FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Bacharach, SL AF Bacharach, SL TI The new-generation positron emission tomography/computed tomography scanners: Implications for cardiac imaging SO JOURNAL OF NUCLEAR CARDIOLOGY LA English DT Editorial Material ID CT ATTENUATION CORRECTION; PET-CT; ORAL CONTRAST; EJECTION FRACTION; VENTRICULAR VOLUMES; RESPIRATORY MOTION; MAGNETIC-RESONANCE; FDG PET; REGISTRATION; IMAGES C1 NIH, Dept Nucl Med, Bethesda, MD 20892 USA. RP Bacharach, SL (reprint author), NIH, Dept Nucl Med, Bldg 10,Room 1C401, Bethesda, MD 20892 USA. EM steve-bacharach@nih.gov NR 48 TC 2 Z9 2 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 1071-3581 J9 J NUCL CARDIOL JI J. Nucl. Cardiol. PD JUL-AUG PY 2004 VL 11 IS 4 BP 388 EP 392 DI 10.1016/j.nuclcard.2004.04.008 PG 5 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 845BI UT WOS:000223210200004 PM 15295407 ER PT J AU Kart, AK Graubard, BI Schatzkin, A AF Kart, AK Graubard, BI Schatzkin, A TI Dietary patterns predict mortality in a national cohort: The National Health Interview Surveys, 1987 and 1992 SO JOURNAL OF NUTRITION LA English DT Article DE dietary patterns; diet quality; factor analysis; cluster analysis; NHIS; all-cause mortality ID MAJOR CHRONIC DISEASE; FOOD FREQUENCY QUESTIONNAIRE; GUIDELINES-FOR-AMERICANS; ELDERLY PEOPLE; EPIC-POTSDAM; WOMEN; QUALITY; RISK; SURVIVAL; MEN AB We examined the association of mortality and dietary patterns using data from the National Health Interview Surveys of 1987 and 1992 (n = 10,084), aged greater than or equal to 45 y at baseline (with 2287 deaths due to all causes over 5.9 median years of follow-up). The similar to 60-item FFQ administered at baseline was examined for mentions of foods and dietary behaviors recommended in current dietary guidance (fruits, vegetables, lean poultry and alternates, low-fat dairy, and whole grains), and the resulting patterns were expressed as follows: 1) a Recommended Foods and Behavior Score (RFBS), 2) factor scores from factor analysis, and 3) clusters from cluster analysis. The multivariate-adjusted relative risk (RR) of mortality for each of the 3 types of dietary patterns was examined using Cox proportional hazards regression analysis. In men, FIR of all-cause mortality was 0.72 (95% CI: 0.56, 0.92, P for trend < 0.001) for RFBS, and 0.74 (95% CI: 0,57, 0.95, P for trend = 0.002) for the fruit-vegetable-whole grain factor score when comparing extreme quartiles. Membership in 1 of the 4 clusters also was associated with lower risk in men (RR = 0.82, 95% CI: 0.66, 1.01). For women, the RFBS was a modest inverse predictor of mortality after multivariate adjustment (RR = 0.80, 95% CI: 0.61, 1.04, P for trend = 0.04), but estimates for factor and cluster patterns were attenuated. The population-attributable fraction due to diet was 0.16 in men and 0.09 in women. Dietary patterns characterized by compliance with prevailing food-based dietary guidance were associated with a lower risk of all-cause mortality. C1 CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Flushing, NY 11367 USA. NCI, Div Canc Epidemiol & Genet, Biostat Branch, NIH, Bethesda, MD USA. NCI, Div Canc Epidemiol & Genet, Nutrit Expidemiol Branch, NIH, Bethesda, MD USA. RP Kart, AK (reprint author), CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Flushing, NY 11367 USA. EM akant@qc.edu NR 42 TC 2 Z9 2 U1 0 U2 7 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD JUL PY 2004 VL 134 IS 7 BP 1793 EP 1799 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 836UP UT WOS:000222581600020 ER PT J AU Freedman, LS Midthune, D Carroll, RJ Krebs-Smith, S Subar, AF Troiano, RP Dodd, K Schatzkin, A Ferrari, P Kipnis, V AF Freedman, LS Midthune, D Carroll, RJ Krebs-Smith, S Subar, AF Troiano, RP Dodd, K Schatzkin, A Ferrari, P Kipnis, V TI Adjustments to improve the estimation of usual dietary intake distributions in the population SO JOURNAL OF NUTRITION LA English DT Article DE biological markers; energy intake; nutrition assessment; questionnaires; reference values; underreporting; surveillance ID FOOD-FREQUENCY QUESTIONNAIRES; DOUBLY LABELED WATER; LOW-ENERGY REPORTERS; MEASUREMENT ERROR; POTASSIUM INTAKE; NUTRIENT INTAKE; BALANCE; ADULTS; WOMEN; EXPENDITURE AB We reexamined the current practice in estimating the distribution of usual dietary nutrient intakes from population surveys when using self-report dietary instruments, particularly the 24-h recall (24HR), in light of the new data from the Observing Protein and Energy Nutrition Study. In this study, reference biomarkers for energy (doubly labeled water) and protein [urinary nitrogen (UN)], together with multiple FFQs and 24HRs, were administered to 484 healthy volunteers. By using the reference biomarkers to estimate the distributions for energy and protein, the data confirmed previous reports that FFQs generally do not give an accurate impression of the distribution of usual dietary intake. The traditional method applied to 24HRs performed poorly because of underestimating the mean and overestimating the SD of the usual energy and protein intake distributions, and, although the National Research Council and the Iowa State University methods generally give better estimates of the shape of the distribution, they did not improve the estimates of the mean (10-15% underestimation for energy and 6-7% underestimation for protein). Results for urinary potassium, a putative biomarker for potassium intake, and reported potassium intake did not display this underestimation and may reflect either differential underreporting of foods or inadequacy of the potassium biomarker. A large controlled feeding study is required to validate conclusively the potassium biomarker. For energy intake, adjusting its 24HR-based distribution by using the UN biomarker appeared to capture the usual intake distribution quite accurately. Incorporating UN assessments into nutritional surveys, therefore, deserves serious consideration. C1 NCI, Biometry Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. Bar Ilan Univ, Dept Math Stat & Comp Sci, Ramat Gan, Israel. Gertner Inst Epidemiol & Hlth Policy Res, Tel Hashomer, Israel. Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Int Agcy Res Canc, F-69372 Lyon, France. RP Kipnis, V (reprint author), NCI, Biometry Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. EM victor_kipnis@nih.gov OI Troiano, Richard/0000-0002-6807-989X FU NCI NIH HHS [CA-57030]; NIEHS NIH HHS [ES-09106] NR 49 TC 48 Z9 51 U1 0 U2 6 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD JUL PY 2004 VL 134 IS 7 BP 1836 EP 1843 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 836UP UT WOS:000222581600027 PM 15226478 ER PT J AU Ariga, T Nakajima, M Yoshida, J Yamato, K Nagatoshi, Y Yanai, F Caviles, AP Nelson, DL Sakiyama, Y AF Ariga, T Nakajima, M Yoshida, J Yamato, K Nagatoshi, Y Yanai, F Caviles, AP Nelson, DL Sakiyama, Y TI Confirming or excluding the diagnosis of Wiskott-Aldrich syndrome in children with thrombocytopenia of an unknown etiology SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE Wiskott-Aldrich syndrome; WASP; immune thrombocytopenic purpura; flow cytometry; molecular diagnosis ID FLOW-CYTOMETRIC ANALYSIS; PROTEIN EXPRESSION; CARRIER STATUS; GENE; TRANSPLANTATION; SPLENECTOMY; MUTATIONS; SIZE; WASP; RISK AB Early diagnosis is an important factor in a better prognosis in patients with Wiskott-Aldrich syndrome (WAS), but it is not always easy to distinguish between WAS and immune thrombocytopenic purpura on clinical grounds. To confirm or to exclude a WAS diagnosis promptly for children with thrombocytopenia, the authors performed flow cytometric screening of Wiskott-Aldrich syndrome protein (WASP) for 10 children with thrombocytopenia of an unknown etiology. Five children were diagnosed with WAS, and the remaining 5 were diagnosed as having non-WAS causes of thrombocytopenia. There were no ambiguous results, and these were confirmed by genetic analysis. The authors conclude that screening by flow cytometry for WASP is recommended for boys with persistent thrombocytopenia of an unknown etiology. C1 Hokkaido Univ, Grad Sch Med, Dept Human Gene Therapy, Kita Ku, Sapporo, Hokkaido 0608638, Japan. Osaka City Univ, Dept Pediat, Osaka 558, Japan. Kyushu Natl Canc Ctr, Sect Pediat, Fukuoka, Japan. Fukuoka Univ, Sch Med, Dept Pediat, Fukuoka 81401, Japan. Fdn Philippines, Dr Fe del Mundo Ctr, Hematol Oncol Immunol Unit, Quezon City, Philippines. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Ariga, T (reprint author), Hokkaido Univ, Grad Sch Med, Dept Human Gene Therapy, Kita Ku, N-15 W-7, Sapporo, Hokkaido 0608638, Japan. EM tada-ari@med.hokudai.ac.jp RI Ariga, Tadashi/A-4252-2012 NR 22 TC 7 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-4114 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD JUL PY 2004 VL 26 IS 7 BP 435 EP 440 DI 10.1097/00043426-200407000-00007 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 843VC UT WOS:000223113700007 PM 15218418 ER PT J AU Liu, J Qu, W Saavedra, JE Waalkes, MP AF Liu, J Qu, W Saavedra, JE Waalkes, MP TI The nitric oxide donor, O-2-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO), protects against cadmium-induced hepatotoxicity in mice SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID NECROSIS-FACTOR-ALPHA; CHLORIDE-INDUCED HEPATOTOXICITY; INDUCED APOPTOSIS; NULL MICE; ISCHEMIA-REPERFUSION; LIVER-INJURY; METALLOTHIONEIN; TOXICITY; RATS; STRESS AB The nitric oxide (NO) donor, O-2-vinyl 1-(pyrrolidin-1-yl) diazen-1-ium-1,2-diolate (V-PYRRO/NO), is metabolized by P450 enzymes to release NO within the liver and is effective in protecting against hepatotoxicity of endotoxin and acetaminophen. This study examined the effects of V-PYRRO/NO on cadmium (Cd) hepatotoxicity in mice. Mice were given multiple injections of V-PYRRO/NO (10 mg/kg, s.c. at 2-h intervals) before and after a hepatotoxic dose of Cd (3.7 mg/kg Cd as CdCl2, i.p.). V-PYRRO/NO administration reduced Cd-induced hepatotoxicity as evidenced by reduced serum alanine aminotransferase activity, improved pathology, and reduced hepatic lipid peroxidation. The protection by V-PYRRO/NO was not mediated by altered Cd distribution to the liver or within hepatic subcellular fractions. Similar inductions of metallothionein, a metal-binding protein, were observed in mice receiving Cd alone or Cd plus V-PYRRO/NO. Real-time reverse transcription-polymerase chain reaction analysis revealed that V-PYRRO/NO administration suppressed the expression of inflammation-related genes such as macrophage inflammatory protein-2, CXC chemokine, thrombospondin-1, intracellular adhesion molecular-1, and interleukin-6. V-PYRRO/NO also suppressed the expression of acute phase protein genes and genes related to cell-death pathways, such as c-jun/AP-1, nuclear factor-kappaB, early response growth factor-1, heme oxygenase-1, caspase-3, growth arrest, and DNA-damaging protein-153. In summary, the liver-selective NO donor, V-PYRRO/NO, protects against Cd hepatotoxicity in mice. This protection is not mediated through altered distribution of Cd but may be related to reduced hepatic inflammation, reduced acute phase responses, and the suppression of cell-death-related components. C1 NIEHS, Inorgan Carcinogenesis Sect, Lab Comparat Carcinogenesis, NCI, Res Triangle Pk, NC 27709 USA. NCI, Sci Applicat Int Corp Frederick, Frederick, MD 21701 USA. RP Waalkes, MP (reprint author), NIEHS, Inorgan Carcinogenesis Sect, Lab Comparat Carcinogenesis, NCI, Mail Drop F0-09, Res Triangle Pk, NC 27709 USA. EM Waalkes@niehs.nih.gov FU NCI NIH HHS [N01-CO-12400] NR 38 TC 29 Z9 30 U1 1 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUL 1 PY 2004 VL 310 IS 1 BP 18 EP 24 DI 10.1124/jpet.103.065003 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 830QR UT WOS:000222138300003 PM 15010501 ER PT J AU Reddy, DS Castaneda, DC O'Malley, BW Rogawski, MA AF Reddy, DS Castaneda, DC O'Malley, BW Rogawski, MA TI Anticonvulsant activity of progesterone and neurosteroids in progesterone receptor knockout mice SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID NEUROACTIVE STEROIDS; SEXUAL RECEPTIVITY; GABA(A) RECEPTORS; SEIZURE ACTIVITY; ICTAL ACTIVITY; KAINIC ACID; RAT-BRAIN; GENE; ESTROGEN; EPILEPSY AB Many of the biological actions of progesterone are mediated through the progesterone receptor (PR), a nuclear transcription factor. Progesterone is well recognized to protect against seizures in animal models. Although this activity has been attributed to the progesterone metabolite allopregnanolone, a GABA A receptor-modulating neurosteroid with anticonvulsant properties, PRs could also play a role. Here, we used PR knockout (PRKO-/-) mice bearing a targeted deletion of the PR gene that eliminates both isoforms of the PR to investigate the contribution of the PR to the anticonvulsant activity of progesterone. The protective activity of progesterone was examined in female and male homozygous PRKO mice and isogenic wild-type controls in the pentylenetetrazol (PTZ), maximal electroshock, and amygdala-kindling seizure models. In all three models, the anticonvulsant potency of progesterone was undiminished in PRKO mice compared with control mice. On the contrary, there was a substantial increase in the anticonvulsant potency of progesterone in the PTZ and kindling models. The antiseizure activity of progesterone in PRKO mice was reversed by pretreatment with finasteride, a 5alpha-reductase inhibitor that blocks the metabolism of progesterone to allopregnanolone. Unlike progesterone, the neurosteroids allopregnanolone and allotetrahydrodeoxycorticosterone exhibited comparable anticonvulsant potency in PRKO and wild-type mice. The basis for the heightened progesterone responsiveness of PRKO mice is not attributable to pharmacokinetic factors, because the plasma allopregnanolone levels achieved after progesterone administration were not greater in the PRKO mice. These studies provide strong evidence that the PR is not required for the antiseizure effects of progesterone, which mainly occurs through its conversion to the neurosteroid allopregnanolone. C1 N Carolina State Univ, Coll Vet Med, Dept Mol Biomed Sci, Raleigh, NC 27606 USA. Natl Inst Neurol Disorders & Stroke, Epilepsy Res Sect, NIH, Bethesda, MD USA. Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. RP Reddy, DS (reprint author), N Carolina State Univ, Coll Vet Med, Dept Mol Biomed Sci, 4700 Hillsborough St, Raleigh, NC 27606 USA. EM samba_reddy@ncsu.edu RI Rogawski, Michael/B-6353-2009; OI Rogawski, Michael/0000-0002-3296-8193; Reddy, Samba/0000-0003-2735-9550 FU NICHD NIH HHS [HD 07495, HD 07857] NR 64 TC 90 Z9 91 U1 0 U2 5 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUL 1 PY 2004 VL 310 IS 1 BP 230 EP 239 DI 10.1124/jpet.104.065268 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 830QR UT WOS:000222138300029 PM 14982969 ER PT J AU Knollmann, BC Casimiro, MC Katchman, AN Sirenko, SG Schober, T Rong, Q Pfeifer, K Ebert, SN AF Knollmann, BC Casimiro, MC Katchman, AN Sirenko, SG Schober, T Rong, Q Pfeifer, K Ebert, SN TI Isoproterenol exacerbates a long QT phenotype in Kcnq1-deficient neonatal mice: Possible roles for human-like Kcnq1 isoform 1 and slow delayed rectifier K+ current SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID LANGE-NIELSEN-SYNDROME; CURRENT I-KS; POTASSIUM CHANNEL; MOUSE HEART; DEVELOPMENTAL-CHANGES; TARGETED DISRUPTION; GENE; EXPRESSION; KVLQT1; REPOLARIZATION AB To determine whether the neonatal mouse can serve as a useful model for studying the molecular pharmacological basis of Long QT Syndrome Type 1 (LQT1), which has been linked to mutations in the human KCNQ1 gene, we measured QT intervals from electrocardiogram (ECG) recordings of wild-type (WT) and Kcnq1 knockout (KO) neonates before and after injection with the beta-adrenergic receptor agonist, isoproterenol (0.17 mg/kg, i.p.). Modest but significant increases in JT, QT, and rate-corrected QT (QTc) intervals were found in KO neonates relative to WT siblings during baseline ECG assessments (QTc = 57 +/- 3 ms, n = 22 versus 49 +/- 2 ms, n = 28, respectively, p < 0.05). Moreover, JT, QT, and QTc intervals significantly increased following isoproterenol challenge in the KO (p < 0.01) but not the WT group (p = 0.57). Furthermore, whole-cell patch-clamp recordings show that the slow delayed rectifier K+ current (I-Ks) was absent in KO but present in WT myocytes, where it was strongly enhanced by isoproterenol. This finding was confirmed by showing that the selective I-Ks inhibitor, L-735,821, blocked I-Ks and prolonged action potential duration in WT but not KO hearts. These data demonstrate that disruption of the Kcnq1 gene leads to loss of I-Ks, resulting in a long QT phenotype that is exacerbated by beta-adrenergic stimulation. This phenotype closely reflects that observed in human LQT1 patients, suggesting that the neonatal mouse serves as a valid model for this condition. This idea is further supported by new RNA data showing that there is a high degree of homology (>88% amino acid identity) between the predominant human and mouse cardiac Kcnq1 isoforms. C1 Georgetown Univ, Med Ctr, Dept Pharmacol, Washington, DC 20007 USA. NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Ebert, SN (reprint author), Georgetown Univ, Med Ctr, Dept Pharmacol, 3900 Reservoir Rd NW, Washington, DC 20007 USA. EM eberts@georgetown.edu OI Knollmann, Bjorn/0000-0003-4956-9735; Pfeifer, Karl/0000-0002-0254-682X FU NHLBI NIH HHS [HL071670, HL58743] NR 41 TC 11 Z9 12 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUL 1 PY 2004 VL 310 IS 1 BP 311 EP 318 DI 10.1124/jpet.103.063743 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 830QR UT WOS:000222138300038 PM 15004216 ER PT J AU Ferraris, JD Burg, MB AF Ferraris, JD Burg, MB TI Drying and salting send different messages SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Editorial Material ID RENAL MEDULLARY CELLS; EXPRESSION; NACL C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Ferraris, JD (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, 10 Ctr Dr,MSC 1603, Bethesda, MD 20892 USA. EM ferraris@nhlbi.nih.gov NR 8 TC 5 Z9 5 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD JUL 1 PY 2004 VL 558 IS 1 BP 3 EP 3 DI 10.1113/jphysiol.2004.068064 PG 1 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 840LH UT WOS:000222859600003 PM 15194735 ER PT J AU Blonder, J Rodriguez-Galan, MC Chan, KC Lucas, DA Yu, LR Conrads, TP Issaq, HJ Young, HA Veenstra, TD AF Blonder, J Rodriguez-Galan, MC Chan, KC Lucas, DA Yu, LR Conrads, TP Issaq, HJ Young, HA Veenstra, TD TI Analysis of murine natural killer cell microsomal proteins using two-dimensional liquid chromatography coupled to tandem electrospray ionization mass spectrometry SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE membrane proteins; large-scale membrane proteomics; solution-based multidimensional proteomic analysis ID MEMBRANE-PROTEINS; PROTEOMIC ANALYSIS; COMPLEX; PEPTIDES; TAP AB This study describes the application of a single tube sample preparation technique coupled with multidimensional fractionation for the analysis of a complex membrane protein sample from murine natural killer (NK) cells. A solution-based method that facilitates the solubilization and tryptic digestion of integral membrane proteins is conjoined with strong cation exchange (SCX) liquid chromatography (LC) fractionation followed by microcapillary reversed-phase (muRP) LC tandem mass spectrometric analysis of each SCXLC fraction in second dimension. Sonication in buffered methanol solution was employed to solubilize, and tryptically digest murine NK cell microsomal proteins, allowing for the large-scale identification of integral membrane proteins, including the mapping of the membrane-spanning peptides. Bioinformatic analysis of the acquired tandem mass spectra versus the murine genome database resulted in 11 967 matching tryptic peptide sequences, corresponding to 5782 unique peptide identifications. These peptides resulted in identification of 2563 proteins of which 876 (34%) are classified as membrane proteins. C1 SAIC Frederick Inc, Lab Proteom & Analyt Technol, NCI, Frederick, MD 21702 USA. NCI, Expt Immunol Lab, Frederick, MD 21702 USA. RP Veenstra, TD (reprint author), SAIC Frederick Inc, Lab Proteom & Analyt Technol, NCI, Frederick, MD 21702 USA. EM veenstra@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 17 TC 13 Z9 15 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD JUL-AUG PY 2004 VL 3 IS 4 BP 862 EP 870 DI 10.1021/pr049927e PG 9 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 846ME UT WOS:000223319000022 PM 15359742 ER PT J AU Lipska, BK AF Lipska, BK TI Using animal models to test a neurodevelopmental hypothesis of schizophrenia SO JOURNAL OF PSYCHIATRY & NEUROSCIENCE LA English DT Article DE antipsychotic agents; hippocampus; models, animal; neurons; nucleus accumbens; prefrontal cortex; schizophrenia ID NEONATAL HIPPOCAMPAL DAMAGE; MK-801-INDUCED MOTOR HYPERACTIVITY; RAT VENTRAL HIPPOCAMPUS; PREFRONTAL CORTEX; ADULT RATS; NUCLEUS-ACCUMBENS; IBOTENIC ACID; PREPULSE INHIBITION; ANTIPSYCHOTIC-DRUGS; DOPAMINE RESPONSE AB A series of studies has shown that neonatal excitotoxic disconnection of the rat ventral hippocampus may serve as a heuristic model of schizophrenia. The model mimics a spectrum of neurobiologic and behavioural features of schizophrenia. It produces functional pathology in critical brain regions implicated in schizophrenia and connected with the hippocampal formation, namely, the striatum, nucleus accumbens and the prefrontal cortex. These brain regions are also targeted by antipsychotic drugs. Neonatal insult leads in young adulthood to the emergence of abnormalities in a number of dopamine-related behaviours. It also models some of the negative aspects of schizophrenia, such as social impairments and working memory deficits. Moreover, our data show that even transient inactivation of the ventral hippocampus during a critical period of development that produces subtle anatomical changes in the hippocampus may be sufficient to trigger behavioural changes similar to those observed in animals with the permanent excitotoxic lesion. The results of bromodeoxyuridine (BrdU) incorporation studies show that this transient disconnection in the CA1 and CA2 area of the hippocampus may have long-lasting consequences for neurogenesis in the dentate gyrus. Our data suggest that neonatal disconnection of the ventral hippocampus alters development and plasticity of prefrontal cortical circuitry and produces a constellation of behavioural and cellular changes that mimic many aspects of schizophrenia. The neonatal hippocampal disconnection model represents a potential new model of schizophrenia without a gross anatomical lesion. C1 NIMH, Clin Brain Disorders Branch, Intramural Res Program, Bethesda, MD 20892 USA. RP Lipska, BK (reprint author), 10 Ctr Dr,Bldg 10,Rm 4N306, Bethesda, MD 20892 USA. EM lipskab@intra.nimh.nih.gov RI Lipska, Barbara/E-4569-2017 NR 52 TC 162 Z9 168 U1 0 U2 3 PU CANADIAN MEDICAL ASSOCIATION PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 3Y6, CANADA SN 1180-4882 J9 J PSYCHIATR NEUROSCI JI J. Psychiatry Neurosci. PD JUL PY 2004 VL 29 IS 4 BP 282 EP 286 PG 5 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 838GT UT WOS:000222702200004 PM 15309044 ER PT J AU Perlman, WR Weickert, CS Akil, M Kleinman, JE AF Perlman, WR Weickert, CS Akil, M Kleinman, JE TI Postmortem investigations of the pathophysiology of schizophrenia: the role of susceptibility genes SO JOURNAL OF PSYCHIATRY & NEUROSCIENCE LA English DT Article DE brain-derived neurotrophic factor; catechol-O-methyltransferase; dopamine; genetic predisposition to disease; glutamate; prefrontal cortex; schizophrenia; substantia nigra; tyrosine hydroxylase ID DORSOLATERAL PREFRONTAL CORTEX; NEUROTROPHIC FACTOR BDNF; CEREBRAL BLOOD-FLOW; MESSENGER-RNA EXPRESSION; MONOZYGOTIC TWINS DISCORDANT; DENDRITIC SPINE DENSITY; VENTRAL TEGMENTAL AREA; POSTNATAL RAT-BRAIN; PHYSIOLOGICAL DYSFUNCTION; WORKING-MEMORY AB Despite robust evidence for the heritability of schizophrenia, postmortem studies have not traditionally linked cellular and molecular neuropathology with underlying genetic mechanisms in this disorder. The completion of the first draft of the Human Genome Project and the use of novel strategies in studying complex genetic disorders including schizophrenia have led to the identification of a growing list of schizophrenia susceptibility genes. In this review, we describe the strategy used to incorporate 2 potential schizophrenia susceptibility genes in the postmortem investigation of the pathophysiology of schizophrenia driven by 2 well-established hypotheses, the dopamine hypothesis and the neurodevelopmental hypothesis. The first gene codes for catecho1-O-methyltransferase, an enzyme involved in catecholamine degradation, and the second gene codes for brain-derived neurotrophic factor, a growth factor implicated in cell survival, synaptogenesis and the development of cortical pyramidal neurons. C1 NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Kleinman, JE (reprint author), NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,US Dept HHS, 10 Ctr Dr,Rm 4S237A, Bethesda, MD 20892 USA. EM kleinmaj@intra.nimh.nih.gov RI Shannon Weickert, Cynthia/G-3171-2011 NR 109 TC 11 Z9 11 U1 0 U2 1 PU CANADIAN MEDICAL ASSOCIATION PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 3Y6, CANADA SN 1180-4882 J9 J PSYCHIATR NEUROSCI JI J. Psychiatry Neurosci. PD JUL PY 2004 VL 29 IS 4 BP 287 EP 293 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 838GT UT WOS:000222702200005 PM 15309045 ER PT J AU Hwang, KC Lim, S Kwon, HM Bae, YS Kang, SM Chung, KH Graham, RM Rhee, SG Jang, Y AF Hwang, KC Lim, S Kwon, HM Bae, YS Kang, SM Chung, KH Graham, RM Rhee, SG Jang, Y TI Phospholipase C-delta 1 rescues intracellular Ca2+ overload in ischemic heart and hypoxic neonatal cardiomyocytes SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE phospholipase C-delta 1; ischemic heart; hypoxic neonatal cardiomyocytes ID RAT CARDIAC MYOCYTES; MYOCARDIAL-ISCHEMIA; PROTEIN-KINASES; EXPRESSION; APOPTOSIS; CALCIUM; MECHANISMS; GTP AB Ischemia and simulated ischemic conditions cause intracellular Ca2+ overload in the myocardium. The relationship between ischemia injury and Ca2+ overload has not been fully characterized. The aim of the present study was to investigate the expression and characteristics of PLC isozymes in myocardial infarction- induced cardiac remodeling and heart failure. In normal rat heart tissue, PLC-delta1 (about 44 ng/mg of heart tissue) was most abundant isozymes compared to PLC-gamma1 (6.8 ng/mg) and PLC-beta1 (0.4 ng/mg). In ischemic heart and hypoxic neonatal cardiomyocytes, PLC-delta1, but not PLC-beta1 and PLC-gamma1, was selectively degraded, a response that could be inhibited by the calpain inhibitor, calpastatin, and by the caspase inhibitor, zVAD-fmk. Overexpression of the PLC-delta1 in hypoxic neonatal cardiomyocytes rescued intracellular Ca2+ overload by ischemic conditions. In the border zone and scar region of infarcted myocardium, and in hypoxic neonatal cardiomyocytes, the selective degradation of PLC-delta1 by the calcium sensitive proteases may play important roles in intracellular Ca2+ regulations under the ischemic conditions. It is suggested that PLC isozyme-changes may contribute to the alterations in calcium homeostasis in myocardial ischemia. (C) 2004 Elsevier Ltd. All rights reserved. C1 Yonsei Univ, Coll Med, Inst Cardiovasc Res, Dept Internal Med, Seoul 120752, South Korea. Yonsei Univ, Coll Med, Dept Internal Med, Project Med Sci BK21, Seoul 120752, South Korea. Yonsei Univ, Coll Med, Dept Internal Med, Div Cardiol, Seoul 120752, South Korea. Ewha Womans Univ, Ctr Cell Signaling Res, Seoul 120750, South Korea. Ewha Womans Univ, Dept Biol Sci, Seoul 120750, South Korea. Victor Chang Cardiac Res Inst, Mol Cardiol Unit, Darlinghurst, NSW 2010, Australia. NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. RP Jang, Y (reprint author), Yonsei Univ, Coll Med, Inst Cardiovasc Res, Dept Internal Med, Seoul 120752, South Korea. EM jangys1212@yumc.yonsei.ac.kr NR 27 TC 21 Z9 21 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD JUL PY 2004 VL 91 IS 3 BP 131 EP 138 DI 10.1016/j.jsbmb.2004.02.009 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 847UE UT WOS:000223419600004 PM 15276620 ER PT J AU Dawson, DA Grant, BF Stinson, FS Chou, PS AF Dawson, DA Grant, BF Stinson, FS Chou, PS TI Another look at heavy episodic drinking and alcohol use disorders among college and noncollege youth SO JOURNAL OF STUDIES ON ALCOHOL LA English DT Article ID INTERVIEW SCHEDULE AUDADIS; GENERAL-POPULATION SAMPLE; BINGE-DRINKING; PREVENTION EFFORTS; STUDENTS; RELIABILITY; DEPENDENCE; ABUSE; IV; CONSUMPTION AB Objective: To estimate rates of heavy episodic drinking, alcohol abuse and alcohol dependence among U.S. adults 18-29 years of age and determine the relationship of these rates to student status and residence. Method: The analysis is based on data from a subsample of U.S. adults 18-29 years of age (N = 8,666; 4,849 female) who were interviewed as part of the 2001-02 National Epidemiologic Survey on Alcohol and Related Conditions (N = 43,093). Data were collected in personal interviews from a representative sample of adults 18 and older, living in households and selected group quarters in the United States, including Alaska, Hawaii and the District of Columbia. Results: Of all adults 18-29 years of age, 73.1% reported any drinking in the past year, 39.6% reported any heavy episodic drinking, 21.1% reported heavy drinking more than once a month and 11.0% reported heavy drinking more than once a week. Among past-year drinkers, these correspond to rates of 54.3% for any heavy episodic drinking, 28.9% for heavy drinking more than once a month and 15.0% for heavy drinking more than once a week. Although rates of heavy episodic drinking were slightly higher for college students than for noncollege students (p < .01), differences according to place of residence were greater than differences according to student status. Overall, 7.0% of adults ages 18-29 met the DSM-IV criteria for alcohol abuse in the past year, and 9.2% met the criteria for alcohol dependence. The prevalence of abuse was highest among students living off campus (p < .01), and rates of dependence were highest among students living on campus (p < .01). Conclusions: Heavy episodic drinking and alcohol use disorders are youth as well as college phenomena. Prevention campaigns targeted at all youth are needed to supplement interventions conducted at the campus level. C1 NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Dawson, DA (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH,US Dept Hlth & Human Serv, 5635 Fishers Lane,Room 3083,MSC 9304, Bethesda, MD 20892 USA. EM ddawson@willco.niaaa.nih.gov NR 33 TC 240 Z9 241 U1 5 U2 24 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 0096-882X J9 J STUD ALCOHOL JI J. Stud. Alcohol PD JUL PY 2004 VL 65 IS 4 BP 477 EP 488 PG 12 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 847OY UT WOS:000223406000010 PM 15378804 ER PT J AU Forman, RF Svikis, D Montoya, ID Blaine, J AF Forman, RF Svikis, D Montoya, ID Blaine, J TI Selection of a substance use disorder diagnostic instrument by the National Drug Abuse Treatment Clinical Trials Network SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE substance use disorder; assessment; diagnosis; clinical trials ID CARBOHYDRATE-DEFICIENT TRANSFERRIN; INTERVIEW SCHEDULE DIAGNOSES; SEVERITY SCALE SDSS; PREDICTIVE-VALIDITY; GENERAL-POPULATION; AUDADIS-ADR; RELIABILITY; ALCOHOL; CRITERIA; CIDI AB Several instruments for diagnosing substance use disorders (SUD) have been developed, but to date none has emerged as the standard for community-based clinical studies. To select the most suitable SUD diagnostic instrument for its clinical trials, the National Drug Abuse Treatment Clinical Trials Network (CTN) implemented a procedure in which 36 university-based addiction researchers and 62 community-based addiction treatment providers evaluated and ranked five widely recognized diagnostic instruments: (1) the SUD section of the Structured Clinical Interview for DSM-lV (SCID); (2) the SUD section of the Composite International Diagnostic Interview, 2nd ed. (CIDI-2); (3) the SUD section of the Diagnostic Interview Schedule for DSM-IV Diagnosis (DIS-IV); (4) the Diagnostic Statistical Manual-IV Checklist (DSM-IV Checklist); and (5) the Substance Dependence Severity Scale (SDSS). To assist the evaluation and ranking process, key characteristics of each instrument were presented in tabular and narrative formats. Participants ranked each instrument from I (most preferred) to 5 (least preferred). The SCID received the best overall mean score (2.24) followed by the CIDI-2 (2.59), DIS (2.94), DSM Checklist (3.40) and the SDSS (3.83). After discussing the pragmatic and scientific advantages and disadvantages of each instrument, the CTN Steering Committee selected the CIDI-2. The selection of the CIDI-2 standardizes the collection of diagnostic data and provides a common diagnostic tool for practitioners and clinical researchers in the CTN. Implications for practice/research collaboration and initiatives are explored. (C) 2004 Elsevier Inc. All rights reserved. C1 Treatment Res Inst, Philadelphia, PA USA. Univ Penn, Ctr Studies Addict, Philadelphia, PA 19104 USA. Virginia Commonwealth Univ, Med Coll Virginia, Richmond, VA 23298 USA. NIDA, Div Treatment Res & Dev, Rockville, MD USA. BRCI, Ann Arbor, MI USA. RP Forman, RF (reprint author), Treatment Res Inst, Philadelphia, PA USA. EM bforman@tresearch.org FU Intramural NIH HHS [Z99 DA999999]; NIDA NIH HHS [5 U10 DA 13043-03, U10 DA013043] NR 33 TC 46 Z9 46 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD JUL PY 2004 VL 27 IS 1 BP 1 EP 8 DI 10.1016/j.jsat.2004.03.012 PG 8 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 836AZ UT WOS:000222528400001 PM 15223087 ER PT J AU Cowen, EW Rabel, A Nava, V Turner, M Moss, J AF Cowen, EW Rabel, A Nava, V Turner, M Moss, J TI Eruptive linear papules on the abdomen of a woman with ascites SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Editorial Material ID PULMONARY LYMPHANGIOLEIOMYOMATOSIS; WOMEN C1 NCI, Dermatol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. NCI, Pathol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. NHLBI, Pulm Crit Care Med Branch, Bethesda, MD 20892 USA. RP Cowen, EW (reprint author), NCI, Dermatol Branch, Canc Res Ctr, Bldg 10,Room 12N238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. EM cowene@mail.nih.gov NR 13 TC 2 Z9 2 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD JUL PY 2004 VL 51 IS 1 BP 75 EP 78 DI 10.1016/j.jaad.2003.12.026 PG 4 WC Dermatology SC Dermatology GA 834YL UT WOS:000222446700011 PM 15243527 ER PT J AU DiGiovanna, JJ AF DiGiovanna, JJ TI Ichthyosiform dermatoses: So many discoveries, so little progress SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Editorial Material C1 NCI, DNA Repair Sect, Basic Res Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. Brown Univ, Sch Med, Dept Dermatol, Div Dermatopharmacol, Providence, RI 02912 USA. RP DiGiovanna, JJ (reprint author), Rhode Isl Hosp, Dept Dermatol, Div Dermatopharmacol, JBS-1,593 Eddy St, Providence, RI 02903 USA. EM jdigiovanna@lifespan.org NR 2 TC 6 Z9 6 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD JUL PY 2004 VL 51 IS 1 SU S BP S31 EP S34 DI 10.1016/j.jaad.2004.01.019 PG 4 WC Dermatology SC Dermatology GA 836YP UT WOS:000222592800018 PM 15243501 ER PT J AU Colbert, LH Visser, M Simonsick, EM Tracy, RP Newman, AB Kritchevsky, SB Pahor, M Taaffe, DR Brach, J Rubin, S Harris, TB AF Colbert, LH Visser, M Simonsick, EM Tracy, RP Newman, AB Kritchevsky, SB Pahor, M Taaffe, DR Brach, J Rubin, S Harris, TB TI Physical activity, exercise, and inflammatory markers in older adults: Findings from the health, aging and body composition study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE interleukin-6; C-reactive protein; tumor necrosis factor alpha; physical activity; inflammation; exercise; aging ID C-REACTIVE PROTEIN; NECROSIS-FACTOR-ALPHA; CARDIOVASCULAR-DISEASE; CIRCULATING INTERLEUKIN-6; PLASMA-CONCENTRATION; INSULIN SENSITIVITY; ADIPOSE-TISSUE; US ADULTS; RISK; WOMEN AB OBJECTIVES: To examine the association between physical activity and inflammatory markers, with consideration for body fatness and antioxidant use. DESIGN: Cross-sectional study, using baseline data from the Health, Aging and Body Composition Study. SETTING: Metropolitan areas surrounding Pittsburgh, Pennsylvania, and Memphis, Tennessee. PARTICIPANTS: Black and white, well-functioning men and women (N=3,075), aged 70 to 79. MEASUREMENTS: Interviewer-administered questionnaires of previous-week household, walking, exercise, and occupational/volunteer physical activities. Analysis of covariance was used to examine the association between activity level and serum C-reactive protein (CRP), interleukin-6 (IL-6), and plasma tumor necrosis factor alpha (TNFalpha) with covariate adjustment. Antioxidant supplement use (multivitamin, vitamins E or C, beta carotene) was evaluated as an effect modifier of the association. RESULTS: Higher levels of exercise were associated with lower levels of CRP (P<.01), IL-6 (P<.001), and TNFalpha (P=.02) (e.g., CRP=1.95 mg/L for no exercise and 1.72 for >180 min/wk). Adjustment for body fatness attenuated the associations somewhat. Use of antioxidant supplements modified the CRP (P-interaction=.01) and IL-6 (P-interaction=.08) associations such that concentrations were low in those taking supplements (e.g., CRP=1.79-1.84 across exercise levels) and higher in nonsupplement users who did no exercise (2.03) than in those who did the most (1.72). Among nonexercisers, higher levels of other physical activity were related to lower levels of CRP (P<.01) and IL-6 (P=.02) but not TNFalpha (P=.36), even after accounting for body fat. CONCLUSION: Inflammatory markers are lower in older adults with higher levels of exercise and nonexercise activity and in antioxidant supplement users regardless of exercise level. C1 NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. VU Univ Med Ctr, Inst Res Extramural Med, Amsterdam, Netherlands. NIA, Intramural Res Program, Baltimore, MD 21224 USA. Univ Vermont, Coll Med, Burlington, VT 05405 USA. Univ Pittsburgh, Div Geriatr Med, Sch Hlth & Rehabil Sci, Pittsburgh, PA USA. Univ Pittsburgh, Dept Phys Therapy, Sch Hlth & Rehabil Sci, Pittsburgh, PA USA. Univ Tennessee, Dept Prevent Med, Memphis, TN USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Sticht Ctr Aging, Winston Salem, NC 27103 USA. Univ Queensland, Sch Human Movement Studies, Fac Hlth Sci, Brisbane, Qld, Australia. Univ Calif San Francisco, Dept Med, San Francisco, CA USA. RP Colbert, LH (reprint author), Univ Wisconsin, Dept Kinesiol, 2000 Observ Dr, Madison, WI 53706 USA. EM lhcolbert@education.wisc.edu RI Brach, Jennifer/A-6912-2009; Newman, Anne B./C-6408-2013 OI Newman, Anne B./0000-0002-0106-1150 FU NIA NIH HHS [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] NR 38 TC 209 Z9 212 U1 0 U2 19 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 2004 VL 52 IS 7 BP 1098 EP 1104 DI 10.1111/j.1532-5415.2004.52307.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 829SV UT WOS:000222070900008 PM 15209647 ER PT J AU Penninx, BWJH Kritchevsky, SB Newman, AB Nicklas, BJ Simonsick, EM Rubin, S Nevitt, M Visser, M Harris, T Pahor, M AF Penninx, BWJH Kritchevsky, SB Newman, AB Nicklas, BJ Simonsick, EM Rubin, S Nevitt, M Visser, M Harris, T Pahor, M TI Inflammatory markers and incident mobility limitation in the elderly SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE inflammation; mobility limitation; older; IL-6; CRP ID NECROSIS-FACTOR-ALPHA; C-REACTIVE PROTEIN; OLDER PERSONS; SKELETAL-MUSCLE; CARDIOVASCULAR-DISEASE; HEART-FAILURE; ISCHEMIC-STROKE; IN-VIVO; INTERLEUKIN-6; DISABILITY AB OBJECTIVES: To examine the relationship between indicators of inflammation and the incidence of mobility limitation in older persons. DESIGN: Prospective cohort study: the Health, Aging and Body Composition Study. SETTING: Pittsburgh, Pennsylvania, and Memphis, Tennessee. PARTICIPANTS: A total of 2,979 men and women, aged 70 to 79, without mobility limitation at baseline. MEASUREMENTS: Serum levels of interleukin (IL)-6, tumor necrosis factor alpha (TNFalpha), and C-reactive protein (CRP) and soluble cytokine receptors (IL-2sR, IL-6sR, TNFsR1, TNFsR2) were measured. Mobility limitation was assessed and defined as reporting difficulty or inability to walk one-quarter of a mile or to climb 10 steps during two consecutive semiannual assessments over 30 months. RESULTS: Of the 2,979 participants, 30.1% developed incident mobility limitation. After adjustment for confounders (demographics, prevalent conditions at baseline, body composition), the relative risk (RR) of incident mobility limitation per standard deviation (SD) increase was 1.19 (95% confidence interval (CI)=1.10-1.28) for IL-6, 1.20 (95% CI=1.12-1.29) for TNFalpha, and 1.40 (95% CI=1.18-1.68) for CRP. The association between inflammation and incident mobility limitation was especially strong for the onset of more severe mobility limitation and when the levels of multiple inflammatory markers were high. When persons with baseline or incident cardiovascular disease events or persons who were hospitalized during study follow-up were excluded, findings remained similar. In a subset (n=499), high levels of the soluble receptors IL2sR and TNFsR1 (per SD increase: RR=1.23 (95% CI=1.04-1.46) and RR=1.28 (95% CI=1.04-1.57), respectively) were also associated with incident mobility limitation. CONCLUSION: Findings suggest that inflammation is prognostic for incident mobility limitation over 30 months, independent of cardiovascular disease events and incident severe illness. C1 Vrije Univ Amsterdam, Dept Psychiat, Inst Res Extramural Med, NL-1075 BG Amsterdam, Netherlands. Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Sect Gerontol & Geriatr Med, Winston Salem, NC USA. Univ Tennessee, Memphis, TN USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Univ Calif San Francisco, San Francisco, CA USA. Vrije Univ Amsterdam, Inst Res Extramural Med, Amsterdam, Netherlands. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD USA. RP Penninx, BWJH (reprint author), Vrije Univ Amsterdam, Dept Psychiat, Inst Res Extramural Med, Valeriuspl 9, NL-1075 BG Amsterdam, Netherlands. EM Brendap@ggzba.nl RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU NIA NIH HHS [5P60 AG 10484-07, N01-AG-6-2102, N01-AG-6-2103, N01-AG-6-2106] NR 42 TC 147 Z9 148 U1 0 U2 5 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 2004 VL 52 IS 7 BP 1105 EP 1113 DI 10.1111/j.1532-5415.2004.52308.x PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 829SV UT WOS:000222070900009 PM 15209648 ER PT J AU Yasnoff, WA Humphreys, BL Overhage, JM Detmer, DE Brennan, PF Morris, RW Middleton, B Bates, DW Fanning, JP AF Yasnoff, WA Humphreys, BL Overhage, JM Detmer, DE Brennan, PF Morris, RW Middleton, B Bates, DW Fanning, JP TI A consensus action agenda for achieving the national health information infrastructure SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article AB Background: Improving the safety, quality, and efficiency of health care will require immediate and ubiquitous access to complete patient information and decision support provided through a National Health Information Infrastructure (NHII). Methods: To help define the action steps needed to achieve an NHII, the U.S. Department of Health and Human Services sponsored a national consensus conference in July 2003. Results: Attendees favored a public-private coordination group to guide NHII activities, provide education, share resources, and monitor relevant metrics to mark progress. They identified financial incentives, health information standards, and overcoming a few important legal obstacles as key NHII enablers. Community and regional implementation projects, including consumer access to a personal health record, were seen as necessary to demonstrate comprehensive functional systems that can serve as models for the entire nation. Finally, the participants identified the need for increased funding for research on the impact of health information technology on patient safety and quality of care. Individuals, organizations, and federal agencies are using these consensus recommendations to guide NHII efforts. C1 US Dept HHS, Off Assistant Secretary Planning & Evaluat, Washington, DC 20201 USA. NIH, Natl Lib Med, Bethesda, MD 20892 USA. Indiana Univ, Sch Med, Regenstrief Inst Hlth Care, Indianapolis, IN 46202 USA. Univ Virginia, Charlottesville, VA USA. Univ Cambridge, Cambridge, England. Univ Wisconsin, Madison, WI USA. NIAID, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Boston, MA USA. Brigham & Womens Hosp, Partners HealthCare, Boston, MA 02115 USA. RP Yasnoff, WA (reprint author), US Dept HHS, Off Assistant Secretary Planning & Evaluat, Room 440D,Hubert H Humphrey Bldg,220 Independence, Washington, DC 20201 USA. EM william.yasnoff@hhs.gov OI Overhage, Joseph/0000-0003-0223-0195 NR 23 TC 60 Z9 60 U1 2 U2 7 PU HANLEY & BELFUS INC PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD JUL-AUG PY 2004 VL 11 IS 4 BP 332 EP 338 DI 10.1197/jamia.M1616 PG 7 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Information Science & Library Science; Medical Informatics SC Computer Science; Information Science & Library Science; Medical Informatics GA 837UZ UT WOS:000222667800015 PM 15187075 ER PT J AU Hewitt, SM Dear, J Star, RA AF Hewitt, SM Dear, J Star, RA TI Discovery of protein biomarkers for renal diseases SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Review ID LASER CAPTURE MICRODISSECTION; SURROGATE END-POINTS; MESSENGER-RNA; ALLOGRAFT REJECTION; PROTEOMIC PATTERNS; URINARY BIOMARKER; CANCER-DIAGNOSIS; GENE-EXPRESSION; KIDNEY-DISEASE; INJURY AB Animal models and human studies have been useful in dissecting the molecular mechanisms of renal disease and finding new disease targets; however, translation of these findings to new clinical therapeutics remains challenging. Difficulties with detecting early disease, measuring drug effectiveness, and the daunting cost of clinical trials hampers the development of new therapeutics for renal diseases. Many existing laboratory tests were discovered because of inspired recognition that a particular protein might prove useful in clinical practice. New unbiased genomic and proteomic techniques identify many constituents present in biologic samples and thus may greatly accelerate biomarker research. This review focuses on the steps needed to develop new biomarkers that are useful in laboratory and clinical investigations, with particular focus on new proteomic screening technologies. New biomarkers will speed the laboratory and clinical development of new treatments for renal diseases through mechanistic insights, diagnoses that are more refined, early detection, and enhanced proof of concept testing. C1 NIDDK, Renal Diagnost & Therapeut Unit, NIH, Bethesda, MD 20892 USA. NCI, Tissue Array Res Program, Pathol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. RP Hewitt, SM (reprint author), NIDDK, Renal Diagnost & Therapeut Unit, NIH, 10 Ctr Dr,Bldg 10,Room 3N108, Bethesda, MD 20892 USA. EM Robert_Star@nih.gov OI Hewitt, Stephen/0000-0001-8283-1788 NR 74 TC 192 Z9 209 U1 1 U2 10 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL PY 2004 VL 15 IS 7 BP 1677 EP 1689 DI 10.1097/01.ASN.0000129114.92265.32 PG 13 WC Urology & Nephrology SC Urology & Nephrology GA 832OA UT WOS:000222275600002 PM 15213255 ER PT J AU Meyer, TW Leeper, EC Bartlett, DW Depner, TA Lit, YZ Robertson, CR Hostetter, TH AF Meyer, TW Leeper, EC Bartlett, DW Depner, TA Lit, YZ Robertson, CR Hostetter, TH TI Increasing dialysate flow and dialyzer mass transfer area coefficient to increase the clearance of protein-bound solutes SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID UREMIC SOLUTES; HEMODIALYSIS; MEMBRANE; TOXINS; FAILURE; REMOVAL; PARAMETERS; KIDNEY; UREA; FLUX AB Clinical hemodialysis systems achieve high single pass extraction of small solutes that are not bound to plasma proteins. But they clear protein-bound solutes much less effectively. This study examines the extent to which clearance of a protein-bound test solute is improved by increasing the dialyzer mass transfer area coefficient (K(o)A) and the dialysate flow rate (Q(d)). A reservoir containing test solutes and artificial plasma with albumin concentration approximately 4 g/dl was dialyzed with a standard clinical dialysate delivery system. The clearance of phenol red (Cl-PR) was compared with the clearances of urea and creatinine at a plasma flow rate (Q(p)) of 200 ml/min with varying values of K(o)A and Q(d). Cl-PR increased from 11 +/- 2 ml/min to 23 +/- 2 ml/min when K(o)A for phenol red, K(o)A(PR), was increased from 238 to 640 ml/min and Q, was increased from 286 +/- 6 ml/min to 734 +/- 9 ml/min. Increasing either K(o)A(PR) or Q(d) alone had lesser effects. Clearance values for phenol red were much lower than clearance values for the unbound solutes urea and creatinine, which ranged from 150 to 200 ml/min and were less affected by varying K(o)A and Q(d). A mathematical model was developed to predict Cl-PR from values of Q(p), Q(d), the fraction of phenol red bound to albumin (94% +/- 1%) and K(o)A(PR). The model accurately predicts the pattern of measured results and shows further that Cl-PR can be made to approach Q(p) only by very large increases in both K(o)A(PR) and Q(d). C1 VAHCS, Dept Med, Palo Alto, CA 94303 USA. Stanford Univ, Palo Alto, CA 94303 USA. Univ Calif Davis, Dept Med, Sacramento, CA 95817 USA. Stanford Univ, Dept Chem Engn, Stanford, CA 94305 USA. Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. NIDDK, Bethesda, MD USA. RP Meyer, TW (reprint author), VAHCS, Dept Med, 111R,3801 Miranda Ave, Palo Alto, CA 94303 USA. EM twmeyer@stanford.edu FU NIDDK NIH HHS [R01 DK52841] NR 24 TC 62 Z9 65 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL PY 2004 VL 15 IS 7 BP 1927 EP 1935 DI 10.1097/01.asn.0000131521.62256.f0 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 832OA UT WOS:000222275600030 PM 15213283 ER PT J AU McInerney-Leo, A Gwinn-Hardy, K Nussbaum, RL AF McInerney-Leo, A Gwinn-Hardy, K Nussbaum, RL TI Prevalence of Parkinson's disease in populations of African ancestry: A review SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Review DE Parkinson's; Parkinsonism; African; prevalence; etiology ID CLINICAL-TRIALS; EPIDEMIOLOGY; MORTALITY; SEX; AGE AB There have been a number of studies looking at the prevalence of Parkinson's disease (PD) in different racial and geographical populations. Some of the earliest studies suggested a difference in the prevalence of PD in African Americans as compared with Caucasians. As such a difference would have important implications for healthcare and research into the etiology of PD, we undertook a review of published studies to determine whether evidence suggested that such a difference exists. We reviewed 20 studies that looked at incidence, prevalence, and percentages of neurology patients with PD and Parkinsonism in Africa and in African-American populations. Two of these were door-to-door studies that relied on questionnaires for initial ascertainment, another was performed by review of outpatient records of a large health maintenance organization, while the remainder were based on hospital admissions, diagnosis in the community, or death certificate reports. In the aggregate, these studies suggest PD may be less frequent among Africans and African Americans than among Caucasians, although the most well-designed study showed only a statistically insignificant reduction in the prevalence of PD among African Americans. Although an apparently lower disease frequency among people of African origin may have a basis in the pathobiology of the disease, nearly all of these studies were vulnerable to a variety of ascertainment biases, and many lacked stringent application of diagnostic criteria applied by specialists trained in movement disorders. We conclude that a difference in the prevalence of PID and Parkinsonism between black and other populations is unproven and will require additional well-designed studies to determine if previously reported ethnic differences in disease prevalence are real. C1 NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. NINDS, NIH, Bethesda, MD 20892 USA. RP McInerney-Leo, A (reprint author), NHGRI, Med Genet Branch, Bldg 10,Room 3C710,10 Ctr Dr,MSC 1253, Bethesda, MD 20892 USA. EM amcinern@nhgri.nih.gov RI Gwinn, Katrina/C-2508-2009 NR 33 TC 24 Z9 24 U1 0 U2 1 PU NATL MED ASSOC PI WASHINGON PA 1012 10TH ST, N W, WASHINGON, DC 20001 USA SN 0027-9684 J9 J NATL MED ASSOC JI J. Natl. Med. Assoc. PD JUL PY 2004 VL 96 IS 7 BP 974 EP 979 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 851DN UT WOS:000223665800011 PM 15253330 ER PT J AU Drachenberg, DE Mena, OJ Choyke, PL Linehan, WM Walther, MM AF Drachenberg, DE Mena, OJ Choyke, PL Linehan, WM Walther, MM TI Parenchymal sparing surgery for central renal tumors in patients with hereditary renal cancers SO JOURNAL OF UROLOGY LA English DT Article DE kidney; kidney neoplasms; carcinoma, renal cell; nephrectomy; Hippel-Lindau disease ID CELL CARCINOMA; RADICAL NEPHRECTOMY; 4 CM.; CLASSIFICATION; ENUCLEATION; EXPERIENCE; MANAGEMENT; INVASION; FAMILIES; LESS AB Purpose: Nephron sparing surgery has become accepted surgical practice for removing of renal tumors. The resection of central lesions has been thought to be more surgically challenging than that of peripheral tumors. We analyzed our experience with renal preservation surgery in patients with small hereditary central renal tumors. Materials and Methods: From 1992 to 2000 we performed 116 partial nephrectomies with 44 kidneys (38%) demonstrating central renal masses. Central renal tumors were defined radiologically as those completely encircled by parenchyma or transgressing the interpapillary line on computerized tomography. We compared this group to a similar series of 67 patients with hereditary renal cancer with only peripheral based tumors. Results: Mean tumor size was 3.2 cm (range 1.5 to 7.5). Mean operative time was 352 minutes (range 70 to 830). Renal hypothermia and vascular clamping were used in 19 of 44 procedures (41%). Mean ischemic time was 55 minutes (range 16 to 143). Mean blood loss was 4.61 (range 0.1 to 23). The complication rate was 23% (10 of 44 cases) and with 18% (8 of 44) directly related to surgical technique. The mean transfusion requirement was 6.7 U (range 0 to 32) and 12 of 44 procedures (27%) required no blood products. Mean preoperative and postoperative serum creatinine was 1.05 (range 0.6 to 1.8) and 1.08 mg/dl (range 0.6 to 2.1), respectively. Mean followup was 33.7 months. No metastasis developed during followup. Conclusions: Central renal tumors are a common manifestation of hereditary renal cell carcinoma. There was no statistical difference found between common operative parameters when central and peripheral nephron sparing surgeries were compared. However, mean operative blood loss and transfusion requirements were increased in the central tumor group. C1 NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. RP Walther, MM (reprint author), NCI, Urol Oncol Branch, NIH, Bldg 10,2B47,10 Ctr Dr, Bethesda, MD 20892 USA. NR 20 TC 10 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JUL PY 2004 VL 172 IS 1 BP 49 EP 53 DI 10.1097/01.ju.0000130930.70356.28 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 830IN UT WOS:000222115700010 PM 15201735 ER PT J AU Duffey, BG Choyke, PL Glenn, G Grubb, RL Venzon, D Linehan, WM Walther, MM AF Duffey, BG Choyke, PL Glenn, G Grubb, RL Venzon, D Linehan, WM Walther, MM TI The relationship between renal tumor size and metastases in patients with von Hippel-Lindau disease SO JOURNAL OF UROLOGY LA English DT Article DE carcinoma, renal cell; growth, Hippel-Lindau disease; kidney neoplasms, observation ID PARENCHYMAL SPARING SURGERY; THAN 3 CM.; CELL CARCINOMA; 10-YEAR EXPERIENCE; NATURAL-HISTORY; LESS; PREVALENCE; LESIONS AB Purpose: Patients with von Hippel-Lindau disease are at risk for multiple, bilateral, recurrent renal tumors and metastases. We previously evaluated the relationship between tumor size and metastases in families with hereditary renal cancer. We update our findings with about twice the number of patients with von Hippel-Lindau disease. Materials and Methods: Screening affected kindred or retrospective review of medical records identified 181 patients with von Hippel-Lindau disease and renal cell carcinoma. Patients with small tumors were followed with serial imaging until the largest tumor reached 3 cm, at which point surgery was recommended. Surgical resection was recommended to patients with tumors larger than 3 cm. Patients not undergoing screening often had large renal tumors. Results: A total of 108 patients with von Hippel-Lindau disease and solid renal tumors on computerized tomography imaging smaller than 3 cm (group 1) were followed a mean of 58 months (range 0 to 244). Metastatic disease did not develop in any of these patients. Renal tumors larger than 3 cm developed in 73 patients with von Hippel-Lindau disease (group 2). Mean followup of group 2 was 72.9 months (range 0 to 321). The proportion of procedures that were nephron sparing was higher in group 1 than in group 2 (120 of 125 [97%] compared to 85 of 125 [69%], Fisher's exact test p <0.00001). Metastases developed in 20 of 73 (27.4%) patients in group 2. The frequency of renal tumor metastases increased with increasing tumor size. Conclusions: No renal tumor metastases were found in patients with renal tumors less than 3 cm in diameter. We advocate a 3 cin threshold for parenchymal sparing surgery in patients with von Hippel-Lindau disease to decrease the risk of metastatic disease while preserving renal function, avoiding or delaying the need for dialysis and/or renal transplant, and decreasing the number of operations which a patient may undergo. We stress the importance of early screening in the kindred of patients with von Hippel-Lindau disease and vigilant followup thereafter. C1 NCI, Urol Oncol Branch, DCS, NIH, Bethesda, MD 20892 USA. NCI, Dept Radiol, NIH, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. RP Walther, MM (reprint author), NCI, Urol Oncol Branch, DCS, NIH, Bldg 10,Room 2B-413,10 Ctr Dr,MSC 1501, Bethesda, MD 20892 USA. EM macw@nih.gov RI Venzon, David/B-3078-2008 NR 20 TC 82 Z9 89 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JUL PY 2004 VL 172 IS 1 BP 63 EP 65 DI 10.1097/01.ju.0000132127.79974.3f PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 830IN UT WOS:000222115700013 PM 15201738 ER PT J AU Forbes, JG Wang, K AF Forbes, JG Wang, K TI Simultaneous dynamic stiffness and extension profiles of single titin molecules: Nanomechanical evidence for unfolding intermediates SO JOURNAL OF VACUUM SCIENCE & TECHNOLOGY A LA English DT Article; Proceedings Paper CT 50th AVS International Symposium CY NOV 02-07, 2003 CL Baltimore, MD SP AVS ID ATOMIC-FORCE MICROSCOPY; MUSCLE PROTEIN TITIN; MECHANICAL-PROPERTIES; PEPTIDE MOLECULE; STRIATED-MUSCLE; CROSS-BRIDGES; IMMUNOGLOBULIN; MODULATION; TWEEZERS; SKELETAL AB Striated muscle is the primary source of biomechanical force in organisms from worms to man, and is organized as a composite material from nanometer to meter scales. At nanometer scale, an array of cytoskeletal proteins are required to regulate the size, assembly and function of the sarcomere, as well as transmit force and provide elasticity for restoring the structure. One such protein is the giant protein titin (Mr 3-4 x 10(6)), which spans half of the muscle sarcomere length. The passive elasticity of muscle at a physiological range of stretch arises primarily from the extension of titin. We have measured both the extension force and the dynamic stiffness of native titin with the atomic force microscope. We found that the stiffness of a single molecule of titin varied between 1 and 4 pN/nm over an extension of >1 mum. Regions showing globular domains unfolding in the sawtooth pattern of force versus extension curve exhibit periodic spikes in the stiffness. The results of this study show that simultaneous stiffness and force measurements of single molecules can provide new information on the elastic behavior and structural transitions of elastic proteins and their physiological roles in muscle elasticity. C1 NIAMS, DHHS, Lab Muscle Biol, Muscle Proteom & Nanotechnol Sect, Bethesda, MD 20892 USA. RP Wang, K (reprint author), NIAMS, DHHS, Lab Muscle Biol, Muscle Proteom & Nanotechnol Sect, Bldg 50, Bethesda, MD 20892 USA. EM wangk@exchange.nih.gov NR 39 TC 10 Z9 10 U1 0 U2 0 PU A V S AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0734-2101 J9 J VAC SCI TECHNOL A JI J. Vac. Sci. Technol. A PD JUL-AUG PY 2004 VL 22 IS 4 BP 1439 EP 1443 DI 10.1116/1.1692417 PG 5 WC Materials Science, Coatings & Films; Physics, Applied SC Materials Science; Physics GA 846NI UT WOS:000223322000060 ER PT J AU Kam, AW Littrup, PJ Walther, MM Hvizda, J Wood, BJ AF Kam, AW Littrup, PJ Walther, MM Hvizda, J Wood, BJ TI Thermal protection during percutaneous thermal ablation of renal cell carcinoma SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID RADIOFREQUENCY ABLATION; PROSTATE-CANCER; TUMORS; CRYOABLATION; OUTCOMES; COMPLICATIONS; THERAPY; MASSES AB Thermal injury to collateral structures is a known complication of thermal ablation of tumors. The authors present the use of CO2 dissection and inserted balloons to protect the bowel during percutaneous radiofrequency (RF) ablation and cryotherapy of primary and locally recurrent renal cell carcinoma. These techniques offer the potential to increase the number of tumors that can be treated with RF ablation or cryotherapy from a percutaneous approach. C1 NCI, Warren G Magnuson Clin Ctr, NIH, Dept Diagnost Radiol,Urol Oncol Branch, Bethesda, MD 20892 USA. Wayne State Univ, Sch Med, Dept Radiol, Detroit, MI USA. Wayne State Univ, Sch Med, Dept Urol, Detroit, MI USA. Wayne State Univ, Sch Med, Dept Radiat Oncol, Detroit, MI USA. RP Kam, AW (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Radiol, Bldg 10,Room 1C660,9000 Rockville Pike, Bethesda, MD 20892 USA. EM akam@mail.cc.nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 27 TC 39 Z9 40 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD JUL PY 2004 VL 15 IS 7 BP 753 EP 758 DI 10.1097/01.RVI.0000133535.16753.58 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 906XO UT WOS:000227678400013 PM 15231890 ER PT J AU Neeman, Z Wood, BJ AF Neeman, Z Wood, BJ TI Re: Metastatic involvement of a retrieved inferior vena cava filter - Response SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Letter C1 NIH, Dept Radiol Special Procedures, Ctr Clin, Bethesda, MD 20892 USA. RP Neeman, Z (reprint author), NIH, Dept Radiol Special Procedures, Ctr Clin, 10 Ctr Dr,Bldg 10,Room 1C 660, Bethesda, MD 20892 USA. EM zneeman@cc.nih.gov NR 3 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD JUL PY 2004 VL 15 IS 7 BP 775 EP 776 DI 10.1097/01.RVI.0000133556.86268.A6 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 906XO UT WOS:000227678400021 ER PT J AU Lu, HX Pise-Masison, CA Linton, R Park, HU Schiltz, RL Sartorelli, V Brady, JN AF Lu, HX Pise-Masison, CA Linton, R Park, HU Schiltz, RL Sartorelli, V Brady, JN TI Tax relieves transcriptional repression by promoting histone deacetylase 1 release from the human T-Cell leukemia virus type 1 long terminal repeat SO JOURNAL OF VIROLOGY LA English DT Article ID GENE-EXPRESSION; PHOSPHORYLATION STATUS; TRANSACTIVATOR TAX; FACTOR-BINDING; BREAST-CANCER; HTLV-1 TAX; IN-VIVO; CHROMATIN; PROTEIN; ACETYLATION AB Expression of human T-cell leukemia virus type 1 (HTLV-1) is regulated by the viral transcriptional activator Tax. Tax activates viral transcription through interaction with the cellular transcription factor CREB and the coactivators CBP/p300. In this study, we have analyzed the role of histone deacetylase 1 (HDAC1) on HTLV-1 gene expression from an integrated template. First we show that trichostatin A, an HDAC inhibitor, enhances Tax expression in HTLV-1-transformed cells. Second, using a cell line containing a single-copy HTLV-1 long terminal repeat, we demonstrate that overexpression of HDAC1 represses Tax transactivation. Furthermore, a chromatin immunoprecipitation assay allowed us to analyze the interaction of transcription factors, coactivators, and HDACs with the basal and activated HTLV-1 promoter. We demonstrate that HDAC1 is associated with the inactive, but not the Tax-transactivated, HTLV-1 promoter. In vitro and in vivo glutathione S-transferase-Tax pull-down and communoprecipitation experiments demonstrated that there is a direct physical association between Tax and HDAC1. Importantly, biotinylated chromatin pull-down assays demonstrated that Tax inhibits and/or dissociates the binding of HDAC1 to the HTLV-1 promoter. Our results provide evidence that Tax interacts directly with HDAC1 and regulates binding of the repressor to the HTLV-1 promoter. C1 NCI, Virus Tumor Biol Sect, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. NIAMSD, Muscle Biol Lab, Muscle Gene Express Grp, NIH, Bethesda, MD 20892 USA. RP Brady, JN (reprint author), NCI, Virus Tumor Biol Sect, Basic Res Lab, Bldg 41,Rm B201, Bethesda, MD 20892 USA. EM bradyj@exchange.nih.gov NR 56 TC 34 Z9 37 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2004 VL 78 IS 13 BP 6735 EP 6743 DI 10.1128/JVI.78.13.6735-6734.2004 PG 9 WC Virology SC Virology GA 830WC UT WOS:000222153800004 PM 15194748 ER PT J AU Ansarah-Sobrinho, C Moss, B AF Ansarah-Sobrinho, C Moss, B TI Vaccinia virus G1 protein, a predicted metalloprotease, is essential for morphogenesis of infectious virions but not for cleavage of major core proteins SO JOURNAL OF VIROLOGY LA English DT Article ID GENE-EXPRESSION; IDENTIFICATION; MEMBRANE; FAMILY AB Genes encoding orthologs of the vaccinia virus G1 protein are present in all poxviruses for which sequence information is available, yet neither the role of the protein nor its requirement for virus replication is known. G1 was predicted to be involved in the cleavage of core proteins, based on a transfection study and the presence of an HXXEH motif found in a subset of metallopeptidases. In the present study, we engineered a recombinant vaccinia virus containing a single copy of the G1L gene with a C-terminal epitope tag that is stringently regulated by the Escherichia coli lac repressor. In the absence of inducer, expression of G1 was repressed and virus replication was inhibited. Rescue of infectious virus was achieved by expression of wild-type G1 in trans, but not when the putative protease active site residues histidine-41, glutamate-44, or histidine-45 were mutated. Nevertheless, the synthesis and proteolytic processing of major core and membrane proteins appeared unaffected under nonpermissive conditions, distinguishing the phenotype of the G1L mutant from one in which the gene encoding the 17 protease was repressed. Noninfectious virus particles, assembled in the absence of inducer, did not attain the oval shape or characteristic core structure of mature virions. The polypeptide composition of these particles, however, closely resembled that of wild-type virus. Full-length and shorter forms of the G1 protein were found in the core fraction of virus particles assembled in the presence of inducer, suggesting that G1 is processed by self-cleavage or by another protease. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. George Washington Univ, Dept Genet, Grad Program, Washington, DC 20052 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 4 Ctr Dr,MSC 0445, Bethesda, MD 20892 USA. EM bmoss@nih.gov NR 19 TC 18 Z9 20 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2004 VL 78 IS 13 BP 6855 EP 6863 DI 10.1128/JVI.78.13.6855-6863.2004 PG 9 WC Virology SC Virology GA 830WC UT WOS:000222153800017 PM 15194761 ER PT J AU Skiadopoulos, MH Biacchesi, S Buchholz, UJ Riggs, JMI Surman, SR Amaro-Carambot, E McAuliffe, JM Elkins, WR St Claire, M Collins, PL Murphy, BR AF Skiadopoulos, MH Biacchesi, S Buchholz, UJ Riggs, JMI Surman, SR Amaro-Carambot, E McAuliffe, JM Elkins, WR St Claire, M Collins, PL Murphy, BR TI The two major human metapneumovirus genetic lineages are highly related antigenically, and the fusion (F) protein is a major contributor to this antigenic relatedness SO JOURNAL OF VIROLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; SEQUENCE-ANALYSIS; ATTENUATION PHENOTYPES; RHESUS-MONKEYS; G-GLYCOPROTEIN; GENOME LENGTH; SUBGROUP-A; TYPE-3; MUTATIONS; INFECTION AB The growth properties and antigenic relatedness of the CAN98-75 (CAN75) and the CAN97-83 (CAN83) human metapneumovirus (HMPV) strains, which represent the two distinct HMPV genetic lineages and exhibit 5 and 63% amino acid divergence in the fusion (F) and attachment (G) proteins, respectively, were investigated in vitro and in rodents and nonhuman primates. Both strains replicated to high titers ( greater than or equal to 6.0 log(10)) in the upper respiratory tract of hamsters and to moderate titers ( greater than or equal to3.6 log(10)) in the lower respiratory tract. The two lineages exhibited 48% antigenic relatedness based on reciprocal cross-neutralization assay with postinfection hamster sera, and infection with each strain provided a high level of resistance to reinfection with the homologous or heterologous strain. Hamsters immunized with a recombinant human parainfluenza virus type 1 expressing the fusion F protein of the CAN83 strain developed a serum antibody response that efficiently neutralized virus from both lineages and were protected from challenge with either HMPV strain. This result indicates that the HMPV F protein is a major antigenic determinant that mediates extensive cross-lineage neutralization and protection. Both HMPV strains replicated to low titers in the upper and lower respiratory tracts of rhesus macaques but induced high levels of HMPV-neutralizing antibodies in serum effective against both lineages. The level of HMPV replication in chimpanzees was moderately higher, and infected animals developed mild colds. HMPV replicated the most efficiently in the respiratory tracts of African green monkeys, and the infected animals developed a high level of HMPV serum-neutralizing antibodies (1:500 to 1:1,000) effective against both lineages. Reciprocal cross-neutralization assays in which postinfection sera from all three primate species were used indicated that CAN75 and CAN83 are 64 to 99% related antigenically. HMPV-infected chimpanzees and African green monkeys were highly protected from challenge with the heterologous HMPV strain. Taken together, the results from hamsters and nonhuman primates support the conclusion that the two HMPV genetic lineages are highly related antigenically and are not distinct antigenic subtypes or subgroups as defined by reciprocal cross-neutralization in vitro. C1 NIAID, Resp Viruses Sect, NIH, DHHS, Bethesda, MD 20892 USA. NIAID, Expt Primae Virol Sect, NIH, DHHS, Bethesda, MD 20892 USA. NIAID, Infect Dis Lab, NIH, DHHS, Bethesda, MD 20892 USA. Bioqual Inc, Rockville, MD 20850 USA. RP Skiadopoulos, MH (reprint author), NIAID, Resp Viruses Sect, NIH, DHHS, Bldg 50,Room 6511,S South Dr,MSC 8007, Bethesda, MD 20892 USA. EM mskiadopoulos@niaid.nih.gov RI Biacchesi, Stephane/A-6924-2010 NR 41 TC 126 Z9 138 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2004 VL 78 IS 13 BP 6927 EP 6937 DI 10.1128/JVI.78.13.6927-6937.2004 PG 11 WC Virology SC Virology GA 830WC UT WOS:000222153800025 PM 15194769 ER PT J AU Jeong, SH Qiao, M Nascimbeni, M Hu, ZY Rehermann, B Murthy, K Liang, TJ AF Jeong, SH Qiao, M Nascimbeni, M Hu, ZY Rehermann, B Murthy, K Liang, TJ TI Immunization with hepatitis C virus-like particles induces humoral and cellular immune responses in nonhuman primates SO JOURNAL OF VIROLOGY LA English DT Article ID B SURFACE-ANTIGEN; CPG DNA; HYPERVARIABLE REGION-1; INSECT CELLS; T-CELLS; INFECTION; VACCINE; CHIMPANZEES; MICE; CD4(+) AB We have previously reported the production of hepatitis C virus-like particles (HCV-LP) using a recombinant baculovirus containing the cDNA of the HCV structural proteins (core, E1, and E2). These particles resemble the putative HCN virions and are capable of inducing strong and broad Immoral and cellular immune responses in mice. Here we present evidence on the immunogenicity of HCV-LP and the effects of novel adjuvant systems in a nonhuman primate model, the baboon. Three groups of four baboons were immunized with HCV-LP, HCV-LP and adjuvant AS01B (monophosphoryl lipid A and QS21), or HCV-LP and the combination of AS01B and CpG oligodeoxynucleotides 10105. After four immunizations over an 8-month period, all animals developed HCV-specific humoral and cellular immune responses including antibodies to HCV structural proteins and gamma interferon(+) (IFN-gamma(+))CD4(+) and IFN-gamma(+)CD8(+) T-cell responses. The immunogenicity of HCV-LP was only marginally enhanced by the use of adjuvants. The overall HCV-specific immune responses were broad and long lasting. Our results suggest that HCV-LP is a potent immunogen to induce HCV-specific Immoral and cellular immune responses in primates and may be a promising approach to develop novel preventive and therapeutic modalities. C1 NIDDKD, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. SW Fdn Biomed Res, Dept Virol & Immunol, San Antonio, TX 78227 USA. RP Liang, TJ (reprint author), NIDDK, Liver Dis Sect, NIH, 10 Ctr Dr,Room 9B16, Bethesda, MD 20892 USA. EM jliang@nih.gov RI Jeong, Sook-Hyang/D-5726-2012; Jeong, Sook-Hyang/J-5642-2012 NR 41 TC 68 Z9 74 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2004 VL 78 IS 13 BP 6995 EP 7003 DI 10.1128/JVI.78.13.6995-7003.2004 PG 9 WC Virology SC Virology GA 830WC UT WOS:000222153800032 PM 15194776 ER PT J AU Snyder, JT Belyakov, IM Dzutsev, A Lemonnier, F Berzofsky, JA AF Snyder, JT Belyakov, IM Dzutsev, A Lemonnier, F Berzofsky, JA TI Protection against lethal vaccinia virus challenge in HLA-A2 transgenic mice by immunization with a single CD8(+) T-cell peptide epitope of vaccinia and variola viruses SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; SMALLPOX VACCINATION; POXVIRUS INFECTION; MONKEYPOX OUTBREAK; NEW-GENERATION; TARGET-CELLS; LYMPHOCYTES; MUCOSAL; IMMUNITY; ANTIGEN AB CD8(+) T lymphocytes have been shown to be involved in controlling poxvirus infection, but no protective cytotoxic T-lymphocyte (CTL) epitopes are defined for variola virus, the causative agent of smallpox, or for vaccinia virus. Of several peptides in vaccinia virus predicted to bind HLA-A2.1, three, VETFsm(498-506), A26L(6-14), and HRP2(74-82), were found to bind HLA-A2.1. Splenocytes from HLA-A2.1 transgenic mice immunized with vaccinia virus responded only to HRP2(74-82) at 1 week and to all three epitopes by ex vivo enzyme-linked immunosorbent spot (ELISPOT) assay at 4 weeks postimmunization. To determine if these epitopes could elicit a protective CD8(+) T-cell response, we challenged peptide-immunized HLA-A2.1 transgenic mice intranasally with a lethal dose of the WR strain of vaccinia virus. HRP2(74-82) peptide-immunized mice recovered from infection, while nalive mice died. Depletion of CD8(+) T cells eliminated protection. Protection of HHD-2 mice, lacking mouse class I major histocompatibility complex molecules, implicates CTLs restricted by human HLA-A2.1 as mediators of protection. These results suggest that HRP2(74-82), which is shared between vaccinia and variola viruses, may be a CD8(+) T-cell epitope of vaccinia virus that will provide cross-protection against smallpox in HLA-A2.1-positive individuals, representing almost half the population. C1 NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Inst Pasteur, Paris, France. RP Berzofsky, JA (reprint author), NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM berzofsk@helix.nih.gov NR 61 TC 88 Z9 89 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2004 VL 78 IS 13 BP 7052 EP 7060 DI 10.1128/JVI.78.13.7052-7060.2004 PG 9 WC Virology SC Virology GA 830WC UT WOS:000222153800037 PM 15194781 ER PT J AU Fitzgerald, W Sylwester, AW Grivel, JC Lifson, JD Margolis, LB AF Fitzgerald, W Sylwester, AW Grivel, JC Lifson, JD Margolis, LB TI Noninfectious X4 but not R5 human immunodeficiency virus type 1 virions inhibit humoral immune responses in human lymphoid tissue ex vivo SO JOURNAL OF VIROLOGY LA English DT Article ID HIV-INFECTED INDIVIDUALS; B-CELL ACTIVATION; ACQUIRED-IMMUNODEFICIENCY; DENDRITIC CELLS; T-CELLS; HOMOSEXUAL MEN; ANTIRETROVIRAL THERAPY; ENVELOPE GLYCOPROTEINS; BIOLOGICAL PHENOTYPE; ANTIBODY-RESPONSES AB Ex vivo human immunodeficiency virus type 1 (HIV-1) infection of human lymphoid tissue recapitulates some aspects of in vivo HIV-1 infection, including a severe depletion of CD4(+) T cells and suppression of humoral immune responses to recall antigens or to polyclonal stimuli. These effects are induced by infection with X4 HIV-1 variants, whereas infection with R5 variants results in only mild depletion of CD4(+) T cells and no suppression of immune responses. To study the mechanisms of suppression of immune responses in this ex vivo system, we used aldrithiol-2 (AT-2)-inactivated virions that have functional envelope glycoproteins but are not infectious and do not deplete CD4(+) T cells in human lymphoid tissues ex vivo. Nevertheless, AT-2-inactivated X4 (but not R5) HIV-1 virions, even with only a brief exposure, inhibit antibody responses in human lymphoid tissue ex vivo, similarly to infectious virus. This phenomenon is mediated by soluble immunosuppressive factor(s) secreted by tissue exposed to virus. C1 NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. NICHHD, NASA, Ctr 3 Dimens Tissue Culture, NIH, Bethesda, MD 20892 USA. SAIC Frederick Inc, AIDS Vaccine Program, Natl Canc Inst, Frederick, MD 21702 USA. RP Lifson, JD (reprint author), NICHHD, Lab Cellular & Mol Biophys, NIH, Bldg 10,Room 10D14,10 Ctr Dr, Bethesda, MD 20892 USA. EM lifson@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400, N01CO12400] NR 57 TC 6 Z9 6 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2004 VL 78 IS 13 BP 7061 EP 7068 DI 10.1128/JVI.78.13.7061-7068.2004 PG 8 WC Virology SC Virology GA 830WC UT WOS:000222153800038 PM 15194782 ER PT J AU Keck, ZY Sung, VMH Perkins, S Rowe, J Paul, S Liang, TJ Lai, MMC Foung, SKH AF Keck, ZY Sung, VMH Perkins, S Rowe, J Paul, S Liang, TJ Lai, MMC Foung, SKH TI Human monoclonal antibody to hepatitis C virus El glycoprotein that blocks virus attachment and viral infectivity SO JOURNAL OF VIROLOGY LA English DT Article ID DENSITY-LIPOPROTEIN RECEPTOR; E2 PROTEIN; CELLS; PARTICLES; BINDING; REPERTOIRE; REGION; CD81 AB Human antibodies elicited in response to hepatitis C virus (HCV) infection are anticipated to react with the native conformation of the viral envelope structure. Isolation of these antibodies as human monoclonal antibodies that block virus binding and entry will be useful in providing potential therapeutic reagents and for vaccine development. H-111, an antibody to HCV envelope 1 protein (E1) that maps to the YEVRNVSGVYH sequence and is located near the N terminus of El and is able to immunoprecipitate E1E2 heterodimers, is described. Binding of H-111 to HCV El genotypes la, 1b, 2b, and 3a indicates that the H-111 epitope is highly conserved. Sequence analysis of antibody V regions showed evidence of somatic and affinity maturation of H-111. Finally, H-111 blocks HCV-Iike particle binding to and HCV virion infection of target cells, suggesting the involvement of this epitope in virus binding and entry. C1 Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA. Univ So Calif, Keck Sch Med, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA. Univ Texas, Houston Med Sch, Dept Pathol & Lab Med, Chem Immunol & Therapeut Res Ctr, Houston, TX 77030 USA. NIDDKD, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. RP Foung, SKH (reprint author), Stanford Med Sch, Ctr Blood, 800 Welch Rd, Palo Alto, CA 94304 USA. EM sfoung@stanford.edu RI Lai, Michael Ming-Chao/I-7001-2012 FU NIAID NIH HHS [AI47355, N01AI40038, R01 AI047355]; NIDA NIH HHS [DA60596] NR 19 TC 59 Z9 61 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2004 VL 78 IS 13 BP 7257 EP 7263 DI 10.1128/JVI.78.13.7257-7263.2004 PG 7 WC Virology SC Virology GA 830WC UT WOS:000222153800057 PM 15194801 ER PT J AU Bao, YM Federhen, S Leipe, D Pham, V Resenchuk, S Rozanov, M Tatusov, R Tatusova, T AF Bao, YM Federhen, S Leipe, D Pham, V Resenchuk, S Rozanov, M Tatusov, R Tatusova, T TI National Center for Biotechnology Information Viral Genomes Project SO JOURNAL OF VIROLOGY LA English DT Editorial Material ID DATABASE; VIRUS; SEQUENCE; HEPATITIS; RNA; DNA; PROTEINS; UPDATE; ENTREZ; GENE C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Tatusova, T (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM tatiana@ncbi.nlm.nih.gov NR 20 TC 47 Z9 47 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2004 VL 78 IS 14 BP 7291 EP 7298 DI 10.1128/JVI.78.14.7291-7298.2004 PG 8 WC Virology SC Virology GA 834JK UT WOS:000222407200001 PM 15220402 ER PT J AU Lawrence, DMP Durham, LC Schwartz, L Seth, P Maric, D Major, EO AF Lawrence, DMP Durham, LC Schwartz, L Seth, P Maric, D Major, EO TI Human immunodeficiency virus type 1 infection of human brain-derived progenitor cells SO JOURNAL OF VIROLOGY LA English DT Article ID POLYMERASE-CHAIN-REACTION; CENTRAL-NERVOUS-SYSTEM; NECROSIS-FACTOR-ALPHA; HUMAN FETAL ASTROCYTES; ACTIVE ANTIRETROVIRAL THERAPY; IN-SITU HYBRIDIZATION; HIV-1 INFECTION; GLIAL-CELLS; PRODUCTIVE INFECTION; CELLULAR RESERVOIRS AB Although cells of monocytic lineage are the primary source of human immunodeficiency virus type 1 (HIV-1) in the brain, other cell types in the central nervous system, including astrocytes, can harbor a latent or persistent HIV-1 infection. In the present study, we examined whether immature, multipotential human brain-derived progenitor cells (nestin positive) are also permissive for infection. When exposed to IIIB and NL4-3 strains of HIV-1, progenitor cells and progenitor-derived astrocytes became infected, with peak p24 levels of 100 to 500 pg/ml at 3 to 6 days postinfection. After 10 days, virus production was undetectable but could be stimulated by the addition of tumor necrosis factor alpha (TNF-alpha). To bypass limitations to receptor entry, we compared the fate of infection in these cell populations by transfection with the infectious HIV-1 clone, pNL4-3. Again, transfected progenitors and astrocytes produced virus for 7 days but diminished to low levels beyond 8 days posttransfection. During the nonproductive phase, TNF-a. stimulated virus production from progenitors as late as 5 weeks posttransfection. Astrocytes produced 5- to 20-fold more infectious virus (27 ng of p24/10(6) cells) than progenitors at the peak of 3 days posttransfection. Differentiation of infected progenitors toward an astrocyte phenotype increased virus production to levels consistent with infected astrocytes, suggesting a phenotypic difference in viral replication. Using this cell culture system of multipotential human brain-derived progenitor cells, we provide evidence that progenitor cells may be a reservoir for HIV-1 in the brains of AIDS patients. C1 NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Major, EO (reprint author), NINDS, Lab Mol Med & Neurosci, NIH, 36 Convent Dr,MSC 4164,Bldg 36,Rm 5W21, Bethesda, MD 20892 USA. EM MajorG@ninds.nih.gov NR 57 TC 80 Z9 84 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2004 VL 78 IS 14 BP 7319 EP 7328 DI 10.1128/JVI.78.14.7319-7328.2004 PG 10 WC Virology SC Virology GA 834JK UT WOS:000222407200004 PM 15220405 ER PT J AU Rawat, SS Gallo, SA Eaton, J Martin, TD Ablan, S KewalRamani, VN Wang, JM Blumenthal, R Puri, A AF Rawat, SS Gallo, SA Eaton, J Martin, TD Ablan, S KewalRamani, VN Wang, JM Blumenthal, R Puri, A TI Elevated expression of GM3 in receptor-bearing targets confers resistance to human immunodeficiency virus type 1 fusion SO JOURNAL OF VIROLOGY LA English DT Article ID ENVELOPE GLYCOPROTEIN; MEDIATED FUSION; GANGLIOSIDE GM3; T-CELLS; PLASMA-MEMBRANE; BROAD RANGE; CD4; HIV-1; CXCR4; ENTRY AB GM3, a major ganglioside of T lymphocytes, promotes human immunodeficiency virus type 1 (HIV-1) entry via interactions with HIV-1 receptors and the viral envelope glycoprotein (Env). Increased GM3 levels in T lymphocytes and the appearance of anti-GM3 antibodies in AIDS patients have been reported earlier. In this study, we investigated the effect of GM3 regulation on HIV-1 entry by utilizing a mouse cell line (B16F10), which expresses exceptionally high levels of GM3. Strikingly, B16 cells hearing CD4, CXCR4, and/or CCR5 were highly resistant to CD4-dependent HIV-1 Env-mediated membrane fusion. In contrast, these targets supported membrane fusion mediated by CD4-requiring HIV-2, SIV, and CD4-independent HIV-1 Envs. Coreceptor function was not impaired by GM3 overexpression as indicated by Ca2+ fluxes mediated by the CXCR4 ligand SDF-1alpha and the CCR5 ligand MIP-1beta. Reduction in GM3 levels of B16 target cells resulted in a significant recovery of CD4-dependent HIV-1 Env-mediated fusion. We propose that GM3 in the plasma membrane blocks HIV-1 Env-mediated fusion by interfering with the lateral association of HIV-1 receptors. Our findings offer a novel mechanism of interplay between membrane lipids and receptors by which host cells may escape viral infections. C1 NCI, Lab Expt & Computat Biol, Ctr Canc Res, NIH, Frederick, MD 21702 USA. NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. NCI, Mol Immunoregulat Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Puri, A (reprint author), NCI, Lab Expt & Computat Biol, Ctr Canc Res, NIH, POB B,Bldg 469,Rm 211,Miller Dr, Frederick, MD 21702 USA. EM apuri@helix.nih.gov OI Gallo, Stephen/0000-0001-6043-2153 NR 43 TC 22 Z9 23 U1 2 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2004 VL 78 IS 14 BP 7360 EP 7368 DI 10.1128/JVI.78.14.7360-7368.2004 PG 9 WC Virology SC Virology GA 834JK UT WOS:000222407200008 PM 15220409 ER PT J AU Letvin, NL Huang, Y Chakrabarti, BK Xu, L Seaman, MS Beaudry, K Korioth-Schmitz, B Yu, F Rohne, D Martin, KL Miura, A Kong, WP Yang, ZY Gelman, RS Golubeva, OG Montefiori, DC Mascola, JR Nabel, GJ AF Letvin, NL Huang, Y Chakrabarti, BK Xu, L Seaman, MS Beaudry, K Korioth-Schmitz, B Yu, F Rohne, D Martin, KL Miura, A Kong, WP Yang, ZY Gelman, RS Golubeva, OG Montefiori, DC Mascola, JR Nabel, GJ TI Heterologous envelope immunogens contribute to AIDS vaccine protection in rhesus monkeys SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL DEPLETION; GAG-POL; GENETIC IMMUNIZATION; MUCOSAL CHALLENGE; IMMUNE-RESPONSES; INFECTION; MACAQUES; ENV; VIREMIA AB Because a strategy to elicit broadly neutralizing anti-human immunodeficiency virus type 1 (HIV-1) antibodies has not yet been found, the role of an Env immunogen in HIV-1 vaccine candidates remains undefined. We sought to determine whether an HIV-1 Env immunogen genetically disparate from the Env of the challenge virus can contribute to protective immunity. We vaccinated Indian-origin rhesus monkeys with Gag-Pol-Nef immunogens, alone or in combination with Env immunogens that were either matched or mismatched with the challenge virus. These animals were then challenged with a pathogenic simian-human immunodeficiency virus. The vaccine regimen included a plasmid DNA prime and replication-defective adenoviral vector boost. Vaccine regimens that included the matched or mismatched Env immunogens conferred better protection against CD4(+) T-lymphocyte loss than that seen with comparable regimens that did not include Env immunogens. This increment in protective immunity was associated with anamnestic Env-specific cellular immunity that developed in the early days following viral challenge. These data suggest that T-lymphocyte immunity to Env can broaden the protective cellular immune response to HIV despite significant sequence diversity of the strains of the Env immunogens and can contribute to immune protection in this AIDS vaccine model. C1 Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Duke Univ, Med Ctr, Durham, NC 27710 USA. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Letvin, NL (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. EM nletvin@bidmc.harvard.edu RI Korioth-Schmitz, Birgit/M-7816-2015 OI Korioth-Schmitz, Birgit/0000-0002-5271-9223 NR 24 TC 114 Z9 120 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2004 VL 78 IS 14 BP 7490 EP 7497 DI 10.1128/JVI.78.14.7490-7497.2004 PG 8 WC Virology SC Virology GA 834JK UT WOS:000222407200021 PM 15220422 ER PT J AU Nicola, AV Straus, SE AF Nicola, AV Straus, SE TI Cellular and viral requirements for rapid endocytic entry of herpes simplex virus SO JOURNAL OF VIROLOGY LA English DT Article ID HAMSTER OVARY CELLS; EPSTEIN-BARR-VIRUS; GLYCOPROTEIN-D; LOW-PH; MONOCLONAL-ANTIBODIES; NEUTRALIZING ANTIBODY; MOLECULAR-GENETICS; SURFACE RECEPTORS; TYPE-1; MUTANT AB It was recently demonstrated that herpes simplex virus (HSV) successfully infects Chinese hamster ovary (CHO) cells expressing glycoprotein D (gD) receptors and HeLa cells by an endocytic mechanism (A. V. Nicola, A. M. McEvoy, and S. E. Straus, J. Virol. 77:5324-5332, 2003). Here we define cellular and viral requirements of this pathway. Uptake of intact, enveloped HSV from the cell surface into endocytic vesicles was rapid (t(1/2) of 8 to 9 min) and independent of the known cell surface gD receptors. Following uptake from the surface, recovery of intracellular, infectious virions increased steadily up to 20 min postinfection (p.i.), which corresponds to accumulation of enveloped virus in intracellular compartments. There was a sharp decline in recovery by 30 min p.i., suggesting loss of the virus envelope as a result of capsid penetration from endocytic organelles into the cytosol. In the absence of gD receptors, endocytosed virions did not successfully penetrate into the cytosol but were instead transported to lysosomes for degradation. Inhibitors of phosphatidylinositol (PI) 3-kinase, such as wortmannin, blocked transport of incoming HSV to the nuclear periphery and virus-induced gene expression but had no effect on virus binding or uptake. This suggests a role for PI 3-kinase activity in trafficking of HSV through the cytosol. Viruses that lack viral glycoproteins gB, gD, or gH-gL were defective in transport to the nucleus and had reduced infectivity. Thus, similar to entry via direct penetration at the cell surface, HSV entry into cells by wortmannin-sensitive endocytosis is efficient, involves rapid cellular uptake of viral particles, and requires gB, gD, and gH-gL. C1 NIAID, Med Virol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Nicola, AV (reprint author), 10 Ctr Dr,Rm 11N228, Bethesda, MD 20892 USA. EM anicola@niaid.nih.gov NR 51 TC 116 Z9 117 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2004 VL 78 IS 14 BP 7508 EP 7517 DI 10.1128/JVI.78.14.7508-7517.2004 PG 10 WC Virology SC Virology GA 834JK UT WOS:000222407200023 PM 15220424 ER PT J AU Kawamura, T Bruce, SE Abraha, A Sugaya, M Hartley, O Offord, RE Arts, EJ Zimmerman, PA Blauvelt, A AF Kawamura, T Bruce, SE Abraha, A Sugaya, M Hartley, O Offord, RE Arts, EJ Zimmerman, PA Blauvelt, A TI PSC-RANTES blocks R5 human immunodeficiency virus infection of langerhans cells isolated from individuals with a variety of CCR5 diplotypes SO JOURNAL OF VIROLOGY LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; HIV-1 INFECTION; TYPE-1 INFECTION; DENDRITIC CELLS; PROMOTER POLYMORPHISM; DISEASE PROGRESSION; IN-VITRO; TRANSMISSION; AIDS; INHIBITION AB Topical microbicides that effectively block interactions between CCR5(+) immature Langerhans cells (LC) residing within genital epithelia and R5 human immunodeficiency virus (HIV) may decrease sexual transmission of HIV. Here, we investigated the ability of synthetic RANTES analogues (AOP-, NNY-, and PSC-RANTES) to block R5 HIV infection of human immature LC by using a skin explant model. In initial experiments using activated peripheral blood mononuclear cells, each analogue compound demonstrated marked antiviral activity against two R5 HIV isolates. Next, we found that 20-min preincubation of skin explants with each RANTES analogue blocked R5 HIV infection of LC in a dose-dependent manner (1 to 100 nM) and that PSC-RANTES was the most potent of these compounds. Similarly, preincubation of LC with each analogue was able to block LC-mediated infection of cocultured CD4(+) T cells. Competition experiments between primary R5 and X4 HIV isolates showed blocking of R5 HIV by PSC-RANTES and no evidence of increased propagation of X4 HIV, data that are consistent with the specificity of PSC-RANTES for CCR5 and the CCR5(+) CXCR4(-) phenotype of immature LC. Finally, when CCR5 genetic polymorphism data were integrated with results from the in vitro LC infection studies, PSC-RANTES was found to be equally effective in inhibiting R5 HIV in LC isolated from individuals with CCR5 diplotypes known to be associated with low, intermediate, and high cell surface levels of CCR5. In summary, PSC-RANTES is a potent inhibitor of R5 HIV infection in immature LC, suggesting that it may be useful as a topical microbicide to block sexual transmission of HIV. C1 Natl Canc Inst, Dermatol Branch, Ctr Canc Res, Bethesda, MD USA. Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. Case Western Reserve Univ, Ctr Global Hlth & Dis, Cleveland, OH 44106 USA. Univ Geneva, Dept Biochim Med, Geneva, Switzerland. RP Blauvelt, A (reprint author), Oregon Hlth & Sci Univ, 3710 SW US Vet Hosp Rd,Mail Code R&D 55, Portland, OR 97239 USA. EM blauvela@ohsu.gov RI Hartley, Oliver/H-3593-2013 FU NIAID NIH HHS [P01 AI051649, AI51649] NR 46 TC 48 Z9 54 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2004 VL 78 IS 14 BP 7602 EP 7609 DI 10.1128/JVI.78.14.7602-7609.2004 PG 8 WC Virology SC Virology GA 834JK UT WOS:000222407200034 PM 15220435 ER PT J AU Chien, PC Cohen, S Tuen, M Arthos, J Chen, PD Patel, S Hioe, CE AF Chien, PC Cohen, S Tuen, M Arthos, J Chen, PD Patel, S Hioe, CE TI Human immunodeficiency virus type 1 evades T-helper responses by exploiting antibodies that suppress antigen processing SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN MONOCLONAL-ANTIBODIES; CD4 BINDING DOMAIN; CELL RESPONSES; HIV-1 GP120; NEUTRALIZATION; EPITOPE; CLONES; GLYCOPROTEIN-120; GLYCOSYLATION; PROTEOLYSIS AB T-helper responses are important for controlling chronic viral infections, yet T-helper responses specific to human immunodeficiency virus type 1 (HIV-1), particularly to envelope glycoproteins, are lacking in the vast majority of HIV-infected individuals. It was previously shown that the presence of antibodies to the CD4-binding domain (CD4bd) of HIV-1 glycoprotein 120 (gp120) prevents T-helper responses to gp120, but their suppressive mechanisms were undefined (C. E. Hioe et al., J. Virol. 