-1-ANTITRYPSIN DEFICIENCY; ALPHA1-ANTITRYPSIN PI-TYPES; ALPHA(1)-ANTITRYPSIN DEFICIENCY; CLINICAL-FEATURES; LIVER-DISEASE; Z ALLELE; GENERAL-POPULATION; PULMONARY-DISEASE; PUBLISHED SURVEYS; LUNG-FUNCTION AB Alpha-1-antitrypsin deficiency (AAT deficiency) is one of the most common serious hereditary disorders in the world because it affects all major racial subgroups worldwide and there are at least 120.5 million carriers and deficient subjects worldwide. This genetic disease is related to a high risk for development of jaundice in infants, liver disease in children and adults, and pulmonary emphysema in adults. Moreover, AAT-deficiency carrier phenotypes (PiMS and PiMZ) and deficiency-allele phenotypes (PiSS, PiSZ, and PiZZ) are suspected to make subjects susceptible to a variety of other adverse health effects. As there is a limited database on the number of individuals affected by this disease worldwide, the authors of the present report collected data on control cohorts in genetic epidemiological studies published in the peer-reviewed literature worldwide. The data collected were used to estimate the numbers of carriers and deficiency-allele combinations for the two most common defective alleles, namely PiS and PiZ, in over 58 countries worldwide. The present report focuses on the distribution of the PiS and PiZ deficiency alleles in France, Italy, Portugal, and Spain. The total number of individuals at risk for adverse health effects were as follows: 9, 101, 739 in France; 4, 289, 566 in Italy; 2, 659, 241 in Portugal; and 8, 903, 773 in Spain. The geographical distribution of individual control cohorts and estimates of the numbers of carriers and deficiency-allele phenotypes in each of these four southern European countries are shown in individual tables and maps. This report will be followed by other reports on the remaining countries in Europe, as well as worldwide. C1 NIEHS, Mol Toxicol Lab, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. Hosp Valle del Nalon, Resp Dis Branch, Sama De Langreo, Principado de A, Spain. Hosp Cent Asturias, Biostat Unit, Oviedo, Principado de A, Spain. RP de Serres, FJ (reprint author), NIEHS, Mol Toxicol Lab, Environm Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. NR 99 TC 31 Z9 31 U1 0 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD JUN PY 2003 VL 63 IS 6 BP 490 EP 509 DI 10.1034/j.1399-0004.2003.00078.x PG 20 WC Genetics & Heredity SC Genetics & Heredity GA 685TC UT WOS:000183278500009 PM 12786756 ER PT J AU Grossman, Z AF Grossman, Z TI Mathematical modeling of thymopoiesis in HIV infection: real data, virtual data, and data interpretation SO CLINICAL IMMUNOLOGY LA English DT Editorial Material ID THYMIC FUNCTION C1 Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, IL-69978 Tel Aviv, Israel. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Grossman, Z (reprint author), Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, IL-69978 Tel Aviv, Israel. NR 5 TC 3 Z9 3 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2003 VL 107 IS 3 BP 137 EP 139 DI 10.1016/S1521-6616(03)00122-0 PG 3 WC Immunology SC Immunology GA 692MR UT WOS:000183665300001 PM 12804526 ER PT J AU Chan, CC AF Chan, CC TI Primary intraocular lymphoma: Clinical features, diagnosis, and treatment SO CLINICAL LYMPHOMA LA English DT Editorial Material ID MASQUERADE SYNDROMES C1 NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Chan, CC (reprint author), NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. NR 16 TC 10 Z9 11 U1 0 U2 1 PU CANCER INFORMATION GROUP, LP PI DALLAS PA 3535 WORTH ST, SAMMONS TOWER, STE 4802, DALLAS, TX 75246 USA SN 1526-9655 J9 CLIN LYMPHOMA JI Clin. Lymphoma PD JUN PY 2003 VL 4 IS 1 BP 30 EP 31 PG 2 WC Oncology SC Oncology GA 693VH UT WOS:000183738700009 PM 12837151 ER PT J AU Seeliger, S Hausberg, M Eue, I Usdin, T Rahn, KH Kosch, M AF Seeliger, S Hausberg, M Eue, I Usdin, T Rahn, KH Kosch, M TI The parathyroid hormone-2 receptor is expressed on human leukocytes and down-regulated in hyperparathyroidism SO CLINICAL NEPHROLOGY LA English DT Article DE parathyroid hormone; parathyroid hormone-2; receptor; leukocytes; receptor expression; receptor regulation ID CHRONIC-RENAL-FAILURE; BINDING PROTEINS MRP8; PTH-PTHRP RECEPTOR; FUNCTIONAL EXPRESSION; CALCIUM; CELLS; MONOCYTES; PEPTIDE; TIP39; RATS AB Background: Parathyroid hormone (PTH) has specific effects on function, migration and proliferation of human leukocytes. These effects may contribute to accelerated atherosclerosis and impaired immune response observed in patients with renal insufficiency. Recently, a new G protein-coupled receptor with substantial implications for vascular function-the PTH2 receptor (PTH2-R)-has been identified, however, expression and distribution in humans and a possible regulation has not yet been studied. We therefore investigated the expression of the PTH2 receptor on human leukocytes in healthy subjects and in patients with hyperparathyroidism. Methods: PTH2 receptor expression was quantified by flow cytometry (FACS) analysis on monocytes, lymphocytes and granulocytes that were isolated from peripheral blood ( hypotonic density gradient centrifugation) and by immunohistochemistry using a specific -PTH2-R antibody produced in rabbit. Results of 22 patients with hyperparathyroidism ( 12 renal allograft recipients, 10 hemodialysis patients, mean age 43+/-8 years) were compared to 22 age and sex-matched healthy controls. Results: Mean relative antigen density of the PTH2 receptor and percentage of positive cells in healthy subjects was 19+/-5 and 90+/-6% on granulocytes, 5+/-2 and 55+/-19% on monocytes, and 24+/-7 and 21+/-7% on lymphocytes. In patients with hyperparathyroidism, mean antigen density was significantly lower on granulocytes and monocytes (17+/-4% and 3+/-1%, p<0.01, respectively). The percentage of positive cells and mean expression on lymphocytes was not significantly different. A significant and inverse correlation was found between plasma PTH concentrations and the mean PTH2 receptor expression on granulocytes (r=-0.41, p<0.05). Conclusions: The PTH2 receptor is expressed on human granulocytes and-to a lesser degree-on monocytes and lymphocytes. In patients with hyperparathyroidism the PTH2 receptor is downregulated as function of plasma PTH levels. C1 Univ Hosp Munster, Dept Paediat, Munster, Germany. Univ Hosp Munster, Dept Int Med D Nephrol, Munster, Germany. NIH, Cell Biol Unit, Genet Lab, Bethesda, MD 20892 USA. RP Kosch, M (reprint author), Univ Munster, Dept Med D, Albert Schweitzer Str 33, D-48129 Munster, Germany. NR 24 TC 4 Z9 4 U1 0 U2 0 PU DUSTRI-VERLAG DR KARL FEISTLE PI OBERHACHING PA BAJUWARENRING 4, D-82041 OBERHACHING, GERMANY SN 0301-0430 J9 CLIN NEPHROL JI Clin. Nephrol. PD JUN PY 2003 VL 59 IS 6 BP 429 EP 435 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 684WP UT WOS:000183200600005 PM 12834174 ER PT J AU Gan, JC Ducheyne, P Vresilovic, EJ Swaim, W Shapiro, IM AF Gan, JC Ducheyne, P Vresilovic, EJ Swaim, W Shapiro, IM TI Intervertebral disc tissue engineering I: Characterization of the nucleus pulposus SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID ALKALINE-PHOSPHATASE; VI COLLAGEN; X COLLAGEN; PROTEIN; PROTEOGLYCANS; METABOLISM; CARTILAGE; NUTRITION; CALCIUM; CELLS AB The characteristics of the nucleus pulposus cells from adult rabbits maintained in in vitro cultures were described in another study. Herein, the authors provide a parallel profile of adult rabbit nucleus pulposus in situ, therefore allowing direct comparisons between in vitro and in situ investigations. Nucleus pulposus specimens from adult rabbits were evaluated using biochemical and immunohistochemical morphologic techniques. The nucleus pulposus from adult rabbits contained cell clusters embedded in proteoglycan-collagen matrix. The cells exhibited a well-defined Golgi system, an extensive endoplasmic reticulum, and a complex vesicular system filled with beaded structures (proteoglycans). Neither necrotic nor apoptotic cells were evident. There was a lack of mitochondria. The extensive extracellular matrix contained amorphous, beaded, and fibrillar components. The fibrillar banding was indicative of Type VI collagen. The nucleus pulposus of adult rabbits expressed aggrecan, collagen Type I and Type II, and CD44, but not collagen Type X and displayed low alkaline phosphatase activity. C1 Univ Penn, Ctr Bioact Mat & Tissue Engn, Dept Bioengn, Philadelphia, PA 19104 USA. Univ Penn, Dept Orthopaed Surg, Sch Med, Philadelphia, PA 19104 USA. Univ Penn, Dept Biochem, Sch Dent Med, Philadelphia, PA 19104 USA. NIDCR, NIH, Bethesda, MD USA. RP Ducheyne, P (reprint author), Univ Penn, Ctr Bioact Mat & Tissue Engn, Dept Bioengn, Suite 120,Hayden Hall,3320 Smith Walk, Philadelphia, PA 19104 USA. FU NIDCR NIH HHS [R01-DE 13051] NR 26 TC 30 Z9 35 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD JUN PY 2003 IS 411 BP 305 EP 314 DI 10.1097/01.blo.0000063796.98363.9a PG 10 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 687LW UT WOS:000183379000037 PM 12782889 ER PT J AU Goldstein, DS Holmes, C Patronas, N Kopin, IJ AF Goldstein, DS Holmes, C Patronas, N Kopin, IJ TI Cerebrospinal fluid levels of catechols in patients with neurogenic orthostatic hypotension SO CLINICAL SCIENCE LA English DT Article DE dihydroxyphenylglycol; multiple system atrophy; noradrenaline; pure autonomic failure; sympathetic nervous system ID MULTIPLE SYSTEM ATROPHY; PARKINSONS-DISEASE; PLASMA 3-METHOXY-4-HYDROXYPHENYLGLYCOL; AUTONOMIC FAILURE; NOREPINEPHRINE; HYPERTENSION; LEVODOPA; PATTERNS AB In multiple system atrophy (MSA) and pure autonomic failure (PAF), orthostatic hypotension (OH) results from deficient noradrenaline release from sympathetic nerves during standing. Postmortem findings have indicated loss of central noradrenergic cells in both diseases. The present study sought in vivo neurochemical evidence for central noradrenergic deficiency in patients with OH due to MSA or PAF A total of 28 patients with OH (18 with MSA; 10 with PAF) had cerebrospinal fluid and blood sampled for levels of noradrenaline and its neuronal metabolite dihydroxyphenylglycol. A control group of 44 subjects included 10 elderly normal volunteers, 10 patients with Alzheimer's disease, I S patients with dysautonomia (postural tachycardia syndrome or neurocardiogenic syncope) and six patients with MSA in the absence of OH. Patients with OH had lower cerebrospinal fluid concentrations of noradrenaline (0.53 +/- 0.07 nmol/l) and dihydroxyphenylglycol (6.52 +/- 0.46nmol/l) than did control subjects (0.90 +/- 0.09 and 9.64 +/- 0.46 nmol/l respectively; P = 0.0001). The MSA + OH group had higher plasma levels of both catechols (noradrenaline, 1.31 +/- 0.16nmol/l; dihydroxyphenylglycol, 5.08 +/- 0.43 nmol/l) than did the PAF group (noradrenaline, 0.38 +/- 0.08nmol/l; dihydroxyphenylglycol, 2.53 +/- 0.30nmol/l; P < 0.001), despite similarly low cerebrospinal fluid levels. Among MSA patients, those with OH had lower cerebrospinal fluid levels of noradrenaline and dihydroxyphenylglycol than those without OH (noradrenaline, 1.71 +/- 0.64 nmol/l; dihydroxyphenylglycol, 10.41 +/- 1.77 nmol/l respectively; P = 0.006). The findings are consistent with central noradrenergic deficiency in both MSA + OH and PAIR In MSA, central noradrenergic deficiency seems to relate specifically to OH. C1 NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Radiol, Bethesda, MD 20892 USA. RP Goldstein, DS (reprint author), NINDS, Clin Neurocardiol Sect, NIH, Bldg 10,Room 6N252,10 Ctr Dr,MSC-1620, Bethesda, MD 20892 USA. NR 31 TC 6 Z9 6 U1 0 U2 1 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0143-5221 J9 CLIN SCI JI Clin. Sci. PD JUN PY 2003 VL 104 IS 6 BP 649 EP 654 DI 10.1042/CS20020315 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 689TW UT WOS:000183509900014 PM 12540289 ER PT J AU Low, NCP Merikangas, KR AF Low, NCP Merikangas, KR TI The comorbidity of migraine SO CNS SPECTRUMS LA English DT Review ID CHRONIC DAILY HEADACHE; PSYCHIATRIC COMORBIDITY; GENERAL-POPULATION; PHYSICIANS HEALTH; MAJOR DEPRESSION; ISCHEMIC STROKE; PANIC DISORDER; BLOOD-PRESSURE; UNITED-STATES; YOUNG-ADULTS AB This review addresses the methodologic issues relevant to the study Of comorbidity and provides a broad overview of the medical and psychiatric conditions associated with migraine. Since the body of literature examining the comorbidity a ne is enormous, the scope of this review will largely-focus on community and case-control studies. Among the selected comorbid medical conditions, including disorders of the cardiovascular, respiratory, neurologic, gastrointestinal and immunologic systems, stroke, asthma, and allergies appear to be most strongly associated with migraine. Among the psychiatric illnesses, mood and anxiety disorders have been shown to be most strongly associated with migraine in the general population. Further research, is indicated and necessary to elucidate the precise mechanism of migraine comorbidity. C1 NIMH, Dept Hlth & Human Serv, Sect Dev Genet Epidemiol,Intramural Res Program, Mood & Anxiety Disorders Program,NIH, Bethesda, MD 20892 USA. RP Merikangas, KR (reprint author), NIMH, Dept Hlth & Human Serv, Sect Dev Genet Epidemiol,Intramural Res Program, Mood & Anxiety Disorders Program,NIH, 15K N Dr,MSC 2670, Bethesda, MD 20892 USA. NR 118 TC 42 Z9 43 U1 0 U2 0 PU M B L COMMUNICATIONS, INC PI NEW YORK PA 333 HUDSON ST, 7TH FLOOR, NEW YORK, NY 10013 USA SN 1092-8529 J9 CNS SPECTR JI CNS Spectr. PD JUN PY 2003 VL 8 IS 6 BP 433 EP + PG 10 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 710ML UT WOS:000184683900010 PM 12858133 ER PT J AU Watanabe, K AF Watanabe, K TI Differential effect of distractor timing on localizing versus identifying visual changes SO COGNITION LA English DT Article DE change blindness; attention; localization; identification ID HUMAN EXTRASTRIATE CORTEX; CHANGE-BLINDNESS; SELECTIVE ATTENTION; SPATIAL ATTENTION; OBJECT; DISSOCIATION; SCENES; PERCEPTION; POSITION; VISION AB When visual changes are accompanied by visual transients, such as in the case of saccades, eye blinks, and brief flickers, they often go unnoticed; this phenomenon is called change blindness (Rensink, R. A. (2002). Change detection. Annual Review of Psychology 53, 245; Simons, D. J., & Levin, D. T. (1997). Change blindness. Trends in Cognitive Sciences 1, 261). Change blindness occurs even when the position of visual transients does not cover the location of the change (as in the 'mudsplash' paradigm) (O'Regan, J. K., Rensink, R. A., & Clark, J. J. (1999). Change blindness as a result of 'mudsplashes'. Nature 398, 34). By using a simplified mudsplash display, the present study investigated whether change blindness depends on (a) the timing of visual transients, and (b) the task that observers perform. Eight Gabor elements with random orientations were presented. One element (target) was rotated 45 degrees clockwise or counterclockwise without a temporal gap. High contrast visual transients, not overlapping with the elements, appeared at various times with respect to the target change. Observers reported where the change was (change localization), or in which direction the target rotated (change identification). Change localization was impaired primarily when the onset of the transient was at or after the change. In contrast, change identification was impaired mainly when the transient preceded the change. These results suggest that change localization and change identification are mediated in part by different mechanisms. (C) 2003 Elsevier Science B.V. All rights reserved. C1 CALTECH, Pasadena, CA 91125 USA. RP Watanabe, K (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Room 2A50,49 Convent Dr, Bethesda, MD 20892 USA. NR 52 TC 19 Z9 19 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0010-0277 J9 COGNITION JI Cognition PD JUN PY 2003 VL 88 IS 2 BP 243 EP 257 DI 10.1016/S0010-0277(03)00025-8 PG 15 WC Psychology, Experimental SC Psychology GA 684ZH UT WOS:000183236000005 PM 12763321 ER PT J AU Thayer, JF Rossy, LA Ruiz-Padial, E Johnsen, BH AF Thayer, JF Rossy, LA Ruiz-Padial, E Johnsen, BH TI Gender differences in the relationship between emotional regulation and depressive symptoms SO COGNITIVE THERAPY AND RESEARCH LA English DT Article DE depression; emotional regulation; gender; rumination ID GENERALIZED ANXIETY DISORDER; HEART-RATE-VARIABILITY; NEUROVISCERAL CONCOMITANTS; SEX-DIFFERENCES; AWARENESS; DYSREGULATION; INHIBITION; JUDGMENT; CORTEX; MODEL AB Reports of gender differences in depressive symptoms are one of the most pervasive findings in the literature. In addition, women are frequently reported to be more emotionally sensitive than men. However, the paradox of women being more emotionally responsive and yet at greater risk for psychopathology is still to be unraveled. In the present study we examined emotional regulation as a possible factor in the gender difference in depressive symptom reporting. In a sample of young adults we replicated the frequently reported finding of greater depressive symptom reporting in women. In addition, we found women to report greater attention to emotions. This is consistent with the idea that women tend to think more and ruminate more about their emotions. However, when the variance associated with this greater attention to emotions was statistically controlled, the gender difference in depressive symptoms was no longer significant. Subsequent analyses found that women with low depressive symptoms reported greater attention to emotions without evidencing greater depressive symptoms. However, women with high depressive symptoms exhibited greater attention to emotions, more impaired antirumination emotional repair strategies, and greater reports of depressive symptoms than men with high depressive symptoms. We close by speculating about the neural concomitants of these findings. C1 NIA, GRC, LPC, Baltimore, MD 21224 USA. Univ Missouri, Columbia, MO USA. Univ Jaen, Jaen, Spain. Univ Bergen, Bergen, Norway. RP Thayer, JF (reprint author), NIA, GRC, LPC, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Ruiz Padial, Elisabeth/G-8962-2011 NR 31 TC 79 Z9 83 U1 0 U2 11 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0147-5916 J9 COGNITIVE THER RES JI Cogn. Ther. Res. PD JUN PY 2003 VL 27 IS 3 BP 349 EP 364 DI 10.1023/A:1023922618287 PG 16 WC Psychology, Clinical SC Psychology GA 684KM UT WOS:000183205900008 ER PT J AU Lacy, SH Gardner, DJ Olson, LC Ding, L Holland, SM Bryant, MA AF Lacy, SH Gardner, DJ Olson, LC Ding, L Holland, SM Bryant, MA TI Disseminated trichosporonosis in a murine model of chronic granulomatous disease SO COMPARATIVE MEDICINE LA English DT Article ID COLONY-STIMULATING FACTOR; INFECTION; CUTANEUM; THERAPY; INKIN; MICE; ASAHII AB Over a period of ten months, five mice submitted to our service (the Pathology Section of the Veterinary Resources Program, Office of Research Services at the National Institutes of Health, Bethesda, Md.) were diagnosed with disseminated trichosporonosis. These mice had pyogranulomatous inflammation in multiple organs, including lung, liver, lymph nodes, salivary gland, and skin. Fungal elements in many of the lesions were identified, using special histochemical stains, and Trichosporon beigelii was obtained by use of culture of specimens at affected sites. This saprophytic fungus has caused disseminated disease in immunosuppressed humans. However, despite widespread use of immunosuppressed rodents in research, to the authors' knowledge, this organism had not previously been reported to cause spontaneous disseminated disease in laboratory mice. All affected mice had a genetically engineered defect in p47(phox), a critical component of the nicotinamide dinucleotide phosphate (NADPH) oxidase, the enzyme responsible for generating the phagocyte oxidative burst. These animals are used as a murine model of human chronic granulomatous disease. We discuss the lesions, differential diagnosis, identification of the organism, and the role of NADPH oxidase in protecting against disseminated trichosporonosis. C1 NIAID, Vet Pathol Sect, Vet Resources Program, Off Res Serv,NIH, Bethesda, MD 20892 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Bryant, MA (reprint author), NIAID, Vet Pathol Sect, Vet Resources Program, Off Res Serv,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 28 TC 4 Z9 4 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1532-0820 J9 COMPARATIVE MED JI Comparative Med. PD JUN PY 2003 VL 53 IS 3 BP 303 EP 308 PG 6 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 697FW UT WOS:000183932400015 PM 12868577 ER PT J AU Minasian, L Croker, KS Ryan, A Voss, A Cave, L Klein, E Ford, L AF Minasian, L Croker, KS Ryan, A Voss, A Cave, L Klein, E Ford, L TI Effectiveness of a media-based launch to recruit to a prostate cancer prevention trial SO CONTROLLED CLINICAL TRIALS LA English DT Meeting Abstract CT Joint International Conference of the International-Society-for-Clinical-Biostatistics/Society-for-Clinical-Tr ials CY JUL 20-24, 2003 CL LONDON, ENGLAND SP Int Soc Clin Biostat, Soc Clin Trials C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD JUN PY 2003 VL 24 SU 3 MA 14 BP 50S EP 50S PG 1 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 686TP UT WOS:000183337300016 ER PT J AU Fagerstrom, RM Marcus, PM Prorok, PC Kramer, BS Greenwald, P Gohagan, JK AF Fagerstrom, RM Marcus, PM Prorok, PC Kramer, BS Greenwald, P Gohagan, JK TI Issues in the design, operations, and analysis of multi-disease screening trials: The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial experience SO CONTROLLED CLINICAL TRIALS LA English DT Meeting Abstract CT Joint International Conference of the International-Society-for-Clinical-Biostatistics/Society-for-Clinical-Tr ials CY JUL 20-24, 2003 CL LONDON, ENGLAND SP Int Soc Clin Biostat, Soc Clin Trials C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD JUN PY 2003 VL 24 SU 3 MA 29 BP 57S EP 57S PG 1 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 686TP UT WOS:000183337300031 ER PT J AU Wakim, P Nunes, E Feaster, D AF Wakim, P Nunes, E Feaster, D TI Choice of control treatment in multi-site effectiveness behavioral trials SO CONTROLLED CLINICAL TRIALS LA English DT Meeting Abstract CT Joint International Conference of the International-Society-for-Clinical-Biostatistics/Society-for-Clinical-Tr ials CY JUL 20-24, 2003 CL LONDON, ENGLAND SP Int Soc Clin Biostat, Soc Clin Trials C1 Natl Inst Drug Abuse, Bethesda, MD USA. RI Feaster, Daniel/I-6079-2013 NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD JUN PY 2003 VL 24 SU 3 MA P258 BP 223S EP 223S PG 1 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 686TP UT WOS:000183337300362 ER PT J AU Marcus, P Fagerstrom, R Church, T Prorok, P Gohagan, J AF Marcus, P Fagerstrom, R Church, T Prorok, P Gohagan, J TI Choosing a control-arm intervention in cancer screening trials when standard of care is unclear SO CONTROLLED CLINICAL TRIALS LA English DT Meeting Abstract CT Joint International Conference of the International-Society-for-Clinical-Biostatistics/Society-for-Clinical-Tr ials CY JUL 20-24, 2003 CL LONDON, ENGLAND SP Int Soc Clin Biostat, Soc Clin Trials C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD JUN PY 2003 VL 24 SU 3 MA P261 BP 224S EP 224S PG 1 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 686TP UT WOS:000183337300365 ER PT J AU Li, D Thompson, B Wang, W Ware, R Driscoll, C Waclawiw, M Bonds, DR AF Li, D Thompson, B Wang, W Ware, R Driscoll, C Waclawiw, M Bonds, DR TI Height and weight reference curves for children with sickle cell anemia SO CONTROLLED CLINICAL TRIALS LA English DT Meeting Abstract CT 3rd Joint Conference of the International-Society-for-Clinical-Biostatistics/Society-for-Clinical-Tr ials CY JUL 20-24, 2003 CL LONDON, ENGLAND SP Int Soc Clin Biostat, Soc Clin Trials C1 Clin Trials & Surveys Corp, Baltimore, MD USA. St Jude Childrens Res Hosp, Memphis, TN 38105 USA. Duke Univ, Med Ctr, Durham, NC 27706 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD JUN PY 2003 VL 24 SU 3 MA P273 BP 229S EP 230S PG 2 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 686TP UT WOS:000183337300377 ER PT J AU Hallstrom, A Friedman, L Denes, P Rizo-Patron, C Morris, M AF Hallstrom, A Friedman, L Denes, P Rizo-Patron, C Morris, M CA CAST AVID Investigators TI Do arrhythmia patients improve survival by participating in randomized clinical trials? Observations from the cardiac arrhythmia suppression trial (CAST) and the Antiarrhythmics Versus Implantable Defibrillators trial (AVID) SO CONTROLLED CLINICAL TRIALS LA English DT Article DE patient participants; randomized clinical trials; enrollees and nonenrollees; trial participants ID LEFT-VENTRICULAR DYSFUNCTION; SATISFACTION; TERM AB It is debatable whether patients benefit directly from participation in a randomized clinical trial. We attempt to address this question for participants in the Cardiac Arrhythmia Suppression Trial (CAST) and the Antiarrhythmics Versus Implantable Defibrillators (AVID) studies. Survival rates were compared between eligible patients who enrolled in the trials and eligible patients who did not enroll, adjusting for baseline covariates. In CAST, despite that the active therapy was found to confer an almost threefold increased risk of death, survival was similar between the 3163 enrolled and the 1363 nonenrolled eligible patients. However, when patients were under study management, their risk of death was approximately 20% lower than when they left study management. In AVID, overall survival was similar between the 1016 enrolled and the 