75:10950-10957, 2001). The present study demonstrates that gp120, when complexed to anti-CD4bd antibodies, becomes more resistant to proteolysis by lysosomal enzymes from antigen-presenting cells such that peptide epitopes are not released and presented efficiently by major histocompatibility complex class II molecules to gp120-specific CD4 T cells. Antibodies to other gp120 regions do not confer this effect. Thus, HIV may evade anti-viral T-helper responses by inducing and exploiting antibodies that conceal the virus envelope antigens from T cells. C1 NYU, Sch Med & Vet Affairs, Dept Pathol, New York Harbor Healthcare Syst, New York, NY 10010 USA. NIAID, Immunoregulat Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Hioe, CE (reprint author), NYU, Sch Med & Vet Affairs, Dept Pathol, New York Harbor Healthcare Syst, 423 E 23rd St,Rm 18-124N, New York, NY 10010 USA. EM catarina.hioe@med.nyu.edu FU NIAID NIH HHS [AI-48371, R01 AI048371, AI-27742, P30 AI027742] NR 46 TC 14 Z9 14 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2004 VL 78 IS 14 BP 7645 EP 7652 DI 10.1128/JVI.78.14.7645-7652.2004 PG 8 WC Virology SC Virology GA 834JK UT WOS:000222407200038 PM 15220439 ER PT J AU Silvestri, LS Taraporewala, ZF Patton, JT AF Silvestri, LS Taraporewala, ZF Patton, JT TI Rotavirus replication: Plus-sense templates for double-stranded RNA synthesis are made in viroplasms SO JOURNAL OF VIROLOGY LA English DT Article ID NONSTRUCTURAL PROTEIN NSP2; MESSENGER-RNA; CULTURED-CELLS; INFECTED-CELLS; VIRAL-RNA; IN-VITRO; PARTICLES; INTERFERENCE; VIRUS; PHOSPHORYLATION AB Rotavirus plus-strand RNAs not only direct protein synthesis but also serve as templates for the synthesis of the segmented double-stranded RNA (dsRNA) genome. In this study, we identified short-interfering RNAs (siRNAs) for viral genes 5, 8, and 9 that suppressed the expression of NSP1, a nonessential protein; NSP2, a component of viral replication factories (viroplasms); and VP7, an outer capsid protein, respectively. The loss of NSP2 expression inhibited viroplasm formation, genome replication, virion assembly, and synthesis of the other viral proteins. In contrast, the loss of VP7 expression had no effect on genome replication; instead, it inhibited only outer-capsid morphogenesis. Similarly, neither genome replication nor any other event of the viral life cycle was affected by the loss of NSP1. The data indicate that plus-strand RNAs templating dsRNA synthesis within viroplasms are not susceptible to siRNA-induced RNase degradation. In contrast, plus-strand RNAs templating protein synthesis in the cytosol are susceptible to degradation and thus are not the likely source of plus-strand RNAs for dsRNA synthesis in viroplasms. Indeed, immunofluorescence analysis of bromouridine (BrU)-labeled RNA made in infected cells provided evidence that plus-strand RNAs are synthesized within viroplasms. Furthermore, transfection of BrU-Iabeled viral plus-strand RNA into infected cells suggested that plus-strand RNAs introduced into the cytosol do not localize to viroplasms. From these results, we propose that plus-strand RNAs synthesized within viroplasms are the primary source of templates for genome replication and that trafficking pathways do not exist within the cytosol that transport plus-strand RNAs to viroplasms. The lack of such pathways confounds the development of reverse genetics systems for rotavirus. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Patton, JT (reprint author), NIAID, Infect Dis Lab, NIH, 50 S Dr,MSC 8026,Rm 6314, Bethesda, MD 20892 USA. EM jpatton@niaid.nih.gov RI Patton, John/P-1390-2014 NR 35 TC 125 Z9 136 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2004 VL 78 IS 14 BP 7763 EP 7774 DI 10.1128/JVI.78.14.7763-7774.2004 PG 12 WC Virology SC Virology GA 834JK UT WOS:000222407200049 PM 15220450 ER PT J AU Hoshino, Y Jones, RW Ross, J Honma, S Santos, N Gentsch, JR Kapikian, AZ AF Hoshino, Y Jones, RW Ross, J Honma, S Santos, N Gentsch, JR Kapikian, AZ TI Rotavirus serotype G9 strains belonging to VP7 gene phylogenetic sequence lineage 1 may be more suitable for serotype G9 vaccine candidates than those belonging to lineage 2 or 3 SO JOURNAL OF VIROLOGY LA English DT Article ID GEL-ELECTROPHORESIS; MOLECULAR CHARACTERIZATION; REASSORTANT ROTAVIRUSES; MONOCLONAL-ANTIBODIES; HIGH-FREQUENCY; UNITED-STATES; CHILDREN; JAPAN; NEUTRALIZATION; PROTEINS AB A safe and effective group A rotavirus vaccine that could prevent severe diarrhea or ameliorate its symptoms in infants and young children is urgently needed in both developing and developed countries. Rotavirus VP7 serotypes G1, G2, G3, and G4 have been well established to be of epidemiologic importance worldwide. Recently, serotype G9 has emerged as the fifth globally common type of rotavirus of clinical importance. Sequence analysis of the VP7 gene of various G9 isolates has demonstrated the existence of at least three phylogenetic lineages. The goal of our study was to determine the relationship of the phylogenetic lineages to the neutralization specificity of various G9 strains. We generated eight single VP7 gene substitution reassortants, each of which bore a single VP7 gene encoding G9 specificity of one of the eight G9 strains (two lineage 1, one lineage 2 and five lineage 3 strains) and the remaining 10 genes of bovine rotavirus strain UK, and two hyperimmune guinea pig antisera to each reassortant, and we then analyzed VP7 neutralization characteristics of the eight G9 strains as well as an additional G9 strain belonging to lineage 1; the nine strains were isolated in five countries. Antisera to lineage 1 viruses neutralized lineage 2 and 3 strains to at least within eightfold of the homotypic lineage viruses. Antisera to lineage 2 virus neutralized lineage 3 viruses to at least twofold of the homotypic lineage 2 virus; however, neutralization of lineage 1 viruses was fourfold (F45 and AU32) to 16- to 64-fold (WI61) less efficient. Antisera to lineage 3 viruses neutralized the lineage 2 strain 16- to 64-fold less efficiently, the lineage 1 strains F45 and AU32 8- to 128-fold less efficiently, and WI61 (prototype G9 strain) 128- to 1,024-fold less efficiently than the homotypic lineage 3 viruses. These findings may have important implications for the development of G9 rotavirus vaccine candidates, as the strain with the broadest reactivity (i.e., a prime strain) would certainly be the ideal strain for inclusion in a vaccine. C1 NIAID, Epidemiol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Univ Fed Rio de Janeiro, Inst Microbiol, Rio De Janeiro, Brazil. Ctr Dis Control & Prevent, Div Viral & Rickettsial Dis, Viral Gastroenteritis Sect, Atlanta, GA USA. RP Hoshino, Y (reprint author), NIAID, Epidemiol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM THOSHINO@niaid.nih.gov RI Santos, Norma/H-6986-2015 OI Santos, Norma/0000-0002-5123-9172 NR 53 TC 39 Z9 39 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2004 VL 78 IS 14 BP 7795 EP 7802 DI 10.1128/JVI.78.14.7795-7802.2004 PG 8 WC Virology SC Virology GA 834JK UT WOS:000222407200052 PM 15220453 ER PT J AU Ward, MM AF Ward, MM TI Prevalence of physician-diagnosed systemic lupus erythematosus in the United States: Results from the Third National Health and Nutrition Examination Survey SO JOURNAL OF WOMENS HEALTH LA English DT Article ID ETHNIC-GROUPS; RISK-FACTORS; EPIDEMIOLOGY; DISORDERS; ROCHESTER; DISEASES AB Objective: To determine the prevalence of physician-diagnosed systemic lupus erythematosus (SLE) in a national population-based sample in the United States. Methods: Data from the Third National Health and Nutrition Examination Survey (NHANES III) were used to estimate the prevalence of self-reported physician-diagnosed SLE. Adult participants (agegreater than or equal to17; sample n=20,050) were asked if they had been diagnosed with SLE by a physician. All medications currently being taken by survey participants were recorded. Two definitions were used to classify participants with SLE: self-reported physician diagnosis and self-reported physician diagnosis and a current prescription for antimalarials, corticosteroids, or other immunosuppressive medications. Results: The prevalence of SLE in adults agegreater than or equal to17 based on self-reported physician diagnosis was 241 per 100,000 (95% confidence interval [CI] 130-352). The prevalence of SLE in adults agegreater than or equal to17 based on self-reported physician diagnosis and current prescription for antimalarials, corticosteroids, or immunosuppressive medications was 53.6 per 100,000 (95% Cl 12.2-95.0). Among adult women, the prevalence of treated SLE was 100 per 100,000 (95% Cl 19.8-179.3). Conclusions: Projecting a prevalence of 100 per 100,000 to the population of the United States, approximately 108,300 adult women had a self-reported physician diagnosis of SLE and were receiving specific treatment in 2000. This estimate is a reasonable lower boundary, as it does not include undiagnosed persons or those not being treated with antimalarials, corticosteroids or immunosuppressive medications. C1 NIAMSD, Intramural Res Program, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), NIAMS, NIH, IRP, Bldg 10,Room 9S205,10 Ctr Dr,MSC 1828, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov NR 22 TC 44 Z9 48 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD JUL-AUG PY 2004 VL 13 IS 6 BP 713 EP 718 DI 10.1089/jwh.2004.13.713 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 849BV UT WOS:000223513700008 PM 15333286 ER PT J AU Charurat, M Blattner, W Hershow, R Buck, A Zorrilla, CD Watts, DH Paul, M Landesman, S Adeniyi-Jones, S Tuomala, R AF Charurat, M Blattner, W Hershow, R Buck, A Zorrilla, CD Watts, DH Paul, M Landesman, S Adeniyi-Jones, S Tuomala, R CA Women Infants Transmission Study TI Changing trends in clinical AIDS presentations and survival among HIV-1-infected women SO JOURNAL OF WOMENS HEALTH LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; INTRAVENOUS-DRUG-USERS; ACTIVE ANTIRETROVIRAL THERAPY; RISK-FACTORS; BACTERIAL PNEUMONIA; HIV-INFECTION; VIRAL LOAD; OPPORTUNISTIC INFECTIONS; DISEASE PROGRESSION; ORAL CANDIDIASIS AB Objectives: To profile trends of clinical AIDS-defining illness (ADI) among a cohort of human immunodeficiency virus (HIV)-infected women over a 12-year period. Methods: In a prospective evaluation of AIDS clinical presentation in the Women and Infants Transmission Study (WITS), 2255 subjects were enrolled and followed between December 1989 and June 2002 (total, 4993 person-years). Data on clinical AIDS presentation of 140 (6.2%) HIV-seropositive subjects were evaluated across three calendar periods corresponding to the use of different therapy regimens. Incidence rates (per 1000 woman-years) for AIDS and specific ADIs were compared between periods using Poisson regression methods. Results: Incidence rates of AIDS, Mycobacterium tuberculosis, recurrent bacterial pneumonia, herpes simplex disease, esophageal/bronchial candidiasis, wasting syndrome, and neurological diseases have showed significant downward trends. Among women with ADI, the frequency of either esophageal or bronchial candidiasis as initial ADI showed an increasing trend (p(trend)=0.03), whereas a decrease in proportion of cases with nontuberculosis mycobacterial infection (P-trend=0.05) was observed over the same periods. In the multivariate analysis, both the CD4(+) lymphocyte count and HIV-1 RNA at the time of diagnosis were independently associated with survival after AIDS. Highly active antiretroviral therapy (HAART) was associated with a 70% reduction in progression to death following AIDS. Conclusions: Temporal changes in the incidence and clinical presentations in HIV-positive women in our cohort reflect an increased use of HAART that may have a differential effect on reduction in the risk of ADIs. These illnesses, although considerably less frequent in recent years, are still important contributors to morbidity in HIV-positive women. C1 Univ Maryland, Inst Human Virol, Div Epidemiol & Prevent, Baltimore, MD USA. Univ Illinois, Coll Med, Chicago, IL USA. Univ Illinois, Sch Publ Hlth, Chicago, IL USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Univ Puerto Rico, San Juan, PR 00936 USA. NICHHD, Bethesda, MD 20892 USA. Baylor Coll Med, Houston, TX 77030 USA. SUNY, Brooklyn, NY USA. NIAID, Div AIDS, Bethesda, MD 20892 USA. RP Charurat, M (reprint author), 725 W Lombard St,Suite N452, Baltimore, MD 21201 USA. EM charurat@umbi.umd.edu NR 43 TC 16 Z9 18 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD JUL-AUG PY 2004 VL 13 IS 6 BP 719 EP 730 DI 10.1089/jwh.2004.13.719 PG 12 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 849BV UT WOS:000223513700009 PM 15333287 ER PT J AU Harman, SM Blackman, MR AF Harman, SM Blackman, MR TI Use of growth hormone for prevention or treatment of effects of aging SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Review ID GH-DEFICIENT ADULTS; QUALITY-OF-LIFE; IGF-BINDING PROTEIN-3; SERUM SEX-HORMONES; HEALTHY OLDER MEN; LEAN BODY-MASS; FACTOR-I; REPLACEMENT THERAPY; TESTOSTERONE LEVELS; RISK-FACTORS AB Decreases in growth hormone (GH) and insulin-like growth factor-I, estrogen deficiency in women, diminished testosterone in men, and loss of lean body mass, increased fat, and other changes consistent with hormone deficiencies occur during aging. Treatment of nonelderly GH-deficient adults with recombinant human GH (rhGH) improves body composition, muscle strength, physical function, and bone density, and reduces blood cholesterol and cardiovascular disease risk, but is often accompanied by carpal tunnel syndrome, peripheral edema, joint pain and swelling, gynecomastia, glucose intolerance, and possibly increased cancer risk. Reports that rhGH augments lean body mass and reduces body fat in aged individuals increased use of rhGH to delay aging effects. However, clinically significant functional benefits, prolongation of youth, and life extension have not been demonstrated. Moreover, marketing of rhGH and other hormone supplements largely ignores adverse effects. Until more research has better defined the risk/benefit relationships, treatment of elderly individuals with rhGH should be confined to controlled research studies. C1 Kronos Longev Res Inst, Phoenix, AZ USA. Natl Ctr Complementary & Alternat Med, NIH, Bethesda, MD USA. RP Harman, SM (reprint author), Kronos Longev Res Inst, Phoenix, AZ USA. EM mitch.harman@kronosinstitute.org NR 112 TC 29 Z9 33 U1 1 U2 2 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUL PY 2004 VL 59 IS 7 BP 652 EP 658 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 845JQ UT WOS:000223239100002 PM 15304529 ER PT J AU Warner, HR AF Warner, HR TI Current status of efforts to measure and modulate the biological rate of aging SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID GENETICALLY HETEROGENEOUS MICE; ELEGANS LIFE-SPAN; AMES DWARF MICE; MUTANT MICE; CAENORHABDITIS-ELEGANS; CALORIC RESTRICTION; GENE-EXPRESSION; C-ELEGANS; EXTENDED LONGEVITY; STRESS RESISTANCE AB Biomarkers of aging would be highly desirable, but so far, a definitive panel of biomarkers to predict mortality risk has not been obtained, even though many traits that vary with age have been identified. This lack hinders the search for interventions that may retard the rate of aging in mammals. The recent discovery and characterization of many longevity genes in animal model systems, such as nematodes, fruit flies, and mice, are providing new targets for research by providing insight into mechanisms of longevity regulation in these model systems. It is hoped that this will ultimately lead to interventions to delay the development of age-related pathology in humans. C1 NIA, Biol Aging Program, NIH, Bethesda, MD 20892 USA. RP Warner, HR (reprint author), NIA, Biol Aging Program, NIH, Bldg 31, Bethesda, MD 20892 USA. EM warnerh@nia.nih.gov NR 55 TC 25 Z9 28 U1 1 U2 1 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUL PY 2004 VL 59 IS 7 BP 692 EP 696 PG 5 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 845JQ UT WOS:000223239100006 PM 15304533 ER PT J AU Shi, YM Li, CL Thomsen, K Jorgensen, TM Knepper, MA Nielsen, S Djurhuus, JC Frokiaer, J AF Shi, YM Li, CL Thomsen, K Jorgensen, TM Knepper, MA Nielsen, S Djurhuus, JC Frokiaer, J TI Neonatal ureteral obstruction alters expression of renal sodium transporters and aquaporin water channels SO KIDNEY INTERNATIONAL LA English DT Article DE obstructive nephropathy; kidney tubules; urinary concentrating capacity; sodium excretion; aquaporin; sodium transporter; rat ID THICK ASCENDING LIMB; MEDULLARY COLLECTING DUCT; RENIN-ANGIOTENSIN SYSTEM; DOWN-REGULATION; NEWBORN RATS; CONCENTRATING DEFECT; NEPHRON SEGMENTS; KIDNEY; HYDRONEPHROSIS; PERMEABILITY AB Background. Congenital urinary tract obstruction is a common cause of renal insufficiency in the neonate and during infancy. Recently, we demonstrated that ureteral obstruction in adult rats is associated with reduction in the abundance of renal aquaporins (AQPs) and renal sodium transporters, which paralleled an impaired urinary concentrating capacity. Methods. In the present study, renal handling of sodium and water, together with the expression of renal aquaporins and major renal sodium transporters, was examined in rats with neonatally induced partial unilateral ureteral obstruction (PUUO) within the first 48 hours of life to clarify the molecular mechanisms involved in the tubular functional defects in response to congenital obstruction. Rats were then followed for 12 or 24 weeks. Results. Neonatal PUUO caused a progressive reduction in single kidney glomerular filtration rate (SKGFR) on the obstructed side to 43% of controls at 12 weeks (115 +/- 28 vs. 267 +/- 36 muL/min/100g bw, P < 0.05), and 31% of controls at 24 weeks (106 &PLUSMN; 24 vs. 343 &PLUSMN; 41 μL/min/100g bw, P < 0.05). Na-K-ATPase abundance was decreased in the obstructed kidney compared with the nonobstructed kidney at 24 weeks (79 +/- 6%, P < 0.05), and the abundance of bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1) located to the medullary thick ascending limb (mTAL) of the obstructed kidney was significantly reduced both at 12 weeks (42 &PLUSMN; 10%, P < 0.05) and 24 weeks (50 +/- 10%, P < 0.05). Immunohistochemistry confirmed down-regulation of BSC-1 both at 12 and 24 weeks after onset of obstruction. Consistent with this, sodium excretion from the obstructed kidney was increased at 12 weeks (0.13 &PLUSMN; 0.03 vs. 0.04 &PLUSMN; 0.01 μmol/min/100g bw, P < 0.05), and persisted 24 weeks after onset of PUUO (0.15 +/- 0.02 vs. 0.06 +/- 0.01 mumol/min/100g bw, P < 0.05). AQP2 abundance in the collecting duct was also reduced both at 12 weeks (68 &PLUSMN; 5%, P < 0.05) and at 24 weeks (69 +/- 13%, P < 0.05). Consistent with this, solute-free water reabsorption was decreased in the obstructed kidney at 12 weeks (0.61 &PLUSMN; 0.42 vs. 1.97 &PLUSMN; 0.63 μL/min/100g bw, P < 0.05) and remained decreased after 24 weeks of PUUO (0.42 +/- 0.04 vs. 1.56 +/- 0.39 muL/min/100g bw, P < 0.05). Conclusion. Major sodium transporters and aquaporins in the obstructed kidney are down-regulated in response to neonatally induced PUUO, which indicates that these transporters may play a crucial role for the persistent reduction in renal handling of sodium and water in response to PUUO. C1 Aarhus Univ, Inst Expt Clin Res, DK-8000 Aarhus, Denmark. Aarhus Univ, Water & Salt Res Ctr, Aarhus, Denmark. Aarhus Univ Hosp, Dept Clin Physiol, DK-8000 Aarhus, Denmark. Aarhus Univ, Inst Anat, Dept Cell Biol, DK-8000 Aarhus, Denmark. Aarhus Univ Hosp, Dept Biol Psychiat, Inst Basic Psychiat Res, DK-8000 Aarhus, Denmark. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Frokiaer, J (reprint author), Univ Aarhus, Aarhus Univ Hosp Skejby, Inst Expt Clin Res, Water & Salt Res Ctr, DK-8200 Aarhus, Denmark. EM JF@IEKF.AU.DK FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 43 TC 23 Z9 29 U1 0 U2 1 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JUL PY 2004 VL 66 IS 1 BP 203 EP 215 DI 10.1111/j.1523-1755.2004.00721.x PG 13 WC Urology & Nephrology SC Urology & Nephrology GA 827NO UT WOS:000221906900021 PM 15200427 ER PT J AU Zalups, RK Aslamkhan, AG Ahmad, S AF Zalups, RK Aslamkhan, AG Ahmad, S TI Human organic anion transporter 1 mediates cellular uptake of cysteine-S conjugates of inorganic mercury SO KIDNEY INTERNATIONAL LA English DT Article DE hOAT1; transport of inorganic mercury; mercuric conjugates; proximal tubule; MDCK cells ID RENAL TUBULAR UPTAKE; LATERAL MEMBRANE-VESICLES; RAT-KIDNEY CELLS; PROXIMAL TUBULE; BASOLATERAL UPTAKE; N-ACETYLCYSTEINE; LUMINAL TRANSPORT; GLUTATHIONE; RABBIT; AMINOHIPPURATE AB Background. The epithelial cells lining the renal proximal tubule have been shown to be the primary cellular targets where mercuric ions gain entry, accumulate, and induce pathologic effects in vivo. Recent data have implicated at least one of the organic anion transport systems in the basolateral uptake of inorganic mercury (Hg2+). Methods. Using a line of Madin-Darby canine kidney (MDCK) II cells transfected stably with the human organic anion transporter 1 (hOAT1), and oocytes from Xenopus laevis microinjected with cRNA for hOAT1, we tested the hypothesis that hOAT1 can transport biologically relevant mercuric conjugates of cysteine (Cys). Results. Indeed, MDCK II cells expressing a functional form of hOAT1 gained the ability to transport the mercuric conjugate 2-Amino-3-(2-amino-2-carboxy- ethylsulfanyl-mercuricsulfanyl)-propionic acid (Cys-S-Hg-S-Cys), but not the corresponding di-glutathione S-conjugate of Hg2+ (G-S-Hg-SG). Moreover, p-aminohippurate (PAH), adipate, and glutarate (but not succinate or malonate) inhibited individually the uptake of Cys-S-Hg-S-Cys in a dose-dependent manner. Uptake of Cys-S-Hg-S-Cys, but not G-S-Hg-S-G, was also documented in Xenopus oocytes expressing hOAT1. Conclusion. These data represent ostensibly the most direct line of evidence implicating a specific membrane protein (i.e., hOAT1) in the transport of a biologically relevant molecular species of Hg2+ in a mammalian cell. Moreover, these data indicate that the organic anion transporter(s) likely play a prominent role in the basolateral transport of mercuric ions by proximal tubular cells and in the nephropathy induced by Hg2+. C1 Mercer Univ, Sch Med, Div Basic Med Sci, Macon, GA 31207 USA. NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Zalups, RK (reprint author), Mercer Univ, Sch Med, Div Basic Med Sci, 1550 Coll St, Macon, GA 31207 USA. EM zalups_rk@mercer.edu FU NIEHS NIH HHS [ES05157, ES05980, ES11288] NR 45 TC 31 Z9 31 U1 1 U2 13 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JUL PY 2004 VL 66 IS 1 BP 251 EP 261 DI 10.1111/j.1523-1755.2004.00726.x PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 827NO UT WOS:000221906900025 PM 15200431 ER PT J AU Francis, ME Eggers, PW Hostetter, TH Briggs, JP AF Francis, ME Eggers, PW Hostetter, TH Briggs, JP TI Association between serum homocysteine and markers of impaired kidney function in adults in the United States SO KIDNEY INTERNATIONAL LA English DT Article DE chronic kidney disease (CKD); cardiovascular disease; folate; B vitamins; NHANES ID GLOMERULAR-FILTRATION RATE; MILD RENAL-INSUFFICIENCY; NUTRITION EXAMINATION SURVEY; TOTAL PLASMA HOMOCYSTEINE; CORONARY-ARTERY DISEASE; 3RD NATIONAL-HEALTH; CARDIOVASCULAR-DISEASE; VASCULAR-DISEASE; DIABETIC-NEPHROPATHY; RISK FACTOR AB Background. Circulating homocysteine, a risk factor for cardiovascular disease (CVD), is often elevated in chronic kidney disease and end-stage renal disease (ESRD) patients. Little is known about the risk of elevated homocysteine associated with less advanced renal insufficiency in the community. Methods. Serum homocysteine concentration measures (umol/L) from the National Health and Nutrition Examination Survey (NHANES) 1991-1994 participants who were aged greater than or equal to40 years and fasted greater than or equal to6 hours (1558 men and 1829 women) were categorized as <9, 9 to 11.9, 12 to 14.9, and &GE;15. Renal function levels were determined by Modified Diet in Renal Disease (MDRD) estimated glomerular filtration rate (GFRest) (mL/min/ 1.73 m(2)) and the urinary albumin-to-creatinine ratio (ACR) (mg/g). Cumulative odds ratios (OR) of exceeding any given homocysteine cut point were computed by gender, using ordinal logistic regression. Each model included GFRest (<60, 60 to 90, greater than or equal to90), ACR (<15, 15 to <30, greater than or equal to30), age, race/ethnicity, red blood cell folate, serum vitamin B-12, and dietary vitamin B-6 intake as independent variables. Results. The adjusted ORs for elevated homocysteine risk were 9 to 11 times greater in adults with the lowest GFRest levels (<60mL/min/1.73 m(2)) compared to those with normal GFRest levels. Association measures for marginal GFRest levels (60 to 90 mL/min/1.73 m(2)) were weaker but significant. Albuminuria (ACR &GE;30 mg/g) was a significant, independent renal risk factor for elevated homocysteine in men and women (adjusted OR = 1.78, 95% CI 1.08-2.93, and adjusted OR = 1.83, 95% CI 1.21-2.76, respectively) relative to those with low normal albumin excretion, but high normal albuminuria (ACR = 15-30 mg/g) was not. Conclusion. In the general population, renal insufficiency is strongly associated with an increased risk of elevated circulating homocysteine, independent of B vitamin status. These results raise the possibility that elevated homocysteine may be an important risk factor to explain the heavy burden of CVD associated with kidney disease. C1 NIDDK, KUH Div, NIH, Bethesda, MD 20892 USA. Social & Sci Syst Inc, Silver Spring, MD USA. RP Briggs, JP (reprint author), NIDDK, KUH Div, NIH, Bldg 31 C,Rm 9A17,31 Ctr Dr, Bethesda, MD 20892 USA. EM Jbriggs@nih.gov RI Briggs, Josephine/B-9394-2009 OI Briggs, Josephine/0000-0003-0798-1190 NR 72 TC 55 Z9 57 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JUL PY 2004 VL 66 IS 1 BP 303 EP 312 DI 10.1111/j.1523-1755.2004.00732.x PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 827NO UT WOS:000221906900032 PM 15200438 ER PT J AU Unruh, M Benz, R Greene, T Yan, GF Beddhu, S DeVita, M Dwyer, JT Kimmel, PL Kusek, JW Martin, A Rehm-McGillicuddy, J Teehan, BP Meyer, KB AF Unruh, M Benz, R Greene, T Yan, GF Beddhu, S DeVita, M Dwyer, JT Kimmel, PL Kusek, JW Martin, A Rehm-McGillicuddy, J Teehan, BP Meyer, KB CA HEMO Study Grp TI Effects of hemodialysis dose and membrane flux on health-related quality of life in the HEMO Study SO KIDNEY INTERNATIONAL LA English DT Article; Proceedings Paper CT Meeting of the American-Society-of-Nephrology CY NOV, 2002 CL Philadelphia, PA SP Amer Soc Nephrol DE clinical trial; hemodialysis; quality of life; dialysis dose; membrane flux ID STAGE RENAL-DISEASE; RECOMBINANT-HUMAN-ERYTHROPOIETIN; PERITONEAL-DIALYSIS PATIENTS; FUNCTIONAL HEALTH; OUTCOMES; MORTALITY; SURVIVAL; SLEEP; BIOCOMPATIBILITY; HOSPITALIZATION AB Background. It has been widely supposed that high dose and high flux hemodialysis would affect the quality as well as the length of life of patients treated by maintenance hemodialysis. The HEMO Study examined changes in health-related quality of life as a secondary study outcome. Specific hypotheses were that study interventions would affect physical functioning, vitality, Short Form-36 Health Survey (SF-36) physical and mental component summary scores, symptoms and problems associated with kidney disease, and sleep quality. Methods. At baseline and annually, subjects responded to both the Index of Well-Being and the Kidney Disease Quality of Life-Long Form questionnaires. The interventions were assessed on the basis of their average effects over 3 years. Results. At baseline, the SF-36 physical component summary score was lower than in healthy populations, but the mental component score was nearly normal. Over 3-year follow-up, physical health continued to decline; mental health and kidney disease-targeted scores remained relatively stable. The high dose hemodialysis intervention was associated with significantly less pain (4.49 points, P < 0.001) and higher physical component scores (1.23 points P = 0.007), but these effects were small compared to the natural variability in scores. High flux membranes were not associated with statistically significant differences in health-related quality of life. Conclusion. The HEMO Study results demonstrate the marked burden of chronic kidney failure and hemodialysis treatment on daily life. In this trial among patients undergoing maintenance three times a week hemodialysis, the SF-36 physical component summary score and pain scale showed significant but very small clinical effects favoring the higher dialysis dose. No clinically meaningful benefits or either the dose or flux interventions were observed for other indices of health-related quality of life. C1 Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15261 USA. Lankenau Hosp & Med Res Ctr, Wynnewood, PA USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Univ Utah, Salt Lake City, UT USA. Vet Affairs Salt Lake City Hlth Care Syst, Salt Lake City, UT USA. Beth Israel Med Ctr, New York, NY 10003 USA. Tufts new England Med Ctr, Boston, MA USA. NIDDKD, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Unruh, M (reprint author), Univ Pittsburgh, Med Ctr, A909 SCaife Hall,3550 Terrace St, Pittsburgh, PA 15261 USA. EM unruh@pitt.edu OI Dwyer, Johanna/0000-0002-0783-1769; Meyer, Klemens/0000-0001-5253-4950 FU NIDDK NIH HHS [T32-DK07777, U01 DK49271] NR 57 TC 108 Z9 111 U1 1 U2 6 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JUL PY 2004 VL 66 IS 1 BP 355 EP 366 DI 10.1111/j.1523-1755.2004.00738.x PG 12 WC Urology & Nephrology SC Urology & Nephrology GA 827NO UT WOS:000221906900038 PM 15200444 ER PT J AU Westergaard, GC Chavanne, TJ Houser, L Cleveland, A Snoy, PJ Suomi, SJ Higley, JD AF Westergaard, GC Chavanne, TJ Houser, L Cleveland, A Snoy, PJ Suomi, SJ Higley, JD TI Biobehavioural correlates of hand preference in free-ranging female primates SO LATERALITY LA English DT Article ID CEREBROSPINAL-FLUID MONOAMINE; MACAQUES MACACA-MULATTA; MALE RHESUS MACAQUES; LEMUR LEMUR-CATTA; PLASMA-CORTISOL; 5-HYDROXYINDOLEACETIC ACID; AMINE METABOLITES; VIOLENT OFFENDERS; NONHUMAN-PRIMATES; FIRE SETTERS AB In this research we examined biological and behavioural correlates of handedness in a subject cohort of 41 free-ranging young female rhesus macaques (Macaca Mulatta). Specifically, we examined relationships between handedness and cerebrospinal fluid (CSF) concentrations of the monoamine metabolites 5-hydroxymcloleacetic acid (5-HIAA) and homovanillic acid (HVA), plasma concentrations of the hormones cortisol and adrenocorticotropin (ACTH), prolactin, and multiple indices of social behaviour, including proximity to other animals, grooming, submission, and aggression. Handedness was determined through systematic observation of animals reaching for food in their unrestricted home environment. We found a population-level bias for left-hand use in this cohort of young females. The frequency of right versus left hand use was positively correlated with CSF 5-HIAA, plasma cortisol concentrations, the frequency of submissive behaviour, and with the frequency of bouts in which animals received low-level aggression. The positive correlation between right versus left hand use, submissive behaviour, and received aggression found here in females contrasts with the negative correlation among these same variables that we have previously reported in rhesus males. We conclude that these results may be explicable in terms of sex-based differences in rhesus life-history patterns, and that the influence of the serotonergic system on patterns of male aggression, social behaviour, and handedness, and the associations between handedness and social behaviour found previously among males may not be generalised to female rhesus macaques. C1 LABS Virginia Inc, Div Res, Yemassee, SC 29902 USA. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. NICHHD, Poolesville, MD USA. NIAAA, Poolesville, MD USA. RP Westergaard, GC (reprint author), LABS Virginia Inc, Div Res, 95 Castle Hall Rd,POB 557, Yemassee, SC 29902 USA. EM Gwprimate@netscape.net FU NIAAA NIH HHS [N01AA02018, N01AA42002] NR 53 TC 10 Z9 10 U1 2 U2 8 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 1357-650X J9 LATERALITY JI Laterality PD JUL PY 2004 VL 9 IS 3 BP 267 EP 285 DI 10.1080/13576500342000086 PG 19 WC Psychology, Multidisciplinary; Psychology, Experimental SC Psychology GA 839RR UT WOS:000222803100002 PM 15341426 ER PT J AU Reio, TG Czarnolewski, M Eliot, J AF Reio, TG Czarnolewski, M Eliot, J TI Handedness and spatial ability: Differential patterns of relationships SO LATERALITY LA English DT Article ID HUMAN MOTOR CORTEX; HAND PREFERENCE; SEX-DIFFERENCES; HEMISPHERIC LATERALIZATION; SELF-REPORT; PERFORMANCE; ORIENTATION; MEMORY; GENDER; CLASSIFICATION AB The purpose of this exploratory study was to add to our understanding of hemispheric specialisation by examining the relationships between functional laterality (as measured by handedness, eyedness, earedness, and footedness) and spatial tests. A total of 55 males and 170 females were tested for laterality preferences and spatial test performance using a range of six spatial tests. There was a statistically significant relationship between each of the laterality measures employed, with handedness and footedness demonstrating the most robust association. Multiple regression analyses highlighted that once potential confounds were statistically controlled (age, sex, and other types of functional laterality), 3-D rotation/visualisation and speeded visual exploration task performance showed small, but significant, relations with a tendency towards left-handedness over right-handedness in total and secondary (two-handed) scale scores. Flexibility of closure performance was associated with a tendency towards left-handedness in the total and one-handed scale scores. Spatial location memory was the lone spatial ability relating with a tendency towards right-handedness. Overall, these Findings offer new insights into the interplay of handedness with alternative measures of laterality as well as with spatial abilities. C1 Univ Louisville, Coll Educ & Human Dev, Louisville, KY 40292 USA. NIMH, Bethesda, MD 20892 USA. Univ Maryland, College Pk, MD 20742 USA. RP Reio, TG (reprint author), Univ Louisville, Coll Educ & Human Dev, Room 331, Louisville, KY 40292 USA. EM thomas.reio@louisville.edu NR 81 TC 10 Z9 11 U1 2 U2 20 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 1357-650X J9 LATERALITY JI Laterality PD JUL PY 2004 VL 9 IS 3 BP 339 EP 358 DI 10.1080/13576500342000220 PG 20 WC Psychology, Multidisciplinary; Psychology, Experimental SC Psychology GA 839RR UT WOS:000222803100007 PM 15341431 ER PT J AU Slape, C Aplan, PD AF Slape, C Aplan, PD TI The role of NUP98 gene fusions in hematologic malignancy SO LEUKEMIA & LYMPHOMA LA English DT Article DE NUP98; HOX; leukemia; myelodysplastic syndrome; 11p15.5 translocation ID ACUTE MYELOID-LEUKEMIA; NUCLEAR-PORE COMPLEX; HOX HOMEOBOX GENES; ACUTE LYMPHOBLASTIC-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; MESSENGER-RNA EXPORT; BONE-MARROW-CELLS; DE-NOVO AML; CHROMOSOME-TRANSLOCATION; HOMEODOMAIN PROTEINS AB Chromosomal aberrations occur with great frequency and some specificity in leukemia and other hematologic malignancies. The most common outcome of these rearrangements is the formation of a fusion gene, comprising portions of 2 genes normally present in the cell. These fusion proteins are presumed to be oncogenic; in many cases, animal models have proven them to be oncogenic. One of the most promiscuous fusion partner genes is the newly identified NUP98 gene, located on chromosome 11p15.5, which to date has been observed fused to 15 different fusion partners. NUP98 encodes a 98 kD protein that is an important component of the nuclear pore complex, which mediates nucleo-cytoplasmic transport of protein and RNA. The fusion partners of NUP98 form 2 distinct groups: homeobox genes and non-homeobox genes. All NUP98 fusions join the N-terminal GLFG repeats of NUP98 to the C-terminal portion of the partner gene, which, in the case of the homeobox gene partners, includes the homeodomain. Clinical findings are reviewed here, along with the findings of several in vivo and in vitro models have been employed to investigate the mechanisms by which NUP98 fusion genes contribute to the pathogenesis of leukemia. C1 NCI, Genet Branch, Ctr Canc Res, NIH,Navy 8, Bethesda, MD 20889 USA. RP Aplan, PD (reprint author), NCI, Genet Branch, Ctr Canc Res, NIH,Navy 8, Room 5101,8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM aplanp@mail.nih.gov RI Slape, Christopher/H-8586-2016; Aplan, Peter/K-9064-2016 OI Slape, Christopher/0000-0002-8407-3092; NR 96 TC 64 Z9 66 U1 0 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD JUL PY 2004 VL 45 IS 7 BP 1341 EP 1350 DI 10.1080/10428190310001659325 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA 819OF UT WOS:000221323800004 PM 15359631 ER PT J AU Chen, ZG Li, SS Yang, JH Letizia, D Shen, J AF Chen, ZG Li, SS Yang, JH Letizia, D Shen, J TI Measurement and automatic correction of high-order B-0 inhomogeneity in the rat brain at 11.7 Tesla SO MAGNETIC RESONANCE IMAGING LA English DT Article DE shimming; EPI; spectroscopy; rat brain ID STATIC MAGNETIC-FIELD; PULSE SEQUENCE; HUMAN HEAD; ADJUSTMENT; REDUCTION; ARTIFACTS; GHOST; COILS; NMR AB In vivo 13, inhomogeneity in the rat brain at 11.7 Tesla was measured and decomposed up to the fourth-order spherical harmonic terms using an automatic slice shimming routine derived from the FLATNESS method. In vivo shimming of horizontal slices showed that significant improvement in the T-2*-weighted echo-planar imaging was achieved after correction of all first-, second- and third-order in-slice shims. For localized proton spectroscopy, reproducible, high quality data were obtained after correcting all first- and second-order shims. The measured high-order in vivo B-o inhomogeneity in terms of spherical harmonic terms should provide a useful guide for designing shims to meet in vivo requirements. (C) 2004 Elsevier Inc. All rights reserved. C1 NIMH, Mol Imaging Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. NIMH, Spect Core Facil, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Shen, J (reprint author), NIMH, Mol Imaging Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. EM shenj@intra.nimh.nih.gov NR 19 TC 39 Z9 39 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD JUL PY 2004 VL 22 IS 6 BP 835 EP 842 DI 10.1016/j.mri.2004.01.062 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 835ON UT WOS:000222493200010 PM 15234452 ER PT J AU Mun, CW Cho, JY Shin, WJ Choi, KS Eun, CK Cha, SS Lee, J Yang, YII Nam, SH Kim, J Lee, SY AF Mun, CW Cho, JY Shin, WJ Choi, KS Eun, CK Cha, SS Lee, J Yang, YII Nam, SH Kim, J Lee, SY TI Ex vivo proton MR spectroscopy (H-1-MRS) for evaluation of human gastric carcinoma SO MAGNETIC RESONANCE IMAGING LA English DT Article DE magnetic resonance spectroscopy (MRS); stomach; gastric tissue; cancer; specimens AB The present study was performed to determine the characteristics of the biochemical metabolites related to gastric cancer using ex vivo H-1 magnetic resonance spectroscopy (MRS), and to assess the clinical usefulness. A total of 35 gastric specimens resected during surgery for gastric cancer were used to compare MR spectra. A 1.5-T (64-MHz) clinical MR imager equipped with facilities for spectroscopy was used to obtain MR spectra from 3 3 gastric specimens. High-resolution H-1 nuclear magnetic resonance (NMR) spectra of the remains of two specimens were also examined with a 9.4-T (400-MHz) NMR spectrometer. Localized spectroscopic measurements were performed in two layers of gastric tissue, the proper muscle layer and the composite mucosa/submucosa layer. T-2 FSE and 3D SPGR images were used to determine the voxel size and the location for MRS data collection. MR spectra were obtained using the single-voxel PRESS technique with parameters of TR/TE = 2000/30 ms, NA = 256, and voxel size = 3 X 3 X 3 mm(3) (27 muL). Cancerous and noncancerous gastric tissues in the voxel were determined by histopathological analysis. On 9.4-T ex vivo NMR spectroscopy, the following metabolite peaks were found: lipids at 0.9 ppm (CH3) and 1.3 ppm (CH2); alanine (beta-CH3) at 1.58 ppm; N-Acetyl neuraminic acid (NANA: sialic acid) at 2.03 ppm; and glutathione at 2.25 ppm in normal gastric tissue layers. In the 1.5-T MR system, broad and featureless spectral peaks of the various metabolites in normal human gastric tissue were observed at 0.9 ppm, 1.3 ppm, 2.0 ppm, and 2.2 ppm regardless of gastric tissue layer. In specimens (Borrmann type III) with tubular adenocarcinoma, resonance peaks were observed at 1.26 ppm, 1.36 ppm (doublet of lactate), and 3.22 ppm (choline). Cancer lesions showed decreased levels of lipid peaks, showing the significant lactate doublet peaks, and increased intensity of the choline peak as compared with noncancerous gastric tissue. We found that decreased levels of lipids and increases in lactate and choline peaks in gastric tissue were markers for malignancy in gastric lesions. Information provided by ex vivo H-1 MRS, together with the development of in vivo H-1 MRS with high field strength and high resolution, may be very useful for the diagnosis of gastric cancer in clinical situation. (C) 2004 Elsevier Inc. All rights reserved. C1 Inje Univ, Dept Biomed Engn, Kyongnam, South Korea. Busan Paik Hosp, Dept Diagnost Radiol, Pusan, South Korea. Inje Univ, Dept Diagnost Radiol, Coll Med, Pusan, South Korea. Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, Natl Inst Hlth, Bethesda, MD USA. Busan Paik Hosp, Dept Pathol, Pusan, South Korea. Paik Inje Mem Inst, Pusan, South Korea. Kyung Hee Univ, Grad Sch EW Med Sci, Kyungki, South Korea. RP Mun, CW (reprint author), Inje Univ, Dept Biomed Engn, Kyongnam, South Korea. EM mcw@bse.inje.ac.kr NR 17 TC 20 Z9 21 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD JUL PY 2004 VL 22 IS 6 BP 861 EP 870 DI 10.1016/j.mri.2004.01.045 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 835ON UT WOS:000222493200014 PM 15234456 ER PT J AU Fourie, L Govender, T Hariprakasha, HK Kruger, HG Raasch, T AF Fourie, L Govender, T Hariprakasha, HK Kruger, HG Raasch, T TI Complete NMR elucidation of a novel trishomocubane hydantoin and its mono- and bis-t-Boc protected derivatives SO MAGNETIC RESONANCE IN CHEMISTRY LA English DT Article DE NMR; H-1 NMR; C-13 NMR; trishomocubane; cage hydantoin; t-Boc protection ID CLEMMENSEN REDUCTION; AMINO-ACIDS; HYDROLYSIS; LACTAMS; MILD; H-1 AB The syntheses of a novel trishomocubane hydantoin and its mono- and bis-protected t-Boc derivatives are described. The less nucleophilic N-3' nitrogen of the hydantoin ring is protected first when treated with ditert-butyl dicarbonate (t-Boc anhydride), possibly owing to steric hindrance by the bulky trishomocubane cage skeleton. More basic conditions were required to form the bis-protected t-Boc hydantoin with the same reagent. The structures of these novel compounds were elucidated with 2D NMR techniques. The proton spectrum of the trishomocubane skeleton is complex owing to major overlap of proton signals. A high-level DFT calculation was used to determine some of the crucial interatomic positions, which assisted with the elucidation of the structures. The assignment of proton and carbon signals of the three structures is described and it differs significantly from each other and also from the trishomocubanol precursor. The bis-Boc hydantoin is required for a more facile hydrolysis to the corresponding trishomocubane amino acid at room temperature. Copyright (C) 2004 John Wiley Sons, Ltd. C1 Univ Kwazulu Natal, Dept Chem, ZA-4041 Durban, South Africa. Potchefstroom Univ Christian Higher Educ, Dept Chem, ZA-2520 Potchefstroom, South Africa. NCI, Frederick, MD 21702 USA. RP Kruger, HG (reprint author), Univ Kwazulu Natal, Dept Chem, ZA-4041 Durban, South Africa. EM kruger@ukzn.ac.za RI Govender, Thavendran/H-6838-2013; Kruger, Gert/B-1687-2009 OI Govender, Thavendran/0000-0003-2511-2503; Kruger, Gert/0000-0003-0606-2053 NR 24 TC 15 Z9 15 U1 2 U2 11 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0749-1581 J9 MAGN RESON CHEM JI Magn. Reson. Chem. PD JUL PY 2004 VL 42 IS 7 BP 617 EP 623 DI 10.1002/mrc.1397 PG 7 WC Chemistry, Multidisciplinary; Chemistry, Physical; Spectroscopy SC Chemistry; Spectroscopy GA 833MW UT WOS:000222342600008 PM 15181632 ER PT J AU Keilholz, SD Silva, AC Raman, M Merkle, H Koretsky, AP AF Keilholz, SD Silva, AC Raman, M Merkle, H Koretsky, AP TI Functional MRI of the rodent somatosensory pathway using multislice echo planar imaging SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE fMRI; BOLD; somatosensory stimulation; multislice ID CEREBRAL-BLOOD-FLOW; RAT OLFACTORY-BULB; BOLD FMRI; FOREPAW STIMULATION; ANESTHETIZED RATS; SIGNAL CHANGES; 9.4 T; BRAIN; ACTIVATION; RESOLUTION AB A multislice EPI sequence was used to obtain functional MR images of the entire rat brain with BOLD contrast at 11.7 T. Ten to 11 slices covering the rat brain, with an in-plane resolution of 300 mum, provided enough sensitivity to detect activation in brain regions known to be involved in the somatosensory pathway during stimulation of the forelimbs. These regions were identified by warping a digitized rat brain atlas to each set of images. Data analysis was constrained to four major areas of the somatosensory pathway: primary and secondary somatosensory cortices, thalamus, and cerebellum. Incidence maps were generated. Electrical stimulation at 3 Hz led to significant activation in the primary sensory cortex in all rats. Activation in the secondary sensory cortex and cerebellum was observed in 70% of the studies, while thalamic activation was observed in 40%. The amplitude of activation was measured for each area, and average response time courses were calculated. Finally, the frequency dependence of the response to forepaw stimulation was measured in each of the activated areas. Optimal activation occurred in all areas at 3 Hz. These results demonstrate that whole-brain fMRI can be performed on rodents at 11.7 T to probe a well-defined neural network. Published 2004 Wiley-Liss, Inc.