1246 nonenrolled eligible patients. However, mortality was substantially higher among patients not enrolled because the referring physician mandated the type of therapy. Overall these observational analyses suggest a net improvement in survival for the participants in these two trials. (C) 2003 by Elsevier Inc. All rights reserved. C1 Univ Washington, Clin Trial Ctr, Seattle, WA 98105 USA. NHLBI, Bethesda, MD 20892 USA. NW Univ, Chicago, IL USA. Cardiol Associates Lubbock, Lubbock, TX USA. RP Hallstrom, A (reprint author), Univ Washington, Clin Trial Ctr, 1107 NE 45th St,Suite 505, Seattle, WA 98105 USA. FU NHLBI NIH HHS [N01 HC 25117, N01 HC 65042] NR 22 TC 11 Z9 11 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD JUN PY 2003 VL 24 IS 3 BP 341 EP 352 DI 10.1016/S0197-2456(03)00002-3 PG 12 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 685HA UT WOS:000183255400008 PM 12757998 ER PT J AU Menotti-Raymond, M David, V Wachter, L Yuhki, N O'Brien, SJ AF Menotti-Raymond, M David, V Wachter, L Yuhki, N O'Brien, SJ TI Quantitative polymerase chain reaction-based assay for estimating DNA yield extracted from domestic cat specimens SO CROATIAN MEDICAL JOURNAL LA English DT Article DE cats; forensic medicine; polymerase chain reaction; short interspersed nucleotide elements; tandem repeat sequences ID RNA-DERIVED RETROPOSONS; HAIR; AMPLIFICATION; CHROMOSOME; SEQUENCE; SINES; MTDNA; DOG AB A quantitative polymerase chain reaction (PCR) assay has been developed for the quantification of genomic DNA extracted from domestic cat samples. The assay, which targets highly repetitive genomic short interspersed nuclear elements (SINE), can be performed rapidly and is highly sensitive, detecting as little as 10 fg of feline genomic DNA. The assay was linear over a 10(6) dilution range. We have recently developed a short tandem repeat (STR) multiplex panel for forensic analysis of feline specimens. The SINE assay is an integral part of the forensic typing system. The sensitivity of the assay will enable forensic examiners to determine the likelihood of success of genotyping sample extracts with the STR panel without sacrificing valuable DNA necessary to perform genotyping of samples. C1 Natl Canc Inst, Lab Genom Divers, Ft Detrick, MD 21702 USA. Natl Canc Inst, SAIC Frederick, Basic Res Program, Frederick, MD USA. RP Menotti-Raymond, M (reprint author), Natl Canc Inst, Lab Genom Divers, Ft Detrick, MD 21702 USA. EM raymond@ncifcrf.gov NR 26 TC 10 Z9 10 U1 0 U2 1 PU MEDICINSKA NAKLADA PI ZAGREB PA VLASKA 69, HR-10000 ZAGREB, CROATIA SN 0353-9504 J9 CROAT MED J JI Croat. Med. J. PD JUN PY 2003 VL 44 IS 3 BP 327 EP 331 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 698LJ UT WOS:000184000800013 PM 12808727 ER PT J AU Manolio, TA Olson, J Longstreth, WT AF Manolio, TA Olson, J Longstreth, WT TI Hypertension and cognitive function: Pathophysiologic effects of hypertension on the brain SO CURRENT HYPERTENSION REPORTS LA English DT Article ID WHITE-MATTER LESIONS; CEREBRAL AMYLOID ANGIOPATHY; CORONARY HEART-DISEASE; BLOOD-PRESSURE LEVEL; CARDIOVASCULAR HEALTH; VASCULAR DEMENTIA; ALZHEIMERS-DISEASE; STROKE; AGE; RISK AB Accumulating evidence supports a causal role of hypertension for cognitive decline above and beyond its relationship to frank stroke. Hypertension-associated pathologic changes in the brain and its vasculature include vascular remodeling, impaired cerebral autoregulation, cerebral microbleeds, white matter lesions, unrecognized lacunar infarcts, and Alzheimer-like changes such as amyloid angiopathy and cerebral atrophy. White matter lesions and retinal vascular changes, both of which can be imaged noninvasively, may reveal the general condition of the cerebral vasculature or the presence of arteriosclerotic or hypertensive encephalopathy. These noninvasive indicators may also identify a subgroup in whom infarct prevention, particularly via blood pressure reduction, is of paramount importance. Optimal control of blood pressure on a population-wide basis, but particularly in those prone to cognitive loss, is thus a critically important but as yet elusive goal that should be fully exploited for its potential to reduce future cognitive impairment. C1 NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Manolio, TA (reprint author), NHLBI, Div Epidemiol & Clin Applicat, 6701 Rockledge Dr,MSC 7934, Bethesda, MD 20892 USA. NR 50 TC 83 Z9 93 U1 0 U2 1 PU CURRENT SCIENCE INC PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1522-6417 J9 CURR HYPERTENS REP JI Curr. Hypertens. Rep. PD JUN PY 2003 VL 5 IS 3 BP 255 EP 261 DI 10.1007/s11906-003-0029-6 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 685KR UT WOS:000183262900011 PM 12724059 ER PT J AU Lawrence, JB Hager, GL AF Lawrence, JB Hager, GL TI Nucleus and gene expression: motion meets architecture SO CURRENT OPINION IN CELL BIOLOGY LA English DT Editorial Material C1 Univ Massachusetts, Sch Med, Worcester, MA 01655 USA. NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Lawrence, JB (reprint author), Univ Massachusetts, Sch Med, 55 Lake Ave N, Worcester, MA 01655 USA. NR 1 TC 2 Z9 2 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD JUN PY 2003 VL 15 IS 3 BP 255 EP 258 DI 10.1016/S0955-0674(03)00053-X PG 4 WC Cell Biology SC Cell Biology GA 689VC UT WOS:000183512800001 ER PT J AU Quimby, BB Dasso, M AF Quimby, BB Dasso, M TI The small GTPase Ran: interpreting the signs SO CURRENT OPINION IN CELL BIOLOGY LA English DT Review ID XENOPUS EGG EXTRACTS; NUCLEAR-PORE COMPLEX; GUANINE-NUCLEOTIDE EXCHANGE; IMPORTIN-BETA; BINDING-PROTEIN; MITOTIC SPINDLE; IN-VIVO; ENVELOPE; TRANSPORT; RCC1 AB The small GTPase Ran has roles in nuclear transport, mitotic spindle assembly and nuclear envelope assembly. During the past three years, it has become clear that many of these processes rely on conserved molecular mechanisms involving Ran-GTP-binding proteins of the importin-beta superfamily. Moreover, recent experimental evidence has documented the distribution of Ran-GTP within cells and supported the notion that Ran plays a central role in the spatial and temporal organization of the eukaryotic cell. C1 NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Quimby, BB (reprint author), NICHHD, Lab Gene Regulat & Dev, NIH, Bldg 18T,Room 106,18 Lib Dr, Bethesda, MD 20892 USA. OI Dasso, Mary/0000-0002-5410-1371 NR 44 TC 131 Z9 137 U1 2 U2 7 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD JUN PY 2003 VL 15 IS 3 BP 338 EP 344 DI 10.1016/S0955-0674(03)00046-2 PG 7 WC Cell Biology SC Cell Biology GA 689VC UT WOS:000183512800013 PM 12787777 ER PT J AU Mounkes, L Kozlov, S Burke, B Stewart, CL AF Mounkes, L Kozlov, S Burke, B Stewart, CL TI The laminopathies: nuclear structure meets disease SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Article ID DREIFUSS MUSCULAR-DYSTROPHY; LAMIN A/C GENE; FAMILIAL PARTIAL LIPODYSTROPHY; DILATED CARDIOMYOPATHY; MANDIBULOACRAL DYSPLASIA; MISSENSE MUTATIONS; DEFICIENT MICE; BINDING-SITE; CAAX MOTIF; ROD DOMAIN AB Most inherited diseases are associated with mutations in a specific gene. Sometimes, mutations in two or more different genes result in diseases with a similar phenotype. Rarely do different mutations in the same gene result in a multitude of seemingly different and unrelated diseases. In the past three years, different mutations in LMNA, the gene encoding the A-type lamins, have been shown to be associated with at least six different diseases. These diseases and at least two others caused by mutations in other proteins associated with the nuclear lamina are collectively called the laminopathies. How different tissue-specific diseases arise from unique mutations in the LMNA gene, encoding almost ubiquitously expressed nuclear proteins, are providing tantalizing insights into the structural organization of the nucleus, its relation to nuclear function in different tissues and the involvement of the nuclear envelope in the development of disease. C1 NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. Univ Florida, Dept Anat & Cell Biol, Gainesville, FL 32610 USA. RP Mounkes, L (reprint author), NCI, Canc & Dev Biol Lab, POB B, Frederick, MD 21702 USA. NR 63 TC 142 Z9 145 U1 0 U2 4 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD JUN PY 2003 VL 13 IS 3 BP 223 EP 230 DI 10.1016/S0959-437X(03)00058-3 PG 8 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 691AM UT WOS:000183582700002 PM 12787783 ER PT J AU Jang, IK Gu, H AF Jang, IK Gu, H TI Negative regulation of TCR signaling and T-cell activation by selective protein degradation SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID DOWN-MODULATION; C-CBL; CYTOPLASMIC DOMAINS; POSITIVE SELECTION; ADAPTER PROTEIN-2; RECEPTOR; UBIQUITINATION; ZAP-70; MICE; DIFFERENTIATION AB Protein degradation was previously considered to be a nonspecific cellular process that eradicated abnormal or damaged proteins. Current evidence indicates, however, that T cells use this mechanism to selectively eliminate activated T-cell receptors (TCRs) and signaling molecules, and consequently control the duration and specificity of TCR signaling. C1 NIAID, Immunol Lab, Rockville, MD 20852 USA. RP Gu, H (reprint author), Columbia Univ Coll Phys & Surg, Dept Microbiol, 701 W 168th St, New York, NY 10032 USA. NR 36 TC 36 Z9 36 U1 0 U2 3 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 JUN PY 2003 VL 15 IS 3 BP 315 EP 320 DI 10.1016/S0952-7915(03)00048-7 PG 6 WC Immunology SC Immunology GA 689GT UT WOS:000183483800012 PM 12787757 ER PT J AU Muraro, PA Ingoni, RC Martin, R AF Muraro, PA Ingoni, RC Martin, R TI Hematopoietic stem cell transplantation for multiple sclerosis: current status and future challenges SO CURRENT OPINION IN NEUROLOGY LA English DT Article DE hematopoietic stem cell transplantation; multiple sclerosis; remyelination; stem cells ID BONE-MARROW TRANSPLANTATION; RAT SPINAL-CORD; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; OLFACTORY ENSHEATHING CELLS; SECONDARY-PROGRESSIVE MS; IN-VIVO; PROGENITOR CELLS; DIAGNOSTIC-CRITERIA; MOUSE-BRAIN AB Purpose of review This article reviews recent advances in clinical trials of hematopoietic stem cell transplantation as a therapy for multiple sclerosis, and progress in exploring the potential for neural repair of hematopoietic-derived precursors. Recent findings Important recent findings are that hematopoietic stem cell transplantation can completely suppress the inflammatory component of multiple sclerosis, hematopoietic stem cells can migrate into the central nervous systems of rodents and humans, and can differentiate into cells expressing neural and glial markers. Hematopoietic stem cells also have neural and myelin repair potential. The heterogeneity of transplant regimens, the selection of patients at different stages of disease in clinical trials, and the limited duration of follow-up all currently preclude the evaluation of the long-term clinical benefits of hematopoietic stem cell transplantation for multiple sclerosis. Summary Hematopoietic stem cell transplantation is an experimental treatment that shows strong effects on the inflammatory component of multiple sclerosis. On the basis of experience acquired from initial pilot studies, controlled clinical trials are now being designed to verify long-term clinical efficacy. Selecting patients at high risk in the earlier stages of the disease that is dominated by inflammation, and monitoring objectively disease activity by magnetic resonance imaging will be critically important in these studies. Recent advances on the migratory potential and on the differentiation plasticity of hematopoietic stem cells have opened new opportunities for remyelination and axonal repair strategies for multiple sclerosis. C1 NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Martin, R (reprint author), NINDS, Neuroimmunol Branch, NIH, Bldg 10,Room 5B16,10 Ctr Dr,MSC1400, Bethesda, MD 20892 USA. OI Muraro, Paolo/0000-0002-3822-1218 NR 72 TC 23 Z9 26 U1 0 U2 1 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 JUN PY 2003 VL 16 IS 3 BP 299 EP 305 DI 10.1097/01.wco.0000073930.19076.1b PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 688KM UT WOS:000183433800008 PM 12858065 ER PT J AU Snider, LA Swedo, SE AF Snider, LA Swedo, SE TI Post-streptococcal autoimmune disorders of the central nervous system SO CURRENT OPINION IN NEUROLOGY LA English DT Article DE Group-A beta-hemolytic streptococcal infections; autoimmune disease; post-infectious; central nervous system illness ID OBSESSIVE-COMPULSIVE DISORDER; ACUTE DISSEMINATED ENCEPHALOMYELITIS; NEUROPSYCHIATRIC DISORDERS; SYDENHAMS CHOREA; TOURETTES-SYNDROME; RHEUMATIC-FEVER; BASAL GANGLIA; ANTINEURONAL ANTIBODIES; MOVEMENT-DISORDERS; TIC DISORDERS AB Purpose of review Autoimmune disease has long been intertwined with investigations of infectious causes. Antibodies that are formed against an infectious agent can, through the process of molecular mimicry, also recognize healthy cells. When this occurs, the immune system erroneously destroys the healthy cells causing autoimmune disease in addition to appropriately destroying the offending infectious agent and attenuating the infectious process. The first infectious agent shown to cause a post-infectious autoimmune disorder in the central nervous system was Streptococcus; pyogenes in Sydenham's chorea. The present review summarizes the most recent published findings of central nervous system diseases that have evidence of a post-streptococcal autoimmune etiology. Recent findings Sydenham's chorea and other central nervous system illnesses that are hypothesized to have a post-streptococcal autoimmune etiology appear to arise from targeted dysfunction of the basal ganglia. PANDAS (pediatric autoimmune disorders associated with streptococcal infections) is the acronym applied to a subgroup of children with obsessive-compulsive disorder or tic disorders occurring in association with streptococcal infections. In addition, there are recent reports of dystonia, chorea encephalopathy, and dystonic choreoathetosis occurring as sequelae of streptococcal infection. Investigators have begun to isolate and describe antistreptococcal-antineuronal antibodies as well as possible genetic markers in patients who are susceptible to these illnesses. Summary Clinical and research findings in both immunology and neuropsychiatry have established the existence of post-streptococcal neuropsychiatric disorders and are beginning to shed light on possible pathobiologic processes. C1 NIMH, Pediat & Dev Neuropsychiat Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Snider, LA (reprint author), NIMH, Pediat & Dev Neuropsychiat Branch, Dept Hlth & Human Serv, NIH, 10 Ctr Dr,Room 4n208, Bethesda, MD 20892 USA. NR 38 TC 54 Z9 60 U1 4 U2 5 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 JUN PY 2003 VL 16 IS 3 BP 359 EP 365 DI 10.1097/01.wco.0000073938.19076.31 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 688KM UT WOS:000183433800017 PM 12858074 ER PT J AU Kuddo, T Nelson, KB AF Kuddo, T Nelson, KB TI How common are gastrointestinal disorders in children with autism? SO CURRENT OPINION IN PEDIATRICS LA English DT Review ID RUBELLA VACCINATION; CONSTIPATION; DISEASE; MEASLES; MUMPS AB We could identify no report that describes the prevalence of gastrointestinal disorders in a representative group of children with a diagnosis of autism compared with appropriate controls. Thus, we found no evidence upon which to base a confident conclusion as to whether gastrointestinal symptoms are more common in children with than without autism. However, the frequency of gastrointestinal symptoms observed in population-based samples of autistic children indicate that gastrointestinal problems are not nearly as common in children with autism as reports from pediatric gastroenterology clinics suggest. (C) 2003 Lippincott Williams Wilkins. C1 NINDS, NEB, NIH, Bethesda, MD 20892 USA. RP Nelson, KB (reprint author), NINDS, NEB, NIH, Bldg 10,Room 5S221, Bethesda, MD 20892 USA. NR 30 TC 40 Z9 40 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8703 J9 CURR OPIN PEDIATR JI CURR. OPIN. PEDIATR. PD JUN PY 2003 VL 15 IS 3 BP 339 EP 343 DI 10.1097/00008480-200306000-00020 PG 5 WC Pediatrics SC Pediatrics GA 681BV UT WOS:000183017700019 PM 12806268 ER PT J AU Tumanov, AV Kuprash, DV Nedospasov, SA AF Tumanov, AV Kuprash, DV Nedospasov, SA TI The role of lymphotoxin in development and maintenance of secondary lymphoid tissues SO CYTOKINE & GROWTH FACTOR REVIEWS LA English DT Review DE secondary lymphoid organs; lymphoid organogenesis; lymphotoxin; tumor necrosis factor ID TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; PEYERS-PATCH ORGANOGENESIS; FOLLICULAR DENDRITIC CELLS; BETA-DEFICIENT MICE; CXC CHEMOKINE RECEPTOR-5; MEMBRANE-BOUND TNF; ALPHA LT-ALPHA; T-CELL; ORGAN DEVELOPMENT AB Secondary lymphoid organs provide the necessary microenvironment for the cooperation of antigen-specific T- and B-lymphocytes and antigen-presenting cells in order to initiate an efficient immune response. Remarkable progress in understanding of the mechanisms of lymphoid organogenesis was achieved due to the analysis of various gene-targeted mice. This review primarily focuses on the role of lymphotoxin (LT) in development, maturation and maintenance of secondary lymphoid organs. Published by Elsevier Science Ltd. C1 Russian Acad Sci, VA Engelhardt Mol Biol Inst, Moscow 119991, Russia. NCI, BRP, SAIC Frederick, Frederick, MD 21702 USA. RP Nedospasov, SA (reprint author), Russian Acad Sci, VA Engelhardt Mol Biol Inst, Moscow 119991, Russia. RI Nedospasov, Sergei/J-5936-2013; Nedospasov, Sergei/L-1990-2015; Kuprash, Dmitry/O-4899-2015; Nedospasov, Sergei/Q-7319-2016 OI Kuprash, Dmitry/0000-0002-1488-4148; NR 143 TC 46 Z9 46 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6101 J9 CYTOKINE GROWTH F R JI Cytokine Growth Factor Rev. PD JUN-AUG PY 2003 VL 14 IS 3-4 BP 275 EP 288 DI 10.1016/S1359-6101(03)00026-1 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 692UV UT WOS:000183679400009 PM 12787565 ER PT J AU Dabdoub, A Donohue, MJ Brennan, A Wolf, V Montcouquiol, M Sassoon, DA Hseih, JC Rubin, JS Salinas, PC Kelley, MW AF Dabdoub, A Donohue, MJ Brennan, A Wolf, V Montcouquiol, M Sassoon, DA Hseih, JC Rubin, JS Salinas, PC Kelley, MW TI Wnt signaling mediates reorientation of outer hair cell stereociliary bundles in the mammalian cochlea SO DEVELOPMENT LA English DT Article DE planar polarity; organ of Corti; sensory epithelium; mechanosensory hair cells; mouse ID WINGLESS MORPHOGEN GRADIENT; GUINEA-PIG COCHLEA; LONG-RANGE ACTION; SYNDROME TYPE 1D; PLANAR POLARITY; SPEMANN ORGANIZER; SECRETED PROTEIN; GOLDEN-HAMSTERS; DROSOPHILA EYE; CADHERIN GENE AB In the mammalian cochlea, stereociliary bundles located on mechanosensory hair cells within the sensory epithelium are unidirectionally oriented. Development of this planar polarity is necessary for normal hearing as stereociliary bundles are only sensitive to vibrations in a single plane; however, the mechanisms governing their orientation are unknown. We report that Wnt signaling regulates the development of unidirectional stereociliary bundle orientation. In vitro application of Wnt7a protein or inhibitors of Wnt signaling, secreted Frizzled-related protein 1 or Wnt inhibitory factor 1, disrupts bundle orientation. Moreover, Wnt7a is expressed in a pattern consistent with a role in the polarization of the developing stereociliary bundles. We propose that Wnt signaling across the region of developing outer hair cells gives rise to planar polarity in the mammalian cochlea. C1 NIDCD, Sect Dev Neurosci, NIH, Rockville, MD 20850 USA. Univ London Imperial Coll Sci Technol & Med, Dept Biol Sci, London SW7 2AZ, England. NCI, Cellular & Mol Biol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Mt Sinai Sch Med, Dept Biochem & Mol Biol, New York, NY 10029 USA. SUNY Stony Brook, Dept Biochem & Cell Biol, Stony Brook, NY 11794 USA. RP Dabdoub, A (reprint author), NIDCD, Sect Dev Neurosci, NIH, Rockville, MD 20850 USA. OI montcouquiol, mireille/0000-0001-8739-6519 NR 70 TC 145 Z9 150 U1 0 U2 8 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD JUN PY 2003 VL 130 IS 11 BP 2375 EP 2384 DI 10.1242/dev.00448 PG 10 WC Developmental Biology SC Developmental Biology GA 691UF UT WOS:000183623400008 PM 12702652 ER PT J AU Nissen, RM Yan, JZ Amsterdam, A Hopkins, N Burgess, SM AF Nissen, RM Yan, JZ Amsterdam, A Hopkins, N Burgess, SM TI Zebrafish foxi one modulates cellular responses to Fgf signaling required for the integrity of ear and jaw patterning SO DEVELOPMENT LA English DT Article DE Foxi1; otic placode; pharyngeal pouch; fgf8; fgf3; pax8 ID MIDBRAIN-HINDBRAIN BOUNDARY; NEURAL CREST CELLS; PAIRED BOX GENE; INNER-EAR; INSERTIONAL MUTAGENESIS; TRANSCRIPTION FACTORS; PLACODE INDUCTION; BRANCHIAL ARCH; HEAD SKELETON; OTIC PLACODE AB We identified four insertional alleles of foxi one (foo), an embryonic lethal mutation in zebrafish that displays defects in both otic placode and the jaw. In foo/foo embryos the otic placode is split into two smaller placodes and mutant embryos show a dorsoventral (DV) cartilage defect manifested as a reduced hyomandibular and reduced third and fourth branchial arches. We identified foxi one (foo), the zebrafish ortholog of Foxi1 (FREAC6, FKHL10, HFH3, Fkh10) and a member of the forkhead domain transcriptional regulator family, as the gene mutated in foo/foo embryos. foo is expressed in otic placode precursor cells, and foo/foo embryos lack placodal pax8 expression and have disorganized otic expression of pax2.1 and dlx3. Third stream neural crest cell migration, detected by dlx2 and krox20 expression, is aberrant in that it invades the otic placode territory. foo is expressed in pharyngeal pouch endoderm and is required for pouch expression of pax8 and proper patterning of other markers in the pouch such as nkx2.3. In foo/foo embryos, we observed a failure to maintain fgf3 expression in the pouches, followed by apoptosis of neural crest cells in adjacent arches. We conclude that foo expression is essential for pax8 expression probably downstream of Fgf signaling in a conserved pathway jointly required for integrity of patterning in the otic placode and pharyngeal pouches. We propose that correct placement of survival/proliferation cues is essential for shaping the pharyngeal cartilages and that evolutionary links between jaw and ear formation can be traced to Fgf-Foxi1-Pax8 pathways. C1 NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. MIT, Canc Res Ctr, Cambridge, MA 02139 USA. MIT, Dept Biol, Cambridge, MA 02139 USA. RP Burgess, SM (reprint author), NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. OI Burgess, Shawn/0000-0003-1147-0596 NR 50 TC 105 Z9 106 U1 0 U2 6 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD JUN PY 2003 VL 130 IS 11 BP 2543 EP 2554 DI 10.1242/dev.00455 PG 12 WC Developmental Biology SC Developmental Biology GA 691UF UT WOS:000183623400023 PM 12702667 ER PT J AU Jaubert, J Cheng, J Segre, JA AF Jaubert, J Cheng, J Segre, JA TI Ectopic expression of Kruppel like factor 4 (Klf4) accelerates formation of the epidermal permeability barrier SO DEVELOPMENT LA English DT Article DE KLF4; epidermis; permeability barrier; perinatal mortality; mouse ID ZINC-FINGER PROTEIN; GENE-EXPRESSION; SKIN; MICE; INFANTS; CELLS; PREMATURE; CANCER; COLON AB Dysfunction of the epidermal permeability barrier can result in dehydration, electrolyte imbalance and poor thermoregulation. Immature skin is a portal of entry for infectious agents and potential toxins in topically applied substances. As the skin is one of the last organs to mature in utero, premature infants born before 34 weeks gestation are at great risk for complications. The transcription factor kruppel-like factor 4 (Klf4), has been shown by a targeted ablation, to have an essential function in barrier acquisition. We investigated whether Klf4 expression in utero is sufficient to establish the epidermal barrier. Specifically, we generated lines of mice that express Klf4 from a tetracycline inducible promoter when crossed with transgenic mice expressing the tetracycline transactivator tTA from the epidermal keratin 5 promoter. These mice exhibit acceleration in barrier acquisition as manifest by the exclusion of a dye solution one day earlier in development than controls. Underlying this dye impermeability are morphological changes, including an increased number of stratified layers, expression of terminal differentiation markers and assembly of cornified envelopes. By all criteria, Klf4 ectopic expression accelerates the normal process of terminal differentiation. Premature barrier acquisition in these mice follows the normal pattern rather than the pattern of the transgene promoter, indicating that there are fields of competence in which KLF4 acts. Although other transgenic mice have perturbed barrier acquisition, these mice are the first to accelerate the process of barrier establishment. These studies show that KLF4 regulates barrier acquisition and provides an animal model for studying how to accelerate the process of barrier acquisition for the premature infant. C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Segre, JA (reprint author), NHGRI, NIH, 49 Convent Dr, Bethesda, MD 20892 USA. NR 32 TC 77 Z9 84 U1 0 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD JUN PY 2003 VL 130 IS 12 BP 2767 EP 2777 DI 10.1242/dev.00477 PG 11 WC Developmental Biology SC Developmental Biology GA 694DY UT WOS:000183759600019 PM 12736219 ER PT J AU Crick, NR Zahn-Waxler, C AF Crick, NR Zahn-Waxler, C TI The development of psychopathology in females and males: Current progress and future challenges SO DEVELOPMENT AND PSYCHOPATHOLOGY LA English DT Review ID SOCIAL-PSYCHOLOGICAL ADJUSTMENT; MATERNAL DEPRESSIVE SYMPTOMS; LIFE-COURSE-PERSISTENT; ONTARIO CHILD HEALTH; GENDER-DIFFERENCES; RELATIONAL AGGRESSION; SEX-DIFFERENCES; CONDUCT DISORDER; ADOLESCENT PSYCHOPATHOLOGY; ANTISOCIAL-BEHAVIOR AB In recent years, the role of gender in the development of psychopathology has increasingly attracted the attention of researchers, theoreticians, and other professionals interested in the well-being of children and adolescents. This interest has taken diverse forms, ranging from the examination of sex differences in the prevalence of adjustment difficulties to the exploration of unique etiologies and trajectories in the development of psychopathology for boys versus girls. In this paper we (a) critically examine the current status of available theories, research, and methods related to the study of gender and psychopathology and provide recommendations for future work; (b) identify promising new trends that appear to have utility for enhancing our understanding of the role of gender in the development of adjustment difficulties; and (c) generate conclusions regarding gender and psychopathology by integrating information from past and present work with new ideas about fruitful directions for future inquiry. C1 Univ Minnesota, Inst Child Dev, Minneapolis, MN 55455 USA. NIMH, Bethesda, MD 20892 USA. RP Crick, NR (reprint author), Univ Minnesota, Inst Child Dev, 51 E River Rd, Minneapolis, MN 55455 USA. EM crick001@umn.edu; waxlerc@irp.nimh.nih.gov FU NIMH NIH HHS [MH-01-002] NR 152 TC 251 Z9 251 U1 4 U2 34 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0954-5794 J9 DEV PSYCHOPATHOL JI Dev. Psychopathol. PD SUM PY 2003 VL 15 IS 3 BP 719 EP 742 DI 10.1017/S095457940300035X PG 24 WC Psychology, Developmental SC Psychology GA 721GU UT WOS:000185309300010 PM 14582938 ER PT J AU Buttitta, L Tanaka, TS Chen, AE Ko, MSH Fan, CM AF Buttitta, L Tanaka, TS Chen, AE Ko, MSH Fan, CM TI Microarray analysis of somitogenesis reveals novel targets of different WNT signaling pathways in the somitic mesoderm SO DEVELOPMENTAL BIOLOGY LA English DT Article DE presomitic mesoderm; somite; WNT; microarray; dermomyotome ID N-TERMINAL KINASE; GENE-EXPRESSION; SONIC HEDGEHOG; BETA-CATENIN; SCLEROTOME INDUCTION; MOLECULAR MECHANISM; PARAXIAL MESODERM; PATTERN-FORMATION; MOUSE; PROTEINS AB WNT signaling plays a major role in patterning the dermomyotome of the somitic mesoderm. However, knowledge of downstream target genes and their regulation is limited. To identify new genes involved in the development and early patterning of the somite, we performed a comparison of gene expression by microarray between the presomitic mesoderm and the 5 most recently formed somites of the mouse at embryonic day 9.5. We identified 207 genes upregulated and 120 genes downregulated in somite formation. Expression analysis and functional categorization of these genes demonstrate this to be a diverse pool that provides a valuable resource for studying somite development. Thus far, we have found three genes expressed in the dermomyotome of the early somite. Consistent with their expression patterns, these genes are transcriptional targets of WNT signals, but display differential activation by different WNTs. We further demonstrate that I of these genes, Troy, is a direct target of canonical WNT signaling, while the other 2 genes, Selp and Arl4, are not. Thus, our microarray study using microdissected tissues not only provides global information on gene expression during somite development, it also provides novel targets to study the inductive signaling pathways that direct somite patterning. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Carnegie Inst Washington, Dept Embryol, Baltimore, MD 21210 USA. NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Fan, CM (reprint author), Carnegie Inst Washington, Dept Embryol, 115 W Univ Pkwy, Baltimore, MD 21210 USA. RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 NR 54 TC 34 Z9 36 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2003 VL 258 IS 1 BP 91 EP 104 DI 10.1016/S0012-1606(03)00116-7 PG 14 WC Developmental Biology SC Developmental Biology GA 687MJ UT WOS:000183380300008 PM 12781685 ER PT J AU Kim, JK Fillmore, JJ Gavrilova, O Chao, LL Higashimori, T Choi, H Kim, HJ Yu, CL Chen, Y Qu, XQ Haluzik, M Reitman, ML Shulman, GI AF Kim, JK Fillmore, JJ Gavrilova, O Chao, LL Higashimori, T Choi, H Kim, HJ Yu, CL Chen, Y Qu, XQ Haluzik, M Reitman, ML Shulman, GI TI Differential effects of rosiglitazone on skeletal muscle and liver insulin resistance in A-ZIP/F-1 fatless mice SO DIABETES LA English DT Article ID ACTIVATED RECEPTOR-GAMMA; MAGNETIC-RESONANCE SPECTROSCOPY; NECROSIS-FACTOR-ALPHA; ADIPOSE-TISSUE; TRIGLYCERIDE CONTENT; LIPID-METABOLISM; GENE-EXPRESSION; IN-VIVO; GLYCOGEN-SYNTHESIS; GLUCOSE-UPTAKE AB To determine the role of adipocytes and the tissue-specific nature in the insulin sensitizing action of rosiglitazone, we examined the effects of 3 weeks of rosiglitazone treatment on insulin signaling and action during hyperinsulinemic-euglycemic clamps in awake A-ZIP/F-1 (fatless), fat-transplanted fatless, and wildtype littermate mice. We found that 53 and 66% decreases in insulin-stimulated glucose uptake and insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase activity in skeletal muscle of fatless mice were normalized after rosiglitazone treatment. These effects of rosiglitazone treatment were associated with 50% decreases in triglyceride and fatty acyl-CoA contents in the skeletal muscle of rosiglitazone-treated fatless mice. In contrast, rosiglitazone treatment exacerbated hepatic insulin resistance in the fatless mice and did not affect already reduced IRS-2-associated PI 3-kinase activity in liver. The worsening of insulin action in liver was associated with 30% increases in triglyceride and fatty acyl-CoA contents in the liver of rosiglitazone-treated fatless mice. In conclusion, these data support the hypothesis that rosiglitazone treatment enhanced insulin action in skeletal muscle mostly by its ability to repartition fat away from skeletal muscle. C1 Yale Univ, Sch Med, Dept Internal Med, Endocrinol Sect,Howard Hughes Med Inst, New Haven, CT 06520 USA. NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. Univ Technol Sydney, Dept Hlth Sci, Sydney, NSW 2007, Australia. Yale Univ, Sch Med, Dept Cellular & Mol Physiol, Howard Hughes Med Inst, New Haven, CT 06520 USA. RP Kim, JK (reprint author), Yale Univ, Sch Med, Dept Internal Med, Endocrinol Sect,Howard Hughes Med Inst, S269C CAB,POB 208020, New Haven, CT 06520 USA. RI Reitman, Marc/B-4448-2013 OI Reitman, Marc/0000-0002-0426-9475 FU NIDDK NIH HHS [R01 DK080756, U24 DK 59635, R01 DK 40936, P30 DK 45735, R01 DK040936] NR 56 TC 63 Z9 65 U1 1 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUN PY 2003 VL 52 IS 6 BP 1311 EP 1318 DI 10.2337/diabetes.52.6.1311 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 683UD UT WOS:000183167600001 PM 12765938 ER PT J AU Meigs, JB Muller, DC Nathan, DM Blake, DR Andres, R AF Meigs, JB Muller, DC Nathan, DM Blake, DR Andres, R TI The natural history of progression from normal glucose tolerance to type 2 diabetes in the Baltimore Longitudinal Study of Aging SO DIABETES LA English DT Article ID INSULIN SECRETORY DYSFUNCTION; IMPAIRED FASTING GLUCOSE; DIAGNOSTIC-CRITERIA; LIFE-STYLE; BETA-CELL; HIGH-RISK; RESISTANCE; MELLITUS; NIDDM; PREVENTION AB The natural history of progression from normal glucose tolerance (NOT), to impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes is riot well defined. We studied this progression using biennial oral glucose, tolerance tests performed in the Baltimore Longitudinal Study of Aging, and. survival analysis to assess progression from NGT to abnormal fasting plasma glucose (FPG; greater than or equal to6.1 mmol/l), abnormal 2-h plasma. glucose (2hPG; greater than or equal to7.8. mmol/l), IFG (FPG 6.1-6.9 mmol/l, 2hPG less than or equal to7.8 mmol/l), and IGT (FPG <6.1 mmol/l; 2hPG-7.8-11.0 mmol/l), and from IFG-IGT to diabetes (FPG greater than or equal to7.0 mmol/l or 2hPG greater than or equal to11.1 mmol/l). At baseline, the 815 subjects had a mean age of 57 years, 35% were women, and 60% had NOT. Of the 488 subjects with NOT, over half were followed for at least 10 years. By 10 years, 14% had progressed to abnormal FPG and 48% to abnormal 2hPG. Of the 267 subjects who progressed to IFG-IGT, 216 had additional follow-up. By 10 years, 8% of these progressed to diabetes by FPG whereas 27% progressed by 2hPG. In subsidiary analyses, we defined "abnormal" FPG as greater than or equal to5.55 mmol/l and "diabetic". FPG as greater than or equal to6.1. mmol/l; making the baseline prevalence of IFG similar to that of IGT.. By these criteria, 43% progressed to abnormal FPG and 43% to abnormal 2hPG by 10 years of follow-up; among subjects developing impaired FPG or 2hPG, 22% progressed to diabetes by FPG whereas 17% progressed by 2hPG at 10 years. Nonetheless, 42% of subjects developing abnormal FPG did not develop abnormal 2hPG, and vice versa. We conclude that, although phenotypic differences in rates of progression are partly a function of diagnostic thresholds, fasting and postchallenge hyperglycemia may represent phenotypes with distinct natural histories in the evolution of type 2 diabetes. Diabetes 52: 1415-1484,2003. C1 Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. NIA, Baltimore, MD 21224 USA. RP Meigs, JB (reprint author), Massachusetts Gen Hosp, Div Gen Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. NR 35 TC 158 Z9 165 U1 1 U2 12 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUN PY 2003 VL 52 IS 6 BP 1475 EP 1484 DI 10.2337/diabetes.52.6.1475 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 683UD UT WOS:000183167600023 PM 12765960 ER PT J AU Stefan, N Kovacs, P Stumvoll, M Hanson, RL Lehn-Stefan, A Permana, PA Baier, LJ Tataranni, PA Silver, K Bogardus, C AF Stefan, N Kovacs, P Stumvoll, M Hanson, RL Lehn-Stefan, A Permana, PA Baier, LJ Tataranni, PA Silver, K Bogardus, C TI Metabolic effects of the Gly1057Asp polymorphism in IRS-2 and interactions with obesity SO DIABETES LA English DT Article ID INSULIN SECRETORY DYSFUNCTION; RECEPTOR SUBSTRATE-2 GENE; POLYCYSTIC-OVARY-SYNDROME; X-RAY ABSORPTIOMETRY; PIMA-INDIANS; RESISTANCE; DISRUPTION; VARIANTS; MICE AB Insulin receptor substrate (IRS)-2 plays an important role in insulin signaling and its disruption results in diabetes in mice. In humans, the IRS-2 Gly1057Asp substitution was associated with lower risk of type 2 diabetes in lean individuals, but with a higher risk in obese individuals. To clarify the role of IRS-2 on the development of type 2 diabetes and obesity in Pima Indians, and particularly to investigate whether the effects of the Gly1057Asp polymorphism on metabolism are mediated by obesity, molecular scanning of the gene for mutations was performed and interaction of the polymorphism with obesity was tested. We identified the previously described Gly1057Asp mutation as well as a rare Asp819His mutation and four silent polymorphisms. The effect of the Gly1057Asp mutation on type 2 diabetes and obesity was tested in a large cohort of Pima Indians (n = 998). A subgroup of nondiabetic full-heritage Pima Indians (n = 233) had measurements of body composition, glucose tolerance, insulin action (M), endogenous glucose production (EGP; hyperinsulinemic clamp), acute insulin response (AIR, 25-g intravenous glucose tolerance test, n = 118 normal glucose-tolerant subjects), and percutaneous fat biopsy specimens from the periumbilical region (n = 160). A total of 132 nondiabetic subjects were included in longitudinal analyses. The frequency of the Asp1057 allele was 0.6. In cross-sectional analyses, subjects homozygous for the Asp1057 allele (Asp/Asp) had a higher prevalence of type 2 diabetes than heterozygote individuals and subjects homozygous for the Gly1057 allele (X/Gly, P = 0.04). There was no effect on BMI (P = 0.78) or gene-BMI interaction on the prevalence of type 2 diabetes (P = 0.57). In the nondiabetic subgroup, subjects with Asp/Asp had higher percent body fat (P = 0.01), BMI (P = 0.02), and waist circumference (P = 0.004), but there was no difference in metabolic characteristics (all P > 0.2). However, the relationship between percent body fat and fasting glucose, basal EGP, EGP during the clamp, AIR, and subcutaneous abdominal adipocyte size was significantly different in the Asp/Asp group (P for interaction = 0.02, 0.06, 0.0007, 0.08, and 0.006, respectively) compared with the X/Gly group, suggesting a more detrimental effect of Asp homozygosity on these traits with increasing percent body fat. In longitudinal analyses, among subjects in the upper tertile of change in percent body fat, those with Asp/Asp had a larger increase in fasting and postprandial glycemia and basal EGP and a larger decrease in M and AIR than subjects with X/Gly, independent of change in obesity (all P < 0.05). In conclusion, our findings suggest that the association of homozygosity for the Asp1057 allele in IRS-2 with type 2 diabetes in Pima Indians may be mediated by interaction of the polymorphism with obesity on several diabetes-related traits. Diabetes 52:1544-1550, 2003. C1 NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. Univ Tubingen, Dept Endocrinol & Metab, Tubingen, Germany. Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. RP Stefan, N (reprint author), NIDDKD, Clin Diabet & Nutr Sect, NIH, 4212 N 16Th St,Rm 5-41, Phoenix, AZ 85016 USA. RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU NIDDK NIH HHS [1K23 DK 02945-01] NR 31 TC 26 Z9 33 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUN PY 2003 VL 52 IS 6 BP 1544 EP 1550 DI 10.2337/diabetes.52.6.1544 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 683UD UT WOS:000183167600031 PM 12765968 ER PT J AU Krakoff, J Funahashi, T Stehouwer, CDA Schalkwijk, CG Tanaka, S Matsuzawa, Y Kobes, S Tataranni, PA Hanson, RL Knowler, WC Lindsay, RS AF Krakoff, J Funahashi, T Stehouwer, CDA Schalkwijk, CG Tanaka, S Matsuzawa, Y Kobes, S Tataranni, PA Hanson, RL Knowler, WC Lindsay, RS TI Inflammatory markers, adiponectin, and risk of type 2 diabetes in the Pima Indian SO DIABETES CARE LA English DT Article ID TUMOR-NECROSIS-FACTOR; C-REACTIVE PROTEIN; VON-WILLEBRAND-FACTOR; INSULIN-RESISTANCE ATHEROSCLEROSIS; FACTOR-ALPHA; ADIPOSE-TISSUE; TNF-ALPHA; ENDOTHELIAL DYSFUNCTION; PLASMA-PROTEIN; KAPPA-B AB OBJECTIVE - To examine the association between adiponectin, a known predictor of diabetes in Pima Indians, and markers of inflammation and endothelial function in nondiabetic subjects and to assess whether these markers predict later diabetes in a case-control study within a longitudinal health study in Pima Indians. RESEARCH DESIGN AND METHODS - Participants with normal glucose tolerance at baseline were selected. Case subjects (who later developed type 2 diabetes), and control subjects (n = 71 pairs) were matched for BMI, age, and sex. Adiponectin, C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor-alpha, phospholipase A2 (sPLA2), soluble E-selectin (SE-selectin), soluble intracellular adhesion molecule-1, soluble vascular adhesion molecule-1, and von Willebrand factor (vWF) were measured in baseline samples. RESULTS - Adiponectin was negatively correlated with CRP (r = -0.25, P < 0.05), IL-6 (r = -0.20, P < 0.05), sPLA2 (r = -0.22, P < 0.05), and SE-selectin (r = -0.20, P < 0.05). CRP and IL-6 did not predict diabetes. Only vWF predicted the development of diabetes (incidence rate ratio 0.67 for a 1-SD difference, 95% CI 0.41-1.00, P = 0.05), but this was not significant after adjustment for age, glucose, HbA(1c), waist circumference, and fasting insulin (hazard rate ratio 0.73, 95% CI 0.46-1.16, P = 0.18). CONCLUSIONS - Adiponectin is negatively correlated with markers of inflammation in vivo. In case and control subjects matched for BMI, with the exception of vWF, none of the inflammatory markets predicted diabetes. Adiponectin may be the link between adiposity, inflammation, and type 2 diabetes. C1 NIDDKD, Diabet & Arthrit Epidemiol Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85014 USA. Osaka Univ, Dept Internal Med & Mol Sci, Osaka, Japan. Univ Hosp Vrije Univ, Dept Internal Med, Amsterdam, Netherlands. RP Krakoff, J (reprint author), NIDDKD, Diabet & Arthrit Epidemiol Sect, Phoenix Epidemiol & Clin Res Branch, NIH, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 NR 46 TC 196 Z9 212 U1 1 U2 7 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD JUN PY 2003 VL 26 IS 6 BP 1745 EP 1751 DI 10.2337/diacare.26.6.1745 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 724UR UT WOS:000185505500014 PM 12766104 ER PT J AU Looker, HC Fagot-Campagna, A Gunter, EW Pfeiffer, CM Narayan, KMV Knowler, WC Hanson, RL AF Looker, HC Fagot-Campagna, A Gunter, EW Pfeiffer, CM Narayan, KMV Knowler, WC Hanson, RL TI Homocysteine as a risk factor for nephropathy and retinopathy in Type 2 diabetes SO DIABETOLOGIA LA English DT Article DE homocysteine; diabetic retinopathy; diabetic nephropathy; diabetes mellitus; type 2 ID PLASMA TOTAL HOMOCYSTEINE; CARDIOVASCULAR-DISEASE; INSULIN-RESISTANCE; PIMA-INDIANS; MELLITUS; HYPERHOMOCYSTEINEMIA; HOMOCYST(E)INE; ASSOCIATION; HISTORY; INJURY AB Aims/hypothesis. The aim of this study was to examine the relation between serum total homocysteine concentrations and microvascular complications in Pima Indians with Type 2 diabetes. Methods. Homocysteine concentrations were measured in frozen sera of 396 diabetic participants in a longitudinal study who were 40 years of age or older and who had attended one or more examinations between 1982 and1985. Retinopathy was assessed by fundoscopy and nephropathy by an albumin:creatinine ratio greater than 300 mg/g. The incidence rate ratio for a 5 mumol/l difference in homocysteine was calculated using proportional hazard regression. Results. The incidence of each complication was assessed in subjects without that complication at baseline and with more than one follow-up examination: 229 for nephropathy, 212 for retinopathy and 266 for proliferative retinopathy. There were 101 incident cases of nephropathy, 113 of retinopathy and 40 of proliferative retinopathy during a mean follow-up of 8.6, 7.5 and 8.9 years, respectively. Incidence of nephropathy was associated with homocysteine concentrations: IRR=1.42 (95% CI, 1.09-1.84, p=0.01); this remained statistically significant controlled for age, sex and duration of diabetes (p=0.03), but not when controlled for baseline renal function (p=0.4). Homocysteine concentrations were not associated with the incidence of any retinopathy IRR=1.14 (95%CI 0.89-1.46, p=0.3) but were associated with the incidence of proliferative retinopathy IRR=1.62 (95% CI 1.16-2.28, p=0.005); this association remained statistically significant when controlled for baseline renal function and diabetes duration (p=0.02). Conclusions/interpretation. Increased homocysteine concentrations are associated with an increased risk for incidence of nephropathy and proliferative retinopathy; the relation with incidence of nephropathy seems to be explained by an association with baseline albuminuria status concentrations, whereas the relation with incidence of proliferative retinopathy does not. C1 NIDDK, Diabet & Arthrit Epidemiol Sect, Phoenix, AZ USA. Ctr Dis Control, Atlanta, GA 30333 USA. RP Looker, HC (reprint author), 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. RI Narayan, K.M. Venkat /J-9819-2012; Hanson, Robert/O-3238-2015 OI Narayan, K.M. Venkat /0000-0001-8621-5405; Hanson, Robert/0000-0002-4252-7068 NR 28 TC 51 Z9 59 U1 1 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD JUN PY 2003 VL 46 IS 6 BP 766 EP 772 DI 10.1007/s00125-003-1104-x PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 695GY UT WOS:000183823800004 PM 12774164 ER PT J AU Maclaren, NK Lan, MS Schatz, D Malone, J Notkins, AL Krischer, J AF Maclaren, NK Lan, MS Schatz, D Malone, J Notkins, AL Krischer, J TI Multiple autoantibodies as predictors of Type 1 diabetes in a general population SO DIABETOLOGIA LA English DT Article ID CHILDREN C1 Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Notkins, AL (reprint author), Natl Inst Dent & Craniofacial Res, NIH, 9000 Rockville Pike,Bldg 30,Rm 121, Bethesda, MD 20892 USA. NR 8 TC 9 Z9 9 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 JUN PY 2003 VL 46 IS 6 BP 873 EP U22 DI 10.1007/s00125-003-1123-7 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 695GY UT WOS:000183823800020 PM 12802500 ER PT J AU Best, CJM Leiva, IM Chuaqui, RF Gillespie, JW Duray, PH Murgai, M Zhao, YD Simon, R Kang, JJ Green, JE Bostwick, DG Linehan, WM Emmert-Buck, MR AF Best, CJM Leiva, IM Chuaqui, RF Gillespie, JW Duray, PH Murgai, M Zhao, YD Simon, R Kang, JJ Green, JE Bostwick, DG Linehan, WM Emmert-Buck, MR TI Molecular differentiation of high- and moderate-grade human prostate cancer by cDNA microarray analysis SO DIAGNOSTIC MOLECULAR PATHOLOGY LA English DT Article DE aggressive prostate cancer; gene expression profiling; cDNA microarrays ID GENE-EXPRESSION PROFILES; CELL-ADHESION MOLECULE; ALPHA-1-ACID GLYCOPROTEIN; COMPLEMENTARY-DNA; BENIGN; ADENOCARCINOMA; PROGRESSION; HYPERPLASIA; ALCAM; OVEREXPRESSION AB The prognosis of men with moderate-grade prostate cancer is uncertain. At present, there are few if any reliable molecular markers that can distinguish moderate-grade tumors from those that behave more aggressively. To better understand the molecular basis of human prostate cancer and potentially provide information toward more accurate prognosis, we measured and analyzed gene expression profiles of 13 high- and moderate-grade human prostate tumors using cDNA microarrays. The expression of 136 genes was observed to differ significantly (P < 0.001) between normal prostate and tumors using one-sample t testing and Wilcoxon ranking. Hierarchical clustering of genes demonstrated a relatively similar pattern of differential expression across the tumors. However, importantly, permutation t tests (two-tailed P < 0.001) revealed 21 genes whose expression profiles segregated moderate- and high-grade tumors from each other, which was significantly (P < 0.03) Greater than what was expected by chance. These results were compared in silico with prostate cancer profiling efforts performed by other groups, including a meta-analysis of four data sets. which validated many of the dysregulated genes. We suggest that these data provide insight into the molecular nature of clinically aggressive prostate cancer. C1 NCI, Pathogenet Unit, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. Pontificia Univ Catolica Chile, Santiago, Chile. NCI, Sci Applicat Int Corp, Bethesda, MD 20892 USA. NCI, Biomed Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. Mayo Clin, Rochester, MI USA. Bostwick Labs, Richmond, VA USA. RP Emmert-Buck, MR (reprint author), NCI, Pathogenet Unit, Pathol Lab, NIH, Bldg 10,Room 2A33,10 Ctr Dr, Bethesda, MD 20892 USA. NR 40 TC 35 Z9 39 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1052-9551 J9 DIAGN MOL PATHOL JI Diagn. Mol. Pathol. PD JUN PY 2003 VL 12 IS 2 BP 63 EP 70 DI 10.1097/00019606-200306000-00001 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Pathology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Pathology GA 682JG UT WOS:000183087800001 PM 12766610 ER PT J AU White, DG Hershey, HP Moss, JJ Daniels, H Tuan, RS Bennett, VD AF White, DG Hershey, HP Moss, JJ Daniels, H Tuan, RS Bennett, VD TI Functional analysis of fibronectin isoforms in chondrogenesis: Full-length recombinant mesenchymal fibronectin reduces spreading and promotes condensation and chondrogenesis of limb mesenchymal cells SO DIFFERENTIATION LA English DT Article DE alternative splicing; baculoviridae; cell adhesion; cell movement; chondrogenesis; extracellular matrix; recombinant proteins ID AGGLUTININ AFFINITY-CHROMATOGRAPHY; DERMATAN SULFATE PROTEOGLYCAN; IN-VITRO CHARACTERIZATION; SPLICED EDA SEGMENT; PRE-MESSENGER-RNA; EXTRACELLULAR-MATRIX; CARTILAGE DIFFERENTIATION; RAT FIBRONECTIN; BINDING DOMAIN; LECTIN BINDING AB Fibronectin (FN), a large dimeric glycoprotein, functions primarily as a connecting molecule in the extracellular matrices of tissues by mediating both cell-matrix and matrix-matrix interactions. All members of the FN family are products of a single FN gene; heterogeneity arises from the alternative splicing of at least three regions (IIIB, IIIA, and V) during processing of a common primary transcript. During chick embryonic limb chondrogenesis, FN structure changes from B+ A(+) in precartilage mesenchyme to B+ A(-) in differentiated cartilage, and exon IIIA has been shown to be necessary for the process of mesenchymal cellular condensation, a requisite event that precedes overt expression of chondrocyte phenotype. This study aims to investigate the mechanistic action of the FN isoforms in mesenchymal chondrogenesis and, in particular, to identify the specific cellular function in mesenchymal condensation mediated by the mesenchymal (B+ A(+) ) FN isoform. Full-length cDNAs corresponding to four splice variants (B+ A(+) , B+ A(-) , B- A(+) , B- A(-) ) of FN were constructed, and expressed the corresponding proteins using a baculovirus expression vector system. Cell adhesion assays with purified proteins showed that, although the relative levels of cell attachment were approximately the same, chick limb-bud mesenchymal cells spread up to 40 % less on mesenchymal (B+ A(+) ) FN than on cartilage (B+ A(-) ) FN, (B- A(+) ) FN, or plasma (B- A(-) ) FN. Cellular condensation and chondrogenic differentiation were also promoted in high-density micromass cultures of limb mesenchymal cells plated onto B+ A(+) FN. These observations suggest that the process of mesenchymal condensation is mediated at least in part by the enhanced ability of chondrogenic mesenchymal cells to migrate and aggregate as a consequence of residing in and interacting with mesenchymal FN. Our findings are consistent with and provide a mechanistic basis for previous observations that rounding of limb mesenchymal cells precedes the onset of chondrogenesis. C1 NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Dept Orthopaed Surg, Philadelphia, PA 19107 USA. DuPont Co Inc, Agr Prod, Wilmington, DE 19880 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bldg 50,Room 1503,MSC8022, Bethesda, MD 20892 USA. FU NIAMS NIH HHS [AR42887, AR40184]; NIDCR NIH HHS [DE16864] NR 66 TC 25 Z9 26 U1 0 U2 2 PU BLACKWELL VERLAG GMBH PI BERLIN PA KURFURSTENDAMM 57, D-10707 BERLIN, GERMANY SN 0301-4681 J9 DIFFERENTIATION JI Differentiation PD JUN PY 2003 VL 71 IS 4-5 BP 251 EP 261 DI 10.1046/j.1432-0436.2003.7104502.x PG 11 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 692YN UT WOS:000183688000002 PM 12823226 ER PT J AU Drenth, JPH Verlaan, M AF Drenth, JPH Verlaan, M TI Genetic aspects of chronic pancreatitis, and the exploration of an association with keratin 8/18 - Commentary SO DIGESTIVE AND LIVER DISEASE LA English DT Editorial Material DE chronic pancreatitis; genetics; keratin 8/18 ID SERINE-PROTEASE INHIBITOR; KAZAL TYPE-1; MUTATIONS; MICE; DISEASE; LIVER C1 Univ St Radboud, Med Ctr, Dept Med, Div Gastroenterol & Hepatol, Nijmegen, Netherlands. Natl Inst Child Hlth & Human Dev, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Drenth, JPH (reprint author), Univ St Radboud, Med Ctr, Dept Med, Div Gastroenterol & Hepatol, Nijmegen, Netherlands. RI Drenth, J.P.H./H-8025-2014 NR 15 TC 1 Z9 1 U1 0 U2 0 PU PACINI EDITORE PI PISA PA VIA DELLA GHERARDESCA-ZONA INDUSTRIALE OSPEDALETTO, 56121 PISA, ITALY SN 1590-8658 J9 DIGEST LIVER DIS JI Dig. Liver Dis. PD JUN PY 2003 VL 35 IS 6 BP 386 EP 388 DI 10.1016/S1590-8658(03)00163-4 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 700LY UT WOS:000184114500003 PM 12868673 ER PT J AU Chiu, TC Lin, YW Huang, CC Chrambach, A Chang, HT AF Chiu, TC Lin, YW Huang, CC Chrambach, A Chang, HT TI A simple, rapid and sensitive method for analysis of SYPRO Red labeled sodium dodecyl sulfate-protein complexes by capillary electrophoresis with laser-induced fluorescence SO ELECTROPHORESIS LA English DT Article DE capillary electrophoresis; laser-induced fluorescence; poly(ethylene oxide); SYPRO Red; sodium dodecyl sulfate-proteins ID GEL-ELECTROPHORESIS; PROTEOMICS; SEPARATION; SDS; DNA; MEROCYANINE-540; IDENTIFICATION; COATINGS; STAINS; ORANGE AB We describe a segmental filling method for the analysis of SYPRO Red labeled sodium dodecyl sulfate (SDS)-proteins (SRSPs) by capillary electrophoresis-laser induced fluorescence (CE-LIF) with electroosmotic counterflow of poly(ethylene oxide) (PEO). It is shown that SDS and salt play a crucial role in determining the fluorescence intensity of the SRSP. Although the fluorimetric measurements reveal that the SRSPs fluoresce strongly in Tris-borate (TB) buffer containing 0.1% SIDS and high concentrations of NaCl (100 mm), these conditions are not appropriate to CE in view of Joule heating. To overcome that impediment, we applied a plug of 0.1% SIDS (1/5 to 1/3 of the injection volume) prior to injection of samples (0.64 muL) prepared in TB buffer containing 50 mm NaCl and SYPRO Red. When using a background electrolyte of 0.6% PEO in TB buffer containing NaCl, electroosmotic counterflow of the analytes allows one to concentrate large sample volumes (up to 1/3 of effective capillary length) in 21 min, with detection of 0.35 and 0.10 nm for bovine serum albumin and casein, respectively. With a linear dynamic range from 10 nm to 5 muM, this method provides the capability of determining the concentration of casein in cow's milk as 0.45 +/- 0.03 mm (n = 5). C1 Natl Taiwan Univ, Dept Chem, Taipei 10764, Taiwan. NICHHD, NIH, Bethesda, MD 20892 USA. RP Chang, HT (reprint author), Natl Taiwan Univ, Dept Chem, Taipei 10764, Taiwan. RI Chang, Huan-Tsung/C-1183-2011; Chiu, Tai-Chia/I-3827-2013; OI Chiu, Tai-Chia/0000-0002-6297-7883; Lin, Yang-Wei/0000-0001-8667-0811; Chang, Huan-Tsung/0000-0002-5393-1410 NR 39 TC 20 Z9 20 U1 1 U2 9 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD JUN PY 2003 VL 24 IS 11 BP 1730 EP 1736 DI 10.1002/elps.200305428 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 692WG UT WOS:000183682800006 PM 12783449 ER PT J AU Yen, PM Feng, X Flamant, F Chen, YD Walker, RL Weiss, RE Chassande, O Samarut, J Refetoff, S Meltzer, PS AF Yen, PM Feng, X Flamant, F Chen, YD Walker, RL Weiss, RE Chassande, O Samarut, J Refetoff, S Meltzer, PS TI Effects of ligand and thyroid hormone receptor isoforms on hepatic gene expression profiles of thyroid hormone receptor knockout mice SO EMBO REPORTS LA English DT Article ID TR-ALPHA; BETA; TRANSCRIPTION; MICROARRAYS; ACTIVATION; LIVER AB Little is known about the overall patterns of thyroid hormone (Th)-mediated gene regulation by the main Th receptor (Tr) isoforms, Tr-alpha and Tr-beta, in vivo. We used 48 complementary DNA microarrays to examine hepatic gene expression profiles of wildtype and Thra and Thrb knockout mice under different Th conditions: no treatment, treatment with 3,3',5-triiodothyronine (T-3), Th-deprivation using propylthiouracil (PTU), and treatment with a combination of PTU and T-3. Hierarchical clustering analyses showed that positively regulated genes fit into three main expression patterns. In addition, only a subpopulation of target genes repressed basal transcription in the absence of ligand. Interestingly, Thra and Thrb knockout mice showed similar gene expression patterns to wild-type mice, suggesting that these isoforms co-regulate most hepatic target genes. Differences in the gene expression patterns of Thra/Thrb double-knockout mice and Th-deprived wild-type mice show that absence of receptor and of hormone can have different effects. This large-scale study of hormonal regulation reveals the functions of Th and of Tr isoforms in the regulation of gene expression patterns. C1 NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Mol Regulat & Neuroendocrinol Sect, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Ecole Normale Super Lyon, Lab Biol Mol & Cellulaire, UMR 5665,CNRS, INRA, F-69364 Lyon, France. Univ Chicago, Dept Med, Chicago, IL 60637 USA. Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. Univ Chicago, Comm Genet, Chicago, IL 60637 USA. RP Meltzer, PS (reprint author), NHGRI, Canc Genet Branch, NIH, Rm 5140,Bldg 50, Bethesda, MD 20892 USA. FU NIDDK NIH HHS [DK 15070, DK 58281, R01 DK015070, R01 DK058281, R37 DK015070] NR 23 TC 76 Z9 78 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1469-221X J9 EMBO REP JI EMBO Rep. PD JUN PY 2003 VL 4 IS 6 BP 581 EP 587 DI 10.1038/sj.embor.embor862 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 686BA UT WOS:000183299600013 PM 12776178 ER PT J AU Devin, A Lin, Y Liu, ZG AF Devin, A Lin, Y Liu, ZG TI The role of the death-domain kinase RIP in tumour-necrosis-factor-induced activation of mitogen-activated protein kinases SO EMBO REPORTS LA English DT Article ID NF-KAPPA-B; CELL-DEATH; FACTOR RECEPTORS; TERMINAL KINASE; IKK ACTIVATION; MEK KINASE-1; APOPTOSIS; TRAF2; CYTOKINES; MIGRATION AB The death-domain kinase RIP (receptor-interacting protein) is an important effector of tumour necrosis factor (TNF) signalling and is essential for TNF-induced nuclear factor-kappaB activation. However, the function of RIP in the TNF-induced activation of mitogen-activated protein kinases (MAPKs) has not been fully investigated. In this report, using Rip null (Rip(-/-)) mouse fibroblast cells, we investigated whether RIP is required for TNF-induced activation of the MAPKs extracellular-signal-related kinase (ERK), p38 and c-Jun amino-terminal kinase (JNK). We found that TNF-induced activation of ERK, p38 and JNK is decreased in Rip(-/-) cells. The activation of these kinases by interleukin-1 is normal in Rip(-/-) cells. More importantly, we showed that the kinase activity of RIP is needed for ERK activation. C1 NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Liu, ZG (reprint author), CNRS, Inst Biochem & Genet Cellulaire, 1 Rue Camille St Saens, F-33077 Bordeaux, France. NR 24 TC 93 Z9 96 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1469-221X J9 EMBO REP JI EMBO Rep. PD JUN PY 2003 VL 4 IS 6 BP 623 EP 627 DI 10.1038/sj.embor.embor854 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 686BA UT WOS:000183299600019 PM 12776182 ER PT J AU Chiueh, CC Lee, SY Andoh, T Murphy, DL AF Chiueh, CC Lee, SY Andoh, T Murphy, DL TI Induction of antioxidative and antiapoptotic thioredoxin supports neuroprotective hypothesis of estrogen SO ENDOCRINE LA English DT Article DE 17 beta-estradiol; gene induction; SH-SY5Y cells; MnSOD; NOS1; thioredoxin ID DEPENDENT PROTEIN-KINASE; STRESS-INDUCED APOPTOSIS; NITRIC-OXIDE SYNTHASES; OXIDATIVE STRESS; RECEPTOR-ALPHA; DOPAMINERGIC-NEURONS; NEUROTROPHIC FACTOR; GENDER-DIFFERENCES; PC12 CELLS; EXPRESSION AB The original neuroprotective hypothesis of estrogen was based on the gender difference in brain response to the ischemia-reperfusion injury. Additional clinical reports also suggest that estrogen may improve cognition in patients with Alzheimer disease. 17beta-Estradiol is the most potent endogenous ligand of estrogen, which protects against neurodegeneration in both cell and animal models. Estrogen-mediated neuroprotection is probably mediated by both receptor-dependent and -independent mechanisms. Binding of estrogen such as 17beta-estradiol to estrogen receptors (ERs) activates the homodimers of ER-DNA and its binding to estrogen response elements in the promoter region of genes such as neuronal nitric oxide synthase (NOSI) for regulating gene expression in target brain cells. In addition to the induction of NOSI, estrogen increases the expression of antiapoptotic protein such as bcl-2. Furthermore, our recent observations provide new molecular biologic and pharmacologic evidence suggesting that physiologic concentrations of 17beta-estradiol (<10 nM) activate ERs (ER beta > ERalpha) and upregulate a cyclic guanosine 5'-monophosphate (cGMP) -dependent thioredoxin (Trx) and MnSOD expression following the induction of NOSI in human brain-derived SH-SY5Y cells. We thus proposed that the estrogen-mediated gene induction of Trx plays a pivotal role in the promotion of neuroprotection because Trx is a multifunctional antioxidative and antiapoptotic protein. For managing progressive neurodegeneration such as Alzheimer dementia, our estrogen proposal of the signaling pathway of cGMP-dependent protein kinase (PKG) in mediating estrogen-induced cytoprotective genes thus fosters research and development of the new estrogen ligands devoid of female hormonal side effects such as carcinogenesis. C1 NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. RP Chiueh, CC (reprint author), NIMH, Clin Sci Lab, NIH, 10-3 D-41, Bethesda, MD 20892 USA. EM chiueh@helix.nih.gov NR 59 TC 37 Z9 42 U1 1 U2 3 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0969-711X J9 ENDOCRINE JI Endocrine PD JUN PY 2003 VL 21 IS 1 BP 27 EP 31 DI 10.1385/ENDO:21:1:27 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 687TK UT WOS:000183392900005 PM 12777700 ER PT J AU Gaborik, Z Jagadeesh, G Zhang, M Spat, A Catt, KJ Hunyady, L AF Gaborik, Z Jagadeesh, G Zhang, M Spat, A Catt, KJ Hunyady, L TI The role of a conserved region of the second intracellular loop in AT(1) angiotensin receptor activation and signaling SO ENDOCRINOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; II TYPE-1 RECEPTOR; CONSTITUTIVELY ACTIVE MUTANTS; ADRENAL GLOMERULOSA CELLS; CARBOXYL-TERMINAL TAIL; M1 MUSCARINIC RECEPTOR; ALPHA(1B)-ADRENERGIC RECEPTOR; HORMONE RECEPTOR; CYTOPLASMIC LOOP; AMINO-ACIDS AB The pleiotropic actions of angiotensin II are mediated by the primarily G. protein-coupled type I angiotensin (AT(1)) receptor. In this study a mutational analysis of the function of the conserved DRYXXV/IXKPL domain in the second intracellular loop of the rat AT(1A) receptor was performed in COS7 cells. Alanine substitution studies showed that single replacement of the highly conserved Asp(125) and Arg(126), but not Tyr(127), moderately impaired angiotensin II-induced inositol phosphate signaling. However, concomitant substitution of both Asp(125) and Arg(126) caused marked reduction of both inositol phosphate signaling and receptor internalization. Alanine scanning of the adjacent residues showed that substitution of Ile(130), His(132), and Pro(133) reduced agonist-induced inositol phosphate signal generation, whereas mutations of Met(134) also impaired receptor internalization. Expression of the D125A mutant AT(1A) receptor in COS7 cells endowed the receptor with moderate constitutive activity, as indicated by its enhanced basal Elk1 promoter activity and inositol phosphate response to partial agonists. Angiotensin II- induced stimulation of the Elk1 promoter showed parallel impairment with inositol phosphate signal generation in receptors containing mutations in this region of the AT(1A) receptor. These data confirm that Ca2+ signal generation is required for the nuclear effects of angiotensin II-induced ERR activation. They are also consistent with the role of the conserved DRY sequence of the AT(1A) receptor in receptor activation, and of Asp(125) in constraining the receptor in its inactive conformation. Furthermore, in the cytoplasmic helical extension of the third helix, an apolar surface that includes Ile(130) and Met(134) appears to have a direct role in G protein coupling. C1 Semmelweis Univ, Fac Med, Dept Physiol, H-1088 Budapest, Hungary. Semmelweis Univ, Fac Med, Lab Cellular & Mol Physiol, H-1088 Budapest, Hungary. NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. US FDA, Div Cardiorenal Drug Prod, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. RP Hunyady, L (reprint author), Semmelweis Univ, Fac Med, Dept Physiol, 8 POB 259, H-1444 Budapest, Hungary. EM hunyady@puskin.sote.hu NR 68 TC 81 Z9 82 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 J9 ENDOCRINOLOGY JI Endocrinology PD JUN PY 2003 VL 144 IS 6 BP 2220 EP 2228 DI 10.1210/en.2002-0135 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 683KH UT WOS:000183146900009 PM 12746278 ER PT J AU Grumolato, L Elkahloun, AG Ghzili, H Alexandre, D Coulouarn, C Yon, L Salier, JP Eiden, LE Fournier, A Vaudry, H Anouar, Y AF Grumolato, L Elkahloun, AG Ghzili, H Alexandre, D Coulouarn, C Yon, L Salier, JP Eiden, LE Fournier, A Vaudry, H Anouar, Y TI Microarray and suppression subtractive hybridization analyses of gene expression in pheochromocytoma cells reveal pleiotropic effects of pituitary adenylate cyclase-activating polypeptide on cell proliferation, survival, and adhesion SO ENDOCRINOLOGY LA English DT Article ID NERVE GROWTH-FACTOR; PC12 CELLS; SIGNALING PATHWAYS; NEURITE OUTGROWTH; LAMININ RECEPTOR; TYROSINE KINASE; CANCER CELLS; CLONAL LINE; LUNG-CANCER; PROTEIN AB Pituitary adenylate cyclase-activating polypeptide (PACAP) exerts trophic effects on several neuronal, neuroendocrine, and endocrine cells. To gain insight into the pattern of the transcriptional modifications induced by PACAP during cell differentiation, we studied the effects of this neuropeptide on rat pheochromocytoma, PC12 cells. We first analyzed the transcriptome of PC12 cells in comparison to that of terminally differentiated rat adrenomedullary chromaffin cells, using a high-density microarray, to identify genes associated with the proliferative phenotype that are possible targets of PACAP during differentiation of sympathoadrenal normal and tumoral cells. We then studied global gene expression in PC12 cells after 48 h of exposure to PACAP, using both cDNA microarray and suppression subtractive hybridization technologies. These complementary approaches resulted in the identification of 75 up-regulated and 70 down-regulated genes in PACAP-treated PC 12 cells. Among the genes whose expression is modified in differentiated cells, a vast majority are involved in cell proliferation, survival, and adhesion/motility. Expression changes of most of these genes have been associated with progression of several neoplasms. A kinetic study of the effects of PACAP on some of the identified genes showed that the neuropeptide likely exerts early as well as late actions to achieve the gene expression program necessary for cell differentiation. In conclusion, the results of the present study underscore the pleiotropic role of PACAP in cell differentiation and provide important information on novel targets that could mediate the effects of this neuropeptide in normal and tumoral neuroendocrine cells. C1 Univ Rouen, European Inst Peptide Res, IFRMP 23, Lab Cellular & Mol Neuroendocrinol,CNRS,INSERM,U4, F-76821 Mont St Aignan, France. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. Fac Med & Pharm, IFRMP 23, INSERM, U519, F-76183 Rouen, France. NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. Univ Quebec, Inst Natl Rech Sci Sante, Inst Armand Frappier, Pointe Claire, PQ H9R 1G6, Canada. RP Vaudry, H (reprint author), Univ Rouen, European Inst Peptide Res, IFRMP 23, Lab Cellular & Mol Neuroendocrinol,CNRS,INSERM,U4, F-76821 Mont St Aignan, France. RI Grumolato, Luca/A-1697-2015; Coulouarn, Cedric/E-5472-2011; OI Grumolato, Luca/0000-0001-8231-3032; Eiden, Lee/0000-0001-7524-944X NR 65 TC 41 Z9 44 U1 0 U2 4 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD JUN PY 2003 VL 144 IS 6 BP 2368 EP 2379 DI 10.1210/en.2002-0106 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 683KH UT WOS:000183146900028 PM 12746297 ER PT J AU Duan, WZ Guo, ZH Jiang, HY Ware, M Mattson, MP AF Duan, WZ Guo, ZH Jiang, HY Ware, M Mattson, MP TI Reversal of behavioral and metabolic abnormalities, and insulin resistance syndrome, by dietary restriction in mice deficient in brain-derived neurotrophic factor SO ENDOCRINOLOGY LA English DT Article ID LEPTIN GENE-THERAPY; BODY-WEIGHT; ADULT MICE; RAT-BRAIN; HIGH-FAT; DISEASE; HIPPOCAMPUS; NEURONS; GLUCOSE; HYPERINSULINEMIA AB Dietary restriction (DR) extends life span and improves glucose metabolism in mammals. Recent studies have shown that DR stimulates the production of brain-derived neurotrophic factor (BDNF) in brain cells, which may mediate neuroprotective and neurogenic, actions of DR. Other studies have suggested a role for central BDNF signaling in the regulation of glucose metabolism and body weight. BDNF heterozygous knockout (BDNF+/-) mice are obese and exhibit features of insulin resistance. We now report that an intermittent fasting DR regimen reverses several abnormal phenotypes of BDNF(+/-) mice including obesity, hyperphagia, and increased locomotor activity. DR increases BDNF levels in the brains of BDNF(+/-) mice to the level of wild-type mice fed ad libitum. BDNF(+/-) mice exhibit an insulin-resistance syndrome phenotype characterized by elevated levels of circulating glucose, insulin, and leptin; DR reduces levels of each of these three factors. DR normalizes blood glucose responses in glucose tolerance and insulin tolerance tests in the BDNF(+/-) mice. These findings suggest that BDNF is a major regulator of energy metabolism and that beneficial effects of DR on glucose metabolism are mediated, in part, by BDNF signaling. Dietary and pharmacological manipulations of BDNF signaling may prove useful in the prevention and treatment of obesity and insulin resistance syndrome-related diseases. C1 NIA, Neurosci Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. NIA, Comparat Med Sect, Gerontol Res Ctr, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 48 TC 95 Z9 99 U1 3 U2 5 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD JUN PY 2003 VL 144 IS 6 BP 2446 EP 2453 DI 10.1210/en.2002-0113 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 683KH UT WOS:000183146900037 PM 12746306 ER PT J AU Cheng, CM Kelley, B Wang, J Strauss, D Eagles, DA Bondy, CA AF Cheng, CM Kelley, B Wang, J Strauss, D Eagles, DA Bondy, CA TI A ketogenic diet increases brain insulin-like growth factor receptor and glucose transporter gene expression SO ENDOCRINOLOGY LA English DT Article ID FACTOR-I; MESSENGER-RNA; RAT-BRAIN; IGF-I; NUTRITIONAL REGULATION; CALORIE RESTRICTION; METABOLISM; BARRIER; SYSTEM; LOCALIZATION AB A ketogenic diet suppresses seizure activity in children and in juvenile rats. To investigate whether alteration in brain IGF activity could be involved in the beneficial effects of the ketogenic diet, we examined the effects of this diet on IGF system gene expression in the rat brain. Juvenile rats were fed one of three different diets for 7 d: ad libitum standard rat chow (AL-Std), calorie-restricted standard chow (CR-Std), or a calorie-restricted ketogenic diet (CR-Ket). The calorie-restricted diets contained 90% of the rats' calculated energy requirements. The AL-Std diet group increased in weight, whereas the two CR groups merely maintained their weight during the 7-d diet. Glucose levels were significantly reduced in both CR groups compared with the AL-Std group, but only the CR-Ket group developed ketonemia. IGF1 mRNA levels were reduced by 30-50% in most brain regions in both CR groups. IGF1 receptor (IGF1R) mRNA levels were decreased in the CR-Std group but were increased in the CR-Ket diet group. Brain IGF binding protein (IGFBP)-2 and -5 mRNA levels were not altered by diet, but IGFBP-3 mRNA levels were markedly increased by the ketogenic diet while not altered by calorie restriction alone. Brain glucose transporter expression was also investigated in this study. Glucose transporter (GLUT) 4 mRNA levels were quite low and not appreciably altered by the different diets. Parenchymal GLUT1 mRNA levels were increased by the CR-Ket diet, but endothelial GLUT1 mRNA levels were not affected. Neuronal GLUT3 expression was decreased with the CR-Std diet and increased with the CR-Ket diet, in parallel with the IGF1R pattern. These observations reveal divergent effects of dietary caloric content and macronutrient composition on brain IGF system and GLUT expression. In addition, the data may be consistent with a role for enhanced IGF1R and GLUT expression in ketogenic diet-induced seizure suppression. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Dept Biol, Washington, DC 20057 USA. RP Bondy, CA (reprint author), NICHHD, Dev Endocrinol Branch, NIH, Bldg 10-10N262,10 Ctr Dr, Bethesda, MD 20892 USA. NR 33 TC 35 Z9 36 U1 0 U2 3 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD JUN PY 2003 VL 144 IS 6 BP 2676 EP 2682 DI 10.1210/en.2002-0057 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 683KH UT WOS:000183146900063 PM 12746332 ER PT J AU Lee, AV Zhang, P Ivanova, M Bonnette, S Oesterreich, S Rosen, JM Grimm, S Hovey, RC Vonderhaar, BK Kahn, CR Torres, D George, J Mohsin, S Allred, DC Hadsell, DL AF Lee, AV Zhang, P Ivanova, M Bonnette, S Oesterreich, S Rosen, JM Grimm, S Hovey, RC Vonderhaar, BK Kahn, CR Torres, D George, J Mohsin, S Allred, DC Hadsell, DL TI Developmental and hormonal signals dramatically alter the localization and abundance of insulin receptor substrate proteins in the mammary gland SO ENDOCRINOLOGY LA English DT Article ID BREAST-CANCER CELLS; END BUD FORMATION; GROWTH-FACTOR-I; PROLACTIN RECEPTOR; IGF-I; DUCTAL MORPHOGENESIS; PROGESTERONE RECEPTORS; NUCLEAR TRANSLOCATION; TARGETED DISRUPTION; POSTNATAL-GROWTH AB Insulin receptor substrates (IRS) are central integrators of hormone, cytokine, and growth factor signaling. IRS proteins can be phosphorylated by a number of signaling pathways critical to normal mammary gland development. Studies in transgenic mice that overexpress IGF-I in the mammary gland suggested that IRS expression is important in the regulation of normal postlactational mammary involution. The goal of these studies was to examine IRS expression in the mouse mammary gland and determine the importance of IRS-1 to mammary development in the virgin mouse. IRS-1 and -2 show distinct patterns of protein expression in the virgin mouse mammary gland, and protein abundance is dramatically increased during pregnancy and lactation, but rapidly lost during involution. Consistent with hormone regulation, IRS-1 protein levels are reduced by ovariectomy, induced by combined treatment with estrogen and progesterone, and vary considerably throughout the estrous cycle. These changes occur without similar changes in mRNA levels, suggesting post-transcriptional control. Mammary glands from IRS-1 null mice have smaller fat pads than wild-type controls, but this reduction is proportional to the overall reduction in body size. Development of the mammary duct (terminal endbuds and branch points) is not altered by the loss of IRS-1, and pregnancy-induced proliferation is not changed. These data indicate that IRS undergo complex developmental and hormonal regulation in the mammary gland, and that IRS-1 is more likely to regulate mammary function in lactating mice than in virgin or pregnant mice. C1 Baylor Coll Med, Breast Ctr, Dept Med, Houston, TX 77030 USA. Baylor Coll Med, Breast Ctr, Dept Mol & Cellular Biol, Houston, TX 77030 USA. Baylor Coll Med, Breast Ctr, Dept Pediat, Houston, TX 77030 USA. Baylor Coll Med, Breast Ctr, Dept Pathol, Houston, TX 77030 USA. ARS, USDA, Childrens Nutr Res Ctr, Bethesda, MD 20892 USA. NCI, Mol & Cellular Endocrinol Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dept Med, Joslin Diabet Ctr,Res Div, Boston, MA 02215 USA. RP Lee, AV (reprint author), Baylor Coll Med, Breast Ctr, Dept Med, Room N1110,1 Baylor Plaza,MS 600, Houston, TX 77030 USA. FU NCI NIH HHS [CA-94118]; NIDDK NIH HHS [DK-52197] NR 61 TC 31 Z9 31 U1 0 U2 3 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD JUN PY 2003 VL 144 IS 6 BP 2683 EP 2694 DI 10.1210/en.2002-221103 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 683KH UT WOS:000183146900064 PM 12746333 ER PT J AU Nieman, LK AF Nieman, LK TI Management of surgically hypogonadal patients unable to take sex hormone replacement therapy SO ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA LA English DT Article ID BREAST-CANCER SURVIVORS; HOT FLASHES; POSTMENOPAUSAL WOMEN; PROSTATE-CANCER; OSTEOPOROTIC FRACTURES; RANDOMIZED TRIAL; TRANSDERMAL CLONIDINE; CIMICIFUGA-RACEMOSA; UROGENITAL ATROPHY; SOY PHYTOESTROGENS AB After surgical castration, most men and women develop hot flashes and osteoporosis and many women have symptoms of urogenital atrophy. When patients cannot or do not wish to take gonadal steroids for the prevention or treatment of these problems, alternative approaches can be offered. These include lifestyle modifications, traditional medications and possibly some complementary and alternative approaches such as herbs, acupuncture or soy foods. C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Nieman, LK (reprint author), NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Room 9D42 MSC 1583,10 Ctr Dr, Bethesda, MD 20892 USA. NR 49 TC 7 Z9 9 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0889-8529 J9 ENDOCRIN METAB CLIN JI Endocrinol. Metabol. Clin. North Amer. PD JUN PY 2003 VL 32 IS 2 BP 325 EP + DI 10.1016/S0889-8529(03)00011-2 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 685BE UT WOS:000183240300002 PM 12800534 ER PT J AU Shevtsov, S Petrotchenko, EV Pedersen, LC Negishi, M AF Shevtsov, S Petrotchenko, EV Pedersen, LC Negishi, M TI Crystallographic analysis of a hydroxylated polychlorinated biphenyl (OH-PCB) bound to the catalytic estrogen binding site of human estrogen sulfotransferase SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE crystal structure; estrogen; PCB; polychlorinated biphenyl; sulfotransferase ID SULFURYL TRANSFER; CRYSTAL-STRUCTURE; METABOLITES; EXPRESSION; INHIBITION; DISRUPTION; SULFATION; SUITE AB Certain hydroxylated polychlorinated biphenyls (OH-PCBs) inhibit the human estrogen sulfotransferase (hEST) at subnanomolar concentrations, suggesting a possible pathway for PCB toxicity due to environmental exposure in humans. To address the structural basis of the inhibition, we have determined the crystal structure of hEST in the presence of the sulfuryl donor product 3'-phosphoadenosine 5'-phosphate and the OH-PCB 4,4'-OH 3,5,3',5'-tetraCB. The OH-PCB binds in the estrogen binding site with the position of the first phenolic ring in an orientation similar to the phenolic ring of 17beta-estradiol. Interestingly, the OH-PCB does not bind in a planar conformation, but rather with a 30-degree twist between the phenyl rings. The crystal structure of hEST with the OH-PCB bound gives physical evidence that certain OH-PCBs can mimic binding of estrogenic compounds in biological systems. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Reprod & Dev Toxicol Lab, Pharmacogenet Sect, Res Triangle Pk, NC 27709 USA. RP Pedersen, LC (reprint author), NIEHS, Struct Biol Lab, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 26 TC 45 Z9 47 U1 4 U2 11 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 JUN PY 2003 VL 111 IS 7 BP 884 EP + DI 10.1289/ehp.6056 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 689ND UT WOS:000183498900024 PM 12782487 ER PT J AU Burkhart, J Goehl, TJ AF Burkhart, J Goehl, TJ TI Environmental Health Reviews, 2003 - Introduction SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Burkhart, J (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 16 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 JUN PY 2003 VL 111 IS 8 BP 993 EP 993 DI 10.1289/ehp.0311993 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 700QG UT WOS:000184122200001 ER PT J AU Flake, GP Andersen, J Dixon, D AF Flake, GP Andersen, J Dixon, D TI Etiology and pathogenesis of uterine leiomyomas: A review SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review DE estrogen; fibroids; genetics; growth factors; progesterone; risk factors ID ENDOTHELIAL GROWTH-FACTOR; MESSENGER-RIBONUCLEIC-ACID; SMOOTH-MUSCLE CELLS; HORMONE REPLACEMENT THERAPY; HUMAN ESTROGEN-RECEPTOR; SEX STEROID-RECEPTORS; FAMILIAL CUTANEOUS LEIOMYOMATOSIS; COMPARATIVE GENOMIC HYBRIDIZATION; PATIENT RECEIVING TAMOXIFEN; NORMAL HUMAN MYOMETRIUM AB Uterine leiomyomas, or fibroids, represent a major public health problem. It is believed that these tumors develop in the majority of American women and become symptomatic in one-third of these women. They are the most frequent indication for hysterectomy in the United States. Although the initiator or initiators of fibroids are unknown, several predisposing factors have been identified, including age (late reproductive years), African-American ethnicity, nulliparity, and obesity. Nonrandom cytogenetic abnormalities have been found in about 40% of tumors examined. Estrogen and progesterone are recognized as promoters of tumor growth, and the potential role of environmental estrogens has only recently been explored. Growth factors with mitogenic activity, such as transforming growth factor-beta(3), basic fibroblast growth factor, epidermal growth factor, and insulin-like growth factor-I, are elevated in fibroids and may be the effectors of estrogen and progesterone promotion. These data offer clues to the etiology and pathogenesis of this common condition, which we have analyzed and summarized in this review. C1 NIEHS, Lab Expt Pathol, Comparat Pathobiol Grp, Res Triangle Pk, NC 27709 USA. SUNY Stony Brook, Sch Med, Dept Pathol, Stony Brook, NY 11794 USA. RP Dixon, D (reprint author), NIEHS, Lab Expt Pathol, Comparat Pathobiol Grp, Res Triangle Pk, NC 27709 USA. NR 302 TC 236 Z9 255 U1 0 U2 18 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 JUN PY 2003 VL 111 IS 8 BP 1037 EP 1054 PG 18 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 700QG UT WOS:000184122200005 PM 12826476 ER PT J AU Kelada, SN Eaton, DL Wang, SS Rothman, NR Khoury, MJ AF Kelada, SN Eaton, DL Wang, SS Rothman, NR Khoury, MJ TI The role of genetic polymorphisms in environmental health SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review DE disease susceptibility; environmental health; genetics; polymorphism ID S-TRANSFERASE M1; LUNG-CANCER RISK; ARYLAMINE-N-ACETYLTRANSFERASE; ACID DEHYDRATASE GENOTYPE; VITAMIN-D-RECEPTOR; HYDROXYARYLAMINE-O-ACETYLTRANSFERASE; SINGLE-NUCLEOTIDE POLYMORPHISMS; MICROSOMAL EPOXIDE HYDROLASE; SISTER-CHROMATID EXCHANGES; UPPER AERODIGESTIVE TRACT AB Interest is increasing in the role of variations in the human genome (polymorphisms) in modifying the effect of exposures to environmental health hazards (often referred to as gene-environment interaction), which render some individuals or groups in the population more or less likely to develop disease after exposure. This review is intended for an audience of environmental health practitioners and students and is designed to raise awareness about this rapidly growing field of research by presenting established and novel examples of gene-environment interaction that illustrate the major theme of effect modification. Current data gaps are identified and discussed to illustrate limitations of past research and the need for the application of more robust methods in future research projects. Two primary benefits of incorporating genetics into the existing environmental health research framework are illustrated: a) the ability to detect different levels of risk within the population, and b) greater understanding of etiologic mechanisms. Both offer opportunities for developing new methods of disease prevention. Finally, we describe a basic framework for researchers interested in pursuing health effects research that incorporates genetic polymorphisms. C1 Univ Washington, Sch Publ Hlth & Community Med, Dept Environm Hlth, Seattle, WA 98195 USA. Univ Washington, Ctr Ecogenet & Environm Hlth, Seattle, WA 98195 USA. NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Off Genom & Dis Prevent, Natl Ctr Environm Hlth, Atlanta, GA USA. RP Eaton, DL (reprint author), Univ Washington, Sch Publ Hlth & Community Med, Dept Environm Hlth, Seattle, WA 98195 USA. EM deaton@u.washington.edu OI Kelada, Samir/0000-0003-2676-9232 FU NIEHS NIH HHS [P30ES07033]; PHS HHS [5T3207032, S1946-21/21] NR 161 TC 76 Z9 80 U1 0 U2 6 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 2003 VL 111 IS 8 BP 1055 EP 1064 DI 10.1289/ehp.6065 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 700QG UT WOS:000184122200006 PM 12826477 ER PT J AU Liu, B Gao, HM Hong, JS AF Liu, B Gao, HM Hong, JS TI Parkinson's disease and exposure to infectious agents and pesticides and the occurrence of brain injuries: Role of neuroinflammation SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review DE bacterium; cytokine; dopamine; environmental factor; free radical; head injury; microglia; Parkinson's disease; pesticide; virus ID NECROSIS-FACTOR-ALPHA; ENVIRONMENTAL RISK-FACTORS; NIGRAL DOPAMINERGIC-NEURONS; NITRIC-OXIDE SYNTHASE; ETHYLENE-BIS-DITHIOCARBAMATE; GROWTH-FACTOR-ALPHA; CLOSED-HEAD INJURY; SUBSTANTIA-NIGRA; RAT-BRAIN; POLYCHLORINATED-BIPHENYLS AB Idiopathic Parkinson's disease (PD) is a devastating movement disorder characterized by selective degeneration of the nigrostriatal dopaminergic pathway. Neurodegeneration usually starts in the fifth decade of life and progresses over 5-10 years before reaching the fully symptomatic disease state. Despite decades of intense research, the etiology of sporadic PD and the mechanism underlying the selective neuronal loss remain unknown. However, the late onset and slow-progressing nature of the disease has prompted the consideration of environmental exposure to agrochemicals, including pesticides, as a risk factor. Moreover, increasing evidence suggests that early-life occurrence of inflammation in the brain, as a consequence of either brain injury or exposure to infectious agents may play, a role in the pathogenesis of PD. Most important, there may be a self-propelling cycle of inflammatory process involving brain immune cells (microglia and astrocytes) that drives the slow yet progressive neurodegenerative process. Deciphering the molecular and cellular mechanisms governing those intricate interactions would significantly advance our understanding of the etiology and pathogenesis of PD and aid the development of therapeutic strategies for the treatment of the disease. C1 NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Liu, B (reprint author), NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RI gao, huiming/C-8454-2012; liu, Bin/A-7695-2009 NR 196 TC 150 Z9 157 U1 4 U2 16 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 JUN PY 2003 VL 111 IS 8 BP 1065 EP 1073 DI 10.1289/ehp.6361 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 700QG UT WOS:000184122200007 PM 12826478 ER PT J AU Metcalfe, DD AF Metcalfe, DD TI Introduction: What are the issues in addressing the allergenic potential of genetically modified foods? SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE biotechnology; decision tree; food allergy; genetically modified crops; IgE; immunology; sensitization ID BIOTECHNOLOGY; PREVALENCE; BENEFITS; PLANTS; US AB There is growing concern among the general public and the scientific community regarding the potential toxicity of genetically modified organisms (GMOs). The use of biotechnology to enhance pest resistance or nutritional value has raised a number of fundamental questions including the consequences of insertion of reporter genes, the spread of resistance genes to surrounding plants, and the use of suicide genes to prohibit reuse of seed from engineered plants. Of particular interest is the ability of proteins from GMOs to elicit potentially harmful immunologic responses, including allergic hypersensitivity. The lack of information of the potential toxicity of these products suggests a need to identify the critical issues and research needs regarding these materials and to develop testing strategies to examine the allergenicity of these compounds. C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Metcalfe, DD (reprint author), NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 28 TC 16 Z9 18 U1 4 U2 20 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 JUN PY 2003 VL 111 IS 8 BP 1110 EP 1113 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 700QG UT WOS:000184122200011 PM 12826482 ER PT J AU Germolec, DR Kimber, I Goldman, L Selgrade, M AF Germolec, DR Kimber, I Goldman, L Selgrade, M TI Key issues for the assessment of the allergenic potential of genetically modified foods: Breakout group reports SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE animal models; food allergy; hazard identification; IgE; immunoassay; postmarket surveillance; safety assessment; sensitization; skin prick test; threshold ID LEGUME BOTANICAL FAMILY; DOUBLE-BLIND; CROSS-REACTIVITY; PEANUT ALLERGY; HYPERSENSITIVITY REACTIONS; INHALATION EXPOSURE; ATOPIC-DERMATITIS; CHILDREN; CHALLENGES; SENSITIZATION AB On the final afternoon of the workshop "Assessment of the Allergenic Potential of Genetically Modified Foods," held 10-12 December 2001 in Chapel Hill, North Carolina, USA, speakers and participants met in breakout groups to discuss specific questions in the areas of use of human clinical data, animal models to assess food allergy, biomarkers of exposure and effect, sensitive populations, dose-response assessment, and postmarket surveillance. Each group addressed general questions regarding allergenicity of genetically modified foods and specific questions for each subject area. This article is a brief summary of the discussions of each of the six breakout groups regarding our current state of knowledge and what information is needed to advance the field. C1 NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. Syngenta Cent Toxicol Lab, Macclesfield, Cheshire, England. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. US EPA, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. RP Germolec, DR (reprint author), NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. NR 57 TC 5 Z9 5 U1 0 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 JUN PY 2003 VL 111 IS 8 BP 1131 EP 1139 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 700QG UT WOS:000184122200015 PM 12826486 ER PT J AU Selgrade, MK Kimber, I Goldman, L Germolec, DR AF Selgrade, MK Kimber, I Goldman, L Germolec, DR TI Assessment of allergenic potential of genetically modified foods: An agenda for future research SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE biotechnology; food allergy; genetically modified food; hazard identification; research needs AB Speakers and participants in the workshop "Assessment of the Allergenic Potential of Genetically Modified Foods" met in breakout groups to discuss a number of issues including needs for future research. These groups agreeed that research should progress quickly in the area of hazard identification and that a need exists for more basic research to understand the mechanisms underlying food allergy. A list of research needs was developed. C1 US EPA, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. Syngenta Cent Toxicol Lab, Macclesfield, Cheshire, England. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Selgrade, MK (reprint author), US EPA, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. NR 2 TC 13 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 JUN PY 2003 VL 111 IS 8 BP 1140 EP 1141 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 700QG UT WOS:000184122200016 PM 12826487 ER PT J AU Tchounwou, PB Ayensu, WK Ninashvili, N Sutton, D AF Tchounwou, PB Ayensu, WK Ninashvili, N Sutton, D TI Environmental exposure to mercury and its toxicopathologic implications for public health SO ENVIRONMENTAL TOXICOLOGY LA English DT Review DE mercury exposure; systemic toxicity; immunotoxicity; health risk assessment; management ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; ANTI-FIBRILLARIN AUTOANTIBODIES; AMYOTROPHIC-LATERAL-SCLEROSIS; COLLAGEN-INDUCED ARTHRITIS; IN-UTERO EXPOSURE; BROWN-NORWAY RATS; INORGANIC MERCURY; METHYL MERCURY; METHYLMERCURY EXPOSURE; AUTOIMMUNE-DISEASE AB Mercury is a toxic and hazardous metal that occurs naturally in the earth's crust. Natural phenomena such as erosion and volcanic eruptions, and anthropogenic activities like metal smelting and industrial production and use may lead to substantial contamination of the environment with mercury. Through consumption of mercury in food, the populations of many areas, particularly in the developing world, have been confronted with catastrophic outbreaks of mercury-induced diseases and mortality. Countries such as Japan, Iraq, Ghana, the Seychelles, and the Faroe Islands have faced such epidemics, which have unraveled the insidious and debilitating nature of mercury poisoning. Its creeping neurotoxicity is highly devastating, particularly in the central and peripheral nervous systems of children. Central nervous system defects and erethism as well as arrythmias, cardiomyopathies, and kidney damage have been associated with mercury exposure. Necrotizing bronchitis and pneumonitis arising from inhalation of mercury vapor can result in respiratory failure. Mercury is also considered a potent immunostimulant and -suppressant, depending on exposure dose and individual susceptibility, producing a number of pathologic sequelae including lymphoproliferation, hypergammaglobulinemia, and total systemic hyper- and hyporeactivities. In this review we discuss the sources of mercury and the potential for human exposure; its biogeochemical cycling in the environment; its systemic, immunotoxic, genotoxic/carcinogenic, and teratogenic health effects; and the dietary influences on its toxicity; as well as the important considerations in risk assessment and management of mercury poisoning. (C) 2003 Wiley Periodicals, Inc. C1 Jackson State Univ, NIH Ctr Environm Hlth, Sch Sci & Technol, Cellom & Toxicogenom Res Lab, Jackson, MS 39217 USA. RP Tchounwou, PB (reprint author), Jackson State Univ, NIH Ctr Environm Hlth, Sch Sci & Technol, Cellom & Toxicogenom Res Lab, 1400 Lynch St,Box 18540, Jackson, MS 39217 USA. FU NCRR NIH HHS [5P20RR16470-02] NR 219 TC 590 Z9 613 U1 43 U2 263 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1520-4081 J9 ENVIRON TOXICOL JI Environ. Toxicol. PD JUN PY 2003 VL 18 IS 3 BP 149 EP 175 DI 10.1002/tox.10116 PG 27 WC Environmental Sciences; Toxicology; Water Resources SC Environmental Sciences & Ecology; Toxicology; Water Resources GA 689FU UT WOS:000183481600001 PM 12740802 ER PT J AU Salazar, P Tapia, R Rogawski, MA AF Salazar, P Tapia, R Rogawski, MA TI Effects of neurosteroids on epileptiform activity induced by picrotoxin and 4-aminopyridine in the rat hippocampal slice SO EPILEPSY RESEARCH LA English DT Article DE neurosteroid; picrotoxin; 4-aminopyridine; hippocampal slice; epilepsy ID D-ASPARTATE RECEPTOR; GABA-A RECEPTOR; PREGNENOLONE SULFATE POTENTIATION; NMDA-INDUCED SEIZURES; SYSTEM IN-VITRO; SYNAPTIC-TRANSMISSION; NEUROACTIVE STEROIDS; DEHYDROEPIANDROSTERONE-SULFATE; ANTICONVULSANT DRUGS; TRANSMITTER RELEASE AB The neurosteroids allopregnanolone (5alpha-pregnan-3alpha-ol-20-one: 5alpha,3alpha-P) and its 5beta-epimer pregnanolone (5beta,3alpha-P). and pregnenolone sulfate (PS) were examined for effects on spontaneous epileptiform discharges induced by 100 muM picrotoxin (PTX) and 55 muM 4-aminopyridine (4-AP) in the CA3 region of the rat hippocampal slice. At a concentration of 10 muM, 5alpha,3alpha-P partially reduced PTX-induced bursting and at 30 and 90 muM completely suppressed bursting. In contrast, 100 muM 5beta,3alpha-P failed to alter the discharge frequency. 5alpha,3alpha-P depressed 4-AP-induced bursting with similar potency as in the PTX model: 100 muM 5beta,3alpha-P was also partially effective. In the 4-AP model, 5alpha,3alpha-P inhibited both the more frequent predominantly positive-going potentials as well as the less frequent negative-going potentials that may be generated by synchronous GABAergic interneuron firings. PS enhanced the PTX bursting, frequency and. in the 4-AP model. increased the frequency of negative potentials but did not alter the frequency of positive potentials. By itself, PS did not induce bursting. The effects of the steroids in the in vitro seizure models largely correspond with their activities on GABA(A) receptors; suppression of discharges may occur as a result of direct activation of these receptors rather than modulation of GABA-mediated synaptic responses. PTX and 4-AP-induced bursting in the hippocampal slice are useful models for directly assessing neurosteroid effects on seizure susceptibility under conditions that eliminate the factor of brain bioavailability. (C) 2003 Elsevier B.V. All rights reserved. C1 Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Dept Neurociencias, Mexico City 04510, DF, Mexico. NINDS, Epilepsy Res Sect, NIH, Bethesda, MD 20892 USA. RP Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Dept Neurociencias, AP 70-253, Mexico City 04510, DF, Mexico. EM rtapia@itisiol.unam.mx; michael.rogawski@nih.gov RI Rogawski, Michael/B-6353-2009 OI Rogawski, Michael/0000-0002-3296-8193 NR 83 TC 25 Z9 25 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-1211 EI 1872-6844 J9 EPILEPSY RES JI Epilepsy Res. PD JUN-JUL PY 2003 VL 55 IS 1-2 BP 71 EP 82 DI 10.1016/S0920-1211(03)00112-8 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA 721PX UT WOS:000185325700008 PM 12948618 ER PT J AU Hall, WD Feng, ZD George, VA Lewis, CE Oberman, A Huber, M Fouad, M Cutler, JA AF Hall, WD Feng, ZD George, VA Lewis, CE Oberman, A Huber, M Fouad, M Cutler, JA TI Low-fat diet: Efect on anthropometrics, blood pressure, glucose, and insulin in older women SO ETHNICITY & DISEASE LA English DT Article DE African American; blood pressure; clinical trial; dietary fat; glucose; hispanic; insulin; Women's Health ID HEALTH TRIAL FEASIBILITY; ABDOMINAL ADIPOSITY; BREAST-CANCER; MINORITY POPULATIONS; BODY-FAT; DISEASE; RISK; PATTERNS; OBESITY; LIPIDS AB Objective: The Women's Health Trial: Feasibility Study in Minority Populations (WHT: FSMP) documented that a low-fat diet was associated with a reduced fat intake in older women of diverse ethnic backgrounds. The purpose of the current study was to examine the effect of the low-fat diet on anthropometric and biochemical variables. Design: Randomized clinical trial in 2,208 postmenopausal women, 50 to 79 years of age. Results: The decrease in fat intake correlated directly with a decrease in body weight (r=.22, P<.001). After 6 months, the intervention group had an average weight loss of 1.8 kg. Body mass index decreased 0.7 kg/m(2). Waist circumference decreased 1.8 cm. All of these changes were statistically significant, compared to changes in the control group (P<.01). Changes in systolic (-3.1 mm Hg) and diastolic (-1.1 min Hg) blood pressures (BP) occurred in the intervention group. The decrease in systolic BP reached statistical significance (P=.02), relative to the control group. Decreases in plasma glucose were small (-0.2 mmol/L) in the intervention group, although there was a trend for difference from the control group (P=.11). Decreases in serum insulin levels were small (-0.5 muIU/mL) in the intervention group, although there was, again, a trend for difference from the control group (P=.07). Conclusions: In older White, Black, and Hispanic women, a long-term low-fat dietary intervention was accompanied by modest, but statistically significant, decreases in body weight and anthropometric indices, without any particular attempt being made to reduce calories. Changes in glucose and insulin were small. The long-term biological significance of the glucose and insulin changes is unknown. C1 Emory Univ, Sch Med, Dept Med, Atlanta, GA 30324 USA. Univ Miami, Dept Epidemiol & Publ Hlth, Miami, FL 33152 USA. Univ Alabama, Div Prevent Med, Dept Med, Birmingham, AL USA. Fred Hutchinson Canc Res Ctr, Dept Biostat, Seattle, WA 98104 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Hall, WD (reprint author), Emory Univ, Sch Med, Dept Med, W Dallas Hall,1100 Parker Pl, Atlanta, GA 30324 USA. EM whall@emory.edu FU NCI NIH HHS [N01-CN-25427, N01-CN-25426, N01-CN-15343, N01-CN-25425] NR 25 TC 21 Z9 21 U1 1 U2 2 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X J9 ETHNIC DIS JI Ethn. Dis. PD SUM PY 2003 VL 13 IS 3 BP 337 EP 343 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 802MS UT WOS:000220168200006 PM 12894958 ER PT J AU Maital, SL Bornstein, MH AF Maital, SL Bornstein, MH TI The ecology of collaborative child rearing: A systems approach to child care on the kibbutz SO ETHOS LA English DT Review ID INFANT-MOTHER ATTACHMENT; REARED ISRAELI CHILDREN; OUT-OF-HOME; SOCIAL-BEHAVIOR; DYNAMICS; FAMILY; CITY; PERSPECTIVES; CAREGIVERS; METAPELET AB Collective child rearing on the Israeli kibbutz serves as a model for articulating changes in patterns of familial and nonfamilial child rearing associated with cultural change. Kibbutz children, like other children with working parents, are cared for by multiple caregivers in multiple settings. Historically, kibbutz child care has been communally run in keeping with the collective beliefs and organization of the setting. As collective practices have been relaxed, the contemporary kibbutz children's house has been likened to other day care arrangements. In this article, we examine the process of change in collective child-care arrangements on kibbutz as a dynamic system involving patterns of reciprocal relations among parts of a collaborative child-care system. Influences of the views of developmental experts and economic forces impact reciprocal relations among the physical and social setting, changing practices, and beliefs of kibbutz members. A system dynamics approach turns our focus to feedback loops among parts of the eco-cultural child-care niche rather than developmental outcomes resulting from static features of kibbutz and other child-care arrangements. Contrasting different feedback systems points to cultural conditions under which some stability in demand for collective child care may be maintained, as compared with conditions that might lead to the demise of collective child care. C1 Univ Haifa, Dept Educ, IL-31905 Haifa, Israel. NICHHD, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Maital, SL (reprint author), Univ Haifa, Dept Educ, IL-31905 Haifa, Israel. NR 104 TC 3 Z9 3 U1 2 U2 5 PU AMER ANTHROPOLOGICAL ASSOC PI ARLINGTON PA 4350 NORTH FAIRFAX DRIVE SUITE 640, ARLINGTON, VA 22203 USA SN 0091-2131 J9 ETHOS JI Ethos PD JUN PY 2003 VL 31 IS 2 BP 274 EP 306 DI 10.1525/eth.2003.31.2.274 PG 33 WC Anthropology; Psychology, Multidisciplinary SC Anthropology; Psychology GA 762UD UT WOS:000187999800006 ER PT J AU Hofmann, A Delmer, DP Wlodawer, A AF Hofmann, A Delmer, DP Wlodawer, A TI The crystal structure of annexin Gh1 from Gossypium hirsutum reveals an unusual S-3 cluster - Implications for cellulose synthase complex formation and oxidative stress response SO EUROPEAN JOURNAL OF BIOCHEMISTRY LA English DT Article DE calcium; cellulose synthase; cotton; oxidative stress response; plant annexin ID ELECTRON-DENSITY MAPS; ARABIDOPSIS-THALIANA; MEMBRANE-BINDING; CHANNEL ACTIVITY; PROTEIN; CELLS; LOCALIZATION; DIFFRACTION; EXPRESSION; MOLSCRIPT AB The three-dimensional crystal structure of recombinant annexin Gh1 from Gossypium hirsutum (cotton fibre) has been determined and refined to the final R -factor of 0.219 at the resolution of 2.1 Angstrom. This plant annexin consists of the typical 'annexin fold' and is similar to the previously solved bell pepper annexin Anx24(Ca32), but significant differences are seen when compared to the structure of nonplant annexins. A comparison with the structure of the mammalian annexin AnxA5 indicates that canonical calcium binding is geometrically possible within the membrane loops in domains I and II of Anx(Gh1) in their present conformation. All plant annexins possess a conserved tryptophan residue in the AB loop of the first domain; this residue was found to adopt both a loop-in and a loop-out conformation in the bell pepper annexin Anx24(Ca32). In Anx(Gh1), the conserved tryptophan residue is in a surface-exposed position, half way between both conformations observed in Anx24(Ca32). The present structure reveals an unusual sulfur cluster formed by two cysteines and a methionine in domains II and III, respectively. While both cysteines adopt the reduced thiolate forms and are separated by a distance of about 5.5 Angstrom, the sulfur atom of the methionine residue is in their close vicinity and apparently interacts with both cysteine sulfur atoms. While the cysteine residues are conserved in at least five plant annexins and in several mammalian members of the annexin family of proteins, the methionine residue is conserved only in three plant proteins. Several of these annexins carrying the conserved residues have been implicated in oxidative stress response. We therefore hypothesize that the cysteine motif found in the present structure, or possibly even the entire sulfur cluster, forms the molecular basis for annexin function in oxidative stress response. C1 Univ Edinburgh, Inst Cell & Mol Biol, Edinburgh EH9 3JR, Midlothian, Scotland. Rockefeller Fdn, New York, NY 10018 USA. NCI, Macromol Crystallog Lab, Frederick, MD 21701 USA. RP Hofmann, A (reprint author), Univ Edinburgh, Inst Cell & Mol Biol, Edinburgh EH9 3JR, Midlothian, Scotland. RI Hofmann, Andreas/B-9515-2008 OI Hofmann, Andreas/0000-0003-4408-5467 NR 36 TC 37 Z9 41 U1 0 U2 7 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0014-2956 J9 EUR J BIOCHEM JI Eur. J. Biochem. PD JUN PY 2003 VL 270 IS 12 BP 2557 EP 2564 DI 10.1046/j.1432-1033.2003.03612.x PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 686YM UT WOS:000183348600002 PM 12787021 ER PT J AU Yang, KL Gao, X Lin, PY AF Yang, KL Gao, X Lin, PY TI Recognition of HLA-A*0248 in a Chinese donor SO EUROPEAN JOURNAL OF IMMUNOGENETICS LA English DT Article C1 Buddhist Compass Relief Tzu Chi Fdn, Tzu Chi Marrow Donor Registry, Tzu Chi Immunogenet Ctr & Cord Blood Bank, Hualien 970, Taiwan. NCI, SAIC Frederick, Lab Genom Divers, Frederick, MD 21701 USA. Buddhist Compass Relief Tzu Chi Fdn, Tzu Chi Med Ctr, Hualien 970, Taiwan. RP Yang, KL (reprint author), Buddhist Compass Relief Tzu Chi Fdn, Tzu Chi Marrow Donor Registry, Tzu Chi Immunogenet Ctr & Cord Blood Bank, 707,Sect 3,Chung Yang Rd, Hualien 970, Taiwan. NR 2 TC 4 Z9 4 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0960-7420 J9 EUR J IMMUNOGENET JI Eur. J. Immunogenet. PD JUN PY 2003 VL 30 IS 3 BP 185 EP 186 DI 10.1046/j.1365-2370.2003.00386.x PG 2 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 686DN UT WOS:000183306000003 PM 12786994 ER PT J AU Lewis, C Lamb, ME AF Lewis, C Lamb, ME TI Fathers' influences on children's development: The evidence from two-parent families SO EUROPEAN JOURNAL OF PSYCHOLOGY OF EDUCATION LA English DT Review DE attachment; child development; family; father ID PARENT-INFANT INTERACTION; SINGLE-EARNER FAMILIES; MOTHER-INFANT; PATERNAL INVOLVEMENT; MIDDLE CHILDHOOD; MARITAL QUALITY; INTERACTION BEHAVIOR; MATERNAL EMPLOYMENT; TODDLER DEVELOPMENT; SEPARATION ANXIETY AB Although it is often assumed that men have an important influence on their children's development, the supportive evidence can be difficult to locate and summarize. In this paper, we analyse the evidence with respect to four emergent themes. First, men often appear to interact with their children less sensitively than mothers do, and many children thus appear to form closer attachments to their mothers than to their fathers. Second, the data also indicate that fathers may play specific and important roles, with men in some cultures having clearly defined roles as playmates to their children. Third, paternal play styles predict later socio-emotional development while paternal involvement seems to predict adult adjustment better than maternal involvement does. Such evidence suggests, fourth, that we need appropriate measures of fatherhood that are not simply borrowed from the study of motherhood. C1 Univ Lancaster, Ctr Res Human Dev, Dept Psychol, Lancaster LA1 4YF, England. NICHHD, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Lewis, C (reprint author), Univ Lancaster, Ctr Res Human Dev, Dept Psychol, Lancaster LA1 4YF, England. NR 149 TC 99 Z9 104 U1 7 U2 57 PU INST SUPERIOR PSICOLOGIA APLICADA PI LISBOA PA RUA JARDIM DO TABACO, 34, LISBOA 1149-041, PORTUGAL SN 0256-2928 J9 EUR J PSYCHOL EDUC JI Eur. J. Psychol. Educ. PD JUN PY 2003 VL 18 IS 2 BP 211 EP 228 PG 18 WC Psychology, Educational SC Psychology GA 734EJ UT WOS:000186042000008 ER PT J AU Roth, SM Martel, GF Ferrell, RE Metter, EJ Hurley, BF Rogers, MA AF Roth, SM Martel, GF Ferrell, RE Metter, EJ Hurley, BF Rogers, MA TI Myostatin gene expression is reduced in humans with heavy resistance strength training: A brief communication SO EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Article DE GDF8; skeletal muscle; transcription ID GROWTH-FACTOR-I; SKELETAL-MUSCLE; HIGH-VOLUME; OLDER MEN; CATTLE; YOUNG; LOCALIZATION; RESPONSES; MUTATIONS; DAMAGE AB This study examined changes in myostatin gene expression in response to strength training (ST). Fifteen young and older men (n = 7) and women (n = 8) completed a 9-week heavy-resistance unilateral knee extension ST program. Muscle biopsies were obtained from the dominant vastus lateralis before and after ST. In addition to myostatin mRNA levels, muscle volume and strength were measured. Total RNA was reverse transcribed into cDNA, and myostatin mRNA was quantified using quantitative PCR by standard fluorescent chemistries and was normalized to 18S rRNA levels. A 37% decrease in myostatin expression was observed in response to ST in all subjects combined (2.70 +/- 0.36 vs 1.69 +/- 0.18 U, arbitrary units; P < 0.05). Though the decline in myostatin expression was similar regardless of age or gender, the small number of subjects in these subgroups suggests that this observation needs to be confirmed. No significant correlations were observed between myostatin expression and any muscle strength or volume measure. Although further work is necessary to clarity the findings, these data demonstrate that myostatin mRNA levels are reduced in response to heavy-resistance ST in humans. C1 Univ Maryland, Dept Kinesiol, College Pk, MD 20742 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. Univ Maryland Eastern Shore, Dept Phys Therapy, Princess Anne, MD 21853 USA. NIA, Clin Invest Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Roth, SM (reprint author), Univ Maryland, Dept Kinesiol, College Pk, MD 20742 USA. EM sroth1@umd.edu OI Roth, Stephen/0000-0002-7841-3695 FU NIA NIH HHS [AG-05893, AG-42148]; NIDDK NIH HHS [DK-46204] NR 20 TC 106 Z9 115 U1 0 U2 2 PU SOC EXPERIMENTAL BIOLOGY MEDICINE PI MAYWOOD PA 195 WEST SPRING VALLEY AVE, MAYWOOD, NJ 07607-1727 USA SN 1535-3702 J9 EXP BIOL MED JI Exp. Biol. Med. PD JUN PY 2003 VL 228 IS 6 BP 706 EP 709 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 833ES UT WOS:000222319800009 PM 12773702 ER PT J AU de Cabo, R Furer-Galban, S Anson, RM Gilman, C Gorospe, M Lane, MA AF de Cabo, R Furer-Galban, S Anson, RM Gilman, C Gorospe, M Lane, MA TI An in vitro model of caloric restriction SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE stress-response; hepatocytes; heat shock; oxidative stress; aging ID HEAT-SHOCK PROTEIN; GENE-EXPRESSION PROFILE; LIFE-SPAN; DIETARY RESTRICTION; RHESUS-MONKEYS; AGE; RATS; STRESS; CELLS; TERM AB The mechanisms underlying the ability of caloric restriction (CR) to extend life span and enhance stress responsiveness remain elusive. Progress in this area has been slow due to the complexities of using animals for CR studies and assessing life span as the measure of CR effectiveness. It is therefore of great interest to develop in vitro models of CR. Here we use sera obtained from either Fisher 344 rats or Rhesus monkeys that were fed ad libitum (AL) or CR diets to culture various cell types. We show that treatment of cultured cells with CR sera caused reduced cell proliferation, enhanced tolerance to oxidants and heat, and heightened expression of stress-response genes. These phenotypic features mirror the effects of CR in animals. Supplementation of CR serum with insulin and insulin-like growth factor (IGF)-1 partially restored the proliferative and stress-response phenotype that was seen in cells cultured with AL serum, indicating that reduced levels of insulin and IGF-1 likely contribute to the CR-related effects. This in vitro cell culture model recapitulates key in vivo proliferative and stress-response phenotypic features of CR, and further suggests that endocrine mechanisms contribute to the enhanced stress responsiveness observed in CR animals. (C) 2003 Elsevier Science Inc. All rights reserved. C1 NIA, Intramural Res Program, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. NIA, Intramural Res Program, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. RP Gorospe, M (reprint author), NIA, Intramural Res Program, Lab Expt Gerontol, NIH, 5600 Nathan Shock Dr,Box 12, Baltimore, MD 21224 USA. RI de Cabo, Rafael/E-7996-2010; de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 NR 35 TC 72 Z9 72 U1 0 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD JUN PY 2003 VL 38 IS 6 BP 631 EP 639 DI 10.1016/S0531-5565(03)00055-X PG 9 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 701NW UT WOS:000184174500005 PM 12814798 ER PT J AU Shigeeda, N Uchida, M Barrett, JC Tsutsui, T AF Shigeeda, N Uchida, M Barrett, JC Tsutsui, T TI Candidate chromosomal regions for genes involved in activation of alternative lengthening of telomeres in human immortal cell lines SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE loss of heterozygosity; alternative lengthening of telomeres; telomerase; senescence; human immortal cells ID TUMOR-SUPPRESSOR GENE; HUMAN FIBROBLASTS; FREQUENT LOSS; ALLELIC LOSS; SHORT ARM; MALIGNANT MESOTHELIOMA; OVARIAN-CARCINOMA; BREAST-CANCER; COMMON REGION; LIFE-SPAN AB Either telomerase or alternative mechanisms known as alternative lengthening of telomeres (ALT) are activated in human immortal cells to maintain or lengthen their telomeres. To screen candidate chromosomes harboring gene(s) involved in activation of the telomere maintenance mechanisms that are repressed in normal, mortal cells and lost in immortal cells, we examined loss of heterozygosity (LOH) on the 22 autosomes and the X chromosome in 22 in vitro established human immortal cell lines consisting of 9 telomerase-positive cell lines and 13 ALT-positive cell lines. For detecting LOH, PCR analysis was performed with 66 polymorphic microsatellite markers from candidate genomic regions previously implicated for putative human senescence genes, telomerase repressor genes, or tumor suppressor genes. LOH involving chromosome 8 was observed at 25 of 62 (40%) informative loci in 8 of 13 (61%) ALT-positive cell lines. Particularly, when assayed with D8S339 adjacent to the Werner's syndrome gene, LOH was found in 6 of 12 (50%) informative ALT-positive cell lines. In contrast, no LOH on chromosome 8 was detected at 41 informative loci in any of 9 telomerase-positive cell lines. No other chromosomes showed high frequencies of LOH common in either ALT-positive or telomerase-positive cell lines. Although further LOH analysis with additional markers remains to define the specific region on chromosome 8, our results suggest that gene(s) involved in activation of the ALT pathway in human immortal cell lines may localize on chromosome 8. (C) 2003 Elsevier Science Inc. All rights reserved. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Nippon Dent Univ Hosp, Tokyo 1028158, Japan. NCI, Canc & Aging Sect, Lab Biosyst & Canc, Bethesda, MD 20892 USA. Nippon Dent Univ Tokyo, Sch Dent Tokyo, Dept Pharmacol, Tokyo 1028159, Japan. RP Barrett, JC (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 68 TC 3 Z9 4 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD JUN PY 2003 VL 38 IS 6 BP 641 EP 651 DI 10.1016/S0531-5565(03)00072-X PG 11 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 701NW UT WOS:000184174500006 PM 12814799 ER PT J AU Segal, R Dayan, M Zinger, H Habut, B Shearer, GM Mozes, E AF Segal, R Dayan, M Zinger, H Habut, B Shearer, GM Mozes, E TI The effect of IL-12 on clinical and laboratory aspects of experimental SLE in young and aging mice SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE aging; cytokine profile; experimental SLE; IL-12 ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; BLOOD MONONUCLEAR-CELLS; CYTOKINE PRODUCTION; DISEASE-ACTIVITY; AFFLICTED MICE; ANTI-DNA; INTERLEUKIN-12; INDUCTION; GAMMA; EXPRESSION AB IL-12 plays a crucial role in a variety of immune responses that are involved in immuno-senesence and autoimmune diseases. Experimental SLE can be induced in mice by the monoclonal anti-DNA autoantibody bearing the 16/6Id. Aging mice are less susceptible to disease induction. We evaluated the in vivo effects of IL-12 on several parameters related to aging and to experimental SLE. Young (2 months) and aging (10 months) mice that were or were not immunized with the 16/6Id were treated with IL-12. IL-12 treated unimmunized BALB/c and C3H.SW mice had significant elevated levels of anti-DNA antibodies. A high percentage of these mice had glomerular immune complex deposits (ICD). IL-12 treatment resulted in significant increase of IL-1 and IFN-gamma and a decrease of IL-10 production in unimmunized mice. The same IL-12 induced changes were observed in mice with experimental SLE but were less pronounced than in normal mice. In general, all the effects in SLE afflicted mice were more prominent in aging than in young mice. Treatment of mice with experimental SLE upregulated IL-1, IL-2, IFNgamma and downregulated IL-10. These changes were observed in the groups of young as well as old mice. In conclusion, administration of IL-12 to aging mice reversed their Th1/Th2 cytokine profile and thus rendered them vulnerable to the induction of experimental SLE. (C) 2003 Elsevier Science Inc. All rights reserved. C1 Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel. Shmuel Harofeh Geriatr Ctr, Beer Yaagov, Israel. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Dayan, M (reprint author), Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel. NR 35 TC 14 Z9 15 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD JUN PY 2003 VL 38 IS 6 BP 661 EP 668 DI 10.1016/S0531-5565(03)00060-3 PG 8 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 701NW UT WOS:000184174500008 PM 12814801 ER PT J AU TeKippe, M Harrison, DE Chen, JC AF TeKippe, M Harrison, DE Chen, JC TI Expansion of hematopoietic stem cell phenotype and activity in Trp53-null mice SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID NITRIC-OXIDE SYNTHASE; MUTANT MICE; IN-VIVO; P53; DEFICIENT; REPOPULATION; APOPTOSIS; NUMBERS; RESISTANT; SURVIVAL AB Objectives. To study the effects of transformation-related protein 53 (Trp53) and other genes on hematopoiesis and hematopoietic stem cells (HSCs). Methods. Frequencies of murine bone marrow cells (BMCs) with the Lin(-)Sca-1(+)c-kit(+)CD34- phenotype were analyzed by flow cytometry, and were increased in mice with germ-line deletion of the Trp53 (Trp53(-/-)) gene but not in 25 other deletions of genes involved in cell cycling, development, cancer, or hematopoiesis. Therefore, Trp53(-/-) and wild-type Trp53(+/+) mice were compared using the following assays: complete blood counts, day-9 colony-forming unit spleen (CFU-S), and competitive repopulation. In the latter assay, donor repopulating ability was analyzed at one, three, and five months, while recipient survival and recipient blood and bone marrow cell composition were analyzed at five months, after transplantation. Results. In comparison to wild-type controls, Trp53(-/-) mice had normal blood and bone marrow cell counts, increased CD11b(+), and decreased CD45R(+) cell proportions in blood and bone marrow, twice as many Lin(-)Sca-1(+)c-kit(+)CD34(-) BMCs, and 37% more day-9 CFU-S. In the competitive repopulation assay, Trp53(-/-) BMCs engrafted lethally irradiated recipients two to four times better than Trp53(+/+) BMCs. The Trp53(-/-) engraftment advantage increased with time in the recipients. Recipients of Trp53(-/-) donors had two to three times more Lin(-)Sca-1(+)c-kit(+)CD34(-) BMCs than recipients of Trp53(+/+) donors at five months after transplantation. However, only 44% of recipients of Trp53(-/-) donors survived five months after transplantation, compared with 92% of recipients of Trp53(+/+) donors. Conclusion. The Trp53-null allele expands bone marrow Lin(-)Sca-1(+)c-kit(+)CD34(-) cells and the overall activity of HSCs; however, it increases recipient mortality. (C) 2003 International Society for Experimental Hematology. Published by Elsevier Inc. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. Jackson Lab, Bar Harbor, ME 04609 USA. RP Chen, JC (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Room 7C118,900 Rockville Pike, Bethesda, MD 20892 USA. NR 36 TC 70 Z9 74 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUN PY 2003 VL 31 IS 6 BP 521 EP 527 DI 10.1016/S0301-472X(03)00072-9 PG 7 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 714UF UT WOS:000184931300011 PM 12829028 ER PT J AU Sproull, M Brechbiel, M Camphausen, K AF Sproull, M Brechbiel, M Camphausen, K TI Antiangiogenic therapy through copper chelation SO EXPERT OPINION ON THERAPEUTIC TARGETS LA English DT Review DE angiogenesis; chelation; copper; tumour ID RECOMBINANT HUMAN ENDOSTATIN; WILSONS-DISEASE; TUMOR-GROWTH; PHASE-I; INITIAL THERAPY; ZINC THERAPY; ANGIOGENESIS; TETRATHIOMOLYBDATE; CERULOPLASMIN; CELLS AB As new compounds are being evaluated for use in clinical trials involving antiangiogenic therapies, two important factors must be considered. Independent of clinical efficacy, the potential drug must be cost-effective and have reasonable ease of production. The compound endostatin (Entremed, Inc.) has recently completed two Phase I trials with minimal toxicity to the patients treated [1,2]. However, due to the difficulty and expense of producing large quantities of a recombinant protein, Entremed Inc. has experienced financial difficulties [3]. As this company's fate indicates, a drug must not only be clinically effective, but must also possess reasonable production economics. Another interesting component of compound development is selectivity. Highly selective antiangiogenic compounds such as the tyrosine kinase inhibitor SU-5416 are being replaced by less selective compounds such as SU-6668, which acts on a broader spectrum of tyrosine kinase receptors [4]. This move towards using less selective antiangiogenic compounds is based on preclinical models that demonstrate both better clinical efficacy when using less specific molecules and low response rates from the more selective compounds. With the aim of further examining broadly-acting antiangiogenic agents, the authors are currently evaluating new classes of agents that preferentially bind copper and inhibit angiogenesis. Copper has been known to be a significant target for antiangiogenic therapy for a number of years [5]. Recently, through the use of molecular techniques, the target enzymes that utilise copper as a cofactor are being elucidated. This review will describe the historical use of anticopper therapy for the treatment of Wilson's disease and evaluate some of the new anticopper compounds currently under consideration for use in antiangiogenic therapy. C1 NCI, Imaging & Mol Therapeut Sect, Radiat Oncol Branch, Radiat Oncol Sci Program,Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Camphausen, K (reprint author), NCI, Imaging & Mol Therapeut Sect, Radiat Oncol Branch, Radiat Oncol Sci Program,Ctr Canc Res,NIH, Bldg 10,B3B69, Bethesda, MD 20892 USA. NR 44 TC 12 Z9 12 U1 1 U2 4 PU ASHLEY PUBLICATIONS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1472-8222 J9 EXPERT OPIN THER TAR JI Expert Opin. Ther. Targets PD JUN PY 2003 VL 7 IS 3 BP 405 EP 409 DI 10.1517/14728222.7.3.405 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 691XV UT WOS:000183632000008 PM 12783576 ER PT J AU Geiszt, M Witta, J Baffi, J Lekstrom, K Leto, TL AF Geiszt, M Witta, J Baffi, J Lekstrom, K Leto, TL TI Dual oxidases represent novel hydrogen peroxide sources supporting mucosal surface host defense SO FASEB JOURNAL LA English DT Article DE ThOx1 protein; ThOx2 protein; duox protein; lactoperoxidase; reactive oxygen species ID CHRONIC GRANULOMATOUS-DISEASE; NADPH OXIDASE; SYSTEM; IDENTIFICATION; THIOCYANATE; NEUTROPHILS; CEPACIA; CLONING; SALIVA; CELLS AB Lactoperoxidase (LPO) is an enzyme with antimicrobial properties present in saliva, milk, tears, and airway secretions. Although the formation of microbial oxidants by LPO has been recognized for some time, the source of hydrogen peroxide (H(2)O(2)) for LPO-catalyzed reactions remains unknown. Reactive oxygen species produced by the phagocyte NADPH oxidase (phox) play a critical role in host defense against pathogens; however, analogous oxidant-generating systems in other tissues have not been associated with antimicrobial activity. Several homologues of gp91(phox), the catalytic core of this enzyme, were described recently; dual oxidase (Duox)1/thyroid oxidase 1 and Duox2/thyroid oxidase 2 were identified in the thyroid gland and characterized as H(2)O(2) donors for thyroxin biosynthesis. We examined Duox1 and Duox2 expression in secretory glands and on mucosal surfaces and give evidence for their presence and activity in salivary glands, rectum, trachea, and bronchium. Epithelium cells in salivary excretory ducts and rectal glands express Duox2, whereas tracheal and bronchial epithelial cells express Duox1. Furthermore, we detected Duox1-dependent H(2)O(2) release by cultured human bronchial epithelial cells. Our observations suggest that Duox1 and Duox2 are novel H(2)O(2) sources that can support LPO-mediated antimicrobial defense mechanisms on mucosal surfaces. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Semmelweis Univ, Fac Med, Dept Physiol, H-1444 Budapest, Hungary. Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD 20814 USA. NEI, Ocular Gene Therapy Sect, NIH, Bethesda, MD 20892 USA. RP Leto, TL (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Rm 11N106, Bethesda, MD 20892 USA. EM tleto@nih.gov NR 33 TC 303 Z9 317 U1 3 U2 15 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUN PY 2003 VL 17 IS 9 BP 1502 EP + DI 10.1096/fj.02-1104fje PG 14 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 695EK UT WOS:000183818000030 PM 12824283 ER PT J AU Alesci, S De Martino, MU Mirani, M Benvenga, S Trimarchi, F Kino, T Chrousos, GP AF Alesci, S De Martino, MU Mirani, M Benvenga, S Trimarchi, F Kino, T Chrousos, GP TI L-Carnitine: a nutritional modulator of glucocorticoid receptor functions SO FASEB JOURNAL LA English DT Article DE GR; immunity; cytokines ID PHOSPHATIDYLCHOLINE SPECIES COMPOSITION; RESPIRATORY-DISTRESS SYNDROME; FETAL-RAT LUNGS; PROPIONIC ACIDEMIA; BETAMETHASONE; TRANSPORT; CELLS; SHOCK; INTERLEUKIN-12; COMBINATIONS AB L-Carnitine is an essential nutrient with a major role in cellular energy production. There is evidence that, at high doses, L-carnitine might mimic some of the biological activities of glucocorticoids, especially immunomodulation. To explore the molecular basis of this effect, we tested the influence of L-carnitine on glucocorticoid receptor-alpha (GRalpha) functions. Millimolar concentrations of L-carnitine, which were not cytotoxic in vitro, significantly reduced the whole cell binding of [H-3]dexamethasone to GRalpha by decreasing the affinity of this receptor for its steroid ligand. At the same concentrations, L-carnitine was able to trigger nuclear translocation of green fluorescent protein (GFP)-fused human GRalpha and transactivate the glucocorticoid-responsive mouse mammary tumor virus (MMTV) and TAT3 promoters in a dose-dependent fashion. This effect was solely dependent on the presence of glucocorticoid-responsive elements on the promoter and on the expression of functional GRalpha by the cell. Finally, similarly to glucocorticoids, L-carnitine suppressed tumor necrosis factor-alpha (TNFalpha) and interleukin-12 release by human primary monocytes stimulated with lipopolysaccharide ex vivo. Both GRalpha transactivation and cytokine suppression by L-carnitine were abrogated by the GRalpha-antagonist RU 486. Taken together, our results suggest that pharmacological doses of L-carnitine can activate GRalpha and, through this mechanism, regulate glucocorticoid-responsive genes, potentially sharing some of the biological and therapeutic properties of glucocorticoids. C1 NICHD, PREB, NIH, Bethesda, MD 20892 USA. Univ Messina, Dipartimento Clin Sperimentale Med & Farmacol, Sez Endocrinol, I-98100 Messina, Italy. RP Alesci, S (reprint author), NICHD, PREB, NIH, 10 Ctr Dr,Bldg 10,Room 9D42, Bethesda, MD 20892 USA. EM alescis@mail.nih.gov NR 49 TC 29 Z9 30 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUN PY 2003 VL 17 IS 9 BP 1553 EP + DI 10.1096/fj.02-1024fje PG 20 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 695EK UT WOS:000183818000017 PM 12824292 ER PT J AU Uhler, ML Zinaman, MJ Brown, CC Clegg, ED AF Uhler, ML Zinaman, MJ Brown, CC Clegg, ED TI Relationship between sperm characteristics and hormonal parameters in normal couples SO FERTILITY AND STERILITY LA English DT Article DE human; FSH; inhibin B; male fertility; semen quality; hormonal evaluation ID FOLLICLE-STIMULATING-HORMONE; SEMEN QUALITY; INHIBIN-B; HUMAN-FERTILITY; INFERTILE MEN; LOAD TESTS; SPERMATOGENESIS; BIOASSAY; MARKER AB Objective: To examine the relationships between hormone profiles and semen analysis measures and fertility in the male partners of presumed normal couples. Design: Prospective clinical study. Setting: Healthy volunteers in an academic research environment. Patient(s): One hundred forty-five reproductive age couples without known risk factors for infertility and who had discontinued contraception to achieve pregnancy completed this component of this study. Each couple was followed for less than or equal to12 menstrual cycles while they attempted to conceive. Intervention(s): Semen quality measures for the first ejaculates were obtained at the start of the study along with a single blood sample. Levels of FSH, bioactive FSH, inhibin 13, LH, and T were measured for each man. Main Outcome Measure(s): Semen analysis, FSH, inhibin B, LH, T, and clinical pregnancy. Result(s): Significant positive relationships were observed between the two measures of FSH as well as between both of the FSH measures and LH. Follicle-stimulating hormone as measured by RIA was significantly negatively correlated with inhibin B. Inhibin B showed a marginally significant negative correlation with LH, and LH and T had a marginally significant positive correlation. Inhibin B increased significantly, and both measures of FSH activity showed significant decreases, with increasing levels in several semen quality measures. There was no significant relationship between the measured hormones and the pregnant and nonpregnant groups or time to pregnancy. Conclusion(s): These results contribute additional information on the utility of reproductive hormone measurements for predicting semen quality in couples without known reduced fertility. C1 Loyola Univ, Med Ctr, Dept Obstet & Gynecol, Stritch Sch Med, Maywood, IL 60153 USA. Georgetown Univ, Med Ctr, Dept Obstet & Gynecol, Washington, DC 20007 USA. NCI, Div Canc Prevent & Control, Bethesda, MD 20892 USA. RP Zinaman, MJ (reprint author), Loyola Univ, Med Ctr, Dept Obstet & Gynecol, Stritch Sch Med, 2160 S 1st Ave, Maywood, IL 60153 USA. NR 26 TC 25 Z9 28 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD JUN PY 2003 VL 79 SU 3 BP 1535 EP 1542 DI 10.1016/S0015-0282(03) PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 688VP UT WOS:000183457900004 PM 12801556 ER PT J AU Kennedy, CH Pass, HI Mitchell, JB AF Kennedy, CH Pass, HI Mitchell, JB TI Expression of human MutT homologue (hMTH1) protein in primary non-small-cell lung carcinomas and histologically normal surrounding tissue SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE carcinogenesis; DNA repair; hMTH1; human MutT homologue; lung cancer; oxidative DNA damage; oxidative stress; 8-oxo-dGTPase; free radicals ID OXIDATIVE DNA-DAMAGE; MESSENGER-RNA; BASE DAMAGE; MUTAGENIC SUBSTRATE; HYDROGEN-PEROXIDE; EPITHELIAL-CELLS; CIGARETTE-SMOKE; REPAIR PATHWAY; TUMOR-CELLS; HUMAN MTH1 AB In situ, oxidation of deoxyguanosine yields 8-hydroxy-2'-deoxyguanosine (8-oxo-dG), which is mutation prone and results in a G:C --> T:A transversion following DNA replication. Another pathway to the formation of DNA containing 8-oxo-dG is by the misincorporation of 8-oxo-dGTP via DNA polymerase. Human MutT homologue (hMTH1), an 8-oxo-dGTPase, prevents misincorporation of this oxidized nucleotide by hydrolyzing 8-oxo-dGTP to 8-oxo-dGMP. Previous studies have shown that hMTH1 mRNA is overexpressed in human renal cell carcinomas and breast tumors. Elevated levels of hMTH1 protein have also been detected in brain tumors. In the current study, we determined whether hMTH1 protein is overexpressed in primary non-small-cell lung carcinomas as compared to adjacent histologically normal lung tissue. Twenty matched human lung tumor/normal pairs were examined by Western analysis for expression of hMTH1 protein. Overexpression in the tumors was detected in 4/8 (50%) adenocarcinomas, 4/4 (100%) adenocarcinomas with bronchioalveolar (BAC) features, 2/2 (100%) BACs, and 3/6 (50%) squamous cell carcinomas. The data from Western analysis were validated by immunohistochemical staining for hMTH1 protein. The results of this study indicate that hMTH1 protein may be a potential marker for the detection of persistent oxidative stress in lung cancer. (C) 2003 Elsevier Inc. C1 NCI, Dept Hlth & Human Serv, Canc Res Ctr, Radiat Oncol Sci Program,Radiat Biol Branch,NIH, Bethesda, MD 20892 USA. NCI, Canc Prevent Fellowship Program, Off Prevent Oncol, Div Canc Prevent, Bethesda, MD 20892 USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI 48202 USA. RP Kennedy, CH (reprint author), NCI, Dept Hlth & Human Serv, Canc Res Ctr, Radiat Oncol Sci Program,Radiat Biol Branch,NIH, 10 Ctr Dr,Bldg 10, Bethesda, MD 20892 USA. NR 61 TC 30 Z9 31 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUN 1 PY 2003 VL 34 IS 11 BP 1447 EP 1457 DI 10.1016/S0891-5849(03)00106-X PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 679ZQ UT WOS:000182952200011 PM 12757855 ER PT J AU Holden, JP Selbie, WS Stanhope, SJ AF Holden, JP Selbie, WS Stanhope, SJ TI A proposed test to support the clinical movement analysis laboratory accreditation process SO GAIT & POSTURE LA English DT Article DE movement analysis; gait; laboratory accreditation; accuracy; kinematics; kinetics; force platform ID SPOT CHECK; SYSTEM; ACCURACY; RELIABILITY AB This paper describes a testing methodology and resultant set of four variables that can be used to quickly and easily document the correct installation, configuration, and combined working status of force platform (FP) and three-dimensional (3D) motion capture components of a clinical movement analysis (CMA) laboratory. Using a rigid, rod-shaped testing device, CMA laboratory data are collected simultaneously from the F and motion capture components (typically, video-based kinematic measurements) as the device is manually loaded while being pivoted broadly about a point on the FP. Using a computational method based on static equilibrium, it is possible to independently measure the rod's orientation and tip position during the moving trial, usingFP derived data exclusively, and to compare these estimates to rod orientation and tip position estimates derived exclusively from the motion capture component. The motion laboratory accreditation test (MLAT) variables include: the difference (angle) between the orientation of the long axis of the testing device as independently determined from kinematic measures (motion capture component) and the FP derived data; and the difference (x, y, z) between the center of pressure position (FP derived) and the position of the testing device tip (motion capture derived) that loads the FP. A numerical dynamics model was explored to evaluate the appropriateness of the static equilibrium-based FP data model and to determine guidelines for testing device movement frequency and FP loading. The MLAT technique provides a simple means of detecting the combined presence of errors from many sources, several of which are explored in this paper. The MLAT has been developed to help meet one criteria of the CMA laboratory, accreditation process, and to serve as a routine quality assessment tool. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NIH, Phys Disabilities Branch, Bethesda, MD 20892 USA. US FDA, Ctr Devices & Radiol Hlth, Rockville, MD 20850 USA. C Mot Inc, Rockville, MD 20855 USA. RP Stanhope, SJ (reprint author), NIH, Phys Disabilities Branch, Bldg 10,Room 6s235,MSC 1604, Bethesda, MD 20892 USA. EM steven_stanhope@nih.gov NR 20 TC 21 Z9 22 U1 1 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0966-6362 J9 GAIT POSTURE JI Gait Posture PD JUN PY 2003 VL 17 IS 3 BP 205 EP 213 AR PII S0966-6362(02)00088-7 DI 10.1016/S0966-6362(02)00088-7 PG 9 WC Neurosciences; Orthopedics; Sport Sciences SC Neurosciences & Neurology; Orthopedics; Sport Sciences GA 688KE UT WOS:000183432700002 PM 12770634 ER PT J AU Ruhl, CE Everhart, JE AF Ruhl, CE Everhart, JE TI Relation of elevated serum alanine aminotransferase activity with iron and antioxidant levels in the United States SO GASTROENTEROLOGY LA English DT Article ID FATTY LIVER-DISEASE; NONALCOHOLIC STEATOHEPATITIS; HEPATIC IRON; INSULIN-RESISTANCE; HFE GENE; OVERLOAD; PREVALENCE; FIBROSIS; HEMOCHROMATOSIS; ABNORMALITIES AB Background & Aims: Oxidative stress is thought to play a role In liver injury. Hepatic iron may promote liver injury, whereas antioxidant vitamins and minerals may inhibit it, but few clinical studies have examined such relationships. We analyzed the associations of serum iron measures and antioxidant concentrations with abnormal serum alanine transaminase (ALT) activity in a large, national, population-based study. Methods: A total of :13,605 adult participants in the third U.S. National Health and Nutrition Examination Survey (NHANES III), 1988-1994, underwent phlebotomy. Exclusions included excessive alcohol consumption, hepatitis B and C, and iron overload. Results: Elevated ALT levels were found in 3.1% of the population. In univariate analysis, factors associated with abnormal ALT levels (P < 0.05) included higher transferrin saturation and iron and selenium concentrations, and lower vitamin C, alpha and P carotene, and lutein/zeaxanthin concentrations. In multivariate logistic regression analyses, elevated ALT level was associated positively with increasing deciles of transferrin saturation (odds ratio [OR] per decile, :1.1.0; 95% confidence interval [CI], 1.03-1.18) and iron concentration (OR, 1.13; 95% CI,1.06-1.21). Abnormal ALT level was associated negatively with increasing deciles of a carotene (OR, 0.82; 95% Cl, 0.72-0.94), P carotene (OR, 0.91; 95% CI, 0.86-0.96), P cryptoxanthin (OR, 0.91; 95% CI, 0.84-0.99), lute! n/zeaxanth in (OR, 0.90; 95% CI, 0.84-0.96), and a variable combining the 5 carotenoid measures (OR, 0.89; 95% CI, 0.83-0.95). Vitamin C was associated inversely, but only at the highest concentrations. Conclusions: In this large, national, population-based study, the risk for apparent liver injury was associated with increased iron and decreased antioxidants, particularly carotenoids. C1 Social & Sci Syst Inc, Silver Spring, MD 20910 USA. NIDDKD, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Ruhl, CE (reprint author), Social & Sci Syst Inc, 8757 Georgia Ave,12th Floor, Silver Spring, MD 20910 USA. FU NIDDK NIH HHS [N01 DK 12478] NR 43 TC 57 Z9 59 U1 0 U2 4 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUN PY 2003 VL 124 IS 7 BP 1821 EP 1829 DI 10.1016/S0016-5085(03)00395-0 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 684ZK UT WOS:000183236200015 PM 12806616 ER PT J AU Waters, ST Wilson, CP Lewandoski, M AF Waters, ST Wilson, CP Lewandoski, M TI Cloning and embryonic expression analysis of the mouse Gbx1 gene SO GENE EXPRESSION PATTERNS LA English DT Article DE Gbx1; Gbx2; Fgf8; mid/hindbrain organizer; neurulation ID HOMEOBOX GENE; MID/HINDBRAIN ORGANIZER; HINDBRAIN; OTX2; ESTABLISHMENT; PATTERN; CELLS AB We report the cloning of a cDNA encoding the complete mouse Gbx1 coding region as well as a comparative expression analysis of Gbx1 and Gbx2 during murine development. Gbx1 is expressed first during gastrulation and later in a dynamic pattern in the central nervous system, including rhombomeres 3 and 5, optic vesicles, and the medial ganglionic eminence. Gbx1 expression is not upregulated in Gbx2 null homozygotes. Therefore, the only regions of potential genetic redundancy are where Gbx1 and 2 are normally coexpressed: the primitive streak, regions of the ventricular zone of the neural tube and the medial ganglionic eminence. Finally, we demonstrate that neither Gbx1 nor Gbx2 require FGF8 for expression during gastrulation, contrary to previous published reports. (C) 2003 Elsevier Science B.V. All rights reserved. C1 NCI, Lab Canc & Dev Biol, NIH, Frederick, MD 21702 USA. RP Lewandoski, M (reprint author), NCI, Lab Canc & Dev Biol, NIH, Frederick, MD 21702 USA. NR 17 TC 19 Z9 20 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-133X J9 GENE EXPR PATTERNS JI Gene Expr. Patterns PD JUN PY 2003 VL 3 IS 3 BP 313 EP 317 DI 10.1016/S1567-133X(03)00041-3 PG 5 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 717CY UT WOS:000185069100009 PM 12799077 ER PT J AU Rhen, T Sakata, JT Woolley, S Porter, R Crews, D AF Rhen, T Sakata, JT Woolley, S Porter, R Crews, D TI Changes in androgen receptor mRNA expression in the forebrain and oviduct during the reproductive cycle of female leopard geckos, Eublepharis macularius SO GENERAL AND COMPARATIVE ENDOCRINOLOGY LA English DT Article DE androgen receptor; female; hypothalamus; neuroendocrinology; reproductive cycle ID MEDIAL PREOPTIC AREA; WHIPTAIL LIZARDS; MESSENGER-RNA; SEXUAL-BEHAVIOR; PROGESTERONE-RECEPTOR; VENTROMEDIAL HYPOTHALAMUS; CNEMIDOPHORUS UNIPARENS; SPECIES-DIFFERENCES; ESTROGEN-RECEPTOR; STEROID-LEVELS AB Successful reproduction requires the coordination of reproductive physiology with behavior. The neural correlates of reproductive behavior have been elucidated in a variety of amphibians, mammals, and birds but relatively few studies have examined reptiles. Here we investigate differences in androgen receptor (AR) mRNA expression in the forebrain and oviduct between previtellogenic and late vitellogenic female leopard geckos, Eublepharis macularius. Plasma concentrations of testosterone (T) are low when females are previtellogenic and sexually unreceptive but increase dramatically during late vitellogenesis when females are receptive. In addition, receptivity can be induced by treatment with exogenous T. The relative abundance of AR-mRNA across various nuclei was greater in late vitellogenic than in previtellogenic females. This general pattern was observed in the medial preoptic area, anterior hypothalamus, external nucleus of the amygdala, dorsolateral aspect of the ventromedial hypothalamus, lateral septum, and periventricular hypothalamus. There were also clear differences in AR-mRNA expression among these nuclei. The pattern of gene expression observed in the brain was reversed within stromal cells of the oviduct where expression of AR-mRNA decreased from the previtellogenic stage to the late vitellogenic stage. Overall, these data demonstrate that T concentration in the plasma, abundance of AR-mRNA in the brain and oviduct, and sexual behavior change coordinately during the reproductive cycle of female leopard geckos. Although the function of AR in the female leopard gecko is not yet clear, our results are in accord with growing evidence that androgens regulate numerous aspects of female physiology and behavior in vertebrates. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Univ Texas, Sch Biol Sci, Sect Integrat Biol, Austin, TX 78712 USA. Univ Texas, Inst Neurosci, Austin, TX 78712 USA. RP Rhen, T (reprint author), NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. FU NIMH NIH HHS [MH11369, MH57874]; PHS HHS [T32 18837] NR 41 TC 9 Z9 9 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0016-6480 J9 GEN COMP ENDOCR JI Gen. Comp. Endocrinol. PD JUN 1 PY 2003 VL 132 IS 1 BP 133 EP 141 DI 10.1016/S0016-6480(03)00059-5 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 687TF UT WOS:000183392500016 PM 12765653 ER PT J AU Duggal, P An, P Beaty, TH Strathdee, SA Farzadegan, H Markham, RB Johnson, L O'Brien, SJ Vlahov, D Winkler, CA AF Duggal, P An, P Beaty, TH Strathdee, SA Farzadegan, H Markham, RB Johnson, L O'Brien, SJ Vlahov, D Winkler, CA TI Genetic influence of CXCR6 chemokine receptor alleles on PCP-mediated AIDS progression among African Americans SO GENES AND IMMUNITY LA English DT Article DE chemokine; chemokine receptor; HIV; AIDS; Pneumocystis carinii pneumonia ID EXPRESSION CLONING; HIV-1 INFECTION; T-CELLS; PATHOGENESIS; RESTRICTION; SUBSETS; LIGAND; CCR2 AB CXCR6 is a chemokine receptor and the primary coreceptor in SIV infection. A single nucleotide polymorphism 1469G --> A, results in a nonconservative change in codon 3 (CXCR6-E3K) of the N-terminus of the coreceptor. To investigate the relation between the chemokine receptor CXCR6 genotype and progression to Pneumocystis carinii pneumonia (PCP) and from PCP to death, we clinically assessed and genotyped 805 individuals from an African-American injection drug-using cohort in Baltimore, MD, USA, for this CXCR6-E3K polymorphism. The allele frequency of CXCR6-3K was high (44%) in African Americans and rare in European Americans (f < 1%). Although time to AIDS and PCP was similar for all CXCR6 genotypes, the median survival time from PCP to death for the CXCR6-3E/E and CXCR6-3E/K genotype was 1.5 years compared to 3.1 years for the CXCR6-K/K genotype. Individuals homozygous or heterozygous for the CXCR6-3E allele were 5.6 times more likely to die a PCP-mediated AIDS-related death than were individuals homozygous for CXCR6-3K. This study shows an association between CXCR6 genotype and progression from PCP to death among African-Americans with HIV. We suggest that CXCR6 may play a role in late-stage HIV-1 infection and may alter the progression to death after initial infection with PCP. C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. NCI, Basic Res Program, SAIC Frederick, Frederick, MD 21701 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. NCI, Lab Genom Divers, Frederick, MD 21701 USA. RP Duggal, P (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St,Room E6136, Baltimore, MD 21205 USA. RI Strathdee, Steffanie/B-9042-2009; Beaty, Terri/A-6032-2008 FU NCI NIH HHS [N01-CO-12400]; NIDA NIH HHS [DA04334] NR 22 TC 33 Z9 36 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD JUN PY 2003 VL 4 IS 4 BP 245 EP 250 DI 10.1038/sj.gene.6363950 PG 6 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 683EZ UT WOS:000183136100001 PM 12761559 ER PT J AU Tillinghast, GW Partee, J Albert, P Kelley, JM Burtow, KH Kelly, K AF Tillinghast, GW Partee, J Albert, P Kelley, JM Burtow, KH Kelly, K TI Analysis of genetic stability at the EP300 and CREBBP loci in a panel of cancer cell lines SO GENES CHROMOSOMES & CANCER LA English DT Article ID ADENOVIRAL ONCOPROTEIN E1A; TRANSCRIPTIONAL COACTIVATOR; HISTONE ACETYLTRANSFERASES; LUNG-CANCER; P300; CBP; P53; INHIBITION; ACTIVATION; MUTATIONS AB EP300 (p300) and CREBBP (CBP) are highly related transcriptional co-activators possessing histone acetyltransferase activity. These proteins have been implicated in coordinating numerous transcriptional responses that are important in the processes of proliferation and differentiation. A role for EP300 and CREBBP as tumor suppressors in cancer has been suggested by the fact that they are targeted by viral oncogenes; there is an increased incidence of hematologic malignancies in mice monoallelic for CREBBP; and loss, albeit at a low frequency, of both EP300 alleles in epithelial cancers has been observed. Because the level of EP300/CREBBP appears to have a critical effect on integrating certain transcriptional processes, we sought to determine whether a loss in the combined gene dosage of EP300 and CREBBP might play a role in cancer. Accordingly, we screened a panel of 103 cell lines for loss of heterozygosity and found 35 and 51% LOH for the CREBBP and EP300 loci, respectively. Concordant loss of CREBBP and EP300 was not associated with mutations in important regions of the remaining EP300 or CREBBP genes. In addition, there did not appear to be a statistically significant selection in cancer cells, stratified by various criteria, for the concordant loss of EP300 and CREBBP. We conclude that EP300 and CREBBP rarely act as classical tumor suppressors in human cancer. Published 2003 Wiley-Liss, Inc.(dagger). C1 NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. RP Kelly, K (reprint author), NCI, Cell & Canc Biol Branch, NIH, Bldg 10,Room 3B43,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 31 TC 15 Z9 15 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 JUN PY 2003 VL 37 IS 2 BP 121 EP 131 DI 10.1002/gcc.10195 PG 11 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 674RB UT WOS:000182648800002 PM 12696060 ER PT J AU Lawson, ND Mugford, JW Diamond, BA Weinstein, BM AF Lawson, ND Mugford, JW Diamond, BA Weinstein, BM TI phospholipase C gamma-1 is require downstream of vascular endothelial growth factor during arterial development SO GENES & DEVELOPMENT LA English DT Article DE zebrafish; endothelial; artery; Plcg1; Vegf ID FACTOR VEGF; PLC-GAMMA; ZEBRAFISH; VASCULOGENESIS; DIFFERENTIATION; ANGIOGENESIS; EMBRYOS; HEMATOPOIESIS; KDR/FLK-1; ISOFORMS AB In this study, we utilize transgenic zebrafish with fluorescently labeled blood vessels to identify and characterize a mutant (y10) that displays specific defects in the formation of arteries, but not veins. We find that y10 encodes phospholipase C gamma-1 (plcg1), a known effector of receptor tyrosine kinase signaling. We further show that plcg1(y10) mutant embryos fail to respond to exogenous Vegf. Our results indicate that Plcg1 functions specifically downstream of the Vegf receptor during embryonic development to govern formation of the arterial system. C1 Univ Massachusetts, Sch Med, Program Gene Funct & Express, Worcester, MA 01605 USA. NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Lawson, ND (reprint author), Univ Massachusetts, Sch Med, Program Gene Funct & Express, Worcester, MA 01605 USA. NR 25 TC 145 Z9 147 U1 1 U2 5 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUN 1 PY 2003 VL 17 IS 11 BP 1346 EP 1351 DI 10.1101/gad.1072203 PG 6 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 687VB UT WOS:000183396700006 PM 12782653 ER PT J AU Cherry, JL AF Cherry, JL TI Selection in a subdivided population with local extinction and recolonization SO GENETICS LA English DT Article ID FIXATION; DRIFT; PROBABILITY; FREQUENT; GENE; SIZE AB In a subdivided population, local extinction and subsequent recolonization affect the fate of alleles. Of particular interest is the interaction of this force with natural selection. The effect of selection can be weakened by this additional source of stochastic change in allele frequency. The behavior of a selected allele in such a population is shown to be equivalent to that of an allele with a different selection coefficient in an unstructured population with a different size. This equivalence allows use of established results for panmictic populations to predict such quantities as fixation probabilities and mean times to fixation. The magnitude of the quantity N(e)s(e), which determines fixation probability, is decreased by extinction and recolonization. Thus deleterious alleles are more likely to fix, and advantageous alleles less likely to do so, in the presence of extinction and recolonization. Computer simulations confirm that the theoretical predictions of both fixation probabilities and mean times to fixation are good approximations. C1 Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA. RP Cherry, JL (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, 8600 Rockville Pike,Bldg 45, Bethesda, MD 20894 USA. NR 14 TC 20 Z9 20 U1 0 U2 6 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD JUN PY 2003 VL 164 IS 2 BP 789 EP 795 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 696GV UT WOS:000183880000038 PM 12807797 ER PT J AU O'Brien, TP Bult, CJ Cremer, C Grunze, M Knowles, BB Langowski, J McNally, J Pederson, T Politz, JC Pombo, A Schmahl, G Spatz, JP van Driel, R AF O'Brien, TP Bult, CJ Cremer, C Grunze, M Knowles, BB Langowski, J McNally, J Pederson, T Politz, JC Pombo, A Schmahl, G Spatz, JP van Driel, R TI Genome function and nuclear architecture: From gene expression to nanoscience SO GENOME RESEARCH LA English DT Article ID X-RAY MICROSCOPY; LIVING CELLS; CHROMOSOME TERRITORIES; REGULATORY ELEMENTS; PROTEOMIC ANALYSIS; MAGNETIC TWEEZERS; MOUSE GENOME; CHROMATIN; TRANSCRIPTION; RESOLUTION AB Biophysical, chemical, and nanoscience approaches to the study Of nuclear structure and activity have been developing recently and hold considerable promise. A selection of fundamental problems in genome organization and function are reviewed and discussed in the context of these new perspectives and approaches. Advancing these concepts will require coordinated networks of physicists, chemists, and materials scientists collaborating with cell, developmental, and genome biologists. C1 Jackson Lab, Bar Harbor, ME 04609 USA. Univ Amsterdam, NL-1018 TV Amsterdam, Netherlands. Univ Gottingen, D-37070 Gottingen, Germany. MRC, Ctr Clin Sci, London W12 ONN, England. Univ Massachusetts, Sch Med, Worcester, MA 01605 USA. NCI, Bethesda, MD 20892 USA. German Canc Res Ctr, D-69120 Heidelberg, Germany. Univ Heidelberg, D-69117 Heidelberg, Germany. RP O'Brien, TP (reprint author), Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. EM tpo@jax.org RI Grunze, Michael/H-1600-2013; Pombo, Ana/A-1045-2010; Langowski, Jorg/A-1843-2011; Spatz, Joachim/A-1107-2017; OI Pombo, Ana/0000-0002-7493-6288; Langowski, Jorg/0000-0001-8600-0666; Spatz, Joachim/0000-0003-3419-9807; Ritland, Joan/0000-0001-5229-0087 FU NHGRI NIH HHS [HG/GM02450, HG02669] NR 93 TC 49 Z9 52 U1 1 U2 5 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 J9 GENOME RES JI Genome Res. PD JUN PY 2003 VL 13 IS 6 BP 1029 EP 1041 DI 10.1101/gr.946403 PG 13 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 686XP UT WOS:000183346500001 PM 12743020 ER PT J AU Yuhki, N Beck, T Stephens, RM Nishigaki, Y Newmann, K O'Brien, SJ AF Yuhki, N Beck, T Stephens, RM Nishigaki, Y Newmann, K O'Brien, SJ TI Comparative genome organization of human, murine, and feline MHC class II region SO GENOME RESEARCH LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; NUCLEOTIDE-SEQUENCE; GENE ORGANIZATION; ELEMENTS; CATS; VERTEBRATES; RADIATION; SEARCH; VIRUS; TOOL AB To study comparative molecular dynamics in the genesis of the major histocompatibility complex (MHC), we determined a complete nucleotide sequence spanning 758,291 bp of the domestic cat (Felis catus) extended and classical class II region. The feline class II MHC includes 44 genes (31 predicted to be expressed) which display DNA sequence homology and ordered gene synteny with human HLA and mouse H2, in extended class II and centromere proximal regions [DM to DO) of the classical class II region. However, remarkable genomic alterations including gene gain and loss plus size differentials of 250 kb are evident in comparisons of the cat class II with those of human and mouse. The cat MHC lacks the entire DQ region and retains only relict pseudogene homologs of DP genes, compensated by expansion and reorganization of seven modern DR genes. Repetitive gene families within the feline MHC comprise 35% of the feline MHC with very different density and abundance of GC levels, SINES, LINES, STRs, and retro-elements from the same repeats in human and mouse MHC. Comparison of the feline MHC with the murine and human MHC offers a detailed view of the consequences of genome organization in three mammalian lineages. C1 NCI, Lab Genomic Divers, Frederick, MD 21702 USA. SAIC Frederick, IRSP, Adv Biomed Comp Ctr, Ft Detrick, MD 21702 USA. RP NCI, Lab Genomic Divers, Frederick, MD 21702 USA. EM yuhki@ncifcrf.gov; obrien@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 51 TC 63 Z9 63 U1 0 U2 3 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 JUN PY 2003 VL 13 IS 6 BP 1169 EP 1179 DI 10.1101/gr.976103 PG 11 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 686XP UT WOS:000183346500013 PM 12743023 ER PT J AU Volfovsky, N Haas, BJ Salzberg, SL AF Volfovsky, N Haas, BJ Salzberg, SL TI Computational discovery of internal micro-exons SO GENOME RESEARCH LA English DT Article ID GENOME SEQUENCE; MESSENGER-RNA; MINI-EXON; ALIGNMENT; TOOL; RECOGNITION; DIVERSITY; PROTEINS; FORMS; CDNA AB Very short exons, also known as micro-exons, occur in large numbers in some eukaryotic genomes. Existing annotation tools have a limited ability to recognize these short sequences, which range in length LIP to 25 bp. Here, we describe a computational method for the identification of micro-exons using near-perfect alignments between cDNA and genomic DNA sequences. Using this method, we detected 319 micro-exons in 4 complete genomes, of which 224 were previously Unknown, human (170), the nematode Caenorhabditis elegans (4), the fruit fly Drosophila melanogaster (14), and the mustard plant Arabidopsis thaliana (36). Comparison Of our computational method with popular cDNA alignment programs shows that the new algorithm is both efficient and accurate. The algorithm also aids in the discovery of micro-exon-skipping events and cross-species micro-exon conservation. C1 Inst Genomic Res, Rockville, MD 20850 USA. RP NCI, Adv Biomed Comp Ctr, Frederick SAIC, Frederick, MD 21702 USA. EM natalia@ncifcrf.gov RI Salzberg, Steven/F-6162-2011 OI Salzberg, Steven/0000-0002-8859-7432 FU NLM NIH HHS [R01 LM006845, R01-LM06845] NR 29 TC 41 Z9 42 U1 0 U2 1 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 JUN PY 2003 VL 13 IS 6 BP 1216 EP 1221 DI 10.1101/gr.677503 PG 6 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 686XP UT WOS:000183346500017 PM 12799353 ER PT J AU Carninci, P Waki, K Shiraki, T Konno, H Shibata, K Itoh, M Aizawa, K Arakawa, T Ishii, Y Sasaki, D Bono, H Kondo, S Sugahara, Y Saito, R Osato, N Fukuda, S Sato, K Watahiki, A Hirozane-Kishikawa, T Nakamura, M Shibata, Y Yasunishi, A Kikuchi, N Yoshiki, A Kusakabe, M Gustincich, S Beisel, K Pavan, W Aidinis, V Nakagawara, A Held, WA Iwata, H Kono, T Nakauchi, H Lyons, P Wells, C Hume, DA Fagiolini, M Hensch, TK Brinkmeier, M Camper, S Hirota, J Mombaerts, P Muramatsu, M Okazaki, Y Kawai, J Hayashizaki, Y AF Carninci, P Waki, K Shiraki, T Konno, H Shibata, K Itoh, M Aizawa, K Arakawa, T Ishii, Y Sasaki, D Bono, H Kondo, S Sugahara, Y Saito, R Osato, N Fukuda, S Sato, K Watahiki, A Hirozane-Kishikawa, T Nakamura, M Shibata, Y Yasunishi, A Kikuchi, N Yoshiki, A Kusakabe, M Gustincich, S Beisel, K Pavan, W Aidinis, V Nakagawara, A Held, WA Iwata, H Kono, T Nakauchi, H Lyons, P Wells, C Hume, DA Fagiolini, M Hensch, TK Brinkmeier, M Camper, S Hirota, J Mombaerts, P Muramatsu, M Okazaki, Y Kawai, J Hayashizaki, Y TI Targeting a complex transcriptome: The construction of the mouse full-length cDNA encyclopedia SO GENOME RESEARCH LA English DT Article ID EXPRESSED SEQUENCE TAGS; TRAPPER-SELECTED CDNAS; HUMAN MESSENGER-RNAS; GENE-EXPRESSION; CAP-TRAPPER; DNA-SEQUENCE; REVERSE TRANSCRIPTION; FUNCTIONAL ANNOTATION; LIBRARIES; CLONING AB We report the construction of the mouse full-length cDNA encyclopedia, the most extensive view of a complex transcriptome, on the basis of preparing and sequencing 246 libraries. Before cloning, cDNAs were enriched in full-length by Cap-Trapper, and in most cases, aggressively subtracted/normalized. We have produced 1,442,236 successful 3'-end sequences clustered into 171,144 groups, from which 60,770 clones were fully sequenced cDNAs annotated in the FANTOM-2 annotation. We have also produced 547,149 5' end reads, which clustered into 124,258 groups. Altogether, these cDNAs were further grouped in 70,000 transcriptional units (TU), which represent the best coverage of a transcriptome so far. By monitoring the extent of normalization/subtraction, we define the tentative equivalent coverage (TEC), which was estimated to be equivalent to >12,000,000 ESTs derived from standard libraries. High coverage explains discrepancies between the very large. numbers of clusters (and TUs) of this project, which also include non-protein-coding RNAs, and the lower gene number estimation of genome annotations. Altogether, S'-end clusters identify regions that are potential promoters for 8637 known genes and S'-end clusters suggest the presence of almost 63,000 transcriptional starting points. An estimate of the frequency of polyadenylation signals suggests that at least half of the singletons in the EST set represent real mRNAs. Clones accounting for about half of the predicted TUs await further sequencing. The continued high-discovery rate suggests that the task of transcriptome discovery is not yet complete. C1 RIKEN, Yokohama Inst, GSC, Lab Genome Explorat Res Grp,Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan. RIKEN, Genome Sci Lab, Wako, Saitama 3510198, Japan. Univ Tsukuba, Inst Basic Med Sci, Tsukuba, Ibaraki 3058577, Japan. Yokohama City Univ, Grad Sch Integrated Sci, Japan Div Genom Informat Resources, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan. RIKEN, Tsukuba Inst, Biogen Resources Ctr, Expt Anim Res Div, Tsukuba, Ibaraki 3050074, Japan. Dnaform Int Inc, Ami, Ibaraki 3000332, Japan. Aloka Co Ltd, Kasumigaura Cho, Ibaraki 3000134, Japan. Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. Boys Town Natl Res Hosp, Omaha, NE 68131 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Fleming, Biomed Sci Res Ctr A1, Inst Immunol, Vari 16672, Greece. Chiba Canc Ctr, Inst Res, Div Biochem, Chuo Ku, Chiba 2608717, Japan. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. Kyoto Univ, Inst Frontier Med Sci, Dept Reparat Mat Field Tissue Engn, Sakyo Ku, Kyoto 6068507, Japan. Tokyo Univ Agr, Fac Appl Biosci, Dept Biosci, Setagaya Ku, Tokyo 1568502, Japan. Univ Tokyo, Inst Med Sci, Ctr Med Expt, Lab Stem Cell Therapy,Minato Ku, Tokyo 1088639, Japan. Cambridge Inst Med Res, Diabet & Inflammat Lab DRF WT, Cambridge CB2 2XY, England. Univ Queensland, Inst Mol Biosci, St Lucia, Qld 4072, Australia. RIKEN, BSI, Lab Neuronal Circuit Dev, Neuronal Funct Res Lab, Wako, Saitama 3000198, Japan. Univ Michigan Med, Ann Arbor, MI 48109 USA. Rockefeller Univ, New York, NY 10021 USA. RP Hayashizaki, Y (reprint author), RIKEN, Yokohama Inst, GSC, Lab Genome Explorat Res Grp,Tsurumi Ku, Suehiro Cho, Yokohama, Kanagawa 2300045, Japan. EM rgscerg@gsc.riken.go.jp RI Itoh, Masayoshi/N-5363-2015; Yoshiki, Atsushi/A-6036-2016; shibata, kazuhiro/A-9527-2008; Konno, Hideaki/A-9191-2012; Wells, Christine/A-5071-2010; Hume, David/C-7695-2013; Kawai, Jun/A-6451-2016; Carninci, Piero/K-1568-2014; Konno, Hideaki/N-4366-2014 OI Bono, Hidemasa/0000-0003-4413-0651; Itoh, Masayoshi/0000-0002-1772-318X; Yoshiki, Atsushi/0000-0002-9450-5151; Wells, Christine/0000-0003-3133-3628; Camper, Sally/0000-0001-8556-3379; Carninci, Piero/0000-0001-7202-7243; Konno, Hideaki/0000-0002-8470-4835 NR 64 TC 123 Z9 129 U1 1 U2 11 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD JUN PY 2003 VL 13 IS 6B BP 1273 EP 1289 DI 10.1101/gr.1119703 PG 17 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 692VK UT WOS:000183680800004 PM 12819125 ER PT J AU Schriml, LM Hill, DP Blake, JA Bono, H Wynshaw-Boris, A Pavan, WJ Ring, BZ Beisel, K Setou, M Okazaki, Y AF Schriml, LM Hill, DP Blake, JA Bono, H Wynshaw-Boris, A Pavan, WJ Ring, BZ Beisel, K Setou, M Okazaki, Y CA RIKEN GER Grp GSL Members TI Human disease genes and their cloned mouse orthologs: Exploration of the FANTOM2 cDNA sequence data set SO GENOME RESEARCH LA English DT Article ID GLUCOSEPHOSPHATE ISOMERASE; FUNCTIONAL ANNOTATION; VARIANTS AB The FANTOM2 cDNA sequence data set is an excellent model to demonstrate the power of large-scale cDNA sequencing, with the goal of providing a full-length transcript sequence for each mouse gene. This data set enhances the use of the mouse as a model for human disease. Here we identify mouse cDNA sequences in the FANTOM2 data set for a set of 67 human disease genes that as of May 2002 had no corresponding mouse cDNA annotated in the. Mouse Genome Informatics (MGI) database. These 67 human disease genes include genes related to neurological and eye disorders and cancer. We also present a list of the human disease genes and their cloned mouse orthologs found in two public databases, LocusLink and MGI. Allelic variant and gene functional information available in MGI provides additional information relative to these mouse models, whereas computed sequence-based connections at NCBl support facile navigation through multiple genomes. C1 NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Jackson Lab, Bar Harbor, ME 04609 USA. RIKEN, Yokohama Inst, GSC, Lab Genome Explorat Res Grp,Tsurumi Ku, Kanagawa 2300045, Japan. Univ Calif San Diego, Sch Med, Dept Pediat, San Diego, CA 92103 USA. Univ Calif San Diego, Sch Med, Dept Med, San Diego, CA 92103 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Appl Genom Inc, Sunnyvale, CA 94085 USA. Boys Town Natl Res Hosp, Dept Genet, Omaha, NE 68131 USA. Univ Tokyo, Grad Sch Med, Bunkyo Ku, Tokyo 1130033, Japan. RIKEN, Genome Sci Lab, Wako, Saitama 3510198, Japan. RP Schriml, LM (reprint author), NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. OI Schriml, Lynn/0000-0001-8910-9851; Blake, Judith/0000-0001-8522-334X; Bono, Hidemasa/0000-0003-4413-0651 FU NHGRI NIH HHS [P41 HG002273, HG002273, P40 HG00330, P41 HG000330, R01 HG002273, U41 HG002273]; NICHD NIH HHS [HD33745, R01 HD033745] NR 14 TC 4 Z9 4 U1 0 U2 3 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD JUN PY 2003 VL 13 IS 6B BP 1496 EP 1500 DI 10.1101/gr.979503 PG 5 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 692VK UT WOS:000183680800027 PM 12819148 ER PT J AU Baldarelli, RM Hill, DP Blake, JA Adachi, J Furuno, M Bradt, D Corbani, LE Cousins, S Frazer, KS Qi, D Yang, LL Ramachandran, S Reed, D Zhu, YX Kasukawa, T Ringwald, M King, BL Maltais, LJ McKenzie, LM Schriml, LM Maglott, D Church, DM Pruitt, K Eppig, JT Richardson, JE Kadin, JA Bult, CJ AF Baldarelli, RM Hill, DP Blake, JA Adachi, J Furuno, M Bradt, D Corbani, LE Cousins, S Frazer, KS Qi, D Yang, LL Ramachandran, S Reed, D Zhu, YX Kasukawa, T Ringwald, M King, BL Maltais, LJ McKenzie, LM Schriml, LM Maglott, D Church, DM Pruitt, K Eppig, JT Richardson, JE Kadin, JA Bult, CJ TI Connecting sequence and biology in the laboratory mouse SO GENOME RESEARCH LA English DT Article ID FUNCTIONAL ANNOTATION; GENE; GENOME; DATABASE; NOMENCLATURE; COLLECTION; GUIDELINES; MUTATION C1 Jackson Lab, Mouse Genome Informat Grp, Bar Harbor, ME 04609 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RIKEN, Yokohama Inst, GSC, Lab Genome Explorat Res Grp,Tsurumi Ku, Kanagawa 2300045, Japan. Univ Oregon, Zebrafish Int Resource Ctr, ZFIN, Eugene, OR 97403 USA. RP Baldarelli, RM (reprint author), Jackson Lab, Mouse Genome Informat Grp, 600 Main St, Bar Harbor, ME 04609 USA. EM rmb@informatics.jax.org RI Kasukawa, Takeya/N-5070-2015; OI Kasukawa, Takeya/0000-0001-5085-0802; Schriml, Lynn/0000-0001-8910-9851; Blake, Judith/0000-0001-8522-334X; King, Benjamin/0000-0001-6463-1336 FU NHGRI NIH HHS [HG-00330, P41 HG000330, P41 HG002273, R01 HG002273, U41 HG002273, HG-002273]; NICHD NIH HHS [HD-33745, R01 HD033745] NR 18 TC 12 Z9 12 U1 0 U2 1 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 JUN PY 2003 VL 13 IS 6B BP 1505 EP 1519 DI 10.1101/gr.991003 PG 15 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 692VK UT WOS:000183680800029 PM 12819150 ER PT J AU Kasukawa, T Furuno, M Nikaido, I Bono, H Hume, DA Bult, C Hill, DP Baldarelli, R Gough, J Kanapin, A Matsuda, H Schriml, LM Hayashizaki, Y Okazaki, Y Quackenbush, J AF Kasukawa, T Furuno, M Nikaido, I Bono, H Hume, DA Bult, C Hill, DP Baldarelli, R Gough, J Kanapin, A Matsuda, H Schriml, LM Hayashizaki, Y Okazaki, Y Quackenbush, J TI Development and evaluation of an automated annotation pipeline and cDNA annotation system SO GENOME RESEARCH LA English DT Article ID FUNCTIONAL ANNOTATION; DATABASE; SEQUENCES; RESOURCE; MOUSE; PROTEINS; TOOL AB Manual curation has long been held to be the "gold standard" for functional annotation of DNA sequence. Our experience with the annotation of more than 20,000 full-length cDNA sequences revealed problems with this approach, including inaccurate and inconsistent assignment of gene names, as well as many good assignments that were difficult to reproduce using only computational methods. For the FANTOM2 annotation of more than 60,000 cDNA clones, we developed a number of methods and tools to circumvent some of these problems, including an automated annotation pipeline that provides high-quality preliminary annotation for each sequence by introducing an "uninformative filter" that eliminates uninformative annotations, controlled vocabularies to accurately reflect both the functional assignments and the evidence supporting them, and a highly refined, Web-based manual annotation tool that allows users to view a wide array of sequence analyses and to assign gene names and putative functions using a consistent nomenclature. The ultimate utility of our approach is reflected in the low rate of reassignment of automated assignments by manual curation. Based on these results, we propose a new standard for large-scale annotation, in which the initial automated annotations are manually investigated and then computational methods are iteratively modified and improved based on the results of manual curation. C1 Inst Genom Res, Rockville, MD 20850 USA. RIKEN, Yokohama Inst, GSC, Lab Genome Explorat,Tsurumi Ku, Kanagawa 2300045, Japan. NTT Software Corp, Adv Technol Dev Dept, Multimedia Dev Ctr, Kanagawa 2318554, Japan. Univ Queensland, Inst Mol Biosci, ARC Special Res Ctr Funct & Appl Genom, Brisbane, Qld 4072, Australia. Jackson Lab, Mouse Genome Informat Grp, Bar Harbor, ME 04609 USA. MRC, Mol Biol Lab, Cambridge CB2 2QH, England. European Bioinformat Inst, Cambridge CB10 1SD, England. Osaka Univ, Grad Sch Informat Sci & Technol, Toyonaka, Osaka 5608531, Japan. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. RIKEN, Genome Sci Lab, Wako, Saitama 3510198, Japan. RP Quackenbush, J (reprint author), Inst Genom Res, Rockville, MD 20850 USA. RI Hume, David/C-7695-2013; Kanapin, Alexander/E-7632-2013; NIKAIDO, Itoshi/K-2058-2014; Kasukawa, Takeya/N-5070-2015; Kanapin, Alexander/Q-7590-2016 OI Schriml, Lynn/0000-0001-8910-9851; Bono, Hidemasa/0000-0003-4413-0651; NIKAIDO, Itoshi/0000-0002-7261-2570; Kasukawa, Takeya/0000-0001-5085-0802; Kanapin, Alexander/0000-0001-9802-5297 FU NHGRI NIH HHS [U41 HG002273, HG-002273, HG-00330, P41 HG000330, P41 HG002273, R01 HG002273]; NICHD NIH HHS [HD-33745, R01 HD033745] NR 20 TC 22 Z9 22 U1 0 U2 3 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD JUN PY 2003 VL 13 IS 6B BP 1542 EP 1551 DI 10.1101/gr.992803 PG 10 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 692VK UT WOS:000183680800032 PM 12819153 ER PT J AU Hirsh-Yechezkel, G Chetrit, A Lubin, F Friedman, E Peretz, T Gershoni, R Rizel, S Struewing, JP Modan, B AF Hirsh-Yechezkel, G Chetrit, A Lubin, F Friedman, E Peretz, T Gershoni, R Rizel, S Struewing, JP Modan, B TI Population attributes affecting the prevalence of BRCA mutation carriers in epithelial ovarian cancer cases in Israel SO GYNECOLOGIC ONCOLOGY LA English DT Article DE ovarian cancer; BRCA carriers; Israeli population ID BREAST-CANCER; JEWISH WOMEN; 185DELAG MUTATION; ASHKENAZI JEWS; HIGH-FREQUENCY; FAMILIES; RISK AB Objective. The objective was to evaluate the prevalence of BRCA1/2 mutations in selected categories of ovarian cancer patients in Israel. Methods. Blood samples and specimens of ovarian tumors were obtained in the course of a national case control study of women with ovarian cancer in Israel. Eight hundred ninety-six patients with epithelial ovarian cancer, 40 cases with nonepithelial ovarian cancer, and 68 with primary peritoneal cancer were tested for the BRCA mutations. Analysis of the three common BRCA mutations in Israel (185delAG, 5382insC in BRCA1, and 6174delT in BRCA2) was done using a multiplex polymerase chain reaction assay. A multivariate logistic regression model was used to assess the association of mutation carrier status and other factors (age, origin, family history, and clinical variables). Results. Of the 779 invasive epithelial ovarian cancer cases, 29.4% were mutation carriers. The prevalence of the mutations was higher among women below age 60 and in more advanced cases. The prevalence was low in mucinous tumors. There was almost a twofold excess of mutations among women with positive family history (45.7%), but still 26.5% of the family history negative cases were carriers. As expected, we found a higher rate of mutation carriers among the Ashkenazi group (34.2%) and 55% among Ashkenazi women with positive family history. No subjects born in North Africa were mutation positive. Conclusion. BRCA mutations are strongly associated with ovarian cancer and they are present in variable rates in distinct age, ethnic, and histopathologic categories. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Chaim Sheba Med Ctr, Gertner Inst Epidemiol & Hlth Policy Res, Canc Epidemiol Unit, IL-52621 Tel Hashomer, Israel. Chaim Sheba Med Ctr, Oncogenet Unit, Tel Hashomer, Israel. Hadassah Univ Hosp, Oncol Unit, IL-91120 Jerusalem, Israel. Rambam Med Ctr, Genet Unit, Haifa, Israel. Rabin Med Ctr, Oncol Unit, Petah Tiqwa, Israel. Natl Canc Inst, Lab Populat Genet, Bethesda, MD USA. Tel Aviv Univ, Sackler Sch Med, Stanley Steyer Inst Canc Res, IL-69978 Tel Aviv, Israel. RP Hirsh-Yechezkel, G (reprint author), Chaim Sheba Med Ctr, Gertner Inst Epidemiol & Hlth Policy Res, Canc Epidemiol Unit, IL-52621 Tel Hashomer, Israel. RI Struewing, Jeffery/C-3221-2008; Struewing, Jeffery/I-7502-2013 OI Struewing, Jeffery/0000-0002-4848-3334 FU NCI NIH HHS [CA 61126-03] NR 17 TC 31 Z9 31 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD JUN PY 2003 VL 89 IS 3 BP 494 EP 498 DI 10.1016/S0090-8258(03)00152-5 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 692WB UT WOS:000183682300025 PM 12798717 ER PT J AU Simon, SL Baverstock, KF Lindholm, C AF Simon, SL Baverstock, KF Lindholm, C TI A summary of evidence on radiation exposures received near to the Semipalatinsk nuclear weapons test site in Kazakhstan SO HEALTH PHYSICS LA English DT Article DE radiation dose; biokinetics; fallout; nuclear weapons ID CHROMOSOME-ABERRATIONS; DOSE RECONSTRUCTION; IONIZING-RADIATION; FOLLOW-UP; DOSIMETRY; ACCIDENT; HYBRIDIZATION; IRRADIATION; LYMPHOCYTES; STABILITY AB The presently available evidence about the magnitude of doses received by members of the public living in villages in the vicinity of Semipalatinsk nuclear test in Kazakhstan, particularly with respect to external radiation, while preliminary, is conflicting. The village of Dolon, in particular, has been identified for many years as the most highly exposed location in the vicinity of the test site. Previous publications cited external doses of more than 2 Gy to residents of Dolon while an expert group assembled by the WHO in 1997 estimated that external doses were likely to have been less than 0.5 Gy. In 2001, a larger expert group workshop was held in Helsinki jointly by the WHO, the National Cancer Institute of the United States, and the Radiation and Nuclear Safety Authority of Finland, with the expressed purpose to acquire data to evaluate the state of knowledge concerning doses received in Kazakhstan. This paper summarizes evidence presented at that workshop. External dose estimates from calculations based on sparse physical measurements and biodosimetric estimates based on chromosome abnormalities and electron paramagnetic resonance from a relatively small sample of teeth do not agree well. The physical dose estimates are generally higher than the biodosimetric estimates (1 Gy or more compared to 0.5 Gy or less). When viewed in its entirety, the present body of evidence does not appear to support external doses greater than 0.5 Gy; however, research is continuing to try and resolve the difference in dose estimates from the different methods. Thyroid doses from internal irradiation, which can only be estimated via calculation, are expected to have been several times greater than the doses from external irradiation, especially where received by small children. C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. WHO, Reg Off Europe, Bonn, Germany. STUK, Radiat & Nucl Safety Author, Helsinki, Finland. RP Simon, SL (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,MSC 7238,Execut Plaza S,Room 708, Bethesda, MD 20892 USA. EM ssimon@mail.nih.gov NR 40 TC 23 Z9 26 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD JUN PY 2003 VL 84 IS 6 BP 718 EP 725 DI 10.1097/00004032-200306000-00004 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 682XL UT WOS:000183117600004 PM 12822581 ER EF