(dagger). C1 NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Koretsky, AP (reprint author), NINDS, Lab Funct & Mol Imaging, NIH, 10 Ctr Dr,10 B1D118,MSC 1065, Bethesda, MD 20892 USA. EM KoretskyA@ninds.nih.gov RI Silva, Afonso/A-7129-2009; Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU Intramural NIH HHS [Z01 NS002989-08] NR 40 TC 68 Z9 69 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD JUL PY 2004 VL 52 IS 1 BP 89 EP 99 DI 10.1002/mrm.20114 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 835NY UT WOS:000222491700013 PM 15236371 ER PT J AU Xi, ZX Wu, GH Stein, EA Li, SJ AF Xi, ZX Wu, GH Stein, EA Li, SJ TI Opiate tolerance by heroin self-administration: An MRI study in rat SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE heroin; GABA; gamma-vinyl GABA; fMRI; BOLD; tolerance ID INDUCED BRAIN ACTIVATION; NUCLEUS-ACCUMBENS; BEHAVIORAL SENSITIZATION; FUNCTIONAL MRI; GABAERGIC MECHANISMS; INTRAVENOUS HEROIN; COCAINE ADDICTION; SEEKING BEHAVIOR; G-PROTEINS; DOPAMINE AB Functional MRI (fMRI) was employed to determine whether repeated heroin self-administration (SA) produces tolerance or sensitization in the brain of heroin-SA rats. Twelve rats were evenly divided into saline and heroin (0.06 mg/kg, 4 hr/day) SA groups. There was a progressive increase in drug-SA behavior and daily heroin intake during the 8-9 days of heroin-SA training. Within 24 hr after the last session of daily SA, acute heroin (0.1 mg/kg) administration induced regional blood oxygen level-dependent (BOLD) signals in both groups of rats. The positive BOLD signals appeared mainly in the cortical regions, including the prefrontal cortex, cingulate, and olfactory cortex, while the negative BOLD signals were predominantly located in subcortical regions such as caudate and putamen, nucleus accumbens, thalamus, and hypothalamus. However, the number of activated voxels or BOLD-signal intensity was significantly less in heroin-SA rat in regions of prefrontal cortex, nucleus accumbens, and thalamus, etc., compared to the changes in the saline control rats. Application of gamma-vinyl GABA (100 mg/kg), an irreversible GABA-transaminase inhibitor, failed to block opiate actions in the heroin-SA rats. Together, these data suggest that repeated heroin-SA produces tolerance or desensitization of opiate actions in the rat brain, which may in turn potentiate drug SA behavior and drug intake. (C) 2004 Wiley-Liss, Inc. C1 Med Coll Wisconsin, Dept Biophys, Milwaukee, WI 53226 USA. NIDA, Intramural Res Program, NIH, Baltimore, MD USA. RP Li, SJ (reprint author), Med Coll Wisconsin, Dept Biophys, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM sjli@mcw.edu RI Stein, Elliot/C-7349-2008 FU NIBIB NIH HHS [EB01820, R01 EB001820]; NIDA NIH HHS [DA10214, DA09465, R01 DA009465, R01 DA010214] NR 43 TC 17 Z9 18 U1 2 U2 8 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD JUL PY 2004 VL 52 IS 1 BP 108 EP 114 DI 10.1002/mrm.20119 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 835NY UT WOS:000222491700015 PM 15236373 ER PT J AU Reeder, SB Herzka, DA McVeigh, ER AF Reeder, SB Herzka, DA McVeigh, ER TI Signal-to-noise ratio behavior of steady-state free precession SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE SSFP; SNR; cardiac MRI; gradients; efficiency; fast imaging; real-time imaging ID MAGNETIC-RESONANCE; CARDIAC-FUNCTION; BREATH-HOLD; MRI; HEART; RECONSTRUCTION; SEQUENCE; SSFP AB Steady-state free precession (SSFP) is a rapid gradient-echo imaging technique that has recently gained popularity and is used in a variety of applications, including cardiac and real-time imaging, because of its high signal and favorable contrast between blood and myocardium. The purpose of this work was to examine the signal-to-noise ratio (SNR) behavior of images acquired with SSFP, and the dependence of SNR on imaging parameters such as TR, bandwidth, and image resolution, and the use of multi-echo sequences. In this work it is shown that the SNR of SSFP sequences is dependent only on pulse sequence efficiency, voxel dimensions, and relaxation parameters (T-1 and T-2). Notably, SNR is insensitive to bandwidth unless increases in bandwidth significantly decrease efficiency. Finally, we examined the relationship between pulse sequence performance (TR and efficiency) and gradient performance (maximum gradient strength and slew rate) for several imaging scenarios, including multi-echo sequences, to determine the optimum matching of maximum gradient strength and slew rate for gradient hardware designs. For standard modern gradient hardware (40 mT/m and 150 mT/m/ms), we found that the maximum gradient strength is more than adequate for the imaging resolution that is commonly encountered with rapid scouting (3 mm x 4 mm x 10 mm voxel). It is well matched for typical CINE and real-time cardiac imaging applications (1.5 mm x 2 mm x 6 mm voxel), and is inadequate for optimal matching with slew rate for high-resolution applications such as musculoskeletal imaging (0.5 x 0.8 x 3 mm voxel). For the lower-resolution methods, efficiency could be improved with higher slew rates; this provokes interest in designing methods for limiting dB/dt peripherally while achieving high switching rates in the imaging field of view. The use of multi-echo SSFP acquisitions leads to substantial improvements in sequence performance (i.e., increased efficiency and shorter TR). Published 2004 Wiley-Liss, Inc.(dagger). C1 Stanford Univ, Med Ctr, Dept Radiol, Palo Alto, CA 94304 USA. Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA. NHLBI, Cardiac Energet Lab, NIH, DHHS, Bethesda, MD USA. RP Reeder, SB (reprint author), Stanford Univ, Med Ctr, Dept Radiol, Rm H1307,300 Pasteur Ave, Palo Alto, CA 94304 USA. EM sreeder@stanford.edu OI Herzka, Daniel/0000-0002-9400-7814; Reeder, Scott/0000-0003-4728-8171 FU Intramural NIH HHS [Z01 HL004608-08] NR 30 TC 25 Z9 25 U1 1 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD JUL PY 2004 VL 52 IS 1 BP 123 EP 130 DI 10.1002/mrm.20126 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 835NY UT WOS:000222491700017 PM 15236375 ER PT J AU Talagala, SL Ye, FQ Ledden, PJ Chesnick, S AF Talagala, SL Ye, FQ Ledden, PJ Chesnick, S TI Whole-brain 3D perfusion MRI at 3.0 T using CASL with a separate labeling coil SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE perfusion MRI; arterial spin labeling; human brain; cerebral blood flow; separate labeling coil ID CEREBRAL-BLOOD-FLOW; STEADY-STATE; MULTISLICE PERFUSION; IMAGING TECHNIQUES; ARTERIAL WATER; FAIR TECHNIQUE; SIGNAL; SENSITIVITY; INVERSION; HUMANS AB A variety of continuous and pulsed arterial spin labeling (ASL) perfusion MRI techniques have been demonstrated in recent years. One of the reasons these methods are still not routinely used is the limited extent of the imaging region. Of the ASL methods proposed to date, continuous ASL (CASL) with a separate labeling coil is particularly attractive for whole-brain studies at high fields. This approach can provide an increased signal-to-noise ratio (SNR) in perfusion images because there are no magnetization transfer (MT) effects, and lessen concerns regarding RF power deposition at high field because it uses a local labeling coil. In this work, we demonstrate CASL whole-brain quantitative perfusion imaging at 3.0 T using a combination of strategies: 3D volume acquisition, background tissue signal suppression, and a separate labeling coil. The results show that this approach can be used to acquire perfusion images in all brain regions with good sensitivity. Further, it is shown that the method can be performed safely on humans without exceeding the current RF power deposition limits. The current method can be extended to higher fields, and further improved by the use of multiple receiver coils and parallel imaging techniques to reduce scan time or provide increased resolution. C1 NINDS, NIH, Bethesda, MD USA. NIMH, NIH, Bethesda, MD USA. Nova Med Inc, Wakefield, MA USA. NHLBI, NIH, Bethesda, MD USA. RP Talagala, SL (reprint author), MRI Res Facil, NIH, 10 Ctr Dr,Room B1D69, Bethesda, MD 20892 USA. EM talagala@nih.gov NR 40 TC 80 Z9 81 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD JUL PY 2004 VL 52 IS 1 BP 131 EP 140 DI 10.1002/mrm.20124 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 835NY UT WOS:000222491700018 PM 15236376 ER PT J AU Depinay, JMO Mbogo, CM Killeen, G Knols, B Beier, J Carlson, J Dushoff, J Billingsley, P Mwambi, H Githure, J Toure, AM McKenzie, FE AF Depinay, JMO Mbogo, CM Killeen, G Knols, B Beier, J Carlson, J Dushoff, J Billingsley, P Mwambi, H Githure, J Toure, AM McKenzie, FE TI A simulation model of African Anopheles ecology and population dynamics for the analysis of malaria transmission SO MALARIA JOURNAL LA English DT Article ID SENSU-STRICTO DIPTERA; WESTERN KENYA; BODY-SIZE; GAMBIAE COMPLEX; LARVAL SURVIVAL; CULICIDAE; TEMPERATURE; HABITATS; DENSITY; ARABIENSIS AB Background: Malaria is one of the oldest and deadliest infectious diseases in humans. Many mathematical models of malaria have been developed during the past century, and applied to potential interventions. However, malaria remains uncontrolled and is increasing in many areas, as are vector and parasite resistance to insecticides and drugs. Methods: This study presents a simulation model of African malaria vectors. This individual-based model incorporates current knowledge of the mechanisms underlying Anopheles population dynamics and their relations to the environment. One of its main strengths is that it is based on both biological and environmental variables. Results: The model made it possible to structure existing knowledge, assembled in a comprehensive review of the literature, and also pointed out important aspects of basic Anopheles biology about which knowledge is lacking. One simulation showed several patterns similar to those seen in the field, and made it possible to examine different analyses and hypotheses for these patterns; sensitivity analyses on temperature, moisture, predation and preliminary investigations of nutrient competition were also conducted. Conclusions: Although based on some mathematical formulae and parameters, this new tool has been developed in order to be as explicit as possible, transparent in use, close to reality and amenable to direct use by field workers. It allows a better understanding of the mechanisms underlying Anopheles population dynamics in general and also a better understanding of the dynamics in specific local geographic environments. It points out many important areas for new investigations that will be critical to effective, efficient, sustainable interventions. C1 NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. Kenya Govt Med Res Ctr, Ctr Geog Med Res Coast, Kilifi, Kenya. Int Ctr Insect Physiol & Ecol, Nairobi, Kenya. Ifakara Hlth Res & Dev Ctr, Ifakara, Kilombero Distr, Tanzania. IAEA, Agr & Biotechnol Lab, FAO, Entomol Unit, A-2444 Seibersdorf, Austria. Univ Miami, Global Publ Hlth Program, Miami, FL 33177 USA. Tulane Univ, New Orleans, LA 70118 USA. Univ Aberdeen, Aberdeen AB24 2TZ, Scotland. Univ Natal, Sch Math Stat & IT, ZA-3209 Pietermaritzburg, South Africa. Malaria Res & Training Ctr, Fac Med Pharm & Dent, Bamako, Mali. RP Depinay, JMO (reprint author), NIH, Fogarty Int Ctr, 16 Ctr Dr, Bethesda, MD 20892 USA. EM depinayj@mail.nih.gov; cmbogo@kilifi.mimcom.net; gkilleen@ifakara.mimcom.net; B.Knols@iaea.org; JBeier@med.miami.edu; jcarlso@tulane.edu; dushoff@eno.princeton.edu; p.billingsley@abdn.ac.uk; MwambiH@nu.ac.za; jgithure@icipe.org; atoure@MRTCBKO.org; em225k@nih.gov RI Mwambi, Henry /A-2444-2013 FU Intramural NIH HHS [Z99 TW999999] NR 32 TC 92 Z9 92 U1 2 U2 20 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD JUL PY 2004 VL 3 AR 29 DI 10.1186/1475-2875-3-29 PG 21 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 849JY UT WOS:000223536100001 PM 15285781 ER PT J AU Talman, AM Domarle, O McKenzie, FE Ariey, F Robert, V AF Talman, AM Domarle, O McKenzie, FE Ariey, F Robert, V TI Gametocytogenesis: the puberty of Plasmodium falciparum SO MALARIA JOURNAL LA English DT Review ID HUMAN MALARIA PARASITE; INTERCELLULAR-ADHESION MOLECULE-1; PAPUA-NEW-GUINEA; INFECTED ERYTHROCYTES; ANOPHELES-GAMBIAE; SEX-RATIO; TRANSMISSION STAGES; IN-VITRO; MEMBRANE GLYCOPROTEIN; CONTINUOUS CULTURE AB The protozoan Plasmodium falciparum has a complex life cycle in which asexual multiplication in the vertebrate host alternates with an obligate sexual reproduction in the anopheline mosquito. Apart from the apparent recombination advantages conferred by sex, P. falciparum has evolved a remarkable biology and adaptive phenotypes to insure its transmission despite the dangers of sex. This review mainly focuses on the current knowledge on commitment to sexual development, gametocytogenesis and the evolutionary significance of various aspects of gametocyte biology. It goes further than pure biology to look at the strategies used to improve successful transmission. Although gametocytes are inevitable stages for transmission and provide a potential target to fight malaria, they have received less attention than the pathogenic asexual stages. There is a need for research on gametocytes, which are a fascinating stage, responsible to a large extent for the success of P. falciparum. C1 Inst Pasteur Madagascar, Grp Rech Paludisme, Antananarivo 101, Madagascar. Univ London Imperial Coll Sci Technol & Med, Dept Biol Sci, London SW7 2AZ, England. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. Inst Rech Dev, Antananarivo, Madagascar. RP Robert, V (reprint author), Inst Pasteur Madagascar, Grp Rech Paludisme, BP 1274, Antananarivo 101, Madagascar. EM arthur.talman@imperial.ac.uk; domarle@pasteur.mg; mckenzel@mail.nih.gov; ariey@pasteur.mg; robert@pasteur.mg OI Talman, Arthur/0000-0003-2584-3672 FU Intramural NIH HHS [Z99 TW999999] NR 160 TC 97 Z9 98 U1 2 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD JUL PY 2004 VL 3 AR 24 DI 10.1186/1475-2875-3-24 PG 14 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 849JY UT WOS:000223536100006 PM 15253774 ER PT J AU Bohr, VA Metter, EJ Harrigan, JA von Kobbe, C Liu, JL Gray, MD Majumdar, A Wilson, DA Seidman, MM AF Bohr, VA Metter, EJ Harrigan, JA von Kobbe, C Liu, JL Gray, MD Majumdar, A Wilson, DA Seidman, MM TI Werner syndrome protein 1367 variants and disposition towards coronary artery disease in Caucasian patients SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article DE Werner syndrome; helicase; nuclease; genetic polymorphism; coronary artery disease ID DNA HELICASE; NUCLEAR-LOCALIZATION; JAPANESE POPULATION; POLYMORPHIC VARIANT; AGING PROCESS; GENE; ASSOCIATION; SEQUENCE; BINDING; LOCUS AB The leading causes of death for individuals with Werner syndrome (WS) are myocardial infarction (MI) and stroke. The WS gene encodes a nuclear protein with both helicase and exonuclease activities. While individuals with WS have mutations that result in truncated, inactive proteins, several sequence variants have been described in apparently unaffected individuals. Some of these gene polymorphisms encode non-conservative amino acid substitutions, and it is expected that the changes would affect enzyme activity, although this has not been determined. Two research groups have studied the Cys/Arg 1367 polymorphism (located near the nuclear localization signal) in healthy and MI patients. Their results suggest that the Arg allele is protective against MI. We have characterized the Cys (C) and Arg (R) forms of the protein and find no notable difference in helicase and nuclease activities, or in nuclear/cytoplasmic distribution. The frequency of the C/R alleles in healthy individuals and subjects with coronary artery disease (CAD) drawn from the Baltimore Longitudinal Study of Aging (BLSA) was also examined. There was no indication that the R allele was protective against CAD. We conclude that the C/R polymorphism does not affect enzyme function or localization and does not influence CAD incidence in the BLSA cohort. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. NIA, Clin Resource Branch, NIH, Baltimore, MD 21224 USA. MDG Associates, Seattle, WA 98126 USA. RP Seidman, MM (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM seidmanm@grc.nia.nih.gov NR 22 TC 22 Z9 23 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD JUL PY 2004 VL 125 IS 7 BP 491 EP 496 DI 10.1016/j.mad.2004.05.001 PG 6 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 842FQ UT WOS:000222989200004 PM 15246744 ER PT J AU Yang, QE AF Yang, QE TI Eradication of HIV in infected patients: Some potential approaches SO MEDICAL SCIENCE MONITOR LA English DT Review DE human immunodeficiency virus (HIV); eradication of HIV; antiretroviral therapy; persistent infection; cytotoxic chemotherapy; immunoactivation; gene therapy ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; T-CELL RESPONSES; BONE-MARROW-TRANSPLANTATION; BLOOD MONONUCLEAR-CELLS; ACUTE LYMPHOBLASTIC-LEUKEMIA; MONOCLONAL-ANTIBODY THERAPY; RANDOMIZED CONTROLLED-TRIAL; NON-HODGKIN-LYMPHOMA; RNA DAMAGING AGENTS AB Although at present, highly active antiretroviral therapy (HAART) has greatly reduced the number of viral copies to an undetectable level and has slowed down the progress of the disease in patients with human immunodeficiency virus (HIV) infection, the HIV infected cells are not eradicated by this therapy. Virus replication rebounds once the drug therapy is terminated, regardless of duration of the therapy, primarily due to the establishment of a viral reservoir. Therefore, viral suppressive therapy is a lifelong task and may be accompanied by many as yet unidentified serious side effects. In addition, the maximum therapeutic benefits of HAART appear to have been reached recently in the U. S, and the incidences of multi-drug resistant viral strain infections are slowly but steadily increasing. Without an effective vaccine, which has already proved to be very difficult to develop, for the protection of the uninfected population and a feasible eradication strategy to cure infected patients, the number of HIV infected persons will inevitably continue to rise. While the vast majority of endeavors are focused on developing new drugs that target different steps of HIV replication for suppressive therapy, researchers need to find a therapeutic strategy that directly aims at HIV infected cells to cure the disease. In this article, I review and discuss some potential approaches to eradicate HIV infected cells from the patients. C1 SAIC Frederick Inc, Lab Antiviral Drug Mech, NCI, Frederick, MD 21702 USA. RP Yang, QE (reprint author), SAIC Frederick Inc, Lab Antiviral Drug Mech, NCI, Bldg 440, Frederick, MD 21702 USA. EM yangq@dtpax2.ncifcrf.gov FU PHS HHS [N01-C0-12400] NR 170 TC 10 Z9 10 U1 0 U2 0 PU INT SCIENTIFIC LITERATURE, INC PI ALBERTSON PA 1125 WILLIS AVE, ALBERTSON, NY 11507 USA SN 1234-1010 J9 MED SCI MONITOR JI Med. Sci. Monitor PD JUL PY 2004 VL 10 IS 7 BP RA155 EP RA165 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 867HP UT WOS:000224833600025 PM 15232518 ER PT J AU Musso, C Cochran, E Moran, SA Skarulis, MC Oral, A Taylor, S Gorden, P AF Musso, C Cochran, E Moran, SA Skarulis, MC Oral, A Taylor, S Gorden, P TI Clinical course of genetic diseases of the insulin receptor (Type A and Rabson-Mendenhall syndromes) - A 30-year prospective SO MEDICINE LA English DT Article ID GROWTH-FACTOR-I; POLYCYSTIC-OVARY-SYNDROME; DOMINANT-NEGATIVE MUTATIONS; TYROSINE KINASE-ACTIVITY; ACANTHOSIS NIGRICANS; CULTURED LYMPHOCYTES; MUTANT ALLELES; PRENATAL-DIAGNOSIS; RESISTANT PATIENTS; DIABETES-MELLITUS AB The interaction of insulin with its cell surface receptor is the first step in insulin action and the first identified target of insulin resistance. The insulin resistance in several syndromic forms of extreme insulin resistance has been shown to be caused by mutations in the receptor gene. We studied 8 female patients with the type A form of extreme insulin resistance and 3 patients (2 male and 1 female) with the Rabson-Mendenhall syndrome and followed the natural history of these patients for up to 30 years. The 11 patients ranged in age from 7 to 32 years at presentation. All 11 patients had extreme insulin resistance, acanthosis nigricans, and hyperandrogenism in the female patients, and all but I were of normal body weight. This phenotype strongly predicts mutations in the insulin receptor of the 8 patients Studied, 7 were found to have mutations. Similar results from the literature are found in other patients with type A and Rabson-Mendenhall syndrome; and leprechaunism. The hyperandrogenic state resulting from hyperinsulinemia and insulin resistance in these patients was extreme: 6 of 8 patients had ovarian surgery to correct the polycystic ovarian syndrome and elevation of serum testosterone. By contrast, a larger group of insulin-resistant patients who were obese with hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN syndrome) did not have a high probability of mutations in the insulin receptor. The morbidity and mortality of these patients were high: 3 of 11 died, 9 of 11 were diabetic and 1 had impaired glucose tolerance, and 7 of 9 patients had 1 or more severe complication of diabetes. Our literature review revealed 1 hat the mortality of leprechaunism is so high that the term leprechaunism should be restricted to infants or young children under 2 years of age. Analogous to patients with the common forms of type 2 diabetes, these patients had a heterogeneous course. In 2 patients who were able to maintain extremely high endogenous insulin production, the fasting blood glucose remained normal even though post-glucose-challenge levels were elevated. Most patients, however, required large doses of exogenous insulin to ameliorate the severe hyperglycemia. Preliminary results of a recent study suggest that recombinant leptin administration may benefit these patients with severe insulin resistance. C1 NIDDK, NIH, Bethesda, MD 20892 USA. Bristol Myers Squibb Co, Princeton, NJ 08543 USA. Univ Michigan, Dept Internal Med, Div Endocrinol & Metab, Ann Arbor, MI 48109 USA. RP Musso, C (reprint author), NIDDK, NIH, Bldg 10,Rm 8D20,10 ctr Dr,MSC 1770, Bethesda, MD 20892 USA. EM carlam@intra.nid.dk.nih.gov OI Oral, Elif/0000-0002-9171-1144 NR 98 TC 91 Z9 103 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7974 J9 MEDICINE JI Medicine (Baltimore) PD JUL PY 2004 VL 83 IS 4 BP 209 EP 222 DI 10.1097/01.md.0000133625.73570.54 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 839VO UT WOS:000222813200001 PM 15232309 ER PT J AU Treuth, MS Schmitz, K Catellier, DJ McMurray, RG Murray, DM Almeida, MJ Going, S Norman, JE Pate, R AF Treuth, MS Schmitz, K Catellier, DJ McMurray, RG Murray, DM Almeida, MJ Going, S Norman, JE Pate, R TI Defining accelerometer thresholds for activity intensities in adolescent girls SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE activity monitors; energy expenditure; physical activity assessment; fitness; oxygen consumption ID PHYSICAL-ACTIVITY MONITORS; CHILDREN; CALIBRATION; YOUTH; INTERVENTION; VALIDATION; HEALTH AB Purpose: To derive a regression equation that estimates metabolic equivalent (MET) from accelerometer counts, and to define thresholds of accelerometer counts that can be used to delineate sedentary, light, moderate, and vigorous activity in adolescent girls. Methods: Seventy-four healthy 8th grade girls, age 13-14 yr, were recruited from urban areas of Baltimore, MD, Minneapolis/St. Paul, MN, and Columbia, SC, to participate in the study. Accelerometer and oxygen consumption (VO2) data for 10 activities that varied in intensity from sedentary (e.g., TV watching) to vigorous (e.g., running) were collected. While performing these activities, the girls wore two accelerometers, a heart rate monitor and a Cosmed K4b2 portable metabolic unit for measurement of VO2. A random-coefficients model was used to estimate the relationship between accelerometer counts and VO2. Activity thresholds were defined by minimizing the false positive and false negative classifications. Results: The activities provided a wide range in VO2 (3-36 mL.kg(-1).min(-1)) with a correspondingly wide range in accelerometer counts (1-3928 counts.30 s(-1)). The regression line for MET score versus counts was MET = 2.01 + 0.00171 (counts.30 s(-1)) (mixed model R-2 = 0.84, SEE = 1.36). A threshold of 1500 counts.30 s(-1) defined the lower end of the moderate intensity (similar to4.6 METs) range of physical activity. That cutpoint distinguished between slow and brisk walking, and gave the lowest number of false positive and false negative classifications. The threshold ranges for sedentary, light, moderate, and vigorous physical activity were found to be 0-50, 51-1499, 1500-2600, and >2600 counts.30 s(-1), respectively. Conclusion: The developed equation and these activity thresholds can be used for prediction of MET score from accelerometer counts and participation in various intensities of physical activity in adolescent girls. C1 Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Human Nutr, Baltimore, MD 21205 USA. Univ Minnesota, Div Epidemiol, Minneapolis, MN 55455 USA. Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. Univ Memphis, Dept Psychol, Memphis, TN 38152 USA. Univ S Carolina, Dept Exercise Sci, Columbia, SC 29208 USA. Univ Arizona, Dept Nutr, Tucson, AZ USA. NHLBI, Bethesda, MD 20892 USA. RP Treuth, MS (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Human Nutr, 615 N Wolfe St, Baltimore, MD 21205 USA. EM mtreuth@jhsph.edu RI Schmitz, Kathryn/B-7154-2011 NR 28 TC 302 Z9 308 U1 1 U2 29 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD JUL PY 2004 VL 36 IS 7 BP 1259 EP 1266 DI 10.1249/01.MSS.0000074670.03001.98 PG 8 WC Sport Sciences SC Sport Sciences GA 836WC UT WOS:000222585700026 ER PT J AU Stefan, N Weyer, C Levy-Marchal, C Stumvoll, M Knowler, WC Tataranni, PA Bogardus, C Pratley, RE AF Stefan, N Weyer, C Levy-Marchal, C Stumvoll, M Knowler, WC Tataranni, PA Bogardus, C Pratley, RE TI Endogenous glucose production, insulin sensitivity, and insulin secretion in normal glucose-tolerant Pima Indians with low birth weight SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID INTRAUTERINE GROWTH-RETARDATION; DEPENDENT DIABETES-MELLITUS; X-RAY ABSORPTIOMETRY; BETA-CELL MASS; FETAL-GROWTH; ADULT LIFE; METABOLIC CHARACTERISTICS; ENDOCRINE PANCREAS; GESTATIONAL-AGE; RESISTANCE AB Individuals with low birth weight (LBW) are at increased risk of developing type 2 diabetes in later life. Whether impairments in endogenous glucose production (EGP), insulin action, insulin secretion, or a combination thereof account for this association is unclear. We, therefore, examined these parameters in Pima Indians with normal glucose tolerance. Body composition, glucose and insulin responses during a 75-g oral glucose tolerance test (OGTT), EGP, insulin-stimulated glucose disposal during low- and high-dose insulin infusion (M-low and M-high, hyperinsulinemic glucose clamp), and acute insulin response (AIR) to a 25-g intravenous glucose challenge were measured in 230 Pima Indians (147 men and 83 women, aged 25 +/- 0.4 years [mean SE; range, 18 to 44]) with normal glucose tolerance. A subgroup of 63 subjects additionally underwent biopsies of subcutaneous adipose tissue for determination of adipocyte cell size and lipolysis. Subjects in the lowest quartile of birth weight (birth weight: 2,891 +/- 33 g, LBW, n = 58) were compared to those whose birth weight was in the upper 3 quartiles (birth weight: 3,657 +/- 28 g, NBW, n = 172). Age- and sex-adjusted body mass index (BMI), percent body fat, and waist-to-thigh ratio (WTR) were similar in LBW and NBW subjects. Suppression of EGP during the clamp was less in LBW than in NBW subjects before (P = .002) and after adjustment for age, sex, percent body fat, and M-low (P = .02). M-low and M-high were less in LBW than in NBW subjects before (P = .05 and P = .01) and after adjustment for age, sex, percent body fat, and WTR (P = .04 and P = .05). AIR was not different in LBW compared to NBW subjects before adjustments (P = .06), but it was lower in LBW than in NBW subjects after adjustment for age, sex, percent body fat, and M-low (P = .02), suggesting that AIR did not increase appropriately for the decrease in insulin-stimulated glucose disposal (M). In addition, average adipocyte cell size (P = .08) and basal lipolysis (P = .02) were higher in the LBW than in the NBW group. These results show that Pima Indians with LBW manifest a variety of impairments in metabolism in adulthood. Among these, a lesser insulin-stimulated suppression of EGP and a lesser insulin secretory capacity are the predominant ones. We conclude that interaction of multiple defects may contribute to increased susceptibility to type 2 diabetes among individuals with LBW. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Tubingen, Dept Internal Med, D-72076 Tubingen, Germany. NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. Hop Robert Debre, INSERM, Unit 457, F-75019 Paris, France. RP Stefan, N (reprint author), Univ Tubingen, Dept Internal Med, Otfried Muller Str 10, D-72076 Tubingen, Germany. OI Stefan, Norbert/0000-0002-2186-9595 NR 61 TC 16 Z9 17 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 0026-0495 J9 METABOLISM JI Metab.-Clin. Exp. PD JUL PY 2004 VL 53 IS 7 BP 904 EP 911 DI 10.1016/j.metabol.2004.01.014 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 841EP UT WOS:000222912400014 PM 15254885 ER PT J AU Ramirez, NE Ward, LA Sreevatsan, S AF Ramirez, NE Ward, LA Sreevatsan, S TI A review of the biology and epidemiology of cryptosporidiosis in humans and animals SO MICROBES AND INFECTION LA English DT Review DE Crytosporidium spp.; livestock; companion animals; prevention ID N. SP APICOMPLEXA; SURFACE-WATER SUPPLIES; RIBOSOMAL-RNA GENE; PARVUM OOCYSTS; UNITED-STATES; STOOL SPECIMENS; MOLECULAR CHARACTERIZATION; EQUINE CRYPTOSPORIDIUM; LACTOBACILLUS-REUTERI; MONOCLONAL-ANTIBODIES AB The epidemiology of cryptosporidiosis, an infection caused by several genotypically and phenotypically diverse Cryptosporidium species, has been dynamically changing over the past decade from that of a rare, largely asymptomatic infection to an acute enteric disease of animals and humans. In this review, the current understanding of factors (biology and epidemiology) contributing to the emergence of cryptosporidiosis in animals, including parasite biology, genetic diversity, environmental spread, livestock production trends, presence of the parasite in livestock and companion animals, and potential risk of transmission from animals to humans is highlighted. Potential control measures and the role of veterinary and medical professionals in the prevention of cryptosporidiosis are also discussed. (C) 2004 Elsevier SAS. All rights reserved. C1 Ohio State Univ, Coll Vet Med, Ohio Agr Res & Dev Ctr, Food Anim Hlth Res Program,Dept Vet Prevent Med, Wooster, OH 44691 USA. NIAID, Div Extramural Act, NIH, Bethesda, MD 20892 USA. RP Sreevatsan, S (reprint author), Ohio State Univ, Coll Vet Med, Ohio Agr Res & Dev Ctr, Food Anim Hlth Res Program,Dept Vet Prevent Med, FAHRP Bldg,1680 Madison Ave, Wooster, OH 44691 USA. EM sreevatsan.1@osu.edu OI Sreevatsan, Srinand/0000-0002-5162-2403 NR 167 TC 79 Z9 86 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD JUL PY 2004 VL 6 IS 8 BP 773 EP 785 DI 10.1016/j.micinf.2004.02.021 PG 13 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 836QN UT WOS:000222570700008 PM 15207825 ER PT J AU Fujita, M Akari, H Sakurai, A Yoshida, A Chiba, T Tanaka, K Strebel, K Adachi, A AF Fujita, M Akari, H Sakurai, A Yoshida, A Chiba, T Tanaka, K Strebel, K Adachi, A TI Expression of HIV-1 accessory protein Vif is controlled uniquely to be low and optimal by proteasome degradation SO MICROBES AND INFECTION LA English DT Article DE HIV-1; Vif; proteasome degradation; accessory proteins ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 VIF; ANTIVIRAL ACTIVITY; VIRAL INFECTIVITY; ENZYME APOBEC3G; REPLICATION; COMPLEX; CELL; GENE; DNA AB While the Vif protein of human immunodeficiency virus type 1 (HIV-1) is essential for viral replication in non-permissive cells, it is rapidly degraded intracellularly. We have previously suggested that the rapid turn-over of Vif is biologically meaningful to prevent detrimental effects of this protein at high expression levels. We now studied the mechanism of Vif degradation by examining the blocking effect of protease inhibitors in pulse/chase experiments and by monitoring the extent of Vif ubiquitination. The rapid turn-over of Vif could be blocked by proteasome inhibitors, and Vif was highly ubiquitinated. Cytoskeletal Vif was found to be more stable than soluble cytosolic Vif. These degradation characteristics of Vif were cell type-independent and observed in both non-permissive and permissive cells. Characterization of a series of vif deletion mutants showed that amino acids predicted to be important for formation of beta-strand structures (amino acid nos. 63-70 and 86-89) were critical for maintaining a normal expression level of Vif and for viral infectivity. Finally, we performed comparative stability analysis of the four HIV-1 accessory proteins. Vif was unique in its short half-life and in the magnitude of the degradation. Taken together, we conclude that the proteasome degradation of HIV-1 Vif is a virologically important process and crucial for the function of Vif. (C) 2004 Elsevier SAS. All rights reserved. C1 Univ Tokushima, Grad Sch Med, Dept Virol, Tokushima 7708503, Japan. NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. Tokyo Metropolitan Inst Med Sci, Bunkyo Ku, Tokyo 1138613, Japan. Natl Inst Infect Dis, Tsukuba Primate Ctr Med Sci, Tsukuba, Ibaraki 3050843, Japan. RP Fujita, M (reprint author), Univ Tokushima, Grad Sch Med, Dept Virol, 3-18-15 Kuramoto, Tokushima 7708503, Japan. EM mfujita@basic.med.tokushima-u.ac.jp RI botla, Gomathi/A-5724-2008 NR 34 TC 49 Z9 56 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD JUL PY 2004 VL 6 IS 9 BP 791 EP 798 DI 10.1016/j.micinf.2004.04.011 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 840LN UT WOS:000222860200001 PM 15374000 ER PT J AU Ilias, L Manoli, I Blackman, MR Gold, PW Alesci, S AF Ilias, L Manoli, I Blackman, MR Gold, PW Alesci, S TI L-carnitine and acetyl-L-carnitinde in the treatment of complications associated with HIV infection and antiretroviral therapy SO MITOCHONDRION LA English DT Review DE carnitine; acetylcarnitine; HIV; AIDS; mitochondria; antiretroviral therapy; lipid metabolism; energy metabolism; apoptosis; oxidative stress; immune system; neuropathy; lipodystrophy ID NERVE GROWTH-FACTOR; ALZHEIMERS-DISEASE; AIDS PATIENTS; HIV-1-INFECTED SUBJECTS; MITOCHONDRIAL MYOPATHY; PERIPHERAL NEUROPATHY; LYMPHOCYTE APOPTOSIS; CERAMIDE GENERATION; PLASMA CARNITINE; NEUROTOXICITY AB L-Carnitine (LC) and acetyl-L-carnitine (ALC) play major roles in cell energy and lipid metabolism. Supplementation with these nutrients, which are highly popular in USA, has been associated with favorable effects, including anti-oxidant action, neuro and cardioprotection, immunomodulation, and cognitive enhancement. Patients with HIV infection and undergoing highly active antiretroviral therapy (HAART) often develop complications, such as polyneuropathy, skeletal myopathy, dyslipidernia and lipodystrophy, which have been linked to mitochondrial dysfunction. Moreover, these patients are often LC-deficient. Thus, they may benefit from LC and ALC supplementation. Indeed, oral, i.v., or i.m. administration of large doses of LC and/or ALC to HIV positive subjects untreated/treated with HAART was shown to: (1) increase the number of CD4 cells and reduce lymphocyte apoptosis; (2) improve symptoms of polyneuropathy; (3) prevent cardiovascular damage from wasting and diarrhea syndromes; (4) decrease serum levels of triglycerides and TNFalpha. No significant toxicities were associated with LC and ALC treatment. Although promising, most of these findings derive from small uncontrolled clinical trials. Further research is warranted to prove the efficacy and safety of LC and ALC supplementation in patients with complications of HIV infection and HAART. Published by Elsevier B.V. on behalf of Mitochondria Research Society. C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Univ Patras, Fac Med, Dept Pharmacol, GR-26110 Rion Patras, Greece. NIH, Natl Ctr Complementary & Alternat Med, Clin Invest Lab, Bethesda, MD 20892 USA. NIMH, Clin Neuroendocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Alesci, S (reprint author), NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. EM alescisa@mail.nih.gov NR 54 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1567-7249 J9 MITOCHONDRION JI Mitochondrion PD JUL PY 2004 VL 4 IS 2-3 BP 163 EP 168 DI 10.1016/j.mito.2004.05.012 PG 6 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 865ZU UT WOS:000224743500008 ER PT J AU Bienstock, RJ Copeland, WC AF Bienstock, RJ Copeland, WC TI Molecular insights into NRTI inhibition and mitochondrial toxicity revealed from a structural model of the human mitochondrial DNA polymerase SO MITOCHONDRION LA English DT Article DE mitochondria; DNA polymerase; HIV; nucleotide reverse transcriptase inhibitor ID HIV-1 REVERSE-TRANSCRIPTASE; ANTIVIRAL NUCLEOSIDE ANALOGS; CRYSTAL-STRUCTURE; KLENOW FRAGMENT; ANGSTROM RESOLUTION; ACTIVE-SITE; ZIDOVUDINE THERAPY; ACCESSORY SUBUNIT; GAMMA; TRIPHOSPHATE AB NRTI-based therapy used to treat AIDS can cause mitochondrial toxicity resulting from the incorporation of NRTIs into mitochondrial DNA by DNA polymerase gamma (pol gamma). Pol gamma has poor discrimination against many of the currently used NRTIs resulting in aborted DNA synthesis and subsequent depletion of mtDNA. Pol gamma readily incorporates ddCTP, ddITP and D4T-TP with an efficiency similar to the incorporation of normal nucleotides, whereas AZT-TP, CBV-TP, 3TC-TP and PMPApp act as moderate inhibitors to DNA synthesis. We have sought a structural explanation for the unique selection for NRTIs by the human pol gamma. A structural model of the human pol gamma was developed to ascertain the role of active site amino acids. One residue in particular, Y951 in motif B, is primarily responsible for the selection of dideoxynucleotides and D4T-TP. Our structural model of the human pol gamma should assist in rational design of antiviral nucleoside analogs with higher specificity for HIV-RT and minimal selection and incorporation into mitochondrial DNA. Published by Elsevier B.V. on behalf of Mitochondria Research Society. C1 NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Sci Comp Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Copeland, WC (reprint author), NIEHS, Mol Genet Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM copelan1@niehs.nih.gov OI Bienstock, Rachelle/0000-0001-5228-3610 NR 68 TC 20 Z9 21 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1567-7249 J9 MITOCHONDRION JI Mitochondrion PD JUL PY 2004 VL 4 IS 2-3 BP 203 EP 213 DI 10.1016/j.mito.2004.05.018 PG 11 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 865ZU UT WOS:000224743500013 PM 16120386 ER PT J AU Hashiguchi, K Bohr, VA de Souza-Pinto, NC AF Hashiguchi, K Bohr, VA de Souza-Pinto, NC TI Oxidative stress and mitochondrial DNA repair: implications for NRTIs induced DNA damage SO MITOCHONDRION LA English DT Review DE mtDNA; oxidative stress; 8-oxoguanine; base excision repair; mismatch repair; aging ID BASE EXCISION-REPAIR; TRANSCRIPTION-COUPLED REPAIR; RAT-LIVER MITOCHONDRIA; HAMSTER OVARY CELLS; MISMATCH REPAIR; SACCHAROMYCES-CEREVISIAE; POLYMERASE-GAMMA; ABASIC SITES; MICROSATELLITE INSTABILITY; MAMMALIAN MITOCHONDRIA AB Nucleotide analogue reverse transcriptase inhibitors (NRTI) can be incorporated into mitochondrial DNA (mtDNA), leading to mtDNA depletion and deletions. This is accompanied by elevated mitochondrial oxidative stress, which can cause accumulation of oxidative DNA lesions. Oxidized DNA damage is removed by the base excision repair (BER) pathway, by the sequential action of a DNA glycosylase, an Apurinic/Apyrimidinic endonuclease, DNA polymerase and DNA ligase. Mitochondria are very proficient in BER and various DNA glycosylases have been identified. DNA polymerase gamma is also involved in mitochondrial BER. In addition, there is growing evidence that mammalian mitochondria also possess mismatch repair activity. Published by Elsevier B.V. on behalf of Mitochondria Research Society. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP de Souza-Pinto, NC (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr Box 1, Baltimore, MD 21224 USA. EM souzan@grc.nia.nih.gov RI Souza-Pinto, Nadja/C-3462-2013 OI Souza-Pinto, Nadja/0000-0003-4206-964X NR 62 TC 15 Z9 16 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1567-7249 J9 MITOCHONDRION JI Mitochondrion PD JUL PY 2004 VL 4 IS 2-3 BP 215 EP 222 DI 10.1016/j.mito.2004.05.014 PG 8 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 865ZU UT WOS:000224743500014 PM 16120387 ER PT J AU Arnoult, D Viollet, L Petit, F Lelievre, JD Estaquier, J AF Arnoult, D Viollet, L Petit, F Lelievre, JD Estaquier, J TI HIV-1 triggers mitochondrion death SO MITOCHONDRION LA English DT Review DE apoptosis; HIV; mitochondria; CD4 T cell; drugs ID HUMAN-IMMUNODEFICIENCY-VIRUS; PROGRAMMED CELL-DEATH; CD4(+) T-CELLS; NF-KAPPA-B; ACTIVE ANTIRETROVIRAL THERAPY; DEPENDENT PROTEIN-KINASE; BLOOD MONONUCLEAR-CELLS; TYPE-1 TAT PROTEIN; FAMILY-MEMBER BIM; REVERSE-TRANSCRIPTASE INHIBITORS AB Apoptosis, a phenotype of programmed cell death involved in development and tissue homeostasis of multicellular organisms, brings into two major pathways and implies a central sensor: the mitochondria. Abnormalities in the cell death control can lead to a variety of diseases and many pathogenic agents target the mitochondria, especially affecting its permeability in order to induce cell death. HIV infection is linked to progressive CD4 T cell depletion. Among the different hypothesis that may explain T cell depletion, apoptosis is one of the main described mechanisms. This review provides current knowledge in HIV-mediated mitochondrial damage due to (i) HIV-specific proteins, (ii) death-by-neglect and (iii) side effects of the HIV drugs. (C) 2004 Elsevier B.V. and Mitochondria Research Society. All rights reserved. C1 Inst Pasteur, Unite Physiopathol Infect Lentivirales, F-75724 Paris 15, France. NINDS, Biochem Sect, NIH, Bethesda, MD 20892 USA. Fac Med Henri Mondor, Lab U421, F-94010 Creteil, France. RP Estaquier, J (reprint author), Inst Pasteur, Unite Physiopathol Infect Lentivirales, 28 Rue Dr Roux, F-75724 Paris 15, France. EM jestaqui@pasteur.fr OI Estaquier, Jerome/0000-0002-9432-8044 NR 198 TC 8 Z9 9 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1567-7249 J9 MITOCHONDRION JI Mitochondrion PD JUL PY 2004 VL 4 IS 2-3 BP 255 EP 269 DI 10.1016/j.mito.2004.06.010 PG 15 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 865ZU UT WOS:000224743500017 PM 16120390 ER PT J AU Kaluzova, M Kaluz, S Lerman, MI Stanbridge, EJ AF Kaluzova, M Kaluz, S Lerman, MI Stanbridge, EJ TI DNA damage is a prerequisite for p53-mediated proteasomal degradation of HIF-1 alpha in hypoxic cells and downregulation of the hypoxia marker carbonic anhydrase IX SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CARCINOMA-CELLS; GENE-EXPRESSION; CANCER-THERAPY; UP-REGULATION; SOLID TUMORS; HIF-ALPHA; MN/CA IX; P53; PROTEIN; GROWTH AB We investigated the relationship between the tumor suppressor p53 and the hypoxia-inducible factor-1 (HIF-1)-dependent expression of the hypoxia marker, carbonic anhydrase IX (CAIX). MCF-7 (wt p53) and Saos-2 (p53-null) cells displayed similar induction of CAIX expression and CA9 promoter activity under hypoxic conditions. Activation of p53 by the DNA damaging agent mitomycin C (MC) was accompanied by a potent repression of CAIX expression and the CA9 promoter in MCF-7 but not in Saos-2 cells. The activated p53 mediated increased proteasomal degradation of HIF-1alpha protein, resulting in considerably lower steady-state levels of HIF-1alpha protein in hypoxic MCF-7 cells but not in Saos-2 cells. Overexpression of HIF-1alpha relieved the MC-induced repression in MCF-7 cells, confirming regulation at the HIF-1alpha level. Similarly, CA9 promoter activity was downregulated by MC in HCT 116 p53(+/+) but not the isogenic p53(-/-) cells. Activated p53 decreased HIF-1alpha protein levels by accelerated proteasome-dependent degradation without affecting significantly HIF-1a transcription. In summary, our results demonstrate that the presence of wtp53 under hypoxic conditions has an insignificant effect on the stabilization of HIF-1alpha protein and HIF-1-dependent expression of CAIX. However, upon activation by DNA damage, wt p53 mediates an accelerated degradation of HIF-1alpha protein, resulting in reduced activation of CA9 transcription and, correspondingly, decreased levels of CAIX protein. A model outlining the quantitative relationship between p53, HIF-1alpha, and CAIX is presented. C1 Univ Calif Irvine, Dept Microbiol & Mol Genet, Coll Med, Irvine, CA 92717 USA. Slovak Acad Sci, Inst Virol, Bratislava, Slovakia. NCI, Immunobiol Lab, Frederick, MD 21701 USA. RP Stanbridge, EJ (reprint author), Univ Calif Irvine, Dept Microbiol & Mol Genet, Coll Med, Med Sci 1 B210, Irvine, CA 92697 USA. EM ejstanbr@uci.edu FU NCI NIH HHS [N01-CO-56000] NR 52 TC 61 Z9 64 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2004 VL 24 IS 13 BP 5757 EP 5766 DI 10.1128/MCB.24.13.5757-5766.2004 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 830UL UT WOS:000222149200012 PM 15199132 ER PT J AU Moratz, C Hayman, JR Gu, H Kehrl, JH AF Moratz, C Hayman, JR Gu, H Kehrl, JH TI Abnormal B-cell responses to chemokines, disturbed plasma cell localization, and distorted immune tissue architecture in Rgs1(-/-) mice SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID GTPASE-ACTIVATING PROTEINS; SACCHAROMYCES-CEREVISIAE; SIGNALING PROTEINS; KINASE ACTIVATION; FAMILY-MEMBERS; ALPHA-SUBUNITS; LYMPHOCYTES; RECEPTOR; REGULATORS; RESPONSIVENESS AB Normal lymphoid tissue development and function depend upon chemokine-directed cell migration. Since chemokines signal through heterotrimeric G-protein-coupled receptors, RGS proteins, which act as GTPase-activating proteins for Got subunits, likely fine tune the cellular responses to chemokines. Here we show that Rgs(-/-) mice possess B cells that respond excessively and desensitize improperly to the chemokines CXCL12 and CXCL13. Many of the B-cell follicles in the spleens of RgsI(-/-) mice have germinal centers even in the absence of immune stimulation. Furthermore, immunization of these mice leads to exaggerated germinal center formation; partial disruption of the normal architecture of the spleen and Peyer's patches; and abnormal trafficking of immunoglobulin-secreting cells. These results reveal the importance of a regulatory mechanism that limits and desensitizes chemokine receptor signaling. C1 NIAID, Immunoregulat Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. NIAID, Immunol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. E Tennessee State Univ, Dept Microbiol, James H Quillen Coll Med, Johnson City, TN 37614 USA. RP Kehrl, JH (reprint author), NIAID, Immunoregulat Lab, Natl Inst Hlth, Bldg 10,Room 11B08,10 Ctr Dr,MSC 1876, Bethesda, MD 20892 USA. EM jkehrl@niaid.nih.gov OI Kehrl, John/0000-0002-6526-159X NR 46 TC 63 Z9 63 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2004 VL 24 IS 13 BP 5767 EP 5775 DI 10.1128/MCB.24.13.5767-5775.2004 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 830UL UT WOS:000222149200013 PM 15199133 ER PT J AU Li, CJ Vassilev, A DePamphilis, ML AF Li, CJ Vassilev, A DePamphilis, ML TI Role for Cdk1 (Cdc2)/cyclin A in preventing the mammalian origin recognition complex's largest subunit (Orc1) from binding to chromatin during mitosis SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID EUKARYOTIC DNA-REPLICATION; CYCLIN-DEPENDENT KINASES; XENOPUS EGG EXTRACTS; CELL-CYCLE; PROTEIN-KINASE; RE-REPLICATION; CDC2 MUTANT; IN-VITRO; S-PHASE; INITIATION AB The eukaryotic origin recognition complex (ORC) selects the genomic sites where prereplication complexes are assembled and DNA replication begins. In proliferating mammalian cells, ORC activity appears to be regulated by reducing the affinity of the Orc1 subunit for chromatin during S phase and then preventing reformation of a stable ORC-chromatin complex until mitosis is completed and a nuclear membrane is assembled. Here we show that part of the mechanism by which this is accomplished is the selective association of Orc1 with Cdk1 (Cdc2)/cyclin A during the G(2)/M phase of cell division. This association accounted for the appearance in M-phase cells of hyperphosphorylated Orc1 that was subsequently dephosphorylated during the M-to-G, transition. Moreover, inhibition of Cdk activity in metaphase cells resulted in rapid binding of Orc1 to chromatin. However, chromatin binding was not mediated through increased affinity of Orc1 for Orc2, suggesting that additional events are involved in the assembly of functional ORC-chromatin sites. These results reveal that the same cyclin-dependent protein kinase that initiates mitosis in mammalian cells also concomitantly inhibits assembly of functional ORC-chromatin sites. C1 NICHHD, Natl Inst Hlth, Bethesda, MD 20892 USA. Anim & Nat Resources Inst, Growth Biol Lab, Agr Res Serv, USDA, Beltsville, MD 20705 USA. RP DePamphilis, ML (reprint author), NICHHD, Natl Inst Hlth, Bldg 6-416,9000 Rockville Pike, Bethesda, MD 20892 USA. EM depamphm@mail.nih.gov NR 68 TC 61 Z9 62 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2004 VL 24 IS 13 BP 5875 EP 5886 DI 10.1128/MCB.24.13.5875-5886.2004 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 830UL UT WOS:000222149200023 PM 15199143 ER PT J AU Shen, HM Lin, Y Choksi, S Tran, J Jin, T Chang, LF Karin, M Zhang, JK Liu, ZG AF Shen, HM Lin, Y Choksi, S Tran, J Jin, T Chang, LF Karin, M Zhang, JK Liu, ZG TI Essential roles of receptor-interacting protein and TRAF2 in oxidative stress-induced cell death SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; DOMAIN KINASE RIP; SIGNAL-TRANSDUCTION PATHWAYS; HYDROGEN-PEROXIDE; FREE-RADICALS; INDUCED APOPTOSIS; TNF RECEPTOR-1; INDUCED ACTIVATION; TERMINAL KINASE AB Oxidative stress and reactive oxygen species (ROS) can elicit and modulate various physiological and pathological processes, including cell death. However, the mechanisms controlling ROS-induced cell death are largely unknown. Data from this study suggest that receptor-interacting protein (RIP) and tumor necrosis factor receptor (TNFR)-associated factor 2 (TRAF2), two key effector molecules of TNF signaling, are essential for ROS-induced cell death. We found that RIP-/- or TRAF2(-/-) mouse embryonic fibroblasts (MEF) are resistant to ROS-induced cell death when compared to wild-type cells, and reconstitution of RIP and TRAF2 gene expression in their respective deficient MEF cells restored their sensitivity to H2O2-induced cell death. We also found that RIP and TRAF2 form a complex upon H2O2 exposure, but without the participation of TNFR1. The colocalization of RIP with a membrane lipid raft marker revealed a possible role of lipid rafts in the transduction of cell death signal initiated by H2O2. Finally, our results demonstrate that activation of c-jun NH2-terminal kinase 1 is a critical event downstream of RIP and TRAF2 in mediating ROS-induced cell death. Therefore, our study uncovers a novel signaling pathway regulating oxidative stress-induced cell death. C1 NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. NIAID, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. Natl Univ Singapore, Dept Community Occupat & Family Med, Fac Med, Singapore 117597, Singapore. Univ Calif San Diego, Dept Pharmacol, San Diego, CA 92103 USA. Thomas Jefferson Univ, Coll Med, Dept Microbiol & Immunol, Philadelphia, PA 19107 USA. RP Liu, ZG (reprint author), NCI, Cell & Canc Biol Branch, NIH, Bldg 10,Rm 6N105,9000 Rockville Pike, Bethesda, MD 20892 USA. EM zgliu@helix.nih.gov RI SHEN, Han-Ming/B-5942-2011; OI SHEN, Han-Ming/0000-0001-7369-5227; Zhang, Jianke/0000-0002-5822-2226 NR 63 TC 98 Z9 104 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2004 VL 24 IS 13 BP 5914 EP 5922 DI 10.1128/MCB.24.13.5914-5922.2004 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 830UL UT WOS:000222149200026 PM 15199146 ER PT J AU Nakamura, TM Du, LL Redon, C Russell, P AF Nakamura, TM Du, LL Redon, C Russell, P TI Histone H2A phosphorylation controls Crb2 recruitment at DNA breaks, maintains checkpoint arrest, and influences DNA repair in fission yeast SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID DOUBLE-STRAND BREAKS; SCHIZOSACCHAROMYCES-POMBE RAD32; SACCHAROMYCES-CEREVISIAE; DAMAGE CHECKPOINT; REPLICATION CHECKPOINT; GENOMIC INSTABILITY; EARLY PARTICIPANT; GAMMA-H2AX FOCI; PROTEIN 53BP1; COMPLEX AB Mammalian ATR and ATM checkpoint kinases modulate chromatin structures near DNA breaks by phosphorylating a serine residue in the carboxy-terminal tail SQE motif of histone H2AX. Histone H2A is similarly regulated in Saccharomyces cerevisiae. The phosphorylated forms of H2AX and H2A, known as gamma-H2AX and gamma-H2A, are thought to be important for DNA repair, although their evolutionarily conserved roles are unknown. Here, we investigate gamma-H2A in the fission yeast Schizosaccharomyces pombe. We show that formation of gamma-H2A redundantly requires the ATR/ATM-related kinases Rad3 and Tell. Mutation of the SQE motif to AQE (H2A-AQE) in the two histone H2A genes caused sensitivity to a wide range of genotoxic agents, increased spontaneous DNA damage, and impaired checkpoint maintenance. The H2A-AQE mutations displayed a striking synergistic interaction with rad22Delta (Rad52 homolog) in ionizing radiation (111) survival. These phenotypes correlated with defective phosphorylation of the checkpoint proteins Crb2 and Chk1 and a failure to recruit large amounts of Crb2 to damaged DNA. Surprisingly, the H2A-AQE mutations substantially suppressed the IR hypersensitivity of crb2Delta cells by a mechanism that required the RecQ-like DNA helicase Rqh1. We propose that gamma-H2A modulates checkpoint and DNA repair through large-scale recruitment of Crb2 to damaged DNA. This function correlates with evidence that gamma-H2AX regulates recruitment of several BRCA1 carboxyl terminus domain-containing proteins (NBS1, 53BP1, MDC1/NFBD1, and BRCA1) in mammals. C1 Scripps Res Inst, Dept Biol Mol, La Jolla, CA 92037 USA. Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Russell, P (reprint author), Scripps Res Inst, Dept Biol Mol, MB3,10550 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM prussell@scripps.edu RI Nakamura, Toru/B-2055-2008; OI Nakamura, Toru/0000-0001-5752-0814; Du, Li-Lin/0000-0002-1028-7397 FU NCI NIH HHS [CA77325, R01 CA077325]; NIGMS NIH HHS [R01 GM059447, GM59447] NR 91 TC 130 Z9 141 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2004 VL 24 IS 14 BP 6215 EP 6230 DI 10.1128/MCB.24.14.6215-6230.2004 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 835NQ UT WOS:000222490900010 PM 15226425 ER PT J AU Phair, RD Scaffidi, P Elbi, C Vecerova, J Dey, A Ozato, K Brown, DT Hager, G Bustin, M Misteli, T AF Phair, RD Scaffidi, P Elbi, C Vecerova, J Dey, A Ozato, K Brown, DT Hager, G Bustin, M Misteli, T TI Global nature of dynamic protein-chromatin interactions in vivo: Three-dimensional genome scanning and dynamic interaction networks of chromatin proteins SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID LIVING HUMAN-CELLS; RNA-POLYMERASE-II; GLUCOCORTICOID-RECEPTOR; GENE-EXPRESSION; RAPID EXCHANGE; HIGH-MOBILITY; HISTONE H1; TRANSCRIPTION FACTORS; MOLECULAR CHAPERONES; BINDING-PROTEIN AB Genome structure and gene expression depend on a multitude of chromatin-binding proteins. The binding properties of these proteins to native chromatin in intact cells are largely unknown. Here, we describe an approach based on combined in vivo photobleaching microscopy and kinetic modeling to analyze globally the dynamics of binding of chromatin-associated proteins in living cells. We have quantitatively determined basic biophysical properties, such as off rate constants, residence time, and bound fraction, of a wide range of chromatin proteins of diverse functions in vivo. We demonstrate that most chromatin proteins have a high turnover on chromatin with a residence time on the order of seconds, that the major fraction of each protein is bound to chromatin at steady state, and that transient binding is a common property of chromatin-associated proteins. Our results indicate that chromatin-binding proteins find their binding sites by three-dimensional scanning of the genome space and our data are consistent with a model in which chromatin-associated proteins form dynamic interaction networks in vivo. We suggest that these properties are crucial for generating high plasticity in genome expression. C1 NCI, NIH, Bethesda, MD 20892 USA. NICHHD, Bethesda, MD 20892 USA. BioInformat Serv, Rockville, MD 20854 USA. Acad Sci Czech Republ, Inst Expt Med, Prague, Czech Republic. Fac Med 1, Prague, Czech Republic. Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov RI Bustin, Michael/G-6155-2015 NR 65 TC 312 Z9 316 U1 0 U2 12 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2004 VL 24 IS 14 BP 6393 EP 6402 DI 10.1128/MCB.24.14.6393.6402.2004 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 835NQ UT WOS:000222490900024 PM 15226439 ER PT J AU Stumpo, DJ Byrd, NA Phillips, RS Ghosh, S Maronpot, RR Castranio, T Meyers, EN Mishina, Y Blackshear, PJ AF Stumpo, DJ Byrd, NA Phillips, RS Ghosh, S Maronpot, RR Castranio, T Meyers, EN Mishina, Y Blackshear, PJ TI Chorioallantoic fusion defects and embryonic lethality resulting from disruption of Zfp36L1, a gene encoding a CCCH tandem zinc finger protein of the tristetraprolin family SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; AU-RICH ELEMENTS; MESSENGER-RNA TURNOVER; PRIMARY RESPONSE GENE; GROWTH-FACTOR-I; TIS11 FAMILY; INDUCED APOPTOSIS; TNF-ALPHA; EXPRESSION; RECEPTOR AB The mouse gene Zfp36L1 encodes zinc finger protein 36-like 1 (Zfp36L1), a member of the tristetraprolin (TTP) family of tandem CCCH finger proteins. TrP can bind to AU-rich elements within the 3'-untranslated regions of the mRNAs encoding tumor necrosis factor (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), leading to accelerated mRNA degradation. TTP knockout mice exhibit an inflammatory phenotype that is largely due to increased TNF secretion. Zfp36L1 has activities similar to those of TTP in cellular RNA destabilization assays and in cell-free RNA binding and deadenylation assays, suggesting that it may play roles similar to those of TTP in mammalian physiology. To address this question we disrupted Zfp36L1 in mice. All knockout embryos died in utero, most by approximately embryonic day 11 (Ell). Failure of chorioallantoic fusion occurred in about two-thirds of cases. Even when fusion occurred, by E10.5 the affected placentas exhibited decreased cell division and relative atrophy of the trophoblast layers. Although knockout embryos exhibited neural tube abnormalities and increased apoptosis within the neural tube and also generalized runting, these and other findings may have been due to deficient placental function. Embryonic expression of Zfp36L1 at E8.0 was greatest in the allantois, consistent with a potential role in chorioallantoic fusion. Fibroblasts derived from knockout embryos had apparently normal levels of fully polyadenylated compared to deadenylated GM-CSF mRNA and normal rates of turnover of this mRNA species, both sensitive markers of TTP deficiency in cells. We postulate that lack of Zfp36L1 expression during mid-gestation results in the abnormal stabilization of one or more mRNAs whose encoded proteins lead directly or indirectly to abnormal placentation and fetal death. C1 NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Off Clin Res, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Med & Biochem, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. RP Blackshear, PJ (reprint author), NIEHS, Lab Signal Transduct, A2-05,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM Black009@niehs.nih.gov FU NICHD NIH HHS [HD39948, P01 HD039948] NR 44 TC 88 Z9 91 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2004 VL 24 IS 14 BP 6445 EP 6455 DI 10.1128/MCB.24.14.6445-6455.2004 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 835NQ UT WOS:000222490900029 PM 15226444 ER PT J AU Jiang, Q Li, WQ Hofmeister, RR Young, HA Hodge, DR Keller, JR Khaled, AR Durum, SK AF Jiang, Q Li, WQ Hofmeister, RR Young, HA Hodge, DR Keller, JR Khaled, AR Durum, SK TI Distinct regions of the interleukin-7 receptor regulate different Bcl2 family members SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; DEFECTIVE LYMPHOID DEVELOPMENT; T-CELL DEVELOPMENT; MICE LACKING JAK3; DEFICIENT MICE; IN-VIVO; GAMMA-CHAIN; ALPHA-CHAIN; CYTOPLASMIC TAIL; B-LYMPHOPOIESIS AB The antiapoptotic function of the interleukin-7 (IL-7) receptor is related to regulation of three members of the Bcl2 family: synthesis of Bcl2, phosphorylation of Bad, and cytosolic retention of Bax. Here we show that, in an IL-7-dependent murine T-cell line, different regions of the IL-7 receptor initiate the signal transduction pathways that regulate these proteins. Both Box1 and Y449 are required to signal Bcl2 synthesis and Bax cytosolic retention. This suggests a sequential model in which Jak1, which binds to Box1, is first activated and then phosphorylates Y449, leading to Bcl2 and Bax regulation, accounting for approximately 90% of the survival function. Phosphorylation of Bad required Box1 but not Y449, suggesting that Jak1 also initiates an additional signaling cascade that accounts for approximately 10% of the survival function. Stat5 was activated from the Y449 site but only partially accounted for the survival signal. Proliferation required both Y449 and Box1. Thymocyte development in vivo showed that deletion of Y449 eliminated 90% of up T-cell development and completely eliminated gammadelta T-cell development, whereas deleting Box 1 completely eliminated both alphabeta and gammadelta T-cell development. Thus the IL-7 receptor controls at least two distinct pathways, in addition to Stat5, that are required for cell survival. C1 NCI, Mol Immunoregulat Lab, NIH, Frederick, MD 21702 USA. NCI, Expt Immunol Lab, NIH, Frederick, MD 21702 USA. NCI, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Durum, SK (reprint author), NCI, Mol Immunoregulat Lab, NIH, Bldg 560,Rm 31-71, Frederick, MD 21702 USA. EM durums@mail.ncifcrf.gov NR 42 TC 79 Z9 79 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2004 VL 24 IS 14 BP 6501 EP 6513 DI 10.1128/MCB.24.14.6501-6513.2004 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 835NQ UT WOS:000222490900034 PM 15226449 ER PT J AU Kohn, KW Riss, J Aprelikova, O Weinstein, JN Pommier, Y Barrett, JC AF Kohn, KW Riss, J Aprelikova, O Weinstein, JN Pommier, Y Barrett, JC TI Properties of switch-like bioregulatory networks studied by simulation of the hypoxia response control system SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID INDUCIBLE TRANSCRIPTION FACTOR; FACTOR 1-ALPHA; HIF-1-ALPHA; PATHWAY; INDUCTION; THERAPY; OXYGEN AB A complex bioregulatory network could be more easily comprehended if its essential function could be described by a small "core" subsystem, and if its response characteristics were switch-like. We tested this proposition by simulation studies of the hypoxia response control network. We hypothesized that a small subsystem governs the basics of the cellular response to hypoxia and that this response has a sharp oxygen-dependent transition. A molecular interaction map of the network was prepared, and an evolutionarily conserved core subsystem was extracted that could control the activity of hypoxia response promoter elements on the basis of oxygen concentration. The core subsystem included the hypoxia-inducible transcription factor (HIFalpha:ARNT heterodimer), proline hydroxylase, and the von Hippel-Lindau protein. Simulation studies showed that the same core subsystem can exhibit switch-like responses both to oxygen level and to HIFalpha synthesis rate, thus suggesting a mechanism for hypoxia response promoter element-dependent responses common to both hypoxia and growth factor signaling. The studies disclosed the mechanism responsible for the sharp transitions. We show how parameter sets giving switch-like behavior can be found and how this type of behavior provides a foundation for quantitative studies in cells. C1 NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. NCI, Lab Biosyst & Canc, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kohn, KW (reprint author), NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. EM kohnk@dc37a.nci.nih.gov NR 20 TC 37 Z9 41 U1 1 U2 5 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUL PY 2004 VL 15 IS 7 BP 3042 EP 3052 DI 10.1091/mbc.E03-12-0897 PG 11 WC Cell Biology SC Cell Biology GA 833JJ UT WOS:000222333300004 PM 15107465 ER PT J AU Touz, MC Kulakova, L Nash, TE AF Touz, MC Kulakova, L Nash, TE TI Adaptor protein complex 1 mediates the transport of lysosomal proteins from a golgi-like organelle to peripheral vacuoles in the primitive eukaryote Giardia lamblia SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID NEMATODE CAENORHABDITIS-ELEGANS; CYST WALL; SORTING SIGNALS; GRANULE BIOGENESIS; TOXOPLASMA-GONDII; GENE-EXPRESSION; MEDIUM CHAINS; AP-1 BINDING; CLATHRIN; YEAST AB Giardia lamblia is an early branching protist that possesses peripheral vacuoles (PVs) with characteristics of lysosome-like organelles, located underneath the plasma membrane. In more evolved cells, lysosomal protein trafficking is achieved by cargo recognition involving adaptor protein (AP) complexes that recognize specific amino acid sequences (tyrosine and/or dileucine motifs) within the cytoplasmic tail of membrane proteins. Previously, we reported that Giardia has a tyrosine-based sorting system, which mediates the targeting of a membrane-associated cysteine protease (encystation-specific cysteine protease, ESCP) to the PVs. Here, we show that Giardia AP1 mediates the transport of ESCP and the soluble acid phosphatase (AcPh) to the PVs. By using the yeast two-hybrid assay we found that the ESCP tyrosine-based motif interacts specifically with the medium subunit of AP1 (Gimua). Hemagglutinin-tagged Gimua colocalizes with ESCP and AcPh and coimmunoprecipitates with clathrin, suggesting that protein trafficking toward the PVs is clathrin-adaptin dependent. Targeted disruption of Gimua results in mislocalization of ESCP and AcPh but not of variant-specific surface proteins. Our results suggest that, unlike mammalian cells, only AP1 is involved in anterograde protein trafficking to the PVs in Giardia. Moreover, even though Giardia trophozoites lack a morphologically discernible Golgi apparatus, the presence of a clathrin-adaptor system suggests that this parasite possess a primitive secretory organelle capable of sorting proteins similar to that of more evolved cells. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Touz, MC (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM mtouz@niaid.nih.gov NR 47 TC 34 Z9 35 U1 0 U2 2 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUL PY 2004 VL 15 IS 7 BP 3053 EP 3060 DI 10.1091/mbc.E03-10-0744 PG 8 WC Cell Biology SC Cell Biology GA 833JJ UT WOS:000222333300005 PM 15107467 ER PT J AU Kowanetz, K Husnjak, K Holler, D Kowanetz, M Soubeyran, P Hirsch, D Schmidt, MHH Pavelic, K De Camilli, P Randazzo, PA Dikic, I AF Kowanetz, K Husnjak, K Holler, D Kowanetz, M Soubeyran, P Hirsch, D Schmidt, MHH Pavelic, K De Camilli, P Randazzo, PA Dikic, I TI CIN85 associates with multiple effectors controlling intracellular trafficking of epidermal growth factor receptors SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID GTPASE-ACTIVATING PROTEIN; CLATHRIN-MEDIATED ENDOCYTOSIS; ACTIN-BINDING PROTEIN; ADAPTER PROTEIN; TYROSINE KINASES; DOWN-REGULATION; SH3 DOMAINS; SCAFFOLD PROTEINS; CELL-MIGRATION; SYNAPTOJANIN 2 AB CIN85 is a multidomain adaptor protein involved in Cbl-mediated down-regulation of epidermal growth factor (EGF) receptors. CIN85 src homology 3 domains specifically bind to a proline-arginine (PxxxPR) motif in Cbl, and this association seems to be important for EGF receptor endocytosis. Here, we report identification of novel CIN85 effectors, all containing one or more PxxxPR motifs, that are indispensable for their mutual interactions. These effectors include phosphatidyl-inositol phosphatases SHIP-1 and synaptojanin 2131, Arf GTPase-activating proteins ASAP1 and ARAP3, adaptor proteins Hip1R and STAP1, and a Rho exchange factor, p115Rho GEF. Acting as a molecular scaffold, CIN85 clusters its effectors and recruits them to high-molecular-weight complexes in cytosolic extracts of cells. Further characterization of CIN85 binding to ASAP1 revealed that formation of the complex is independent on cell stimulation. Overexpression of ASAP1 increased EGF receptor recycling, whereas ASAP1 containing mutated PxxxPR motif failed to promote this event. We propose that CIN85 functions as a scaffold molecule that binds to numerous endocytic accessory proteins, thus controlling distinct steps in trafficking of EGF receptors along the endocytic and recycling pathways. C1 Univ Frankfurt, Sch Med, Inst Biochem 2, D-60590 Frankfurt, Germany. Yale Univ, Sch Med, Howard Hughes Med Inst, Dept Cell Biol, New Haven, CT 06510 USA. NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. Rudjer Boskovic Inst, Div Mol Med, Zagreb 10000, Croatia. Ludwig Inst Canc Res, S-75124 Uppsala, Sweden. RP Dikic, I (reprint author), Univ Frankfurt, Sch Med, Inst Biochem 2, D-60590 Frankfurt, Germany. EM ivan.dikic@biochem2.de RI Dikic, Ivan/O-4650-2015 OI Dikic, Ivan/0000-0001-8156-9511 NR 62 TC 89 Z9 92 U1 0 U2 5 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUL PY 2004 VL 15 IS 7 BP 3155 EP 3166 DI 10.1091/mbc.E03-09-0683 PG 12 WC Cell Biology SC Cell Biology GA 833JJ UT WOS:000222333300015 PM 15090612 ER PT J AU Sanni, TB Masilamani, M Kabat, J Coligan, JE Borrego, F AF Sanni, TB Masilamani, M Kabat, J Coligan, JE Borrego, F TI Exclusion of lipid rafts and decreased mobility of CD94/NKG2A receptors at the inhibitory NK cell synapse SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID GREEN FLUORESCENT PROTEIN; NATURAL-KILLER-CELLS; CLASS-I MOLECULES; IMMUNOLOGICAL SYNAPSE; HLA-E; IMMUNE SYNAPSE; CYTOLYTIC INTERACTIONS; SIGNAL-TRANSDUCTION; LIGAND-BINDING; MISSING-SELF AB CD94/NKG2A is an inhibitory receptor expressed by most human natural killer (NK) cells and a subset of T cells that recognizes human leukocyte antigen E (HLA-E) on potential target cells. To elucidate the cell surface dynamics of CD94/NKG2A receptors, we have expressed CD94/NKG2A-EGFP receptors in the rat basophilic leukemia (RBL) cell line. Photobleaching experiments revealed that CD94/NKG2A-EGFP receptors move freely within the plasma membrane and accumulate at the site of contact with ligand. The enriched CD94/NKG2A-EGFP is markedly less mobile than the nonligated receptor. We observed that not only are lipid rafts not required for receptor polarization, they are excluded from the site of receptor contact with the ligand. Furthermore, the lipid raft patches normally observed at the sites where FcepsilonR1 activation receptors are cross-linked were not observed when CD94/NKG2A was coengaged along with the activation receptor. These results suggest that immobilization of the CD94/NKG2A receptors at ligation sites not only promote sustenance of the inhibitory signal, but by lipid rafts exclusion prevent formation of activation signaling complexes. C1 NIAID, Receptor Cell Biol Sect, Lab Allerg Dis, NIH, Rockville, MD 20852 USA. RP Borrego, F (reprint author), NIAID, Receptor Cell Biol Sect, Lab Allerg Dis, NIH, Rockville, MD 20852 USA. EM Fborrego@niaid.nih.gov OI Masilamani, Madhan/0000-0001-8181-8848 NR 55 TC 23 Z9 24 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUL PY 2004 VL 15 IS 7 BP 3210 EP 3223 DI 10.1091/mbc.E03-11-0779 PG 14 WC Cell Biology SC Cell Biology GA 833JJ UT WOS:000222333300019 PM 15133125 ER PT J AU Wakabayashi, Y Lippincott-Schwartz, J Arias, IM AF Wakabayashi, Y Lippincott-Schwartz, J Arias, IM TI Intracellular trafficking of bile salt export pump (ABCB11) in polarized hepatic cells: Constitutive cycling between the canalicular membrane and Rab11-positive endosomes SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID WIF-B CELLS; RAT-LIVER; PLASMA-MEMBRANE; BREFELDIN-A; MDCK CELLS; PHOSPHOINOSITIDE 3-KINASE; EPITHELIAL-CELLS; ACID SECRETION; APICAL DOMAIN; ENDOCYTOSIS AB The bile salt export pump (BSEP, ABCB11) couples ATP hydrolysis with transport of bile acids into the bile canaliculus of hepatocytes. Its localization in the apical canalicular membrane is physiologically regulated by the demand to secrete biliary components. To gain insight into how such localization is regulated, we studied the intracellular trafficking of BSEP tagged with yellow fluorescent protein (YFP) in polarized WIF-B9 cells. Confocal imaging revealed that BSEP-YFP was localized at the canalicular membrane and in tubulo-vesicular structures either adjacent to the microtubule-organizing center or widely distributed in the cytoplasm. In the latter two locations, BSEP-YFP colocalized with rab11, an endosomal marker. Selective photobleaching experiments revealed that single BSEP-YFP molecules resided in canalicular membranes only transiently before exchanging with intracellular BSEP-YFP pools. Such exchange was inhibited by microtubule and actin inhibitors and was unaffected by brefeldin A, dibutyryl cyclic AMP, taurocholate, or PI 3-kinase inhibitors. Intracellular carriers enriched in BSEP-YFP elongated and dissociated as tubular elements from a globular structure adjacent to the microtubule-organizing center. They displayed oscillatory movement toward either canalicular or basolateral membranes, but only fused with the canalicular membrane. The pathway between canalicular and intracellular membranes that BSEP constitutively cycles within could serve to regulate apical pools of BSEP as well as other apical membrane transporters. C1 Tufts Univ, Sch Med, Dept Physiol, Boston, MA 02111 USA. NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Arias, IM (reprint author), Tufts Univ, Sch Med, Dept Physiol, Boston, MA 02111 USA. EM ariasi@mail.nih.gov FU NIDDK NIH HHS [R01 DK054785, 30-DK 34928, DK-35652, P30 DK034928, DK-54785, R01 DK035652] NR 39 TC 60 Z9 61 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUL PY 2004 VL 15 IS 7 BP 3485 EP 3496 DI 10.1091/mbc.E03-10-0737 PG 12 WC Cell Biology SC Cell Biology GA 833JJ UT WOS:000222333300041 PM 15121884 ER PT J AU Yuan, JH Feng, Y Fisher, RH Maloid, S Longo, DL Ferris, DK AF Yuan, JH Feng, Y Fisher, RH Maloid, S Longo, DL Ferris, DK TI Polo-like kinase 1 inactivation following mitotic DNA damaging treatments is independent of ataxia telangiectasia mutated kinase SO MOLECULAR CANCER RESEARCH LA English DT Article ID POLO-LIKE KINASE; SACCHAROMYCES-CEREVISIAE CDC5; SPINDLE-ASSEMBLY CHECKPOINT; ANAPHASE-PROMOTING COMPLEX; CELL-CYCLE CHECKPOINTS; PROTEIN-KINASE; SERINE/THREONINE KINASE; HEMATOPOIETIC-CELLS; REGULATED KINASE; DROSOPHILA POLO AB Polo-like kinase 1 (Plk1) is an important regulator of several events during mitosis. Recent reports show that Plk1 is involved in both G(2) and mitotic DNA damage checkpoints. Ataxia telangiectasia mutated kinase (ATM) is an important enzyme involved in G2 phase cell cycle arrest following interphase DNA damage, and inhibition of Plk1 by DNA damage during G2 occurs in an ATM-/ ATM-Rad3-related kinase (ATR)-dependent fashion. However, it is unclear how Plk1 is regulated in response to M phase DNA damage. We found that treatment of mitotic cells with DNA damaging agents inhibits Plk1 activity primarily through dephosphorylation of Plk1, which occurred in both p53 wild-type and mutant cells. Inhibition of Plk1 is not prevented by caffeine pretreatment that inhibits ATM activity and also occurs in ATM mutant cell lines. Furthermore, ATM mutant cell lines, unlike wild-type cells, fail to arrest after mitotic DNA damaging treatments. The phosphatidylinositol 3-kinase (Pl3K) inhibitor, LY294002, reduces Plk1 dephosphorylation following mitotic DNA damaging treatments, suggesting that the Pl3K pathway may be involved in regulating Plk1 activity. Earlier studies showed that inhibition of Plk1 by G2 DNA damage occurs in an ATM-dependent fashion. Our results extend the previous studies by showing that ATM is not required for dephosphorylation and inhibition of Plk1 activity following mitotic DNA damage, and also suggest that Plk1 is not a principal regulator or mediator of the mitotic DNA damage response. C1 NCI, Sci Applicat Int Corp, Basic Res Program, Frederick, MD 21702 USA. NCI, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Ferris, DK (reprint author), NCI, Sci Applicat Int Corp, Basic Res Program, Bldg 567,Room 218, Frederick, MD 21702 USA. EM ferris@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 55 TC 11 Z9 13 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD JUL PY 2004 VL 2 IS 7 BP 417 EP 426 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 841WF UT WOS:000222961900005 PM 15280449 ER PT J AU Mertins, SD Myers, TG Holbeck, SL Medina-Perez, W Wang, E Kohlhagen, G Pommier, Y Bates, SE AF Mertins, SD Myers, TG Holbeck, SL Medina-Perez, W Wang, E Kohlhagen, G Pommier, Y Bates, SE TI In vitro evaluation of dimethane sulfonate analogues with potential alkylating activity and selective renal cell carcinoma cytotoxicity SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID TUMOR-SUPPRESSOR GENE; TRANSFERASE-ACTIVITY; NITROGEN MUSTARDS; CROSS-LINKING; CYTO-TOXICITY; AGENTS; CYCLE; LINE; P53; IDENTIFICATION AB We identified five structurally related dimethane sulfonates with putative selective cytotoxicity in renal cancer cell lines. These compounds have a hydrophobic moiety linked to a predicted alkylating group. A COMPARE analysis with the National Cancer Institute Anticancer Drug Screen standard agent database found significant correlations between the IC50 of the test compounds and the IC50 of alkylating agents (e.g., r = 0.68, P < 0.00001 for chlorambucil). In this report, we examined whether these compounds had activities similar to those of conventional alkylating agents. In cytotoxicity studies, chlorambucil-resistant Walker rat carcinoma cells were 4- to 11-fold cross-resistant to the test compounds compared with 14-fold resistant to chlorambucil. To determine effects on cell cycle progression, renal cell carcinoma (RCC) line 109 was labeled with bromodeoxyuridine prior to drug treatment. Complete cell cycle arrest occurred in cells treated with an IC90 dose of NSC 268965. p53 protein levels increased as much as 5.7-fold in RCC line 109 and as much as 20.4-foid in breast cancer line MCF-7 following an 18-hour drug exposure. Finally, DNA-protein cross-links were found following a 6-hour pretreatment with all compounds. Thus, the dimethane sulfonate analogues have properties expected of some alkylating agents but, unlike conventional alkylating agents, appear to possess activity against RCC. C1 Natl Canc Inst, Canc Therapeut Branch, Ft Detrick, MD 21702 USA. Natl Canc Inst, Dev Therapeut Program, Ft Detrick, MD 21702 USA. Natl Canc Inst, Mol Pharmacol Lab, Ft Detrick, MD 21702 USA. RP Mertins, SD (reprint author), Natl Canc Inst, Screening Technol Branch, Bldg 440,POB B, Ft Detrick, MD 21702 USA. EM smertins@mail.ncifcrf.gov NR 41 TC 20 Z9 20 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUL PY 2004 VL 3 IS 7 BP 849 EP 860 PG 12 WC Oncology SC Oncology GA 838SB UT WOS:000222732300010 PM 15252146 ER PT J AU Lu, X Burgan, WE Cerra, MA Chuang, EY Tsai, MH Tofilon, PJ Camphausen, K AF Lu, X Burgan, WE Cerra, MA Chuang, EY Tsai, MH Tofilon, PJ Camphausen, K TI Transcriptional signature of flavopiridol-induced tumor cell death SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID DEPENDENT KINASE INHIBITOR; BREAST-CARCINOMA CELLS; GENE-EXPRESSION; CANCER CELLS; CYCLIN D1; THERAPY; DNA; APOPTOSIS; NEOPLASMS; INFUSION AB Flavopiridol has been shown to inhibit the proliferation of a variety of human tumor cells and is currently undergoing clinical evaluation in cancer treatment. Although the anti-proliferative effect of flavopiridol has been attributed to the inhibition of cyclin-dependent kinases 2 and 4, recent reports indicate that the mechanism responsible for the cell death induced by this agent is more complex. To provide insight into the molecular processes mediating flavopiridol-induced cytotoxicity and to investigate the availability of markers indicative of its activity, we have applied cDNA microarray technology. Gene expression profiles were determined for four human tumor cell lines (prostate carcinomas PC3 and DU145 and gliomas SF539 and U251) following exposure to selected concentrations of flavopiridol. Treatment of these cell lines with a concentration of flavopiridol sufficient to reduce survival to 10% resulted in the identification of a set of 209 genes, the expression of which were altered in each of the cell lines. This common set of 209 gene expression changes suggested that flavopiridol-induced cell death can be defined in terms of a specific transcriptome. The flavopiridol death transcriptome consisted primarily of down-regulated genes; however, there were also a significant number of genes with increased expression. Whereas causal relationships were not established, these data suggest molecular events/processes that may be associated with flavopiridol-induced tumor cell death. Moreover, the identification of a set of gene expression changes in four human tumor cell lines suggests that such a transcriptome may be applicable to investigations of flavopiridol pharmacodynamics. C1 NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. NCI, Mol Radiat Therapeut Branch, Bethesda, MD 20892 USA. NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. RP Camphausen, K (reprint author), NCI, Radiat Oncol Branch, 10 Ctr Dr,Bldg 10,Room B3B69, Bethesda, MD 20892 USA. EM camphauk@mail.nih.gov NR 28 TC 28 Z9 29 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUL PY 2004 VL 3 IS 7 BP 861 EP 872 PG 12 WC Oncology SC Oncology GA 838SB UT WOS:000222732300011 PM 15252147 ER PT J AU Swales, K Negishi, M AF Swales, K Negishi, M TI CAR, driving into the future SO MOLECULAR ENDOCRINOLOGY LA English DT Review ID CONSTITUTIVE-ANDROSTANE RECEPTOR; ORPHAN NUCLEAR RECEPTOR; PREGNANE-X-RECEPTOR; BILIRUBIN UDP-GLUCURONOSYLTRANSFERASE; LIGAND-BINDING DOMAIN; MOUSE CYP2B10 GENE; GLUCOCORTICOID-RECEPTOR; XENOBIOTIC RESPONSE; ACTIVATED RECEPTOR; HUMAN HEPATOCYTES AB The nuclear orphan receptor CAR is active in the absence of ligand with the unique capability to be further regulated by activators. A number of these activators, including phenobarbital, do not directly bind to the receptor. Considered a xenobiotic sensing receptor, CAR transcriptionally modifies the expression of genes involved in the metabolism and elimination of xenobiotics and steroids in response to these compounds and other cellular metabolites. Its hepatic expression pattern endows the liver with the ability to protect against not only exogenous but also endogenous insults. The mechanism of CAR activation is complex, involving translocation from the cytoplasm to the nucleus in the presence of activators, followed by further activation steps in the nucleus. Although this mechanism remains under investigation, we have summarized here the cellular signaling pathways elucidated so far and speculate on the mechanism by which CAR activators regulate gene expression through this network. C1 NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM negishi@niehs.nih.gov NR 90 TC 112 Z9 117 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD JUL PY 2004 VL 18 IS 7 BP 1589 EP 1598 DI 10.1210/me.2003-0397 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 832HV UT WOS:000222259000001 PM 14988430 ER PT J AU Ait-Ali, D Turquier, V Grumolato, L Yon, L Jourdain, M Alexandre, D Eiden, LE Vaudry, H Anouar, Y AF Ait-Ali, D Turquier, V Grumolato, L Yon, L Jourdain, M Alexandre, D Eiden, LE Vaudry, H Anouar, Y TI The proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1 stimulate neuropeptide gene transcription and secretion in adrenochromaffin cells via activation of extracellularly regulated kinase 1/2 and p38 protein kinases, and activator protein-1 transcription factors SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID PITUITARY-ADRENAL AXIS; VASOACTIVE INTESTINAL POLYPEPTIDE; CHROMAFFIN CELLS; NITRIC-OXIDE; SIGNAL-TRANSDUCTION; SECRETOGRANIN-II; FACTOR RECEPTOR; CATECHOLAMINE SECRETION; MESSENGER-RNA; IMMUNE-SYSTEM AB Immune-autonomic interactions are known to occur at the level of the adrenal medulla, and to be important in immune and stress responses, but the molecular signaling pathways through which cytokines actually affect adrenal chromaffin cell function are unknown. Here, we studied the effects of the proinflammatory cytokines, TNF-alpha and IL-1, on gene transcription and secretion of bioactive neuropeptides, in primary bovine adrenochromaffin cells. TNF-alpha and IL-1 induced a time- and dose-dependent increase in galanin, vasoactive intestinal polypeptide, and secretogranin II mRNA levels. The two cytokines also stimulated the basal as well as depolarization-provoked release of enkephalin and secretoneurin from chromaffin cells. Stimulatory effects of TNF-alpha on neuropeptide gene expression and release appeared to be mediated through the type 2 TNF-alpha receptor, and required activation of ERK 1/2 and p38, but not Janus kinase, MAPKs. In addition, TNF-alpha increased the binding activity of activator protein-1 (AP-1) and stimulated transcription of a reporter gene containing AP-1-responsive elements in chromaffin cells. The AP-1-responsive reporter gene could also be activated through the ERK pathway. These results suggest that neuropeptide biosynthesis in chromaffin cells is regulated by TNF-alpha via an ERK-dependent activation of AP-1-responsive gene elements. Either locally produced or systemic cytokines might regulate biosynthesis and release of neuropeptides in chromaffin cells, integrating the adrenal medulla in the physiological response to inflammation. This study describes, for the first time, a signal transduction pathway activated by TNF-alpha in a major class of neuroendocrine cells that, unlike TNF-alpha signaling in lymphoid cells, employs ERK and p38 rather than Janus kinase and p38 to transmit gene-regulatory signals to the cell nucleus. C1 Univ Rouen, Lab Cellular & Mol Neuroendocrinol, European Inst Peptide Res IFRMP 23, INSERM,U413,CNRS,Unite Associee, F-76821 Mont St Aignan, France. NIMH, Sect Mol Neurosci, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. RP Vaudry, H (reprint author), Univ Rouen, Lab Cellular & Mol Neuroendocrinol, European Inst Peptide Res IFRMP 23, INSERM,U413,CNRS,Unite Associee, F-76821 Mont St Aignan, France. EM hubert.vaudry@univ-rouen.fr RI Grumolato, Luca/A-1697-2015 OI Grumolato, Luca/0000-0001-8231-3032 NR 73 TC 34 Z9 37 U1 1 U2 4 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD JUL PY 2004 VL 18 IS 7 BP 1721 EP 1739 DI 10.1210/me.2003-0129 PG 19 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 832HV UT WOS:000222259000012 PM 15087472 ER PT J AU Martinez-Fuentes, AJ Hu, L Krsmanovic, LZ Catt, KJ AF Martinez-Fuentes, AJ Hu, L Krsmanovic, LZ Catt, KJ TI Gonadotropin-releasing hormone (GnRH) receptor expression and membrane signaling in early embryonic GnRH neurons: Role in pulsatile neurosecretion SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID GREEN FLUORESCENT PROTEIN; LASER CAPTURE MICRODISSECTION; HYPOTHALAMIC NEURONS; OLFACTORY PLACODE; RHESUS-MONKEY; PITUITARY GONADOTROPHS; AUTOCRINE REGULATION; SECRETING NEURONS; ACTION-POTENTIALS; PULSE-GENERATOR AB The characteristic pulsatile secretion of GnRH from hypothalamic neurons is dependent on an autocrine interaction between GnRH and its receptors expressed in GnRH-producing neurons. The ontogeny and function of this autoregulatory process were investigated in studies on the properties of GnRH neurons derived from the olfactory placode of the fetal rat. An analysis of immunocytochemically identified, laser-captured fetal rat hypothalamic GnRH neurons, and olfactory placode-derived GnRH neurons identified by differential interference contrast microscopy, demonstrated coexpression of mRNAs encoding GnRH and its type I receptor. Both placode-derived and immortalized GnRH neurons (GT1-7 cells) exhibited spontaneous electrical activity that was stimulated by GnRH agonist treatment. This evoked response, as well as basal neuronal firing, was abolished by treatment with a GnRH antagonist. GnRH stimulation elicited biphasic intracellular calcium ([Ca2+](i)) responses, and both basal and GnRH-stimulated [Ca2+](i) levels were reduced by antagonist treatment. Perifused cultures released GnRH in a pulsatile manner that was highly dependent on extracellular Ca2+. The amplitude of GnRH pulses was increased by GnRH agonist stimulation and was diminished during GnRH antagonist treatment. These findings demonstrate that expression of GnRH receptor, GnRH-dependent activation of Ca2+ signaling, and autocrine regulation of GnRH release are characteristics of early fetal GnRH neurons and could provide a mechanism for gene expression and regulated GnRH secretion during embryonic migration. C1 NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Catt, KJ (reprint author), NICHHD, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Room 6A-36, Bethesda, MD 20892 USA. EM catt@helix.nih.gov NR 45 TC 37 Z9 37 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD JUL PY 2004 VL 18 IS 7 BP 1808 EP 1817 DI 10.1210/me.2003-0321 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 832HV UT WOS:000222259000019 PM 15184526 ER PT J AU Bassett, CL Nickerson, ML Farrell, RE Harrison, M AF Bassett, CL Nickerson, ML Farrell, RE Harrison, M TI Multiple transcripts of a gene for a leucine-rich repeat receptor kinase from morning glory (Ipomoea nil) originate from different TATA boxes in a tissue-specific manner SO MOLECULAR GENETICS AND GENOMICS LA English DT Article DE transcription initiation; TATA element; upstream open reading frames (uORFs); RNA ligase-mediated (RLM)-5 ' RACE; translational control ID RNA-POLYMERASE-II; MESSENGER-RNA; INITIATION SITES; PROMOTER ELEMENT; BINDING PROTEIN; MAIZE; TRANSLATION; SEQUENCES; EXPRESSION; DNA AB TATA boxes are the most common regulatory elements found in the promoters of eukaryotic genes because they are associated with basal transcription initiation by RNA polymerase II. Often only a single TATA element is found in a given promoter, and tissue-, stage- and/or stimulus-specific expression occurs because the TATA box is associated with other cis -acting elements that enhance or repress transcription. We used software tools for gene analysis to assist in locating potential TATA box(es) in an AT-rich region of the promoter of a gene, inrpk1, which codes for a leucine-rich receptor protein kinase in morning glory (Ipomoea nil). Through the use of RT-PCR and various combinations of forward primers bracketing most of the promoter region we were able to define the 5'-ends of transcripts in this region. The region was then targeted for analysis by RNA Ligase-Mediated-5' Rapid Amplification of cDNA Ends (RLM-5' RACE) to identify the transcript initiation site(s). Positioning of initiation sites with respect to TATA boxes identified by gene analysis tools allowed us to identify three operational TATA elements which regulate basal transcription from this gene. Two TATA boxes were responsible for all of the inrpk1 transcripts found in leaves and cotyledons, and about 25-30% of the transcripts in roots. A third TATA box was involved only in expression in roots and accounted for the remaining 50-70% of root transcripts. RNAs expressed from this element lack two potentially functional upstream AUG codons, and may be translated more efficiently than transcripts originating from the other TATA boxes. C1 ARS, Appalachian Fruit Res Stn, USDA, Kearneysville, WV 25430 USA. NCI, Immunobiol Lab, Frederick, MD 21702 USA. Penn State Univ, Dept Biol, York, PA 17403 USA. Marshall Univ, Huntington, WV 25755 USA. RP Bassett, CL (reprint author), ARS, Appalachian Fruit Res Stn, USDA, 2217 Wiltshire Rd, Kearneysville, WV 25430 USA. EM cbassett@afrs.ars.usda.gov NR 50 TC 9 Z9 9 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1617-4615 J9 MOL GENET GENOMICS JI Mol. Genet. Genomics PD JUL PY 2004 VL 271 IS 6 BP 752 EP 760 DI 10.1007/s00438-004-1031-7 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 837YJ UT WOS:000222677100012 PM 15221460 ER PT J AU Wong, KD Sidransky, E Verma, A Mixon, TH Sandberg, GD Wakefield, LK Morrison, A Lwin, A Colegial, C Allman, JM Schiffmann, R AF Wong, KD Sidransky, E Verma, A Mixon, TH Sandberg, GD Wakefield, LK Morrison, A Lwin, A Colegial, C Allman, JM Schiffmann, R TI Neuropathology provides clues to the pathophysiology of Gaucher disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Gaucher disease; hippocampus; glucocerebrosidase; calcarine cortex; astrogliosis; neuronal loss; synuclein; Lewy body; Parkinsonism ID MARMOSET CALLITHRIX-JACCHUS; SUPERIOR TEMPORAL SULCUS; CENTRAL NERVOUS-SYSTEM; MT VISUAL AREA; ALPHA-SYNUCLEIN; PARKINSONS-DISEASE; RAT HIPPOCAMPUS; LEWY BODIES; NORRBOTTNIAN TYPE; SQUIRREL-MONKEY AB To better understand the pathogenesis of brain dysfunction in Gaucher disease (GD), we studied brain pathology in seven subjects with type 1 GD (four also exhibited parkinsonism and dementia), three with type 2 GD and four with type 3 GD. Unique pathologic patterns of disease involving the hippocampal CA2-4 regions and layer 4b of the calcarine cortex were identified. While these findings were common to all three GD phenotypes, the extent of the changes varied depending on the severity of disease. Cerebral cortical layers 3 and 5, hippocampal CA2-4, and layer 4b were involved in all GD patients. Neuronal loss predominated in both type 2 and type 3 patients with progressive myoclonic encephalopathy, whereas patients classified as type 1 GD had only astrogliosis. Adjacent regions and lamina, including hippocampal CA1 and calcarine lamina 4a and 4c were spared of pathology, highlighting the specificity of the vulnerability of selective neurons. Elevated glucocerebrosidase expression by immunohistochemistry was found in CA2-4. Hippocampal Ca-45(2+) uptake autoradiography in rat brain was performed demonstrating that hippocampal CA2-4 neurons, rather than CA1 neurons, were calcium-induced calcium release sensitive (CICR-sensitive). These findings match recent biochemical studies linking elevated glucosylceramide levels to sensitization of CA2-4 RyaR receptors and 300% potentiation of neuronal CICR sensitivity. In two patients with type 1 GD and parkinsonism, numerous synuclein positive inclusions, similar to brainstem-type Lewy bodies found in Parkinson disease, were also found hippocampal CA2-4 neurons. These findings argue for a common cytotoxic mechanism linking aberrant glucocerebrosidase activity, neuronal cytotoxicity, and cytotoxic Lewy body formation in GD. Published by Elsevier Inc. C1 Armed Forces Inst Pathol, Dept Neuropathol, Washington, DC 20306 USA. NHGRI, Sect Mol Neurogenet, NIMH, NIH, Bethesda, MD 20892 USA. NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Neurol, Bethesda, MD 20814 USA. CALTECH, Integrat Biol Sect, Div Biol, NIH,NINDS, Bethesda, MD USA. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Armed Forces Inst Pathol, Dept Neuropathol, Washington, DC 20306 USA. EM rs4e@nih.gov NR 88 TC 202 Z9 204 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JUL PY 2004 VL 82 IS 3 BP 192 EP 207 DI 10.1016/j.ymgme.2004.04.011 PG 16 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 840DR UT WOS:000222837700001 PM 15234332 ER PT J AU O'Shea, JJ Husa, M Li, D Hofmann, SR Watford, W Roberts, JL Buckley, RH Changelian, P Candotti, F AF O'Shea, JJ Husa, M Li, D Hofmann, SR Watford, W Roberts, JL Buckley, RH Changelian, P Candotti, F TI Jak3 and the pathogenesis of severe combined immunodeficiency SO MOLECULAR IMMUNOLOGY LA English DT Review DE Jak3; SCID ID PROTEIN-TYROSINE KINASES; RECEPTOR-DEFICIENT MICE; COMMON GAMMA-CHAIN; BONE-MARROW-TRANSPLANTATION; COMBINED IMMUNE-DEFICIENCY; STEM-CELL TRANSPLANTATION; MEDIATED GENE-TRANSFER; NATURAL-KILLER-CELLS; CD8 T-CELLS; JANUS KINASE AB The discovery that Jak3 mutations area significant cause of severe combined immunodeficiency (SCID), a rare inherited defect characterized by lymphopenia, has provided valuable insights into the functions of Jak3 in lymphoid development and function. The current therapy for patients suffering from Jak3 SCID is hematopoetic stem cell transplantation, although gene therapy trials have also been performed. In lieu of crystal Structure data, these patient-derived mutations have aided in the elucidation of the functions and structure of Jak3. By virtue of its requirement for lymphoid functions, Jak3 makes a tantalizing target for immunosuppression and anti-cancer therapy. Herein, we discuss the normal actions of the gamma(c) cytokines, the pathogenesis and treatment of SCID, and finally, the production of a new, selective Jak3 inhibitor capable of preventing transplant rejection in two animal models. Further study of Jak3 will hopefully provide insights into the clinical treatment of patients suffering front immune-mediated diseases. (C) 2004 Published by Elsevier Ltd. C1 NIAMSD, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. Howard Hughes NIH Scholars Program, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA. Pfizer Inc, Cent Res, Groton, CT 06340 USA. NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP NIAMSD, Mol Immunol & Inflammat Branch, MSC 1820,10 Ctr Dr, Bethesda, MD 20892 USA. RI Husa, Matthew/G-4850-2012 NR 108 TC 60 Z9 61 U1 0 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD JUL PY 2004 VL 41 IS 6-7 BP 727 EP 737 DI 10.1016/j.molimm.2004.04.014 PG 11 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 841NW UT WOS:000222938300014 PM 15220007 ER PT J AU Torigoe, C Song, JM Barisas, BG Metzger, H AF Torigoe, C Song, JM Barisas, BG Metzger, H TI The influence of actin microfilaments on signaling by the receptor with high-affinity for IgE SO MOLECULAR IMMUNOLOGY LA English DT Article DE mast cell; cytoskeleton; signal transduction; kinetic proofreading ID FC-EPSILON-RI; BASOPHILIC LEUKEMIA-CELLS; PROTEIN-TYROSINE KINASE; GLYCOSPHINGOLIPID-ENRICHED MICRODOMAINS; RBL-2H3 MAST-CELLS; HISTAMINE-RELEASE; LYN KINASE; CROSS-LINKING; ACTIVATION; DEGRANULATION AB Aggregation of the receptors with high-affinity for IgE (FcepsilonRI) stimulates a variety of cellular responses, but excessive aggregation inhibits such responses. Actin filaments have been implicated in the inhibitory phenomenon because disrupting the filaments enhances the cellular reactions stimulated by the aggregated receptors. To clarify further the molecular mechanism and physiological importance of the actin-mediated inhibition. we assessed the effect of inhibitors of actin polymerization on the initial signaling events of mast cells alternatively stimulated by nitrophenyl ligands that dissociate slowly (high-affinity) or rapidly (low-affinity) from receptor-bound anti-dinitrophenyl IgE. The inhibitors amplified the phosphorylation of FcERI and of Syk induced by addition of either ligand but at physiological temperatures, the augmentation of the response to the low-affinity ligand was especially exaggerated. The effect of actin is on the earliest events, and although the molecular mechanism(s) by which the filaments regulate the intensity of proximal signaling remains unclear, several possibilities have been excluded. That the inhibitors only minimally augment the responses stimulated by preformed dimers of IgE, and in general show smaller effects with more limited aggregation, suggests that the actin-mediated "down-regulation" may be more prominent in laboratory experiments than under physiological circumstances. (C) 2003 Elsevier B.V. All rights reserved. C1 NIAMS, Sect Chem Immunol, Arthritis & Rheumatism Branch, Bethesda, MD 20892 USA. Colorado State Univ, Dept Chem, Ft Collins, CO 80523 USA. Univ New Mexico, Sch Med, Canc Res Facil, Div Cell Pathol,Dept Pathol, Albuquerque, NM 87131 USA. RP Metzger, H (reprint author), NIAMS, Sect Chem Immunol, Arthritis & Rheumatism Branch, Bethesda, MD 20892 USA. EM metzgerh@exchange.nih.gov NR 49 TC 8 Z9 8 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD JUL PY 2004 VL 41 IS 8 BP 817 EP 829 DI 10.1016/j.molimm.2004.03.033 PG 13 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 841VZ UT WOS:000222961200009 PM 15234561 ER PT J AU Gonzales, NR Padlan, EA De Pascalis, R Schuck, P Schlom, J Kashmiri, SVS AF Gonzales, NR Padlan, EA De Pascalis, R Schuck, P Schlom, J Kashmiri, SVS TI SDR grafting of a murine antibody using multiple human germline templates to minimize its immunogenicity SO MOLECULAR IMMUNOLOGY LA English DT Article DE antibodies; tumor immunity; antibody engineering ID COMPLEMENTARITY-DETERMINING REGIONS; SPECIFICITY-DETERMINING RESIDUES; CARCINOEMBRYONIC ANTIGEN; MONOCLONAL-ANTIBODY; ANTI-CD18 ANTIBODY; CYNOMOLGUS MONKEYS; BINDING; PHARMACOKINETICS; HUMANIZATION; EXPRESSION AB The humanization of mAbs by complementarity-determining region (CDR)-grafting has become a standard procedure to improve the clinical utility of xenogeneic Abs by reducing human anti-murine Ab (HAMA) responses elicited in patients. However, CDR-grafted humanized Abs may still evoke anti-V region responses when administered in patients. To minimize anti-V region responses, the Ab may be humanized by grafting onto the human templates only the specificity-determining residues (SDRs), the residues that are essential for the surface complementarity of the Ab and its ligand. Typically, humanization of an Ab, whether by CDR or SDR grafting, involves the use of a single human template for the entire VL or VH domain of an Ab. We hypothesized, however, that the homology between the human template sequences and mAb to be humanized may be maximized by using templates from multiple human germline sequences corresponding to the different segments of the variable domain. This could be more advantageous in reducing the potential immunogenicity of the humanized Ab. This report describes the SDR grafting of the murine anti-carcinoembryonic antigen (CEA) mAb COL-1 using three different human germline V-kappa sequences as templates for the VL CDRs and another human template for the VL frameworks. In competition RIAs, the SDR-grafted COL-1 (HuCOL-1(SDR)) completely inhibited the binding of radiolabeled murine COL-1 (mCOL-1) to CEA, and showed that its binding affinity is comparable to that of the CDR-grafted Ab (HuCOL-1). The HuCOL-1 SDR showed similar binding reactivity to the CEA expressed on the surface of a tumor cell line as the HuCOL-1. More importantly, compared to HuCOL-1 and the "abbreviated" CDR-grafted Ab, HuCOL-1 SDR showed lower reactivity to patients' sera carrying anti-V region Abs to mCOL-1. HuCOL-1 SDR, which shows a lower sera reactivity than that of the parental Abs while retaining its Ag-binding property, is a potentially useful clinical reagent. To the best of our knowledge, this is the first time a VL or VH domain of an Ab has been humanized by grafting the SDRs onto a human template comprised of several Ab sequences. We have shown that humanization of an Ab can be optimized using multiple human templates for a single variable domain of an Ab. This approach maximizes the homology between the target Ab and the human templates in both the frameworks and the CDRs by choosing as the template the human sequence that displays the highest local sequence identity to the frameworks and to each of the CDRs of the target Ab. (C) 2004 Elsevier Ltd. All rights reserved. C1 NCI, Tumor Immunol & Biol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. NIDDKD, Mol Biol Lab, Bethesda, MD 20892 USA. NIH, Div Bioengn & Phys Sci, Off Res Serv, Off Director, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, Canc Res Ctr, Room 8B09,10 Ctr Dr,Bldg 10, Bethesda, MD 20892 USA. EM js141c@nih.gov OI Schuck, Peter/0000-0002-8859-6966 NR 37 TC 29 Z9 32 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD JUL PY 2004 VL 41 IS 9 BP 863 EP 872 DI 10.1016/j.molimm.2004.03.041 PG 10 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 843HO UT WOS:000223069500004 PM 15261458 ER PT J AU Hiremath, MM Mikhael, AI Taylor, LS Musso, T McVicar, DW AF Hiremath, MM Mikhael, AI Taylor, LS Musso, T McVicar, DW TI Complex regulation of the Csk homologous kinase (Chk) by IL-4 family cytokines and IFN-gamma in human peripheral blood monocytes SO MOLECULAR IMMUNOLOGY LA English DT Article DE tyrosine kinase; protein tyrosine phosphorylation; gene regulation; Src-family inhibition ID PROTEIN-TYROSINE KINASE; COLONY-STIMULATING FACTOR; NECROSIS-FACTOR-ALPHA; INTERFERON-GAMMA; FUNCTIONAL ASSOCIATION; MOLECULAR-CLONING; DENDRITIC CELLS; BETA-SUBUNIT; GENE; RECEPTOR AB Csk homologous kinase (Chk) is a tyrosine kinase that shares homology with Csk and, like Csk, has the potential to inhibit src-family kinase function through phosphorylation. In myeloid lineage cells, Chk expression is dependent on monocytic differentiation. IL-4 and IL-13 are cytokines involved in monocytic differentiation that have recently been shown to induce Chk expression in peripheral blood monocytes (PBMs). In this study, we show that two other members of the IL-4 family, IL-3 and GM-CSF, can also induce Chk expression at RNA and protein levels. Interestingly, Chk induction is both blocked and reversed by IFN-gamma treatment. Additionally, a short pretreatment with IFN-gamma is sufficient to prevent Chk induction, and the effects of IFN-gamma are dependent on protein synthesis. Collectively, these results suggest that activation of Chk expression and signaling may have a role in the IL-4 family-mediated differentiation of myeloid cells, and inhibition of Chk activation may be one mechanism by which IFN-gamma alters IL-4-mediated affects. Published by Elsevier Ltd. C1 NCI, Expt Immunol Lab, FCRF, Frederick, MD 21702 USA. RP McVicar, DW (reprint author), NCI, Expt Immunol Lab, FCRF, Bldg 560,Room 31-46, Frederick, MD 21702 USA. EM mcvicar@nih.gov RI McVicar, Daniel/G-1970-2015; OI MUSSO, Tiziana/0000-0002-7487-6078 NR 44 TC 3 Z9 3 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD JUL PY 2004 VL 41 IS 9 BP 901 EP 910 DI 10.1016/j.molimm.2004.04.025 PG 10 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 843HO UT WOS:000223069500008 PM 15261462 ER PT J AU Kino, T Liou, SH Charmandari, E Chrousos, GP AF Kino, T Liou, SH Charmandari, E Chrousos, GP TI Glucocorticoid receptor mutants demonstrate increased motility inside the nucleus of living cells: Time of fluorescence recovery after photobleaching (FRAP) is an integrated measure of receptor function SO MOLECULAR MEDICINE LA English DT Article ID UBIQUITIN-PROTEASOME PATHWAY; LIGAND-BINDING DOMAIN; TRANSCRIPTIONAL ACTIVITY; SUBNUCLEAR TRAFFICKING; CLINICAL PHENOTYPE; POINT MUTATION; BETA-ISOFORM; RESISTANCE; GENE; ACTIVATION AB Natural mutations of the human glucocorticoid receptor (GR) isoform alpha cause the glucocorticoid resistance syndrome. Mutant receptors may have abnormal interactions with the ligand, target DNA sequences, and/or multiple intracellular proteins, as well as aberrant nucleocytoplasmic trafficking. Using fluorescence recovery after photobleaching (FRAP) analysis, all GR pathologic mutant receptors examined, as well as 2 synthetic GR mutants lacking the activation function (AF)-1 or the ligand-binding domain (and hence the AF-2), had defective transcriptional activity and dynamic motility defects inside the nucleus of living cells. In the presence of dexamethasone, these mutants displayed a curtailed 50% recovery time ((1/2)) after photobleaching and, hence, significantly increased intranuclear motility and decreased "chromatin retention." The t(1/2) values of the mutants correlated positively with their transcriptional activities and depended on the GR domain affected. GR beta, a natural splice variant of the GR gene, also demonstrated a shorter t(1/2) than GR alpha. The motility responsiveness of the natural and artificial mutant receptors examined, and of GR beta, to the proteasomal inhibitor MG-132 also depended on the mutant domain. Thus, mutant glucocorticoid receptors possess dynamic motility defects in the nucleus, possibly caused by their inability to properly interact with all key partner nuclear molecules necessary for full activation of glucocorticoid-responsive genes. C1 NICHHD, Pediat Endocrinol Sect, Reprod Biol & Med Branch, NIH,CRC, Bethesda, MD 20892 USA. Univ Athens, Dept Pediat 1, Athens, Greece. RP Kino, T (reprint author), NICHHD, Pediat Endocrinol Sect, Reprod Biol & Med Branch, NIH,CRC, Bldg 10,Room 1-3140,10 Ctr Dr,MSC 110, Bethesda, MD 20892 USA. EM kinot@mail.nih.gov RI Charmandari, Evangelia/B-6701-2011 NR 42 TC 17 Z9 17 U1 0 U2 1 PU NORTH SHORE-LONG ISLAND JEWISH RESEARCH INSTITUTE PI MANHASSET PA 350 COMMUNITY DRIVE, MANHASSET, NY 11030 USA SN 1076-1551 J9 MOL MED JI Mol. Med. PD JUL-DEC PY 2004 VL 10 IS 7-12 BP 80 EP 88 DI 10.2119/2005-00026.Kino PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 994LM UT WOS:000234033300003 PM 16307173 ER PT J AU Li, YG Dabrazhynetskaya, A Youngren, B Austin, S AF Li, YG Dabrazhynetskaya, A Youngren, B Austin, S TI The role of Par proteins in the active segregation of the P1 plasmid SO MOLECULAR MICROBIOLOGY LA English DT Article ID ESCHERICHIA-COLI; PARTITION SITE; DAUGHTER CELLS; CHROMOSOME; SYSTEM; DNA; LOCALIZATION; SPECIFICITY; CENTROMERE; MECHANISMS AB The parS centromere-like site promotes active P1 plasmid segregation in the presence of P1 ParA and ParB proteins. At the modest growth rate used here, time-lapse and still photomicroscopy shows that the plasmid copies are clustered as a focus at the Escherichia coli cell centre. Just before cell division, the focus is actively divided and ejects bidirectionally into opposite halves of the dividing cell. In the absence of the wild-type parS binding protein ParB, a focus was formed, but generally did not go to the cell centre. The randomly placed focus did not divide and was inherited by one daughter cell only. In the absence of ParA, foci formed and frequently fixed to the cell centre. However, they failed to divide or eject and were left at the new cell pole of one cell at division. Thus, ParB appears to be required for recognition of the plasmid and its attachment to the cell centre, and ParA is required for focus division and energetic ejection from the cell centre. The ATPase active site mutation, parAK122E, blocked ejection. Mutant parAM314I ejected weakly, and the daughter foci took two generations to reach a new cell centre. This explains the novel alternation of segregation and missegregation in successive generations seen in time-lapse images of this mutant. C1 NCI, Gene Regulat & Chromosome Biol Lab, CCR, Frederick, MD 21702 USA. RP Austin, S (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, CCR, Frederick, MD 21702 USA. EM austin@ncifcrf.gov NR 25 TC 32 Z9 33 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD JUL PY 2004 VL 53 IS 1 BP 93 EP 102 DI 10.1111/j.1365-2958.2004.04111.x PG 10 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 831PX UT WOS:000222208100009 PM 15225306 ER PT J AU Martin, RG Rosner, JL AF Martin, RG Rosner, JL TI Transcriptional and translational regulation of the marRAB multiple antibiotic resistance operon in Escherichia coli SO MOLECULAR MICROBIOLOGY LA English DT Article ID MESSENGER-RNA; SUPEROXIDE SOXRS; MICROARRAY DATA; MARA; ACTIVATION; BINDING; PROTEIN; REGULON; PROMOTERS; STRESS AB The marRAB multiple antibiotic resistance operon of Escherichia coli is autorepressed by MarR. MarR binds to two palindromic sequences in vitro: site I lies between and overlaps the -35 and -10 hexamers for RNA polymerase binding; site II lies between the transcription start site and the GTG initiation codon of marR. To assess the importance of these sites in vivo, the effects of mutant sites on transcription were analysed using fusions to lacZ in the presence and absence of wild-type MarR. When both sites were wild type, transcription in the derepressed marR-deleted strain was 19-fold that of the wild-type strain; when only site I or site II was wild type, this ratio was reduced to 4.3- and 2.6-fold, respectively, showing that full repression requires both sites, but some repression can occur at one site independently of the other. Translational fusions of the wild-type promoter to lacZ demonstrated that marR translation proceeds at only 4.5% of the transcription rate. Analysis of translational fusions with mutant leader sequences demonstrated that the principal reason for inefficient translation is a weak Shine-Dalgarno (SD) sequence, AGG(G). Although the SD sequence is located within the potential stem-loop structure of site II, no evidence for occlusion of the SD sequence was found in the wild-type strain. However, a single basepair mutation that strengthens the stem-loop structure drastically reduced the translational efficiency. Substitution of ATG for GTG as the initiation codon increased translational efficiency by 50%. Increasing the 5 bp spacing between the SD sequence and the GTG codon by one to four bases reduced the translational efficiency by 50-75%. Inefficient translation of marR may help to sensitize the cell to environmental signals. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Martin, RG (reprint author), NIDDKD, Mol Biol Lab, NIH, Bldg 5,Rm 333, Bethesda, MD 20892 USA. EM rgmartin@helix.nih.gov NR 41 TC 26 Z9 29 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD JUL PY 2004 VL 53 IS 1 BP 183 EP 191 DI 10.1111/j.1365-2958.2004.04080.x PG 9 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 831PX UT WOS:000222208100016 PM 15225313 ER PT J AU Gamain, B Smith, JD Avril, M Baruch, DI Scherf, A Gysin, J Miller, LH AF Gamain, B Smith, JD Avril, M Baruch, DI Scherf, A Gysin, J Miller, LH TI Identification of a 67-amino-acid region of the Plasmodium falciparum variant surface antigen that binds chondroitin sulphate A and elicits antibodies reactive with the surface of placental isolates SO MOLECULAR MICROBIOLOGY LA English DT Article ID ERYTHROCYTE-MEMBRANE PROTEIN-1; INFECTED ERYTHROCYTES; VAR GENE; PARASITE ADHESION; PREGNANT-WOMEN; IN-VITRO; MALARIA; PFEMP1; CD36; EXPRESSION AB The complications of malaria in pregnancy are caused by the massive sequestration of parasitized erythrocytes (PE) in the placenta. Placental isolates of Plasmodium falciparum are unusual in that they do not bind the primary microvasculature receptor CD36 but instead bind chondroitin sulphate A (CSA). Pregnant mothers develop antibodies that recognize placental variants worldwide, suggesting that a vaccine against malaria in pregnancy is possible. Some members of the Duffy binding-like gamma (DBL-gamma) domain of the large and diverse P. falciparum erythrocyte membrane protein-1 (PfEMP-1) family, when expressed on Chinese hamster ovary (CHO) cells, bind CSA. To characterize better the molecular requirements for DBL-gamma adhesion to CSA, we determined the binding of various DBL-gamma domains. Most DBL-gamma did not bind CSA, and no conserved region was identified that strictly differentiated binders from non-binders. Structure-function analysis of the FCR3-CSA DBL-gamma domain localized the minimal CSA binding region to a 67-residue fragment. This region was partially conserved among some binding sequences. Serum from a rabbit immunized with the minimal domain reacted with CSA-binding parasite lines, but not with non-CSA-adherent PE lines that adhered to CD36 and other receptors. The identification of a minimal binding region from a highly variable cytoadherent family may have application for a vaccine against malaria in pregnancy. C1 NIAID, Lab Mol & Vector Res, NIH, Bethesda, MD 20892 USA. Inst Pasteur, URA 2581, Unite Biol Interact Hote Parasite, F-75724 Paris, France. Seattle Biomed Res Inst, Seattle, WA 98109 USA. Univ Washington, Dept Pathobiol, Seattle, WA 98195 USA. Univ Aix Marseille 2, Unite Parasitol Expt, F-13385 Marseille, France. RP Gamain, B (reprint author), NIAID, Lab Mol & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bgamain@pasteur.fr RI Scherf, Artur/A-9674-2014; OI Gamain, Benoit/0000-0002-8255-2145 FU NIAID NIH HHS [R01 AI4795301A1] NR 43 TC 35 Z9 36 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD JUL PY 2004 VL 53 IS 2 BP 445 EP 455 DI 10.1111/j.1365-2958.2004.04145.x PG 11 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 834PM UT WOS:000222423000010 PM 15228526 ER PT J AU Maeda, T Miyata, M Yotsurnoto, T Kobayashi, D Nozawa, T Toyarna, K Gonzalez, FJ Yarnazoe, Y Tamai, I AF Maeda, Tornoji Miyata, Masaaki Yotsurnoto, Takafurni Kobayashi, Daisuke Nozawa, Takashi Toyarna, Keisuke Gonzalez, Frank J. Yarnazoe, Yasushi Tamai, Ikurni TI Regulation of drug transporters by the farnesoid X receptor in mice SO MOLECULAR PHARMACEUTICS LA English DT Article DE drug transporter; farnesoid X receptor; FXR-null mice; regulation AB The farnesoid X receptor (FXR, NR1H4) regulates bile acid and lipid homeostasis by acting as an intracellular bile acid-sensing transcription factor, resulting in altered expression of enzymes and transporters involved in bile acid synthesis and transport. Here, we quantitatively analyzed the alterations in expression levels of drug transporters, mainly organic anion-transporting polypeptides (oatp), in wild-type and FXR-null mice to evaluate the role of FXR in their expression and regulation by cholic acid. Changes in the mRNA amounts in liver, kidney, small intestine, and testis in FXR-null mice fed with or without a supplement of 0.5% cholic acid in the diet were analyzed by semiquantitative RT-PCR. In FXR-null mice, the mRNA levels of oatp1, oatp2, oatp3, and octn1 were lower than those of wild-type mice in kidney and testis, while there was no difference in liver or small intestine. Cholic acid feeding led to significantly decreased levels of expression of oatp1 and oct1 and an increased level of expression of oatp2 in wild-type mouse liver. In FXR-null mice, oatp1 and other transporters were downregulated in liver, kidney, and testis, whereas small intestine ASBT, octn2, and pept1 were upregulated. Our results suggested that FXR is involved in the transcriptional regulation of oatp and other transporters in a tissue-specific manner. Furthermore, the effect of cholic acid treatment indicates the involvement of regulatory mechanism(s) other than FXR. C1 [Maeda, Tornoji; Yotsurnoto, Takafurni; Kobayashi, Daisuke; Nozawa, Takashi; Toyarna, Keisuke; Tamai, Ikurni] Tokyo Univ Sci, Fac Pharmaceut Sci, Dept Mol Biopharmaceut, Chiba 2788510, Japan. [Miyata, Masaaki; Yarnazoe, Yasushi] Tohoku Univ, Sch Pharmaceut Sci, Sendai, Miyagi 980, Japan. [Gonzalez, Frank J.] NCI, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Tamai, I (reprint author), Tokyo Univ Sci, Fac Pharmaceut Sci, Dept Mol Biopharmaceut, 2641 Yamazaki, Chiba 2788510, Japan. EM tainai@rs.iioda.tus.ac.jp RI TAMAI, Ikumi/D-8412-2015 NR 31 TC 14 Z9 14 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD JUL-AUG PY 2004 VL 1 IS 4 BP 281 EP 289 DI 10.1021/mp0499656 PG 9 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA V44EA UT WOS:000202984800005 PM 15981587 ER PT J AU Sung, MH Simon, R AF Sung, MH Simon, R TI In silico simulation of inhibitor drug effects on nuclear factor-kappa B pathway dynamics SO MOLECULAR PHARMACOLOGY LA English DT Article ID TRANSCRIPTION FACTORS; THERAPEUTIC TARGET; MULTIPLE-MYELOMA; CANCER AB NF-kappaB is a transcription factor family that activates numerous genes that are related to cell survival, apoptosis, and cell migration. Its persistent activity is associated with tumor formation, growth, metastasis, and drug resistance in many cancer types, including lymphoma, colon cancer, and breast cancer. Current therapeutic efforts for inhibiting this central "switch" include using small molecules to block a selected target in this pathway. Recognizing the regulatory network structure of the NF-kappaB pathway, we examine in silico the effects of inhibitors targeting various network components, using a kinetic model of the pathway. By simulating the corresponding perturbed system dynamics, we show the resulting time course of inhibition has distinct target-specific profiles. In particular, greater oscillatory potential exists for inhibition of upstream events than for direct inhibition of NF-kappaB, at low drug concentrations. This phenomenon is observed also when we examine the dynamic effects of the recently approved proteasome inhibitor, bortezomib (PS-341), and compare it with other inhibitors, taking its pharmacokinetics into consideration. Such kinetic analyses of the "drugged" molecular system will facilitate optimal drug target selection and the development of treatment protocols for a molecularly targeted therapy. C1 NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. RP Sung, MH (reprint author), NCI, Biometr Res Branch, NIH, 6130 Execut Blvd EPN 8146,MSC 7434, Bethesda, MD 20892 USA. EM sungm@mail.nih.gov NR 11 TC 39 Z9 41 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUL PY 2004 VL 66 IS 1 BP 70 EP 75 DI 10.1124/mol.66.1.70 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 831FJ UT WOS:000222179000009 PM 15213297 ER PT J AU Brodie, C Steinhart, R Kazimirsky, G Rubinfeld, H Hyman, T Ayres, JN Hur, GM Toth, A Yang, DZ Garfield, SH Stone, JC Blumberg, PM AF Brodie, C Steinhart, R Kazimirsky, G Rubinfeld, H Hyman, T Ayres, JN Hur, GM Toth, A Yang, DZ Garfield, SH Stone, JC Blumberg, PM TI PKC delta associates with and is involved in the phosphorylation of RasGRP3 in response to phorbol esters SO MOLECULAR PHARMACOLOGY LA English DT Article ID PROTEIN-KINASE-C; NUCLEOTIDE-RELEASING PROTEIN; DIACYLGLYCEROL-BINDING MOTIFS; EXCHANGE FACTOR; SUBCELLULAR-LOCALIZATION; CELL DEVELOPMENT; TUMOR PROMOTERS; LIGAND-BINDING; RAS; ACTIVATION AB RasGRP is a family of guanine nucleotide exchange factors that activate small GTPases and contain a C1 domain similar to the one present in protein kinase C (PKC). In this study, we examined the interaction of RasGRP3 and PKC in response to the phorbol ester PMA. In Chinese hamster ovary or LN-229 cells heterologously expressing RasGRP3, phorbol 12-myristate 13-acetate (PMA) induced translocation of RasGRP3 to the perinuclear region and a decrease in the electrophoretic mobility of RasGRP3. The mobility shift was associated with phosphorylation of RasGRP3 on serine residues and seemed to be PKCdelta-dependent because it was blocked by the PKCdelta inhibitor rottlerin as well as by a PKCdelta kinase-dead mutant. Using coimmunoprecipitation, we found that PMA induced the physical association of RasGRP3 with PKCdelta and, using in situ methods, we showed colocalization of PKCdelta and RasGRP3 in the perinuclear region. PKCdelta phosphorylated RasGRP3 in vitro. Previous studies suggest that ectopic expression of RasGRP3 increases activation of Erk1/2. We found that overexpression of either PKCdelta or RasGRP3 increased the activation of Erk1/2 by PMA. In contrast, coexpression of PKCdelta and RasGRP3 yielded a level of phosphorylation of Erk1/2 similar to that of control vector cells. Our results suggest that PKCdelta may act as an upstream kinase associating with and phosphorylating RasGRP3 in response to PMA. The interaction between RasGRP3 and PKCdelta points to the existence of complex cross-talk between various members of the phorbol ester receptors which can have important impact on major signal transduction pathways and cellular processes induced by phorbol esters or DAG. C1 Bar Ilan Univ, Fac Life Sci, IL-52900 Ramat Gan, Israel. NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. Univ Alberta, Dept Biochem, Edmonton, AB, Canada. RP Brodie, C (reprint author), Bar Ilan Univ, Fac Life Sci, IL-52900 Ramat Gan, Israel. EM chaya@mail.biu.ac.il RI Toth, Attila/F-4859-2010 OI Toth, Attila/0000-0001-6503-3653 NR 42 TC 34 Z9 35 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUL PY 2004 VL 66 IS 1 BP 76 EP 84 DI 10.1124/mol.66.1.76 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 831FJ UT WOS:000222179000010 PM 15213298 ER PT J AU Gapud, EJ Bai, RL Ghosh, AK Hamel, E AF Gapud, EJ Bai, RL Ghosh, AK Hamel, E TI Laulimalide and paclitaxel: A comparison of their effects on tubulin assembly and their synergistic action when present simultaneously SO MOLECULAR PHARMACOLOGY LA English DT Article ID CANCER CELL-LINES; MICROTUBULE-ASSOCIATED PROTEINS; STABILIZING AGENT (-)-LAULIMALIDE; IN-VITRO; PURIFIED TUBULIN; MARINE SPONGE; EPOTHILONE-B; TAXOID SITE; VINORELBINE; COMBINATIONS AB Previous work has shown that laulimalide, a sponge-derived natural product, resembles paclitaxel in enhancing tubulin assembly and in its effects on cellular microtubules. The two compounds, however, seem to have distinct binding sites on tubulin polymer. Nearly equimolar amounts of tubulin, laulimalide, and paclitaxel are recovered from microtubules formed with both drugs. In the present study, we searched for differences between laulimalide and paclitaxel in their interactions with tubulin polymer. Laulimalide was compared with paclitaxel and epothilone A, a natural product that competes with paclitaxel in binding to microtubules, for assembly properties at different temperatures and for effects of GTP and microtubule-associated proteins on assembly. Although minor differences were observed among the three drugs, their overall effects were highly similar, except that aberrant assembly products were observed more frequently with paclitaxel and that the polymers formed with laulimalide and epothilone A were more stable at 0degreesC. The most dramatic difference observed between laulimalide and epothilone A was that only laulimalide was able to enhance assembly synergistically with paclitaxel, as would be predicted if the two drugs bound at different sites in polymer. Because stoichiometric amounts of laulimalide and paclitaxel can cause extensive tubulin assembly, maximum synergy was observed at lower temperatures under reaction conditions in which each drug alone is relatively inactive. Laulimalide-induced assembly, like paclitaxel-induced assembly, was inhibited by drugs that inhibit tubulin assembly by binding at either the colchicine- or vinblastine-binding site. When radiolabeled GTP is present in a reaction mixture with either laulimalide or paclitaxel, nucleotide hydrolysis occurs with incorporation of radiolabeled GDP into polymer. C1 NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. Univ Illinois, Dept Chem, Chicago, IL 60680 USA. RP Hamel, E (reprint author), NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Bldg 469,Room 104, Frederick, MD 21702 USA. EM hamele@mail.nih.gov NR 45 TC 56 Z9 59 U1 1 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUL PY 2004 VL 66 IS 1 BP 113 EP 121 DI 10.1124/mol.66.1.113 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 831FJ UT WOS:000222179000014 PM 15213302 ER PT J AU Wildman, DE Bergman, TJ al-Aghbari, A Sterner, KN Newman, TK Phillips-Conroy, JE Jolly, CJ Disotell, TR AF Wildman, DE Bergman, TJ al-Aghbari, A Sterner, KN Newman, TK Phillips-Conroy, JE Jolly, CJ Disotell, TR TI Mitochondrial evidence for the origin of hamadryas baboons SO MOLECULAR PHYLOGENETICS AND EVOLUTION LA English DT Article DE baboon; biogeography; Arabia; Africa; mtDNA; phylogeography ID CYTOCHROME-B GENE; PAPIO-HAMADRYAS; PRIMATE DIVERGENCES; MOLECULAR PHYLOGENY; HUMAN-EVOLUTION; HYBRID ZONE; DNA; ANUBIS; SUBSTITUTION; SEQUENCES AB Baboons (Mammalia: Primates, Papio) are found primarily on the continent of Africa, but the range of hamadryas baboons (Papio hamadryas) extends to the Arabian Peninsula, and the origin of Arabian populations is unclear. To estimate the timing of the divergence between Arabian and African hamadryas populations we analyzed mitochondrial DNA (mtDNA) sequences from individuals of Arabian and African origin, and from representatives of the other major baboon taxa. The oldest hamadryas mitochondrial lineages in the Arabian Peninsula form an ancient trichotomy with the two major African lineages. This suggests that Arabia was colonized by hamadryas very soon after the appearance of the distinctive hamadryas phenotype, both events perhaps coinciding with a mid-Pleistocene stage of dry climate and low sea-level. The most closely related Arabian and African mtDNA haplotypes coalesce at approximately 35 ka, suggesting that no gene flow between African and Arabian baboons has occurred since the end of the last ice age, when a land bridge at the southern sill of the Red Sea was submerged. The mitochondrial paraphyly of Ethiopian hamadryas and anubis (P. anubis) baboons suggests an extensive and complex history of sex-specific introgression. (C) 2004 Elsevier Inc. All rights reserved. C1 NYU, Dept Anthropol, New York, NY 10003 USA. Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. Washington Univ, Dept Biol, St Louis, MO 63130 USA. Oregon State Univ, Dept Anim Sci, Corvallis, OR 97331 USA. Sanaa Univ, Fac Agr, Sanaa, Yemen. NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA. New York Consortium Evolutionary Primatol, New York, NY USA. RP Wildman, DE (reprint author), NYU, Dept Anthropol, 550 1St Ave, New York, NY 10003 USA. EM dwildman@genetics.wayne.edu RI Bergman, Thore/B-8196-2008 OI Bergman, Thore/0000-0002-9615-5001 NR 58 TC 40 Z9 42 U1 1 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1055-7903 J9 MOL PHYLOGENET EVOL JI Mol. Phylogenet. Evol. PD JUL PY 2004 VL 32 IS 1 BP 287 EP 296 DI 10.1016/j.ympev.2003.12.014 PG 10 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 832TZ UT WOS:000222291400023 PM 15186814 ER PT J AU Liu, ZT Kilburn, BA Leach, RE Romero, R Paria, BC Armant, DR AF Liu, ZT Kilburn, BA Leach, RE Romero, R Paria, BC Armant, DR TI Histamine enhances cytotrophoblast invasion by inducing intracellular calcium transients through the histamine type-1 receptor SO MOLECULAR REPRODUCTION AND DEVELOPMENT LA English DT Article DE trophoblasts; calcium signaling; histamine; histamine receptors ID GROWTH-FACTOR; BLASTOCYST IMPLANTATION; TROPHOBLAST MIGRATION; ENDOVASCULAR INVASION; MOLECULAR-CLONING; PROTEIN-KINASE; MAST-CELLS; MOUSE; EXPRESSION; DIFFERENTIATION AB Blastocyst implantation and placentation require molecular and cellular interactions between the uterine endometrium and blastocyst trophectoderm. Previous studies showed that histamine produced in the mouse uterine luminal epithelium interacts with trophoblast histamine type-2 receptors (H-2) to initiate blastocyst implantation. However, it is unknown whether similar histamine activity is operative in humans. Using a human cell line (HTR-8/SVneo) derived from first-trimester-cytotrophoblasts that expresses both histamine type-1 receptor (H-1) and H-2, we found that histamine promotes cytotrophoblast invasiveness specifically through activation of H-1. Stimulation of H-1 in human cytotrophoblasts by histamine induced intracellular Ca2+ (Ca-i(2+)) transients by activating phospholipase C and the inositol trisphosphate pathway. The enhanced invasion induced by histamine was blocked by pretreatment with H-1 antagonist or by chelation of Ca(2+)i. These findings suggest possible differences between rodents and humans in histamine signaling to the trophoblast. (C) 2004 Wiley-Liss, Inc. C1 Wayne State Univ, Sch Med, CS Mott Ctr Human Growth & Dev, Dept Obstet & Gynecol, Detroit, MI 48201 USA. Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI 48201 USA. NICHHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD 20892 USA. Vanderbilt Univ, Ctr Med, Div Reprod & Dev Biol, Dept Pediat, Nashville, TN 37232 USA. RP Armant, DR (reprint author), Wayne State Univ, Sch Med, CS Mott Ctr Human Growth & Dev, Dept Obstet & Gynecol, 275 E Hancock Ave, Detroit, MI 48201 USA. EM D.Armant@Wayne.edu OI Armant, D. Randall/0000-0001-5904-9325 FU NIAAA NIH HHS [AA12057]; NICHD NIH HHS [HD 037394, HD36764, HD37500, HD98004] NR 43 TC 13 Z9 13 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 1040-452X J9 MOL REPROD DEV JI Mol. Reprod. Dev. PD JUL PY 2004 VL 68 IS 3 BP 345 EP 353 DI 10.1002/mrd.20082 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology SC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology GA 821WO UT WOS:000221494000011 PM 15112328 ER PT J AU Clark, LN Afridi, S Mejia-Santana, H Harris, J Louis, ED Cote, LJ Andrews, H Singleton, A De-Vrieze, FW Hardy, J Mayeux, R Fahn, S Waters, C Ford, B Frucht, S Ottman, R Marder, K AF Clark, LN Afridi, S Mejia-Santana, H Harris, J Louis, ED Cote, LJ Andrews, H Singleton, A De-Vrieze, FW Hardy, J Mayeux, R Fahn, S Waters, C Ford, B Frucht, S Ottman, R Marder, K TI Analysis of an early-onset Parkinson's disease cohort for DJ-1 mutations SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; DJ-1; mutations; early onset; multiethnic cohort ID AUTOSOMAL RECESSIVE PARKINSONISM; GENE; PHENOTYPE; FAMILIES AB The frequency and relative contribution of DJ-1 mutations in early-onset Parkinson's disease (EOPD) is currently unknown. We analyzed a cohort of 89 EOPD patients (mean age at onset of PD +/- SD, 41.5 +/- 7.2 years), ascertained independent of family history, who participated in a study of the genetic epidemiology of PD. This study includes sequence analysis of the DJ-1 gene in addition to assaying the 14,082-by deletion spanning exons l to 5, previously identified in a Dutch kindred, in 89 EOPD cases. A heterozygous missense mutation in exon 5 (A104T) was identified in an EOPD case of Asian ethnicity; this sequence variant was absent in 308 control chromosomes. We identified additional sequence variation in the DJ-1 gene, including a polymorphism in the coding region in exon 5 (R98Q), three polymorphisms in the 5' untranslated region (exon 1A/1B), and two polymorphisms in intronic regions (IVS1 and IVS5). Mutations in the DJ-1 gene are rare in EOPD in both sporadic and familial cases. (C) 2004 Movement Disorder Society. C1 Columbia Univ, Coll Phys & Surg, Dept Pathol, New York, NY 10032 USA. New York State Psychiat Inst & Hosp, Epidemiol Brain Disorders Dept, New York, NY 10032 USA. Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. NIA, Mol Genet Sect, NIH, Bethesda, MD 20892 USA. Columbia Univ, Coll Phys & Surg, Dept Epidemiol, New York, NY 10032 USA. Columbia Univ, Coll Phys & Surg, Dept Neurol, New York, NY 10032 USA. Columbia Univ, Gertrude H Sergievsky Ctr, New York, NY 10032 USA. Columbia Univ, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY 10032 USA. RP Clark, LN (reprint author), Columbia Univ, Coll Phys & Surg, Dept Pathol, 630 W 168th St, New York, NY 10032 USA. EM lc654@columbia.edu RI Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; Ottman, Ruth/O-2371-2013 FU NCRR NIH HHS [RR00645]; NIA NIH HHS [P01AG07232]; NINDS NIH HHS [NS36630, NS39422] NR 24 TC 50 Z9 54 U1 1 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUL PY 2004 VL 19 IS 7 BP 796 EP 800 DI 10.1002/mds.20131 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 840JQ UT WOS:000222855000007 PM 15254937 ER PT J AU Dogu, O Johnson, J Hernandez, D Hanson, M Hardy, J Apaydin, H Ozekmekci, S Sevim, S Gwinn-Hardy, K Singleton, A AF Dogu, O Johnson, J Hernandez, D Hanson, M Hardy, J Apaydin, H Ozekmekci, S Sevim, S Gwinn-Hardy, K Singleton, A TI A consanguineous Turkish family with early-onset Parkinson's disease and an exon 4 parkin deletion SO MOVEMENT DISORDERS LA English DT Article DE parkin; genetics; dystonia; depression ID RECESSIVE JUVENILE PARKINSONISM; GENE; MUTATIONS AB The importance of parkin in early-onset Parkinson's disease in Japan, Europe, and the United States is well established. The contribution of this gene to the risk of Parkinson's disease in other populations is less well known. To explore the importance of parkin in those of Turkish ancestry, we studied familial cases from that country, and identified a consanguineous family with early-onset Parkinson's disease due to a homozygous mutation in parkin. (C) 2004 Movement Disorder Society. C1 Mersin Univ, Fac Med, Dept Neurol, Movement Disorders Unit, TR-33070 Mersin, Turkey. Istanbul Univ, Cerrahpasa Med Sch, Dept Neurol, Istanbul, Turkey. NINDS, NIH, Bethesda, MD 20892 USA. NIA, Neurogenet Lab, Bethesda, MD 20892 USA. RP Dogu, O (reprint author), Mersin Univ, Fac Med, Dept Neurol, Movement Disorders Unit, Noroloji AD Zeytinlibahce Cad, TR-33070 Mersin, Turkey. EM okandogu@mersin.edu.tr RI Gwinn, Katrina/C-2508-2009; Dogu, Okan/A-2045-2010; Johnson, Janel/A-7136-2010; Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; APAYDIN, HULYA/P-1531-2015; OI Gwinn, Katrina/0000-0002-8277-651X NR 20 TC 15 Z9 15 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUL PY 2004 VL 19 IS 7 BP 812 EP 816 DI 10.1002/mds.20028 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 840JQ UT WOS:000222855000010 PM 15254940 ER PT J AU Fernandez-Capetillo, O Nussenzweig, A AF Fernandez-Capetillo, O Nussenzweig, A TI Aging counts on chromosomes SO NATURE GENETICS LA English DT Editorial Material ID MITOTIC CHECKPOINT; CANCER; CELLS; MAD2; MICE AB The acquisition of an abnormal number of chromosomes is a hallmark of many human cancers. A new study indicates that unequal segregation of genetic material to daughter cells during cell division can also lead to premature senescence and accelerated onset of a variety of aging phenotypes. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Fernandez-Capetillo, O (reprint author), NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. EM andre_nussenzweig@nih.gov RI Fernandez-Capetillo, Oscar/H-3508-2015 OI Fernandez-Capetillo, Oscar/0000-0002-2690-6885 NR 14 TC 6 Z9 6 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUL PY 2004 VL 36 IS 7 BP 672 EP 674 DI 10.1038/ng0704-672 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 833QT UT WOS:000222354100007 PM 15226747 ER PT J AU Kraemer, KH AF Kraemer, KH TI From proteomics to disease SO NATURE GENETICS LA English DT Editorial Material ID XERODERMA-PIGMENTOSUM; DNA-REPAIR; TRANSCRIPTION FACTOR; TRICHOTHIODYSTROPHY; GENE; TFIIH; DISORDER; MUTATION AB The nucleotide excision repair system is essential for repairing DNA damage caused by exposure to sunlight. Now, parallel studies in yeast and individuals with a rare disease called trichothiodystrophy have identified a new component of the DNA repair and basal transcription factor TFIIH. C1 NCI, Basic Res Lab, Bethesda, MD 20892 USA. RP Kraemer, KH (reprint author), NCI, Basic Res Lab, Bethesda, MD 20892 USA. EM kraemerk@nih.gov FU Intramural NIH HHS [Z01 BC004517-31] NR 15 TC 10 Z9 11 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUL PY 2004 VL 36 IS 7 BP 677 EP 678 DI 10.1038/ng0704-676 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 833QT UT WOS:000222354100010 PM 15226750 ER PT J AU Lipkin, SM Rozek, LS Rennert, G Yang, W Chen, PC Hacia, J Hunt, N Shin, B Fodor, S Kokoris, M Greenson, JK Fearon, E Lynch, H Collins, F Gruber, SB AF Lipkin, SM Rozek, LS Rennert, G Yang, W Chen, PC Hacia, J Hunt, N Shin, B Fodor, S Kokoris, M Greenson, JK Fearon, E Lynch, H Collins, F Gruber, SB TI The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer SO NATURE GENETICS LA English DT Article ID MISMATCH-REPAIR; MICROSATELLITE INSTABILITY; MSH6 MUTATIONS; COLON-CANCER; MUTL; EXPRESSION; GENE; IDENTIFICATION; ASHKENAZI; FAMILIES AB Most susceptibility to colorectal cancer (CRC) is not accounted for by known risk factors. Because MLH1, MSH2 and MSH6 mutations underlie high-penetrance CRC susceptibility in hereditary nonpolyposis colon cancer (HNPCC), we hypothesized that attenuated alleles might also underlie susceptibility to sporadic CRC. We looked for gene variants associated with HNPCC in Israeli probands with familial CRC unstratified with respect to the microsatellite instability (MSI) phenotype. Association studies identified a new MLH1 variant (415G-->C, resulting in the amino acid substitution D132H) in similar to1.3% of Israeli individuals with CRC self-described as Jewish, Christian and Muslim. MLH1 415C confers clinically significant susceptibility to CRC. In contrast to classic HNPCC, CRCs associated with MLH1 415C usually do not have the MSI defect, which is important for clinical mutation screening. Structural and functional analyses showed that the normal ATPase function of MLH1 is attenuated, but not eliminated, by the MLH1 415G-->C mutation. The new MLH1 variant confers a high risk of CRC and identifies a previously unrecognized mechanism in microsatellite-stable tumors. These studies suggest that variants of mismatch repair proteins with attenuated function may account for a higher proportion of susceptibility to sporadic microsatellite-stable CRC than previously assumed. C1 Univ Calif Irvine, Dept Med, Div Oncol, Irvine, CA 92697 USA. Univ Calif Irvine, Dept Med, Div Epidemiol, Irvine, CA 92697 USA. Univ Calif Irvine, Dept Biol Chem, Div Oncol, Irvine, CA 92697 USA. Univ Calif Irvine, Dept Biol Chem, Div Epidemiol, Irvine, CA 92697 USA. Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel. Technion Israel Inst Technol, Fac Med, Haifa, Israel. NIDDKD, Mol Struct Sect, Bethesda, MD 20892 USA. Univ So Calif, Inst Med Genet, Los Angeles, CA 90089 USA. Affymetrix Corp, Santa Clara, CA 95051 USA. BioCaptus, Bothell, WA 99164 USA. Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. Creighton Univ, Hereditary Canc Inst, Omaha, NE USA. NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. RP Lipkin, SM (reprint author), Univ Calif Irvine, Dept Med, Div Oncol, Irvine, CA 92697 USA. EM slipkin@uci.edu; sgruber@med.umich.edu RI Yang, Wei/D-4926-2011 OI Yang, Wei/0000-0002-3591-2195 NR 30 TC 70 Z9 76 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUL PY 2004 VL 36 IS 7 BP 694 EP 699 DI 10.1038/ng1374 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 833QT UT WOS:000222354100018 PM 15184898 ER PT J AU Cinamon, G Matloubian, M Lesneski, MJ Xu, Y Low, C Lu, T Proia, RL Cyster, JG AF Cinamon, G Matloubian, M Lesneski, MJ Xu, Y Low, C Lu, T Proia, RL Cyster, JG TI Sphingosine 1-phosphate receptor 1 promotes B cell localization in the splenic marginal zone SO NATURE IMMUNOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTOR; LYMPHOCYTE TRAFFICKING; T-CELLS; SPHINGOSINE-1-PHOSPHATE; FTY720; EXPRESSION; MEMORY; S1P(1); EGRESS; RESPONSIVENESS AB The factors directing marginal zone B cells to the splenic marginal zone are not well understood. Here we report that FTY720, a drug that targets sphingosine 1-phosphate (S1P) receptors, induced marginal zone B cell migration into follicles. Marginal zone B cells expressed S1P receptors 1 and 3 (S1P(1) and S1P(3), respectively). Using gene-targeted mice, we show that S1P(1) but not S1P(3) was required for localization in the marginal zone. In mice lacking the chemokine CXCL13, S1P(1)-deficient marginal zone B cells reacquired a marginal zone distribution. Exposure to lipopolysaccharide or antigen caused marginal zone B cells to downregulate S1P(1) and S1P 3 and to migrate into the splenic white pulp. These data suggest that marginal zone B cell localization to the marginal zone depends on responsiveness to the blood lysophospholipid S1P, with S1P(1) signaling overcoming the recruiting activity of CXCL13. C1 Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Microbiol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Immunol, San Francisco, CA 94143 USA. NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Cyster, JG (reprint author), Univ Calif San Francisco, Howard Hughes Med Inst, 513 Parnassus Ave, San Francisco, CA 94143 USA. EM cyster@itsa.ucsf.edu RI Proia, Richard/A-7908-2012; OI Lu, Theresa/0000-0002-5707-8744 NR 38 TC 238 Z9 245 U1 2 U2 14 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD JUL PY 2004 VL 5 IS 7 BP 713 EP 720 DI 10.1038/ni1083 PG 8 WC Immunology SC Immunology GA 833IO UT WOS:000222331200024 PM 15184895 ER PT J AU Kunos, G Pacher, P AF Kunos, G Pacher, P TI Cannabinoids cool the intestine SO NATURE MEDICINE LA English DT Editorial Material ID INFLAMMATORY-BOWEL-DISEASE; NECROSIS-FACTOR-ALPHA; MAST-CELLS; ANANDAMIDE; RECEPTORS; MICE; INVOLVEMENT; MOTILITY; GUT; CB1 AB Cannabinoids inhibit motility and secretion in the intestine. They are now assigned the additional task of curbing excessive inflammation, suggesting that drugs targeting the endogenous cannabinoid system could be exploited for inflammatory bowel disease. C1 NIAAA, NIH, Bethesda, MD 20892 USA. RP Kunos, G (reprint author), NIAAA, NIH, Bethesda, MD 20892 USA. EM gkunos@mail.nih.gov; pacher@mail.nih.gov RI Pacher, Pal/B-6378-2008 OI Pacher, Pal/0000-0001-7036-8108 FU Intramural NIH HHS [Z01 AA000350-07, Z01 AA000351-07, Z99 AA999999] NR 17 TC 25 Z9 27 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUL PY 2004 VL 10 IS 7 BP 678 EP 679 DI 10.1038/nm0704-678 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 835DM UT WOS:000222460400018 PM 15229512 ER PT J AU Rogawski, MA Loscher, W AF Rogawski, MA Loscher, W TI The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions SO NATURE MEDICINE LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; PLACEBO-CONTROLLED TRIAL; GATED SODIUM-CHANNEL; PAROXYSMAL DYSTONIC CHOREOATHETOSIS; PAINFUL DIABETIC-NEUROPATHY; CONSTRICTION INJURY MODEL; SENSORY NEURONS; SPINAL-CORD; STATUS-EPILEPTICUS; COMMON MECHANISM AB Antiepileptic drugs (AEDs) are commonly prescribed for nonepileptic conditions, including migraine headache, chronic neuropathic pain, mood disorders, schizophrenia and various neuromuscular syndromes. In many of these conditions, as in epilepsy, the drugs act by modifying the excitability of nerve (or muscle) through effects on voltage-gated sodium and calcium channels or by promoting inhibition mediated by gamma-aminobutyric acid (GABA) A receptors. In neuropathic pain, chronic nerve injury is associated with the redistribution and altered subunit compositions of sodium and calcium channels that predispose neurons in sensory pathways to fire spontaneously or at inappropriately high frequencies, often from ectopic sites. AEDs may counteract this abnormal activity by selectively affecting pain-specific firing; for example, many AEDs suppress high-frequency action potentials by blocking voltage-activated sodium channels in a use-dependent fashion. Alternatively, AEDs may specifically target pathological channels; for example, gabapentin is a ligand of alpha2delta voltage-activated calcium channel subunits that are overexpressed in sensory neurons after nerve injury. Emerging evidence suggests that effects on signaling pathways that regulate neuronal plasticity and survival may be a factor in the delayed clinical efficacy of AEDs in some neuropsychiatric conditions, including bipolar affective disorder. C1 NINDS, Epilepsy Res Sect, NIH, Bethesda, MD 20892 USA. Univ Vet Med, Dept Pharmacol Toxicol & Pharm, D-30559 Hannover, Germany. Ctr Syst Neurosci, D-30559 Hannover, Germany. RP Rogawski, MA (reprint author), NINDS, Epilepsy Res Sect, NIH, Bethesda, MD 20892 USA. EM michael.rogawski@nih.gov RI Rogawski, Michael/B-6353-2009 OI Rogawski, Michael/0000-0002-3296-8193 NR 113 TC 256 Z9 271 U1 4 U2 30 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUL PY 2004 VL 10 IS 7 BP 685 EP 692 DI 10.1038/nm1074 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 835DM UT WOS:000222460400021 PM 15229516 ER PT J AU O'Shea, JJ Pesu, M Borie, DC Changelian, PS AF O'Shea, JJ Pesu, M Borie, DC Changelian, PS TI A new modality for immunosuppression: Targeting the JAK/STAT pathway SO NATURE REVIEWS DRUG DISCOVERY LA English DT Review ID SEVERE COMBINED IMMUNODEFICIENCY; PROTEIN-TYROSINE KINASE; VERSUS-HOST DISEASE; CYTOKINE SIGNAL-TRANSDUCTION; BONE-MARROW-TRANSPLANTATION; COMBINED IMMUNE-DEFICIENCY; STEM-CELL TRANSPLANTATION; NATURAL-KILLER-CELLS; RAT-HEART ALLOGRAFTS; JAK-3 JANUS KINASE AB Thousands of organs are transplanted each year and millions of people suffer from autoimmune diseases, which creates a need for an armamentarium of immunosuppressive drugs. Unfortunately, immunosuppressants have unwanted side effects owing, in part, to the fact that they have ubiquitous molecular targets. Cytokines have emerged as important controllers of the immune response, and work during the past decade has identified Janus kinases (JAKs) and signal transducers, and activators of transcription (STATs), as crucial intracellular elements in cytokine signalling. Here, we discuss the potential of the JAK/STAT pathway as a target for new immunosuppressants. In particular, the inhibition of JAK3 seems to be an excellent strategy, because of the selective expression and precise functions of this kinase. C1 NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. Stanford Univ, Sch Med, Transplantat Immunol Program, Stanford, CA 94305 USA. Pfizer Global Res & Dev, Dept Antibacterials Immunol & Canc, Groton, CT 06340 USA. RP O'Shea, JJ (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. EM osheaj@arb.niams.nih.gov; dborie@stanford.edu; paul_s_changelian@groton.pfizer.com RI Pesu, marko/L-6344-2013 NR 138 TC 174 Z9 181 U1 1 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD JUL PY 2004 VL 3 IS 7 BP 555 EP 564 DI 10.1038/nrd1441 PG 10 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 834CJ UT WOS:000222388900017 PM 15232577 ER PT J AU Frolenkov, GI Belyantseva, IA Friedman, TB Griffith, AJ AF Frolenkov, GI Belyantseva, IA Friedman, TB Griffith, AJ TI Genetic insights into the morphogenesis of inner ear hair cells SO NATURE REVIEWS GENETICS LA English DT Review ID ACTIN-BUNDLING PROTEINS; CHICK BASILAR PAPILLA; SYNDROME TYPE 1D; HEARING-LOSS; UNCONVENTIONAL MYOSIN; AMES WALTZER; POSTNATAL-DEVELOPMENT; RECESSIVE DEAFNESS; CUTICULAR PLATE; BIRD COCHLEA AB The mammalian inner ear is a sensory organ that has specialized hair cells that detect sound, as well as orientation and movement of the head. The 'hair' bundle on the apical surface of these cells is a mechanosensitive organelle that consists of precisely organized actin-filled projections known as stereocilia. Alterations in hair-bundle morphogenesis can result in hearing loss, balance defects or both. Positional cloning of genes that underlie hereditary hearing loss, coupled with the characterization of corresponding mouse models, is revealing how hair cells have adapted the molecular mechanisms of intracellular motility and intercellular adhesion for the morphogenesis of their apical surfaces. C1 Natl Inst Deafness & Other Commun Disorders, Sect Gene Struct & Funct, NIH, Rockville, MD 20850 USA. Natl Inst Deafness & Other Commun Disorders, Sect Human Genet, Genet Mol Lab, NIH, Rockville, MD 20850 USA. Natl Inst Deafness & Other Commun Disorders, Hearing Sect, Neurootol Branch, NIH, Rockville, MD 20850 USA. RP Griffith, AJ (reprint author), Natl Inst Deafness & Other Commun Disorders, Sect Gene Struct & Funct, NIH, Rockville, MD 20850 USA. EM griffita@nidcd.nih.gov OI Frolenkov, Gregory/0000-0002-9810-5024 NR 129 TC 124 Z9 128 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 J9 NAT REV GENET JI Nat. Rev. Genet. PD JUL PY 2004 VL 5 IS 7 BP 489 EP 498 DI 10.1038/nrg1377 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 834UA UT WOS:000222435200012 PM 15211351 ER PT J AU Bosselut, R AF Bosselut, R TI CD4/CD8-lineage differentiation in the thymus: From nuclear effectors to membrane signals SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID T-CELL DEVELOPMENT; CD4 GENE-EXPRESSION; SEVERE COMBINED IMMUNODEFICIENCY; CHROMATIN-REMODELING COMPLEXES; POSITIVELY SELECTED THYMOCYTES; TRANSCRIPTION FACTOR GATA-3; P56(LCK) TYROSINE KINASE; LINEAGE COMMITMENT; ANTIGEN RECEPTOR; TRANSGENIC MICE AB During thymocyte development, immature thymocytes that express both CD4 and CD8 genes must choose either a helper CD4(+) or cytotoxic CD8(+) T-cell fate. Over the past two years, there have been some important advances regarding T-cell lineage choice, including the identification of transcription factors required for CD4 gene silencing by CD8-lineage cells (RUNX3) or for CD4(+) T-cell differentiation (GATA3), and a better understanding of how T-cell receptor (TCR) signalling correlates CD4/CD8-lineage differentiation to MHC specificity. This review summarizes these recent advances and highlights potential links between TCR signals and nuclear effectors of lineage differentiation. C1 NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bosselut, R (reprint author), NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM remy@helix.nih.gov NR 155 TC 70 Z9 71 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD JUL PY 2004 VL 4 IS 7 BP 529 EP 540 DI 10.1038/nri1392 PG 12 WC Immunology SC Immunology GA 834UF UT WOS:000222435700015 PM 15229472 ER PT J AU Rogawski, MA Loscher, W AF Rogawski, MA Loscher, W TI The neurobiology of antiepileptic drugs SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID IDIOPATHIC GENERALIZED EPILEPSY; CHILDHOOD ABSENCE EPILEPSY; RAT HIPPOCAMPAL-NEURONS; CALCIUM-CHANNEL SUBUNIT; PERSISTENT NA+ CURRENT; FEBRILE SEIZURES PLUS; VOLTAGE-GATED NA+; TRANSMEMBRANE SEGMENT IVS6; STATUS EPILEPTICUS MODEL; PRIMARY AFFERENT NEURONS AB Antiepileptic drugs (AEDs) provide satisfactory control of seizures for most patients with epilepsy. The drugs have the remarkable ability to protect against seizures while permitting normal functioning of the nervous system. AEDs act on diverse molecular targets to selectively modify the excitability of neurons so that seizure-related firing is blocked without disturbing non-epileptic activity. This occurs largely through effects on voltage-gated sodium and calcium channels, or by promoting inhibition mediated by GABA(A) (gamma-aminobutyric acid, type A) receptors. The subtle biophysical modifications in channel behaviour that are induced by AEDs are often functionally opposite to defects in channel properties that are caused by mutations associated with epilepsy in humans. C1 NINDS, Epilepsy Res Stn, NIH, Bethesda, MD 20892 USA. Univ Vet Med, Dept Pharmacol Toxicol & Pharm, D-30559 Hannover, Germany. Ctr Syst Neurosci, D-30559 Hannover, Germany. RP Rogawski, MA (reprint author), NINDS, Epilepsy Res Stn, NIH, Bethesda, MD 20892 USA. EM michael.rogawski@nih.gov RI Rogawski, Michael/B-6353-2009 OI Rogawski, Michael/0000-0002-3296-8193 NR 144 TC 551 Z9 574 U1 17 U2 95 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0048 J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD JUL PY 2004 VL 5 IS 7 BP 553 EP 564 DI 10.1038/nrn1430 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 834TY UT WOS:000222435000014 PM 15208697 ER PT J AU Yuan, BZ Jefferson, AM Popescu, NC Reynolds, SH AF Yuan, BZ Jefferson, AM Popescu, NC Reynolds, SH TI Aberrant gene expression in human non small cell lung carcinoma cells exposed to demethylating agent 5-aza-2 '-deoxycytidine SO NEOPLASIA LA English DT Article DE human non small cell lung carcinoma; 5-aza-2 '-deoxycytidine; cell growth; inhibition; ABL2 gene; Hint/PKCl-1 gene ID TUMOR-SUPPRESSOR GENE; HIT PROTEIN FAMILY; DNA METHYLATION; FHIT GENE; PROMOTER HYPERMETHYLATION; COLORECTAL-CARCINOMA; ISLAND METHYLATION; RENAL-CARCINOMA; BREAST-CANCER; METHYLTRANSFERASE AB The identification of genes undergoing genetic or epigenetic alterations and contributing to the development of cancer is critical to our understanding of the molecular mechanisms of carcinogenesis. A new approach in identifying alterations of genes that might be relevant to the process of tumor development was used in this study by examining the gene expression profile in human lung cancer cells exposed to 5-aza-2'-deoxycytidine (5-aza-dC). A cDNA array analysis was carried out on 5-aza-dC-treated and untreated non small cell lung cancer (NSCLC) cell line NCI-H522. Sixteen and 14 genes were upregulated and downregulated, respectively, by 5-aza-dC treatment. Among them, downregulation of tyrosine protein kinase ABL2 (ABL2) gene and upregulation of hint/protein kinase C inhibitor 1 (Hint/PKCI-1), DVL1, TIMP-1, and TRP-1 genes were found in expanded observations in two or three of five 5-aza-dC-treated NSCLC cell lines. Among these genes, we found that cDNA transfer of Hint/PKCI-1 resulted in a significant in vitro growth inhibition in two cell lines exhibiting 5-aza-dC-induced upregulation of Hint/PKCI-1 and significantly reduced in vivo tumorigenicity of one NSCLC cell line. Hint/PKCI-1, which is the only other characterized human histidine triad (HIT) nucleotide-binding protein in addition to tumor-suppressor gene FHIT, might be involved in lung carcinogenesis. C1 NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. NIOSH, Canc Genet Lab, Toxicol & Mol Biol Branch, Morgantown, WV 26505 USA. RP Yuan, BZ (reprint author), 1095 Willowdale Rd,M-S L-3014,1095, Morgantown, WV 26505 USA. EM bby1@cdc.gov NR 38 TC 38 Z9 46 U1 0 U2 1 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD JUL-AUG PY 2004 VL 6 IS 4 BP 412 EP 419 DI 10.1593/neo.03490 PG 8 WC Oncology SC Oncology GA 837IZ UT WOS:000222623800013 PM 15256063 ER PT J AU Lehky, SR AF Lehky, SR TI Bayesian estimation of stimulus responses in Poisson spike trains SO NEURAL COMPUTATION LA English DT Article ID HIPPOCAMPAL PLACE CELLS; PATTERNS AB A Bayesian method is developed for estimating neural responses to stimuli, using likelihood functions incorporating the assumption that spike trains follow either pure Poisson statistics or Poisson statistics with a refractory period. The Bayesian and standard estimates of the mean and variance of responses are similar and asymptotically converge as the size of the data sample increases. However, the Bayesian estimate of the variance of the variance is much lower. This allows the Bayesian method to provide more precise interval estimates of responses. Sensitivity of the Bayesian method to the Poisson assumption was tested by conducting simulations perturbing the Poisson spike trains with noise. This did not affect Bayesian estimates of mean and variance to a significant degree, indicating that the Bayesian method is robust. The Bayesian estimates were less affected by the presence of noise than estimates provided by the standard method. C1 RIKEN Brain Sci Inst, Cognit Brain Mapping Lab, Saitama 3510198, Japan. NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Lehky, SR (reprint author), RIKEN Brain Sci Inst, Cognit Brain Mapping Lab, Saitama 3510198, Japan. EM sidney@brain.riken.jp NR 5 TC 5 Z9 5 U1 0 U2 2 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 0899-7667 J9 NEURAL COMPUT JI Neural Comput. PD JUL PY 2004 VL 16 IS 7 BP 1325 EP 1343 DI 10.1162/089976604323057407 PG 19 WC Computer Science, Artificial Intelligence SC Computer Science GA 822AI UT WOS:000221505300001 PM 15165392 ER PT J AU Hardy, J AF Hardy, J TI The uncertain anatomy of Alzheimer's disease SO NEUROBIOLOGY OF AGING LA English DT Editorial Material ID CASCADE HYPOTHESIS; TRANSGENIC MICE; PATHOGENESIS; PATHOLOGY; CORTEX C1 NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. RP Hardy, J (reprint author), NIA, Lab Neurogenet, NIH, Room 6C103,Bldg 10,MSC 1589, Bethesda, MD 20892 USA. EM fvaldivieso@cbm.uam.es RI Hardy, John/C-2451-2009 NR 11 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 IS 6 BP 719 EP 720 DI 10.1016/j.neurobiolaging.2003.12.012 PG 2 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 834PS UT WOS:000222423600004 PM 15165693 ER PT J AU Adighibe, O Arepalli, S Hardy, J Wavrant-De-Vrieze, F AF Adighibe, O Arepalli, S Hardy, J Wavrant-De-Vrieze, F TI The Liver X receptor: Candidate gene for Alzheimer's disease SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 NIA, Bethesda, MD 20892 USA. EM adighibe@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S515 EP S515 DI 10.1016/S0197-4580(04)81699-3 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058701696 ER PT J AU Blom, E Holmans, O Arepalli, S Adighibe, O Hardy, J Lannfelt, L Glaser, A Wavrant-De Vrieze, F AF Blom, E Holmans, O Arepalli, S Adighibe, O Hardy, J Lannfelt, L Glaser, A Wavrant-De Vrieze, F TI Is APOE exclusively responsible for the AD linkage peak on chromosome 19? SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 Univ Uppsala, Dept Publ Hlth & Caring Sci, Sect Mol Geriatr, S-75105 Uppsala, Sweden. Univ Wales Coll Cardiff, Coll Med, Biostat & Bioinformat Unit, Cardiff CF1 3NS, S Glam, Wales. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM elin.blom@pubcare.uu.se RI Holmans, Peter/F-4518-2015 OI Holmans, Peter/0000-0003-0870-9412 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S494 EP S494 DI 10.1016/S0197-4580(04)81628-2 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058701625 ER PT J AU Cai, HB Wen, HJ Laird, FM Chiang, HC Xu, GL Borchelt, DR Price, DL Wong, PC AF Cai, HB Wen, HJ Laird, FM Chiang, HC Xu, GL Borchelt, DR Price, DL Wong, PC TI Deletion of BACE1 prevents age-associated neuropathological abnormalities in mutant APP;PS1 mice SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. EM caih@mail.nih.gov RI Cai, Huaibin/H-3359-2013 OI Cai, Huaibin/0000-0002-8596-6108 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S159 EP S159 DI 10.1016/S0197-4580(04)80535-9 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058700533 ER PT J AU Caughey, B Baron, GS Magalhaes, AC Prado, MA Kocisko, DA AF Caughey, B Baron, GS Magalhaes, AC Prado, MA Kocisko, DA TI Prion protein conversions and TSE infections SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 NIH, NIAID, Rocky Mt Labs, Hamilton, MT USA. NIH, NIAID, Rocky Mt Labs, Hamilton, MT USA. Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil. EM bcaughey@nih.gov 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S47 EP S47 DI 10.1016/S0197-4580(04)80159-3 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058700160 ER PT J AU Davatzikos, C Sheng, DG Wu, XY Resnick, SM AF Davatzikos, C Sheng, DG Wu, XY Resnick, SM TI An image analysis and classification protocol for characterization of normal and abnormal aging via structural MRI SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 Univ Penn, Dept Radiol, Sect Biomed Image Anal, Philadelphia, PA 19104 USA. NIA, Lab Personal & Congnit, NIH, Baltimore, MD 21224 USA. EM christos@rad.upenn.edu 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S293 EP S293 DI 10.1016/S0197-4580(04)80965-5 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058700963 ER PT J AU Doil, L Tacey, K Nowotny, P van Luchene, R Li, YH Holmans, P Smemo, S Garcia, V Rowland, C Leong, D Gogic, G Cravchik, A Ross, D Lau, K Catanese, J Sninsky, J White, T Hardy, J Powell, J Lovestone, S Thal, L Owen, M Williams, J Goate, A Grupe, A AF Doil, L Tacey, K Nowotny, P van Luchene, R Li, YH Holmans, P Smemo, S Garcia, V Rowland, C Leong, D Gogic, G Cravchik, A Ross, D Lau, K Catanese, J Sninsky, J White, T Hardy, J Powell, J Lovestone, S Thal, L Owen, M Williams, J Goate, A Grupe, A TI A systematic scan of chromosome 10 single nucleotide polymorphisms identifies novel candidate genes showing strong association to Alzheimer's disease SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 Celera Diagnost, Alameda, CA USA. Washington Univ, Dept Psychiat, St Louis, MO 63130 USA. Univ Wales Coll Cardiff, Dept Psychol Med, Cardiff CF1 3NS, S Glam, Wales. NIA, Bethesda, MD 20892 USA. Inst Psychiat, Dept Neurosci, London SE5 8AF, England. Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. EM andrew.grupe@celeradiagnostics.com RI Lovestone, Simon/E-8725-2010; Holmans, Peter/F-4518-2015 OI Holmans, Peter/0000-0003-0870-9412 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S505 EP S506 DI 10.1016/S0197-4580(04)81668-3 PG 2 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058701665 ER PT J AU Fung, HC Evans, W Steele, J Morris, H Myers, A Singleton, A Wavrant-De Vrieze, F Hardy, J AF Fung, HC Evans, W Steele, J Morris, H Myers, A Singleton, A Wavrant-De Vrieze, F Hardy, J TI Genetic analysis of a the tau haplotype in the CEPH diversity panel and in Guam disease SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Chang Gung Mem Hosp, Dept Neurol 2, Taipei 10591, Taiwan. Chang Gung Univ, Coll Med, Taipei, Taiwan. Guam Mem Hosp, Guam, GU USA. Univ Wales Coll Cardiff, Dept Neurol, Cardiff CF1 3NS, S Glam, Wales. EM fungp@mail.nih.gov RI Myers, Amanda/B-1796-2010; Singleton, Andrew/C-3010-2009 OI Myers, Amanda/0000-0002-3100-9396; 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S520 EP S520 DI 10.1016/S0197-4580(04)81715-9 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058701712 ER PT J AU Furukawa, K Wang, Y Yao, PJ Mattson, MP Oddo, S LaFerla, FM AF Furukawa, K Wang, Y Yao, PJ Mattson, MP Oddo, S LaFerla, FM TI Ion channel properties of neurons from APP/PS1/tau triple mutant mice SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 NIA, Baltimore, MD 21224 USA. Univ Calif Irvine, Irvine, CA USA. EM furukawaka@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S244 EP S244 DI 10.1016/S0197-4580(04)80818-2 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058700816 ER PT J AU Gandy, SE Saravanapavananthan, P Causevic, M Pedrini, S Brose, N Burgoyne, R Ehrlich, M Petanceska, S AF Gandy, SE Saravanapavananthan, P Causevic, M Pedrini, S Brose, N Burgoyne, R Ehrlich, M Petanceska, S TI Integration of neurotransmitter, hormone, and cholesterol signals by APP alpha secretase SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 Johns Hopkins Univ, Sch Med, Baltimore, MD USA. NIH, Bethesda, MD 20892 USA. EM samgandy@earthlink.net 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S2 EP S2 DI 10.1016/S0197-4580(04)80006-X PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058700007 ER PT J AU Geroldi, C Ferrucci, L Paolisso, G Bandinelli, S Lamponi, M Abbatecola, AM Zanetti, O Guralnik, JM Frisoni, GB AF Geroldi, C Ferrucci, L Paolisso, G Bandinelli, S Lamponi, M Abbatecola, AM Zanetti, O Guralnik, JM Frisoni, GB TI Insulin resistance in cognitive impairment and dementia: Evidence from the Inchianti Study SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 IRCCS, S Giovanni di Dio FBF, Brescia, Italy. NIA, Clin Res Branch, Longitudinal Studies Sect, Baltimore, MD 21224 USA. Univ Naples 2, Dept Geriatr Med & Metab Dis, Naples, Italy. INRCA, Dept Geriatr, Lab Clin Epidemiol, Florence, Italy. IRCCS, S Giovanni di Dio FBF, Alzheimers Unit, Brescia, Italy. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. IRCCS, S Giovanni di Dio FBF, Lab Epidemiol & Neuroimaging, Brescia, Italy. EM gfrisoni@oh-fbf.it NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S394 EP S394 DI 10.1016/S0197-4580(04)81289-2 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058701287 ER PT J AU Ghribi, O Herman, MM Savory, J AF Ghribi, O Herman, MM Savory, J TI A beta-induced p-tau and apoptosis in rabbit brain are two independent events SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 Univ Virginia, Charlottesville, VA USA. IRP, NIMH, NIH, Bethesda, MD USA. EM og2p@virginia.edu 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S199 EP S199 DI 10.1016/S0197-4580(04)80669-9 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058700667 ER PT J AU Goate, AM Nowotny, P Hinrichs, T Smemo, S Kawe, K Williams, J Owen, M Holmans, P Jones, L Myers, A De Vrieze, FW Hardy, J Lovestone, S Lau, K Li, YH Grupe, A AF Goate, AM Nowotny, P Hinrichs, T Smemo, S Kawe, K Williams, J Owen, M Holmans, P Jones, L Myers, A De Vrieze, FW Hardy, J Lovestone, S Lau, K Li, YH Grupe, A TI Progress toward the identification of novel genetic risk factors for late onset Alzheimer's disease SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 Washington Univ, Sch Med, St Louis, MO USA. Univ Wales Coll Med, Cardiff CF4 4XN, S Glam, Wales. NIA, Washington, DC USA. Inst Psychiat, London, England. Celera Diagnost, Alameda, CA USA. EM goate@icarus.wustl.edu RI Lovestone, Simon/E-8725-2010; Myers, Amanda/B-1796-2010; Holmans, Peter/F-4518-2015 OI Myers, Amanda/0000-0002-3100-9396; Holmans, Peter/0000-0003-0870-9412 NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S25 EP S26 DI 10.1016/S0197-4580(04)80082-4 PG 2 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058700083 ER PT J AU Greig, NH Utsuki, T Wang, Y Ingram, DK Mamczar, J Rogers, J Yu, QS Holloway, HW Perry, T Sambamurti, K Scali, C Pepeu, G Lahiri, DK AF Greig, NH Utsuki, T Wang, Y Ingram, DK Mamczar, J Rogers, J Yu, QS Holloway, HW Perry, T Sambamurti, K Scali, C Pepeu, G Lahiri, DK TI Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers amyloid-beta peptide in rodents: A new treatment strategy for Alzheimer's disease SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 NIA, Baltimore, MD USA. Harvard Univ, Boston, MA 02115 USA. Med Univ S Carolina, Charleston, SC USA. Univ Florence, Florence, Italy. Indiana Univ, Sch Med, Indianapolis, IN USA. EM Greign@grc.nia.nih.gov NR 0 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S216 EP S216 DI 10.1016/S0197-4580(04)80726-7 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058700724 ER PT J AU Greig, NH Giordano, T Zhu, XX Yu, QS Holloway, HW Brossi, A Sambamurti, K Lahiri, DK AF Greig, NH Giordano, T Zhu, XX Yu, QS Holloway, HW Brossi, A Sambamurti, K Lahiri, DK TI Novel TNF-alpha inhibitors for neurodegeneration: 3-phthalimidoglutarimide analogues SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 NIA, Baltimore, MD 21224 USA. Louisiana State Univ, Shreveport, LA 71105 USA. Univ N Carolina, Chapel Hill, NC USA. Med Univ S Carolina, Charleston, SC 29425 USA. Indiana Univ, Sch Med, Indianapolis, IN USA. EM Greign@grc.nia.nih.gov 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S199 EP S199 DI 10.1016/S0197-4580(04)80668-7 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058700666 ER PT J AU Holmans, P Nowotny, P Smemo, S Myers, A Wavrant-DeVrieze, F Hardy, J Lovestone, S Jones, L Williams, J Owen, M Goate, A AF Holmans, P Nowotny, P Smemo, S Myers, A Wavrant-DeVrieze, F Hardy, J Lovestone, S Jones, L Williams, J Owen, M Goate, A TI Linkage analysis of AD SIB pairs indicates evidence of interaction between genes regulating beta-amyloid degradation SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 Univ Wales Coll Cardiff, Coll Med, Cardiff CF1 3NS, S Glam, Wales. Washington Univ, Sch Med, St Louis, MO USA. NIA, Bethesda, MD 20892 USA. Inst Psychiat, London, England. EM holman.vpa@cardiff.ac.uk RI Lovestone, Simon/E-8725-2010; Myers, Amanda/B-1796-2010; Holmans, Peter/F-4518-2015 OI Myers, Amanda/0000-0002-3100-9396; Holmans, Peter/0000-0003-0870-9412 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S55 EP S56 DI 10.1016/S0197-4580(04)80188-X PG 2 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058700188 ER PT J AU Irie, FY White, LR Strozyk, D Masaki, KH Petrovitch, H Ross, GW Launer, LJ AF Irie, FY White, LR Strozyk, D Masaki, KH Petrovitch, H Ross, GW Launer, LJ TI Higher levels of endogenous testosterone are associated with a higher risk of cerebral atrophy in elderly men - The Honolulu Asia Aging Study SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. Pacific Hlth Res Inst, Honolulu, HI USA. EM yokotaf@mail.nih.gov 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S52 EP S52 DI 10.1016/S0197-4580(04)80177-5 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058700177 ER PT J AU Jankowsky, JL Wen, J Slunt, HH Gonzales, V Jenkins, NA Copeland, NG Borchelt, DR AF Jankowsky, JL Wen, J Slunt, HH Gonzales, V Jenkins, NA Copeland, NG Borchelt, DR TI Inhibition of beta-amyloid production and clearance of senile plaques in transgenic mice SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 CALTECH, Pasadena, CA 91125 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. EM jlj2@caltech.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S234 EP S234 DI 10.1016/S0197-4580(04)80785-1 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058700783 ER PT J AU Lahiri, DK Bailey, J Alley, G Chen, DM Sambamurti, K Greig, N AF Lahiri, DK Bailey, J Alley, G Chen, DM Sambamurti, K Greig, N TI Effects of diverse cholinesterase inhibitors and memantine on the amyloid pathway and its implications in Alzheimer's disease SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 Indiana Univ, Sch Med, Indianapolis, IN 46204 USA. Med Univ S Carolina, Charleston, SC 29425 USA. Natl Inst Aging, Baltimore, MD USA. EM dlahiri@iupui.edu 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S63 EP S64 DI 10.1016/S0197-4580(04)80214-8 PG 2 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058700214 ER PT J AU Launer, LJ Harris, TB Jonsson, P Eiriksdottir, G Gudnason, V AF Launer, LJ Harris, TB Jonsson, P Eiriksdottir, G Gudnason, V CA AGES Reykjavik Study Executive TI Ages Reykjavik Study: Future phenotypes of neurodegeneration SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 NIA, Bethesda, MD 20892 USA. Iceland Heart Assoc, Reykjavik, Iceland. EM launer1@nia.nih.gov RI Gudnason, Vilmundur/K-6885-2015 OI Gudnason, Vilmundur/0000-0001-5696-0084 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S387 EP S388 DI 10.1016/S0197-4580(04)81267-3 PG 2 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058701265 ER PT J AU Launer, LJ AF Launer, LJ TI Epidemiology of Alzheimer's disease: Lessons from cardiovascular studies SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 NIA, Bethesda, MD 20892 USA. EM launerl@examur.nia.nih.gov 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S1 EP S1 DI 10.1016/S0197-4580(04)80001-0 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058700002 ER PT J AU Leung, DG Gibbs, R Wood, WH Teichberg, D Hardy, JA Becker, KG Myers, AJ AF Leung, DG Gibbs, R Wood, WH Teichberg, D Hardy, JA Becker, KG Myers, AJ TI Microarray analysis of gene expression in the frontal cortex of patients with frontotemporal dementia SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 NIA, NIH, IRP, Bethesda, MD 20892 USA. NIA, NIH, IRP, Baltimore, MD 21224 USA. EM leungd1@mail.nih.gov RI Myers, Amanda/B-1796-2010 OI Myers, Amanda/0000-0002-3100-9396 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S522 EP S522 DI 10.1016/S0197-4580(04)81723-8 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058701720 ER PT J AU Li, YH Hollingworth, P Moore, P Foy, C Archer, N Nowotny, P Holmans, P Smemo, S Tacey, K Doil, L van Luchene, R Lau, K Catanese, J Garcia, V Rowland, C Sninsky, J White, T Hardy, J Thal, L Goate, A Powell, J Lovestone, S Owen, M Williams, J Grupe, A AF Li, YH Hollingworth, P Moore, P Foy, C Archer, N Nowotny, P Holmans, P Smemo, S Tacey, K Doil, L van Luchene, R Lau, K Catanese, J Garcia, V Rowland, C Sninsky, J White, T Hardy, J Thal, L Goate, A Powell, J Lovestone, S Owen, M Williams, J Grupe, A TI Genetic association of an APP binding protein gene with late onset Alzheimer's disease SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 Celera Diagnost, Alameda, CA USA. Univ Wales Coll Cardiff, Dept Psychol Med, Cardiff CF1 3NS, S Glam, Wales. Inst Psychiat, Dept Neurosci, London SE5 8AF, England. Washington Univ, Dept Psychiat, St Louis, MO 63130 USA. NIA, Bethesda, MD 20892 USA. Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. EM yonghong.li@celeradiagnostics.com RI Lovestone, Simon/E-8725-2010; Powell, John/G-4412-2011; Holmans, Peter/F-4518-2015 OI Powell, John/0000-0001-6124-439X; Holmans, Peter/0000-0003-0870-9412 NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S510 EP S510 DI 10.1016/S0197-4580(04)81680-4 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058701677 ER PT J AU Li, YH Nowotny, P Holmans, P Smemo, S Kawa, K Tacey, K Doil, L van Luchene, R Garcia, V Rowland, C Schrodi, S Leong, D Chan, J Lau, K Chang, SY Catanese, J Sninsky, J White, T Hardy, J Lovestone, S Thal, L Owen, M Williams, J Goate, A Grupe, A AF Li, YH Nowotny, P Holmans, P Smemo, S Kawa, K Tacey, K Doil, L van Luchene, R Garcia, V Rowland, C Schrodi, S Leong, D Chan, J Lau, K Chang, SY Catanese, J Sninsky, J White, T Hardy, J Lovestone, S Thal, L Owen, M Williams, J Goate, A Grupe, A TI Association of late onset Alzheimer's disease with genetic variation in multiple members of a gene family involved in neuronal apoptosis SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 Celera Diagnost, Alameda, CA USA. Washington Univ, Dept Psychiat, St Louis, MO 63130 USA. Univ Wales Coll Cardiff, Coll Med, Dept Psychol Med, Cardiff CF1 3NS, S Glam, Wales. NIA, Bethesda, MD 20892 USA. Inst Psychiat, Dept Neurosci, London SE5 8AF, England. Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. EM andrew.grupe@celeradiagnostics.com RI Lovestone, Simon/E-8725-2010; Holmans, Peter/F-4518-2015 OI Holmans, Peter/0000-0003-0870-9412 NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S486 EP S486 DI 10.1016/S0197-4580(04)81604-X PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058701601 ER PT J AU Maki, PM Resnick, SM Brandt, J Dobs, AR Durso, SC McCrae, RR AF Maki, PM Resnick, SM Brandt, J Dobs, AR Durso, SC McCrae, RR TI Changes in self-reported personality coincident with declines in cognition: Results from parallel hormone therapy trials in elderly men and women SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 Univ Illinois, Chicago, IL 60680 USA. NIA, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. Copper Ridge Inst, Sykesville, MD USA. EM pmaki@psych.uic.edu 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S106 EP S107 DI 10.1016/S0197-4580(04)80357-9 PG 2 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058700355 ER PT J AU Mehta, KM Simonsick, EM Rooks, R Newman, AB Pope, SK Rubin, SM Yaffe, K AF Mehta, KM Simonsick, EM Rooks, R Newman, AB Pope, SK Rubin, SM Yaffe, K TI African American and white differences in cognitive function test scores: The effect of socioeconomic indicators SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. NIA, Clin Res Branch, Baltimore, MD 21224 USA. Kent State Univ, Kent, OH 44242 USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. Univ Arkansas Med Sci, Little Rock, AR 72205 USA. EM gcharoonruk@yahoo.com RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S475 EP S475 DI 10.1016/S0197-4580(04)81567-7 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058701564 ER PT J AU Mohanty, JG Ravi, LB Chrest, FJ Nagababu, E Natarajan, V Rifkind, JM AF Mohanty, JG Ravi, LB Chrest, FJ Nagababu, E Natarajan, V Rifkind, JM TI Amyloid beta[1-40] fibrils mediate interactions between erythrocytes and endothelial cells SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 NIH, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. EM mohantyj@grc.nia.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S263 EP S263 DI 10.1016/S0197-4580(04)80881-9 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058700879 ER PT J AU Momeni, P Cairns, N Perry, R Jaros, E Singleton, AB Hardy, J AF Momeni, P Cairns, N Perry, R Jaros, E Singleton, AB Hardy, J TI Molecular study of dementia with neurofilament inclusions SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 NIA, NIH, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. EM momeni@mail.nih.gov RI Singleton, Andrew/C-3010-2009 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S522 EP S522 DI 10.1016/S0197-4580(04)81722-6 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058701719 ER PT J AU Myers, AJ Gibbs, R Leung, D Wood, WH Teichberg, D Hardy, JA Becker, KG AF Myers, AJ Gibbs, R Leung, D Wood, WH Teichberg, D Hardy, JA Becker, KG TI Microarray profiling of Alzheimer's disease: Findings based on segregation by APOE genotype SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 NIA, NIH, IRP, Bethesda, MD 20892 USA. EM orlando571@hotmail.com RI Myers, Amanda/B-1796-2010 OI Myers, Amanda/0000-0002-3100-9396 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S501 EP S501 DI 10.1016/S0197-4580(04)81652-X PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058701649 ER PT J AU Peila, R Yucesoy, B Wu, K Luster, M White, L Launer, LJ AF Peila, R Yucesoy, B Wu, K Luster, M White, L Launer, LJ TI Effect of TGF-beta 1 genetic variability on small vessel ischemia and vascular dementia: The Honolulu-Asia aging study SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 NIA, NIH, Bethesda, MD 20892 USA. NIOSH, Morgantown, WV USA. Univ Hawaii, John A Burns Sch Med, Dept Med, Pacific Hlth Res Inst,Clin Epidemiol & Geriatr Di, Honolulu, HI 96822 USA. EM peilar@mail.nih.gov RI Yucesoy, Berran/B-4497-2009 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S539 EP S539 DI 10.1016/S0197-4580(04)81783-4 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058701780 ER PT J AU Rogers, JT Payton, S Greig, NH Jensen, R Cuny, G Lahiri, DK Morse, LJ Tanzi, RE Westaway, D Bush, A Gullans, S Sarang, S Huang, XD AF Rogers, JT Payton, S Greig, NH Jensen, R Cuny, G Lahiri, DK Morse, LJ Tanzi, RE Westaway, D Bush, A Gullans, S Sarang, S Huang, XD TI Alzheimer's disease drug discovery targeted to the APP MRNA 5 ' untranslated region, a validated target SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 Massachusetts Gen Hosp, Charlestown, MA USA. NIA, Baltimore, MD 21224 USA. Brigham & Womens Hosp, Cambridge, MA USA. Indiana Sch Med, Indianapolis, IN USA. Univ Toronto, Toronto, ON, Canada. EM Rogersj@helix.mgh.harvard.edu NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S589 EP S589 DI 10.1016/S0197-4580(04)81959-6 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058701955 ER PT J AU Saczynski, JS White, L Peila, R Sparks, L Launer, LJ AF Saczynski, JS White, L Peila, R Sparks, L Launer, LJ TI The relationship between apolipoprotein-AI and dementia in the Honolulu-Asia Aging Study SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 NIA, Bethesda, MD 20892 USA. Pacific Hlth Res Inst, Manoa, HI USA. Sun Hlth Res Inst, Phoenix, AZ USA. EM saczynsj@mail.nih.gov 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S398 EP S398 DI 10.1016/S0197-4580(04)81303-4 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058701301 ER PT J AU Teipel, SJ Alexander, GE Schapiro, MB Moller, HE Rapoport, SI Hampel, H AF Teipel, SJ Alexander, GE Schapiro, MB Moller, HE Rapoport, SI Hampel, H TI Age-related cortical grey matter reductions in nondemented Down's syndrome adults determined by magnetic resonance imaging with voxel-based morphometry SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 Univ Munich, Dept Psychiat, Alzheimer Mem Ctr, D-8000 Munich, Germany. Arizona State Univ, Dept Psychol, Neuroimage Anal Lab, Tempe, AZ 85287 USA. Cincinnati Childrens Hosp, Med Ctr, Div Neurol, Cincinnati, OH USA. NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. EM Stefan.Teipel@med.uni-muenchen.de 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S290 EP S290 DI 10.1016/S0197-4580(04)80958-8 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058700956 ER PT J AU Veeranna Kaji, T Boland, B Odrljin, T Mohan, P Basavarajappa, BS Peterhoff, C Cataldo, AM Rudnicki, A Li, BS Pant, HC Hungund, BL Arancio, O Nixon, RA AF Veeranna Kaji, T Boland, B Odrljin, T Mohan, P Basavarajappa, BS Peterhoff, C Cataldo, AM Rudnicki, A Li, BS Pant, HC Hungund, BL Arancio, O Nixon, RA TI Calpain mediates calcium-induced activation of the ERK 1,2 MAPK pathway and cytoskeletal phosphorylation in neurons: Relevance to Alzheimer's disease SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 NYU, Sch Med, Nathan S Kline Inst Psychiat Res, Orangeburg, NY USA. Mitsubishi Tokyo Pharmaceut, Yokohama, Kanagawa, Japan. Nathan S Kline Inst Psychiat Res, NYSPI, Orangeburg, NY 10962 USA. Harvard Univ, McLean Hosp, Coll Med, Belmont, MA 02178 USA. NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. EM veeranna@nki.rfmh.org RI Boland, Barry/D-1235-2010 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S173 EP S173 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058700583 ER PT J AU Wavrant-De Vrieze, F Arepalli, S Hardy, J Crook, R Borgaonkar, D AF Wavrant-De Vrieze, F Arepalli, S Hardy, J Crook, R Borgaonkar, D TI Genetic analysis of a large family with last onset Alzheimer's disease SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 NIH, Bethesda, MD 20892 USA. Mayo Clin, Jacksonville, FL 32224 USA. EM wavrant@mail.nih.gov 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S500 EP S500 DI 10.1016/S0197-4580(04)81649-X PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058701646 ER PT J AU Wong, PC Cai, HB Laird, FM Savonenko, AV Melnikova, T Price, DL Borchelt, DR Xu, GL AF Wong, PC Cai, HB Laird, FM Savonenko, AV Melnikova, T Price, DL Borchelt, DR Xu, GL TI A role for APP and BACE1 in cognition SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 Johns Hopkins Univ, Sch Med, Baltimore, MD USA. NIH, Bethesda, MD 20892 USA. EM wong@jhmi.edu RI Cai, Huaibin/H-3359-2013 OI Cai, Huaibin/0000-0002-8596-6108 NR 0 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S2 EP S2 DI 10.1016/S0197-4580(04)80005-8 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058700006 ER PT J AU Wrenn, CC Dreiling, JL Stephenson, D Sullivan, T Crawley, JN AF Wrenn, CC Dreiling, JL Stephenson, D Sullivan, T Crawley, JN TI Galanin inhibits trace fear conditioning via THEGAL-R1 subtype of galanin receptor SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 9th International Conference on Alzheimers Disease and Related Disorders CY JUL 17-22, 2004 CL Philadelphia, PA SP Alzheimers Assoc C1 NIMH, Bethesda, MD USA. EM wrennc@intra.nimh.nih.gov 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2004 VL 25 SU 2 BP S222 EP S222 DI 10.1016/S0197-4580(04)80744-9 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 843EK UT WOS:000223058700742 ER PT J AU Ghribi, O Herman, MM Pramoonjago, P Spaulding, NK Savory, J AF Ghribi, O Herman, MM Pramoonjago, P Spaulding, NK Savory, J TI GDNF regulates the A beta-induced endoplasmic reticulum stress response in rabbit hippocampus by inhibiting the activation of gadd 153 and the JNK and ERK kinases SO NEUROBIOLOGY OF DISEASE LA English DT Article DE A beta; GDNF; endoplasmic reticulum; grp 78; grp 94; gadd 153; JNK; ERK; tau ID ALUMINUM-INDUCED APOPTOSIS; NEUROTROPHIC FACTOR; CELL-LINE; ALZHEIMERS-DISEASE; AMYLOID-BETA; IN-VIVO; GLUTAMATE TRANSPORT; OXIDATIVE STRESS; PROTEIN-KINASES; PEPTIDE AB Glial cell line-derived neurotrophic factor (GDNF) is a potent survival agent for neurons, however, its effect on Abeta-evoked neuronal death has not been examined. We show that the injection of Abeta into New Zealand white rabbit brain activates the endoplasmic reticulum (ER) chaperones, grp 78 and grp 94, and the transcription factor, gadd 153. These effects correlate with the activation of JNK and ERK as well as of microglia and with the phosphorylation of tau protein. Treatment with GDNF inhibits the activation of gadd 153, reduces the phosphorylation of JNK, abolishes the phosphorylation of ERK, prevents microglial activation, greatly reduces apoptotic cells, and does not affect the phosphorylation of tau. Our data suggest that the tau hyperphosphorylation and apoptosis triggered by Abeta are two independent events, and that the neuroprotective effect of GDNF against Abeta may result either directly by the inhibition of ER stress or indirectly through the inhibition of JNK and ERK activation. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Virginia, Hlth Sci Ctr, Dept Pathol, Charlottesville, VA 22908 USA. NIMH, IRP, NIH, Bethesda, MD 20892 USA. Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. RP Ghribi, O (reprint author), Univ Virginia, Hlth Sci Ctr, Dept Pathol, Box 800214, Charlottesville, VA 22908 USA. EM og2p@virginia.edu NR 42 TC 24 Z9 25 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD JUL PY 2004 VL 16 IS 2 BP 417 EP 427 DI 10.1016/j.nbd.2004.04.002 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 830AG UT WOS:000222093400013 PM 15193298 ER PT J AU Nakagawa, T Schwartz, JP AF Nakagawa, T Schwartz, JP TI Gene expression patterns in in vivo normal adult astrocytes compared with cultured neonatal and normal adult astrocytes SO NEUROCHEMISTRY INTERNATIONAL LA English DT Article DE in vivo normal adult; neonatal; astrocyte; cultured adult astrocytes; striatal ID IDENTIFIED GLIAL-CELLS; HIPPOCAMPAL SLICE; TRANSGENIC MICE; ION CHANNELS; PROTEIN AB This paper presents data on the basal gene expression patterns, determined by microarray analysis, for cultured neonatal and normal adult striatal astrocytes, and for comparison, for astrocytes isolated directly from adult rat striatum (in vivo adult astrocytes). Of the 1176 genes on the Clontech array, 1101 were expressed in one of the three types of astrocyte samples. Nineteen of the genes were expressed only in the astrocytes taken directly from adult rats (in vivo adult). The cultured neonatal astrocytes expressed many genes at a two-fold or greater level than their expression in cultured adult astrocytes, including genes in the adhesion, cytoskeleton, and extracellular matrix (ECM) family, signal transduction genes, and genes related to apoptosis, DNA-binding, and cell cycle regulation. Overall the results support the concept that cultured neonatal astrocytes are more "activated" than cultured adult cells, although the adult cells expressed higher levels of many metabolic enzyme and protease/protease inhibitor genes. Published by Elsevier Ltd. C1 NINDS, Neurotroph Factors Sect, OIR, OD,NIH, Bethesda, MD 20892 USA. Fukui Med Sch, Dept Neurosurg, Matsuoka, Fukui, Japan. RP Schwartz, JP (reprint author), NINDS, Neurotroph Factors Sect, OIR, OD,NIH, Bldg 1,Room 135, Bethesda, MD 20892 USA. EM jps@helix.nih.gov NR 13 TC 20 Z9 23 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0197-0186 J9 NEUROCHEM INT JI Neurochem. Int. PD JUL-AUG PY 2004 VL 45 IS 2-3 BP 203 EP 242 DI 10.1016/j.neuint.2003.09.007 PG 40 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 825UH UT WOS:000221783400003 PM 15145538 ER PT J AU Aoki, I Wu, YJL Silva, AC Lynch, RM Koretsky, AP AF Aoki, I Wu, YJL Silva, AC Lynch, RM Koretsky, AP TI In vivo detection of neuroarchitecture in the rodent brain using manganese-enhanced MRI SO NEUROIMAGE LA English DT Article DE brain cytoarchitecture; cortical layers; molecular imaging; choroid plexus ID MOUSE OLFACTORY-BULB; MAGNETIC-RESONANCE; RAT-BRAIN; GLUTAMINE-SYNTHETASE; SENSORY STIMULATION; PARKINSONS-DISEASE; CONTRAST AGENTS; FUNCTIONAL MRI; BASAL GANGLIA; TRACE-METALS AB Visualizing brain anatomy in vivo could provide insight into normal and pathophysiology. Here it is demonstrated that neuroarchitecture can be detected in the rodent brain using MRI after systemic MnCl2. Administration of MnCl2 leads to rapid T-1 enhancement in the choroid plexus and circumventricular organs, which spreads to the CSF space in ventricles and periventricular tissue. After 1 day, there was MRI enhancement throughout the brain with high intensity in the pituitary, olfactory bulb, cortex, basal forebrain, hippocampus, basal ganglia, hypothalamus, amygdala, and cerebellum. Contrast obtained enabled visualization of specific features of neuroarchitecture. The arrowhead structure of the dentate gyrus as well as the CA1 - CA3 region of the hippocampus and layers in cortex, cerebellum, as well as the olfactory bulb could be readily observed. Preliminary assignments of olfactory bulb layers, cortical layers in frontal and somatosensory cortex, and cerebellum were made. Systemic MnCl2 leads to MRI visualization of neuroarchitecture nondestructively. (C) 2004 Elsevier Inc. All rights reserved. C1 NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. Carnegie Mellon Univ, Pittsburgh NMR Ctr Biomed Res, Pittsburgh, PA 15213 USA. RP Koretsky, AP (reprint author), NINDS, Lab Funct & Mol Imaging, NIH, 10 Ctr Dr,10-B1D118, Bethesda, MD 20892 USA. EM KoretskyA@ninds.nih.gov RI Silva, Afonso/A-7129-2009; Aoki, Ichio/G-2529-2011; Koretsky, Alan/C-7940-2015 OI Aoki, Ichio/0000-0002-4429-5053; Koretsky, Alan/0000-0002-8085-4756 FU Intramural NIH HHS [Z01 NS002989-08] NR 66 TC 170 Z9 172 U1 2 U2 9 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 2004 VL 22 IS 3 BP 1046 EP 1059 DI 10.1016/j.neuroimage.2004.03.031 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 834PO UT WOS:000222423200003 PM 15219577 ER PT J AU Luo, F Xi, ZX Wu, GH Liu, C Gardner, EL Li, SJ AF Luo, F Xi, ZX Wu, GH Liu, C Gardner, EL Li, SJ TI Attenuation of brain response to heroin correlates with the reinstatement of heroin-seeking in rats by fMRI SO NEUROIMAGE LA English DT Article DE heroin; self-administration; reinstatement; relapse; tolerance; fMRI; BOLD ID NUCLEUS-ACCUMBENS DOPAMINE; STRESS-INDUCED RELAPSE; FUNCTIONAL MRI; COCAINE-SEEKING; BEHAVIORAL SENSITIZATION; DRUG-SEEKING; ADDICTION; ACTIVATION; MECHANISMS; NEUROBIOLOGY AB Thirty male Sprague-Dawley rats were divided into two groups and trained to self-administer either saline (n = 14) or heroin (0.1 mg/kg per injection, n = 16) for 10 - 12 days until a stable self-administration (SA) behavior was achieved. After 8-9 days of withdrawal, each group was divided into two subgroups for reinstatement tests and functional magnetic resonance image (fMRI) scanning, respectively, to determine the neural correlates of the reinstatement of heroin-seeking behavior. For reinstatement testing, heroin-SA rats (n = 10) displayed robust reinstatement of drug-seeking behavior triggered by an acute heroin priming injection, whereas saline control rats (n = 8) did not show such a behavioral response. Regional positive or negative blood oxygen level-dependent (BOLD) signals, induced by heroin priming injection, were observed in both groups of rats during fMRI scanning. However, such heroin-induced positive BOLD signal primarily in the prefrontal cortex and parietal cortex was significantly attenuated in heroin-SA rats (n = 6) when compared to saline control rats (n = 6). Similarly, the heroin-induced negative BOLD signal in the subcortical regions, such as in the nucleus accumbens and hippocampus, was also significantly attenuated in both signal intensity and number of brain voxels activated in heroin-SA rats. These data demonstrate that heroin-induced reinstatement of drug-seeking behavior coincides with a significant, enduring reduction in opiate-induced brain activity in heroin-SA rats, suggesting a possible role of opiate tolerance in mediating reinstatement of drug-seeking behavior. (C) 2004 Published by Elsevier Inc. C1 Med Coll Wisconsin, Dept Biophys, Milwaukee, WI 53226 USA. NIDA, Intramural Res Program, Dept Hlth & Human Serv, NIH, Baltimore, MD 21224 USA. Penn State Univ, Coll Med, Dept Behav Sci, Hershey, PA 17033 USA. RP Li, SJ (reprint author), Med Coll Wisconsin, Dept Biophys, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM sjli@mcw.edu FU NIBIB NIH HHS [EB01820, R01 EB001820]; NIDA NIH HHS [R01 DA010214, DA10214] NR 47 TC 25 Z9 27 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 2004 VL 22 IS 3 BP 1328 EP 1335 DI 10.1016/j.neuroimage.2004.03.017 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 834PO UT WOS:000222423200031 PM 15219605 ER PT J AU Ravi, LB Mohanty, JG Chrest, FJ Jayakumar, R Nagababu, E Usatyuk, PV Natarajan, V Rifkind, JA AF Ravi, LB Mohanty, JG Chrest, FJ Jayakumar, R Nagababu, E Usatyuk, PV Natarajan, V Rifkind, JA TI Influence of beta-amyloid fibrils on the interactions between red blood cells and endothelial cells SO NEUROLOGICAL RESEARCH LA English DT Article DE beta amyloid; A beta(1-40); erythrocytes; microvascular cells; endothelial cells; flow cytometry ID ALZHEIMERS-DISEASE; PEPTIDE AB Alzheimer's disease is associated with vascular amyloidosis. As blood flows through the microcirculation, red blood cells (RBCs) come in contact with the vasculature. RBCs as well as endothelial cells (ECs) are known to bind beta amyloid fibrils. This suggests that a potential effect of amyloidosis may involve the interactions of RBCs with ECs lining the wall of the blood vessels mediated by amyloid fibrils. We have studied the effect of beta-amyloid peptide [1-40] (Abeta(1-40)) fibrils on the interactions of murine RBCs with ECs derived from bovine lung microvascular endothelium (BLMVEC) as well as bovine pulmonary arterial endothelium (BPAEC) in culture. We show that the initial incorporation of Abeta fibrils onto either RBCs or ECs cause RBCs to adhere to the ECs with greater affinity for the microvascular cells than the arterial cells. In addition, there is a transfer of Abeta fibrils between the RBCs and the ECs. Both the transfer and adhesion occurs when the amyloid fibrils are on the ECs or on the RBCs. However, with the amyloid fibrils on the RBCs, the adhesion and the transfer are greater than with the fibrils on the ECs. These results suggest that amyloidosis may affect the flow of RBCs through the microcirculation and that RBCs may play a role in propagating amyloidosis through the vasculature. C1 NIA, Mol Dynam Sect, Baltimore, MD 21224 USA. NIA, Res Resources Branch, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Div Pulm & Crit Care Med, Baltimore, MD USA. Cent Leather Res Inst, Bioorgan Lab, Madras 600020, Tamil Nadu, India. RP Rifkind, JA (reprint author), NIA, Mol Dynam Sect, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM rifkindj@grc.nia.nih.gov NR 21 TC 11 Z9 11 U1 0 U2 1 PU MANEY PUBLISHING PI LEEDS PA HUDSON RD, LEEDS LS9 7DL, ENGLAND SN 0161-6412 J9 NEUROL RES JI Neurol. Res. PD JUL PY 2004 VL 26 IS 5 BP 579 EP 585 DI 10.1179/016164104225016227 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 836GZ UT WOS:000222545100018 PM 15265278 ER PT J AU Kernich, CA AF Kernich, CA TI Parkinsonism SO NEUROLOGIST LA English DT Article C1 NINDS, Bethesda, MD 20824 USA. RP Kernich, CA (reprint author), Univ Hosp Hlth Syst, Univ Hosp Fac Serv, Dept Med, Cleveland, OH USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1074-7931 J9 NEUROLOGIST JI Neurologist PD JUL PY 2004 VL 10 IS 4 BP 225 EP 226 DI 10.1097/01.nrl.0000131147.66503.f2 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 838IX UT WOS:000222708000007 PM 15252359 ER PT J AU Benson, BE Carson, RE Kiesewetter, DO Herscovitch, P Eckelman, WC Post, RM Ketter, TA AF Benson, BE Carson, RE Kiesewetter, DO Herscovitch, P Eckelman, WC Post, RM Ketter, TA TI A potential cholinergic mechanism of procaine's limbic activation SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE muscarinic receptors; procaine; FP-TZTP; limbic system; brain imaging; monkey ID POSITRON-EMISSION-TOMOGRAPHY; LOCAL-ANESTHETIC AGENTS; ACETYLCHOLINE-RECEPTOR CHANNELS; PRESS FEEDING-BEHAVIOR; CENTRAL-NERVOUS-SYSTEM; CEREBRAL-BLOOD-FLOW; GUINEA-PIG; SUBSTANTIA INNOMINATA; MUSCARINIC RECEPTORS; RHESUS-MONKEYS AB The local anesthetic procaine, when administered to humans intravenously (i.v,), yields brief intense emotional and sensory experiences, and concomitant increases in anterior paralimbic cerebral blood flow, as measured by positron emission tomography (PET). Procaine's high muscarinic affinity, together with the distribution of muscarinic receptors that overlaps with brain regions activated by procaine, suggests a muscarinic contribution to procaine's emotional and sensory effects. This study evaluates the effects of procaine on cerebral muscarinic cholinergic receptors in the anesthetized rhesus monkey. Whole brain and regional muscarinic receptor binding was measured before and after procaine administration on the same day in three anesthetized rhesus monkeys with PET and the radiotracer 3-(3-(3[F-18]fluoropropyithio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine ([F-18]FP-TZTP), a cholinergic ligand that has preferential binding to muscarinic (M-2) receptors. On separate days each animal received six different doses of i.v, procaine in a randomized fashion. Procaine blocked up to similar to90% of [F-18]FP-TZTP specific binding globally in a dose-related manner, There were no regional differences in procaine's inhibitory concentration for 50% blockade (IC50) for [F-18]FP-TZTP. Tracer delivery, which was highly correlated to cerebral blood flow in previous monkey studies, was significantly increased at all doses of procaine with the greatest increases occurring near procaine's IC50 for average cortex, Furthermore, anterior limbic regions showed greater increases in tracer delivery than nonlimbic regions. Procaine has high affinity to muscarinic M-2 receptors in vivo in the rhesus monkey. This, as well as a preferential increase of tracer delivery to paralimbic regions, suggests that action at these receptors could contribute to i.v. procaine's emotional and sensory effects in man. These findings are consistent with other evidence of cholinergic modulation of mood and emotion. C1 NIMH, Biol Psychiat Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. NIH, Positron Emiss Tomog Dept, Bethesda, MD USA. Univ Maryland, Neurosci & Cognit Sci Program, College Pk, MD USA. Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA USA. RP Benson, BE (reprint author), NIMH, Biol Psychiat Branch, Dept Hlth & Human Serv, NIH, Bldg 10 Rm 35239,10 Ctr Dr, Bethesda, MD 20892 USA. EM bbenson@mail.nih.gov RI Carson, Richard/H-3250-2011 OI Carson, Richard/0000-0002-9338-7966 NR 97 TC 15 Z9 17 U1 3 U2 7 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 2004 VL 29 IS 7 BP 1239 EP 1250 DI 10.1038/sj.npp.1300404 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 830GS UT WOS:000222110700003 PM 14997171 ER PT J AU Solinas, M Panlilio, LV Goldberg, SR AF Solinas, M Panlilio, LV Goldberg, SR TI Exposure to Delta-9-tetrahydrocannabinol (THC) increases subsequent heroin taking but not heroin's reinforcing efficacy: A self-administration study in rats SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE cannabinoids; THC; cannabis; opiates; gateway drug hypothesis; fixed-ratio schedule; behavioral economics; progressive-ratio schedule ID NUCLEUS-ACCUMBENS DOPAMINE; PROGRESSIVE RATIO; BEHAVIORAL SENSITIZATION; INTRAVENOUS HEROIN; MARIJUANA USE; FIXED-RATIO; DRUG INTAKE; COCAINE; DELTA(9)-TETRAHYDROCANNABINOL; AMPHETAMINE AB One concern about the widespread use of cannabis is that exposure to its active ingredient, Delta-9-tetrahydrocannabinol (THC), might increase future reinforcing effects of other abused drugs such as heroin. In this study, we investigated the effects of pre-exposure to THC on subsequent intravenous self-administration of heroin by Sprague-Dawley rats. In one group of rats, we studied (1) acquisition of heroin self-administration behavior using a continuous-reinforcement (fixed-ratio (FR) 1) schedule, (2) heroin dose-response relationships using an FRI/variable-dose schedule, and (3) reinforcing efficacy of heroin using a progressive-ratio schedule. The number of rats pre-exposed to THC that subsequently learned to self-administer 50 mug/kg injections of heroin within 10 daily sessions did not differ from vehicle-pretreated controls. In contrast, rats pre-exposed to THC subsequently self-administered significantly more heroin injections per session and showed significantly shorter post-injection pauses over a range of heroin doses (12.5-100 mug/kg/injection) using the variable-dose schedule. Interestingly, the maximum effort rats would exert to receive an injection of the different doses of heroin under the progressive-ratio schedule was not altered by THC pre-exposure. In a second group of rats, we varied the 'price' of heroin (responses required/dose), by manipulating FR response requirements at different doses of heroin across sessions, to calculate demand and response output curves, Again, consumption was significantly higher in the THC-treated rats at the lowest prices of heroin (FRI/100 mug/kg and FRI/50 mug/kg) but there were no differences in the reinforcing efficacy of heroin between THC- and vehicle-pretreated rats. Altogether, these results demonstrate that pre-exposure to THC alters some pharmacological effects of heroin that determine frequency of heroin taking, but offer no support for the hypothesis that pre-exposure to THC alters heroin's efficacy as a reinforcer. C1 Dept Hlth & Human Serv, Behav Neurosci Branch, Preclin Pharmacol Sect, Baltimore, MD USA. RP Goldberg, SR (reprint author), NIDA, Behav Pharmacol Sect, Behav Neurosci Res Branch, Div Intramural Res,NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM sgoldber@pintra.nida.nih.gov RI Solinas, Marcello/M-3500-2016 OI Solinas, Marcello/0000-0002-0664-5964 NR 47 TC 37 Z9 37 U1 3 U2 9 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 2004 VL 29 IS 7 BP 1301 EP 1311 DI 10.1038/sj.npp.1300431 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 830GS UT WOS:000222110700009 PM 15039767 ER PT J AU Shidara, M Richmond, BJ AF Shidara, M Richmond, BJ TI Differential encoding of information about progress through multi-trial reward schedules by three groups of ventral striatal neurons SO NEUROSCIENCE RESEARCH LA English DT Article DE ventral striatum; single neuron recording; information theoretic analysis; ANOVA; multi-trial reward schedules ID MONKEY; SIGNALS; CORTEX AB In the course of daily activity we continually judge whether the goal sought is worth the work that must be done to obtain it. The ventral striatum is thought to play a central role in making such judgments. When reward schedules are used to investigate these judgments ventral striatum neurons show responses near the time of the cue, the bar-release, and/or the reward delivery. We evaluated the type of coding that occurs at these three time points by using codes or factorizations with: (1) two states for reward versus non-reward, (2) four states for the progress in the reward schedule, and (3) six states for all of the states of the schedule, quantified using information theory and ANOVA. For the bar-release- and reward-related responses the percent variance explained was as high for the two states code as with the six states code. The information for the four state code rose slightly but significantly for the bar-release-related neurons. For the cue-related neurons the code with six states carried more information than the simpler codes. Thus, responses at different times appear to play different roles. Responses occurring early in trials differentiate all states, i.e., the path to a reward, whereas those late in trials code knowledge of impending reward. (C) 2004 Elsevier Ireland Ltd and The Japan Neuroscience Society. All rights reserved. C1 Natl Inst Adv Ind Sci & Technol, Neurosci Res Inst, Tsukuba, Ibaraki 3058568, Japan. NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. RP Shidara, M (reprint author), Natl Inst Adv Ind Sci & Technol, Neurosci Res Inst, 1-1-1 Umezono, Tsukuba, Ibaraki 3058568, Japan. EM m.shidara@aist.go.jp NR 15 TC 15 Z9 15 U1 1 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0168-0102 J9 NEUROSCI RES JI Neurosci. Res. PD JUL PY 2004 VL 49 IS 3 BP 307 EP 314 DI 10.1016/j.neures.2004.03.008 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 835WL UT WOS:000222516100005 PM 15196779 ER PT J AU Vasan, RS Evans, JC Larson, MG Wilson, PWF Meigs, JB Rifai, N Benjamin, EJ Levy, D AF Vasan, RS Evans, JC Larson, MG Wilson, PWF Meigs, JB Rifai, N Benjamin, EJ Levy, D TI Serum aldosterone and the incidence of hypertension in nonhypertensive persons SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PLASMA-RENIN ACTIVITY; BLOOD-PRESSURE; VASCULAR ALDOSTERONE; ANGIOTENSIN-II; SODIUM-INTAKE; HEART; FRAMINGHAM; SALT; POTASSIUM; SYSTEM AB Background: Primary hyperaldosteronism is a well-recognized cause of secondary hypertension. It is unknown whether serum aldosterone levels within the physiologic range influence the risk of hypertension. Methods: We investigated the relation of baseline serum aldosterone levels to increases in blood pressure and the incidence of hypertension after four years in 1688 nonhypertensive participants in the Framingham Offspring Study (mean age, 55 years), 58 percent of whom were women. We defined an increase in blood pressure as an increment of at least one blood-pressure category (as defined by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) and defined hypertension as a systolic blood pressure of 140 mm Hg or higher, a diastolic blood pressure of 90 mm Hg or higher, or the use of antihypertensive medications. Results: At follow-up, the blood-pressure category had increased in 33.6 percent of the participants, and hypertension had developed in 14.8 percent. In multivariable models, a 16 percent increase in the risk of an elevation in blood pressure (P=0.002) and a 17 percent increase in the risk of hypertension (P=0.03) were observed per quartile increment in the serum aldosterone level. The highest serum aldosterone quartile, relative to the lowest, was associated with a 1.60-fold risk of an elevation in blood pressure (95 percent confidence interval, 1.19 to 2.14) and a 1.61-fold risk of hypertension (95 percent confidence interval, 1.05 to 2.46). The associations between the serum aldosterone level and blood-pressure outcomes were not significantly affected by adjustment for urinary sodium excretion or left ventricular thickness or internal dimensions. Conclusions: In our community-based sample, increased aldosterone levels within the physiologic range predisposed persons to the development of hypertension. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Epidemiol & Prevent Med, Boston, MA 02118 USA. Med Univ S Carolina, Dept Endocrinol Diabet & Med Genet, Charleston, SC 29425 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Childrens Hosp, Dept Lab Med, Boston, MA 02115 USA. NHLBI, Bethesda, MD 20892 USA. RP Vasan, RS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM vasan@bu.edu OI Ramachandran, Vasan/0000-0001-7357-5970 FU NHLBI NIH HHS [K24 HL04334, N01-HC-25195] NR 43 TC 306 Z9 317 U1 1 U2 4 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 JUL 1 PY 2004 VL 351 IS 1 BP 33 EP 41 DI 10.1056/NEJMoa033263 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 833QC UT WOS:000222352200007 PM 15229305 ER PT J AU Tipre, DN Fujita, M Chin, FT Seneca, N Vines, D Liow, JS Pike, VW Innis, RB AF Tipre, DN Fujita, M Chin, FT Seneca, N Vines, D Liow, JS Pike, VW Innis, RB TI Whole-body biodistribution and radiation dosimetry estimates for the PET dopamine transporter probe F-18-FECNT in non-human drimates SO NUCLEAR MEDICINE COMMUNICATIONS LA English DT Article DE F-18-FECNT; dopamine transporter; dosimetry; whole-body biodistribution; PET; positron emission tomography ID NEUROPSYCHIATRIC DISORDERS; BRAIN; TRANSMISSION; RADIOTRACER; FECNT AB Background and aim 2beta-Carbomethoxy-3-(4-chloro-phenyl)-8-(2-[F-18]fluoroethyl)nortropane (F-18-FECNT) is a selective radioligand for the in vivo quantification of dopamine transporters by using positron emission tomography. The aim of the current study was to quantify the distribution of radioactivity in three rhesus monkeys after the injection of approximately 185 MBq (5 mCi) of F-18-FECNT. Method Whole-body images were acquired at 23-30 time points for a total of 220 min following injection of the radioligand. Source organs were identified at each time point from planar images. Results The peak activities in planar images in the six identified source organs (expressed as per cent injected dose (%ID)) were lungs (16.5%ID at 2 min), kidneys (12.5%ID at 3 min), brain (9.5%ID at 6 min), liver (7.5%ID at 3 min), red bone marrow (3.5%ID at 12 min), and urinary bladder (2%ID at 98 min). Radiation absorbed doses were calculated using the gastrointestinal tract model in two ways: (1) assuming no urine voiding, and (2) using a dynamic bladder model with voiding intervals of 2.4 and 4.8 h. Using the gastrointestinal tract model and dynamic bladder model with a voiding interval 4.8 h, the three organs with highest exposure (in muGy(.)MBq(-1) (mrad(.)mCi(-1))) were kidneys 75.68 (280), lungs 44.86 (166) and urinary bladder 58.38 (216). Effective doses estimated with and without urine voiding were in the range 21.35-22.70 muGy(.)MBq(-1) (79-84 mrad(.)mCi(-1)). Conclusion The estimated radiation burden of F-18-FECNT is relatively modest and would allow multiple scans per research subject per year. (C) 2004 Lippincott Williams Wilkins. C1 NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Tipre, DN (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 1,Rm B3-10,Ctr Dr,MSC 0135, Bethesda, MD 20892 USA. EM TipreD@intra.nimh.nih.gov FU Intramural NIH HHS [ZIA MH002795-12] NR 20 TC 10 Z9 10 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0143-3636 J9 NUCL MED COMMUN JI Nucl. Med. Commun. PD JUL PY 2004 VL 25 IS 7 BP 737 EP 742 DI 10.1097/01.mnm.0000133074.64669.60 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 836HW UT WOS:000222547500017 PM 15208503 ER PT J AU Maier, MA Choi, Y Gaus, H Barchi, JJ Marquez, VE Manoharan, M AF Maier, MA Choi, Y Gaus, H Barchi, JJ Marquez, VE Manoharan, M TI Synthesis and characterization of oligonucleotides containing conformationally constrained bicyclo[3.1.0]hexane pseudosugar analogs SO NUCLEIC ACIDS RESEARCH LA English DT Article ID (CYTOSINE C5)-METHYLTRANSFERASE; CARBOCYCLIC THYMIDINE; OLIGODEOXYRIBONUCLEOTIDES AB Oligodeoxyribonucleotides containing pseudorotationally locked sites derived from bicyclo[3.1.0]hexane pseudosugars have been synthesized using adenosine, thymidine and abasic versions of North- and South-methanocarba nucleosides. The reaction conditions for coupling and oxidation steps of oligonucleotide synthesis have been investigated and optimized to allow efficient and facile solid-phase synthesis using phosphoramidite chemistry. Our studies demonstrate that the use of iodine for P(III) to P(V) oxidation leads to strand cleavage at the sites where the pseudosugar is North. In contrast, the same cleavage reaction was not observed in the case of South pseudosugars. Iodine oxidation generates a 5'-phosphate oligonucleotide fragment on the resin and releases the North pseudosugar into the solution. This side reaction, which is responsible for the extremely low yields observed for the incorporation of the North pseudosugar analogs, has been studied in detail and can be easily overcome by replacing iodine with t-butylhydroperoxide as oxidant. C1 ISIS Pharmaceut Inc, Carlsbad, CA 92008 USA. NCI, Med Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Marquez, VE (reprint author), Alnylam Pharmaceut, 300 3rd St, Cambridge, MA 02142 USA. EM marquezv@dc37a.nci.nih.gov RI Barchi Jr., Joseph/N-3784-2014; Choi, Yongseok/F-8375-2012 OI Choi, Yongseok/0000-0002-3622-3439 NR 15 TC 13 Z9 13 U1 0 U2 3 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 PY 2004 VL 32 IS 12 BP 3642 EP 3650 DI 10.1093/nar/gkh667 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 846UI UT WOS:000223341900014 PM 15247346 ER PT J AU Babenko, VN Rogozin, IB Mekhedov, SL Koonin, EV AF Babenko, VN Rogozin, IB Mekhedov, SL Koonin, EV TI Prevalence of intron gain over intron loss in the evolution of paralogous gene families SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SPLICE SITES; MOLECULAR CLOCK; ORIGIN; EUKARYOTES; DIVERGENCE; POSITIONS; PROTEINS; CLASSIFICATION; PERSPECTIVE; COMPLEXITY AB The mechanisms and evolutionary dynamics of intron insertion and loss in eukaryotic genes remain poorly understood. Reconstruction of parsimonious scenarios of gene structure evolution in paralogous gene families in animals and plants revealed numerous gains and losses of introns. In all analyzed lineages, the number of acquired new introns was substantially greater than the number of lost ancestral introns. This trend held even for lineages in which vertical evolution of genes involved more intron losses than gains, suggesting that gene duplication boosts intron insertion. However, dating gene duplications and the associated intron gains and losses based on the molecular clock assumption showed that very few, if any, introns were gained during the last similar to100 million years of animal and plant evolution, in agreement with previous conclusions reached through analysis of orthologous gene sets. These results are generally compatible with the emerging notion of intensive insertion and loss of introns during transitional epochs in contrast to the relative quiet of the intervening evolutionary spans. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, 8600 Rockville Pike,Bldg 38A, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov RI Babenko, Vladimir/K-5609-2014; OI Babenko, Vladimir/0000-0002-3077-9559 NR 52 TC 77 Z9 82 U1 2 U2 6 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 PY 2004 VL 32 IS 12 BP 3724 EP 3733 DI 10.1093/nar/gkh686 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 846UI UT WOS:000223341900022 PM 15254274 ER PT J AU Helmberg, W Dunivin, R Feolo, M AF Helmberg, W Dunivin, R Feolo, M TI The sequencing-based typing tool of dbMHC: typing highly polymorphic gene sequences SO NUCLEIC ACIDS RESEARCH LA English DT Article ID NEW-GENERATION; CN3D AB The dbMHC resource (http://www.ncbi.nlm.nih.gov/mhc/sbt.cgi?cmd=main) at the National Center for Biotechnology Information (NCBI) has developed an online tool for evaluating the allelic composition of sequencing-based typing (SBT) results of cDNA or genomic sequences. Whether the samples are heterozygous, haploid or a combination of the two, they can be compared with two up-to-date databases of all known alleles of several human leukocyte antigen (HLA) and killer cell immunoglobulin-like receptor (KIR) loci. The results of the submission are returned as a table of potential allele hits, along with the respective base changes and an interactive sequence viewer for close examination of the alignment. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Helmberg, W (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 45,8600 Rockville Pk, Bethesda, MD 20894 USA. EM helmberg@ncbi.nlm.nih.gov NR 5 TC 23 Z9 23 U1 0 U2 2 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 2004 VL 32 SU 2 BP W173 EP W175 DI 10.1093/nar/gkh424 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 832NB UT WOS:000222273100036 PM 15215374 ER PT J AU Marchler-Bauer, A Bryant, SH AF Marchler-Bauer, A Bryant, SH TI CD-Search: protein domain annotations on the fly SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DATABASE; ENTREZ AB We describe the Conserved Domain Search service (CD-Search), a web-based tool for the detection of structural and functional domains in protein sequences. CD-Search uses BLAST(R) heuristics to provide a fast, interactive service, and searches a comprehensive collection of domain models. Search results are displayed as domain architecture cartoons and pairwise alignments between the query and domain-model consensus sequences. Search results may be visualized in further detail by embedding the query sequence into multiple alignment displays and by mapping onto three-dimensional molecular graphic displays of known structures within the domain family. CD-Search can be accessed at http://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi. C1 NCBI, Computat Biol Branch, Natl Lib Med, NIH, Bethesda, MD 20894 USA. RP Marchler-Bauer, A (reprint author), NCBI, Computat Biol Branch, Natl Lib Med, NIH, Bldg 38A,Room 5S508,8600 Rockville Pike, Bethesda, MD 20894 USA. EM bauer@ncbi.nlm.nih.gov RI Marchler-Bauer, Aron/A-9681-2009; OI Marchler-Bauer, Aron/0000-0003-1516-0712 NR 9 TC 529 Z9 548 U1 2 U2 23 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 2004 VL 32 SU 2 BP W327 EP W331 DI 10.1093/nar/gkh454 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 832NB UT WOS:000222273100066 PM 15215404 ER PT J AU McGinnis, S Madden, TL AF McGinnis, S Madden, TL TI BLAST: at the core of a powerful and diverse set of sequence analysis tools SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SEARCH; DATABASE; DOMAIN AB Basic Local Alignment Search Tool (BLAST) is one of the most heavily used sequence analysis tools available in the public domain. There is now a wide choice of BLAST algorithms that can be used to search many different sequence databases via the BLAST web pages (http://www.ncbi.nlm.nih.gov/BLAST/). All the algorithm-database combinations can be executed with default parameters or with customized settings, and the results can be viewed in a variety of ways. A new online resource, the BLAST Program Selection Guide, has been created to assist in the definition of search strategies. This article discusses optimal search strategies and highlights some BLAST features that can make your searches more powerful. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP McGinnis, S (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 38A,8600 Rockville Pike, Bethesda, MD 20894 USA. EM mcginnis@ncbi.nlm.nih.gov NR 13 TC 457 Z9 471 U1 3 U2 34 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 2004 VL 32 SU 2 BP W20 EP W25 DI 10.1093/nar/gkh435 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 832NB UT WOS:000222273100004 PM 15215342 ER PT J AU Rotmistrovsky, K Jang, W Schuler, GD AF Rotmistrovsky, K Jang, W Schuler, GD TI A web server for performing electronic PCR SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RADIATION HYBRID MAP; HUMAN GENOME AB 'Electronic PCR' (e-PCR) refers to a computational procedure that is used to search DNA sequences for sequence tagged sites (STSs), each of which is defined by a pair of primer sequences and an expected PCR product size. To gain speed, our implementation extracts short 'words' from the 3' end of each primer and stores them in a sorted hash table that can be accessed efficiently during the search. One recent improvement is the use of overlapping discontinuous words to allow matches to be found despite the presence of a mismatch. Moreover, it is possible to allow gaps in the alignment between the primer and the sequence. The effect of these changes is to improve sensitivity without significantly affecting specificity. The new software provides a search mode using a query STS against a sequence database to augment the previously available mode using a query sequence against an STS database. Finally, e-PCR may now be used through a web service, with search results linked to other web resources such as the UniSTS database and the MapViewer genome browser. The e-PCR web server may be found at www.ncbi.nlm.nih.gov/sutils/e-pcr. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20984 USA. RP Schuler, GD (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20984 USA. EM schuler@ncbi.nlm.nih.gov NR 19 TC 31 Z9 33 U1 0 U2 4 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 2004 VL 32 SU 2 BP W108 EP W112 DI 10.1093/gar/nkh450 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 832NB UT WOS:000222273100023 PM 15215361 ER PT J AU Rozanov, M Plikat, U Chappey, C Kochergin, A Tatusova, T AF Rozanov, M Plikat, U Chappey, C Kochergin, A Tatusova, T TI A web-based genotyping resource for viral sequences SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HEPATITIS-C VIRUS; HIV TYPE-1; RECOMBINANT AB The Genotyping tool at the National Center for Biotechnology Information is a web-based program that identifies the genotype (or subtype) of recombinant or non-recombinant viral nucleotide sequences. It works by using BLAST to compare a query sequence to a set of reference sequences for known genotypes. Predefined reference genotypes exist for three major viral pathogens: human immunodeficiency virus 1 (HIV-1), hepatitis C virus (HCV) and hepatitis B virus (HBV). User-defined reference sequences can be used at the same time. The query sequence is broken into segments for comparison to the reference so that the mosaic organization of recombinant sequences could be revealed. The results are displayed graphically using color-coded genotypes. Therefore, the genotype(s) of any portion of the query can quickly be determined. The Genotyping tool can be found at: http://www.ncbi.nih.gov/projects/genotyping/formpage.cgi. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. Virolog Inc, San Francisco, CA 94080 USA. Novartis Pharma AG, Novartis Inst Biomed Res, CH-4002 Basel, Switzerland. RP Tatusova, T (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 38A,Room S602,8600 Rockville Pike, Bethesda, MD 20892 USA. EM tatiana@ncbi.nlm.nih.gov NR 19 TC 107 Z9 113 U1 2 U2 7 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 2004 VL 32 SU 2 BP W654 EP W659 DI 10.1093/nar/gkh419 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 832NB UT WOS:000222273100132 PM 15215470 ER PT J AU Shatsky, M Dror, O Schneidman-Duhovny, D Nussinov, R Wolfson, HJ AF Shatsky, M Dror, O Schneidman-Duhovny, D Nussinov, R Wolfson, HJ TI BioInfo3D: a suite of tools for structural bioinformatics SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ALIGNMENT; DOCKING; PROTEINS AB Here, we describe BioInfo3D, a suite of freely available web services for protein structural analysis. The FlexProt method performs flexible structural alignment of protein molecules. FlexProt simultaneously detects the hinge regions and aligns the rigid subparts of the molecules. It does not require an a priori knowledge of the flexible hinge regions. MultiProt and MASS perform simultaneous comparison of multiple protein structures. PatchDock performs prediction of protein-protein and protein-small molecule interactions. The input to all services is either protein PDB codes or protein structures uploaded to the server. All the services are available at http://bioinfo3d.cs.tau.ac.il. C1 Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Sch Comp Sci, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Sackler Fac Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. NCI Frederick, Basic Res Program, SAIC Frederick Inc, Lab Expt & Computat Biol, Frederick, MD 21702 USA. RP Wolfson, HJ (reprint author), Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Sch Comp Sci, IL-69978 Tel Aviv, Israel. EM wolfson@cs.tau.ac.il RI Wolfson, Haim/A-1837-2011 FU NCI NIH HHS [N01CO12400] NR 14 TC 20 Z9 20 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 2004 VL 32 SU 2 BP W503 EP W507 DI 10.1093/nar/gkh413 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 832NB UT WOS:000222273100099 PM 15215437 ER PT J AU Cusack, G Jones, A Chisholm, L AF Cusack, G Jones, A Chisholm, L TI Patient intensity in an ambulatory oncology research center: A step forward for the field of ambulatory care - Part II SO NURSING ECONOMICS LA English DT Article ID STAFF NURSE ROLE; EXPANDED ROLE; DIMENSIONS; SETTINGS; IMPACT AB In the final part of this series, the authors explore the daily use of the Ambulatory Intensity System (AIS) in resource allocation, critical thinking, and other ambulatory settings. In addition to guiding the assignments for direct patient care responsibilities, the system also helps to allocate resources for indirect care activities such as staff development, project time, coordination of care, and others. The process of applying the tool on a daily basis supports making conscious decisions about delegation of tasks to non-nursing personnel. In addition to providing a level of objectivity to the typical charge nurse role, the AIS supports better organization, provides the ability to anticipate prolonged or delayed care due to intensity, and allows for easier distinction between patient care and systems issues. The AIS has been successfully applied in other ambulatory settings including day hospitals and other clinics. C1 NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Cusack, G (reprint author), NIH, Warren G Magnuson Clin Ctr, Bldg 10, Bethesda, MD 20892 USA. NR 13 TC 1 Z9 1 U1 0 U2 2 PU JANNETTI PUBLICATIONS, INC PI PITMAN PA EAST HOLLY AVENUE, BOX 56, PITMAN, NJ 08071-0056 USA SN 0746-1739 J9 NURS ECON JI Nurs. Econ. PD JUL-AUG PY 2004 VL 22 IS 4 BP 193 EP 195 PG 3 WC Nursing SC Nursing GA 046GX UT WOS:000237800600003 PM 15382394 ER PT J AU Mooney, MM Schoenfeldt, M AF Mooney, MM Schoenfeldt, M TI Current phase II and phase III clinical trials for pancreatic cancer - Referral resource SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID GEMCITABINE; ADENOCARCINOMA C1 NCI, Bethesda, MD 20892 USA. Emmes Corp, Rockville, MD USA. RP Mooney, MM (reprint author), NCI, Bethesda, MD 20892 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD JUL PY 2004 VL 18 IS 8 BP 1008 EP + PG 4 WC Oncology SC Oncology GA 052DN UT WOS:000238211500010 PM 15328895 ER PT J AU Ferre, S Ciruela, F Canals, M Marcellino, D Burgueno, J Casado, V Hillion, J Torvinen, M Fanelli, F de Benedetti, P Goldberg, SR Bouvier, M Fuxe, K Agnati, LF Lluis, C Franco, R Woods, A AF Ferre, S Ciruela, F Canals, M Marcellino, D Burgueno, J Casado, V Hillion, J Torvinen, M Fanelli, F de Benedetti, P Goldberg, SR Bouvier, M Fuxe, K Agnati, LF Lluis, C Franco, R Woods, A TI Adenosine A(2A)-dopamine D-2 receptor-receptor heteromers. Targets for neuro-psychiatric disorders SO PARKINSONISM & RELATED DISORDERS LA English DT Article; Proceedings Paper CT Conference on Striatal Plasticity in Health and Disease CY NOV 28-29, 2003 CL Stockholm, SWEDEN DE adenosine A(2A) receptor; dopamine D-2; receptor; heteromers; epitope-epitope interaction; Parkinson's disease; schizophrenia; drug addiction ID METABOTROPIC GLUTAMATE RECEPTORS; DOPAMINE D2 RECEPTORS; MEDIUM SPINY NEURONS; A(2A) RECEPTORS; BASAL GANGLIA; RAT STRIATUM; BINDING CHARACTERISTICS; ADENYLYL-CYCLASE; IMMUNOCYTOCHEMICAL LOCALIZATION; INTEGRATIVE MECHANISM AB Emerging evidence show; that G protein-coupled receptors can form homo- and heteromers. These include adenosine A(2A) receptor-dopamine D-2 receptor heteromers, which are most probably localized in the dendritic spines of the striatopallidal GABAergic neurons, where they are in a position to modulate glutamatergic neurotransmission. The discovery of A(2A) receptor-dopamine D-2 receptor heteromers gives a frame for the well-known antagonistic interaction between both receptors, which is the bases for a new therapeutic approach for neuropsychiatric disorders, such as Parkinson's disease and schizoprenia. The present review deals mainly with the biochemical and molecular aspects of A(2A) receptor-dopamine D-2 receptor interactions. Recent results at the molecular level show that A(2A) receptor-dopamine D-2 receptor heteromers represent the first example of epitope-epitope electrostatic interaction underlying receptor heteromerization. Most probably A(2A) receptor-D-2 receptor heteromerization is not static, but subject to a dynamic regulation, related to the phosphorylation dependence of the A(2A) receptor epitope and to the ability of the D-2 receptor epitope to bind different partners. Finding out the mechanisms involved in this dynamic regulation can have important implications for the treatment of basal ganglia disorders, schizophrenia and drug addiction. (C) 2004 Elsevier Ltd. All rights reserved. C1 NIDA, IRP, DHHS, NIH, Baltimore, MD 21224 USA. Univ Barcelona, Dept Biochem & Mol Biol, Barcelona 08028, Spain. NINDS, DHHS, NIH, Bethesda, MD 20892 USA. Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden. Univ Modena, Dept Chem, I-41100 Modena, Italy. Univ Modena, Dept Biomed Sci, I-41100 Modena, Italy. Univ Montreal, Dept Biochem, Montreal, PQ H3C 3J7, Canada. RP Woods, A (reprint author), NIDA, IRP, DHHS, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM awoods@intra.nida.nih.gov RI Bouvier, Michel/H-2758-2014; Ferre, Sergi/K-6115-2014; Ciruela, Francisco/A-5096-2013; Franco, Rafael/C-3694-2015; Fanelli, Francesca/O-8807-2014; Casado, Vicent/K-1660-2014; OI Bouvier, Michel/0000-0003-1128-0100; Ferre, Sergi/0000-0002-1747-1779; Ciruela, Francisco/0000-0003-0832-3739; Franco, Rafael/0000-0003-2549-4919; Fanelli, Francesca/0000-0002-7620-6895; Marcellino, Daniel/0000-0002-4618-7267; Canals, Meritxell/0000-0002-7942-5006; Casado, Vicent/0000-0002-1764-3825 NR 49 TC 97 Z9 99 U1 0 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD JUL PY 2004 VL 10 IS 5 BP 265 EP 271 DI 10.1016/j.parkreldis.2004.02.014 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 833ZZ UT WOS:000222381900003 PM 15196504 ER PT J AU Tanganelli, S Nielsen, KS Ferraro, L Antonelli, T Kehr, J Franco, R Ferre, S Agnati, LF Fuxe, K Scheel-Kruger, J AF Tanganelli, S Nielsen, KS Ferraro, L Antonelli, T Kehr, J Franco, R Ferre, S Agnati, LF Fuxe, K Scheel-Kruger, J TI Striatal plasticity at the network level. Focus on adenosine A(2A) and D-2 interactions in models of Parkinson's Disease SO PARKINSONISM & RELATED DISORDERS LA English DT Article; Proceedings Paper CT Conference on Striatal Plasticity in Health and Disease CY NOV 28-29, 2003 CL Stockholm, SWEDEN DE A2A receptors; D2 recptors; glutamate; Parkinson's disease models; microdialysis; locomotion; catalepsy ID RECEPTOR INTERACTIONS; BASAL GANGLIA; INDUCED CATALEPSY; DOPAMINE; RATS; ANTAGONIST; SYSTEM; BRAIN; A(1) AB Behavioral and microdialysis studies have been performed on antagonistic A(2A)/D-2 interactions in animal models of Parkinson's Disease. The behavioral analysis involved studies on locomotor activity in reserpinized mice, haloperidol-induced catalepsy in rats and rotational behavior in rats with unilateral 6-OHDA lesions of the ascending DA pathways (Ungerstedt model). Dual probe microdialysis studies were indirectly performed on the striatopallidal GABA neurons by studying extracellular glutamate levels in the striatum and globus pallidus of the awake freely moving rat. The striatum was perfused with A(2A) and/or D-2 agonists via reverse microdialysis. The results show that the,A(2A) antagonists SCH58261 and KF17837 can increase locomotor activity in reserpinized mice and produce contralateral rotational behavior only after administration of subthreshold doses of L-DOPA or the D-2 like agonist quinpirole. Furthermore, antagonizing the A(2A) receptor (R) reduced haloperidol induced catalepsy. The behavioral results underline the view that A(2A) antagonists act by blocking A(2A) R in A(2A)/D-2, heterodimers where A(2A) R inhibits the D-2 R transduction and D-2 inhibits the adenylate cyclase (AC) activated by A(2A) R. The microdialysis studies show that the A(2A) agonist CGS21680 striatally coperfused with the D-2 agonist quinpirole more potently counteract the D-2 agonist (quinpirole) induced reduction of pallidal glutamate levels in the DA denervated vs the control striatum indicating an enhancement of the inhibitory A(2A)/D-2 interaction. In the DA denervated but not in the control striatum the A(2A) agonist CGS21680 could strongly increase striatal glutamate levels, indicating an increased receptor signaling in the A(2A) R located on the striatal glutamate terminals, where also D-2 like R exist, here probably as D-4. Thus, the signaling of this A(2A) R may be set free by the loss of D-4 tone on the AC activated by A(2A) in this postulated A(2A)/D-4 heteromer on the glutamate terminals. Taken together, the results indicate that the antiparkinsonian actions of A(2A) antagonists probably are produced by blockade of A(2A) R in the A(2A)/D-2 heterodimers mainly located in the striatopallidal GABA neurons. (C) 2004 Elsevier Ltd. All rights reserved. C1 Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden. NeuroSearch AS, DK-2750 Ballerup, Denmark. Univ Ferrara, Dept Clin & Expt Med, Pharmacol Sect, Ferrara, Italy. Univ Barcelona, Dept Biochem & Mol Biol, E-08028 Barcelona, Spain. NIDA, IRP, Dept Hlth & Human Serv, NIH, Baltimore, MD 21224 USA. Univ Modena, Dept Biomed Sci, I-41100 Modena, Italy. RP Fuxe, K (reprint author), Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden. EM kjell.fuxe@r.euro.ki.se RI Ferre, Sergi/K-6115-2014; Franco, Rafael/C-3694-2015; Ferraro, Luca/F-9915-2015; Antonelli, Tiziana/I-7677-2015; Tanganelli, Sergio/I-7704-2015 OI Ferre, Sergi/0000-0002-1747-1779; Franco, Rafael/0000-0003-2549-4919; Ferraro, Luca/0000-0003-2390-6414; Antonelli, Tiziana/0000-0001-5895-7807; Tanganelli, Sergio/0000-0001-7576-3510 NR 29 TC 53 Z9 53 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD JUL PY 2004 VL 10 IS 5 BP 273 EP 280 DI 10.1016/j.parkreldis.2004.02.015 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 833ZZ UT WOS:000222381900004 PM 15196505 ER PT J AU Chase, TN AF Chase, TN TI Striatal plasticity and extrapyramidal motor dysfunction SO PARKINSONISM & RELATED DISORDERS LA English DT Article; Proceedings Paper CT Conference on Striatal Plasticity in Health and Disease CY NOV 28-29, 2003 CL Stockholm, SWEDEN DE Parkinson's disease; dyskinesia; fluctuations; dopamine; serotonin; adenosine; glutamate; levodopa; N-methyl-D-aspartate; alpha-amino-3hydroxy-5-methyl-4-isoxazole proprionic acid; phosphorylation ID LEVODOPA-INDUCED DYSKINESIAS; PROTEIN-KINASE-C; ELEMENT-BINDING PROTEIN; NMDA RECEPTOR SUBUNITS; MPTP-TREATED MONKEYS; CENTRAL PATHOPHYSIOLOGICAL MECHANISMS; EXCITATORY SYNAPTIC TRANSMISSION; 5-HYDROXYTRYPTAMINE 2A RECEPTORS; CENTRAL DOPAMINERGIC MECHANISMS; ADVANCED PARKINSONS-DISEASE AB Knowledge of molecular events contributing to motor dysfunction in Parkinson's disease has advanced rapidly during the past decade. Studies in animal models as well as in patients afflicted by this disorder suggest that the nonphysiologic stimulation of striatal dopamine receptors, first as a result of dopaminergic denervation and later as a consequence of the intermittent high-intensity stimulation produced by standard therapeutic regimens, leads to plastic changes in striatal medium spiny neurons. The clinical appearance of parkinsonism and subsequently of motor response complications is associated with the aberrant activation of signaling cascades within medium spiny neurons that modify the phosphorylation state of their ionotropic glutamatergic receptors. Resultant NMDA and AMPA receptor sensitization augments cortical excitatory input to these spiny efferent neurons, thus altering striatal output in ways that compromise motor function. These findings have already yielded new insight into mechanisms subserving motor memory and synaptic integration as well as accelerated development of novel approaches to the improved treatment of motor disability. Published by Elsevier Ltd. C1 NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Chase, TN (reprint author), NINDS, Expt Therapeut Branch, NIH, Bldg 10,Room 5C103,90900 Rockville Pike, Bethesda, MD 20892 USA. EM chaset@ninds.nih.gov NR 105 TC 40 Z9 40 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD JUL PY 2004 VL 10 IS 5 BP 305 EP 313 DI 10.1016/j.parkreldis.2004.02.012 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 833ZZ UT WOS:000222381900009 PM 15196510 ER PT J AU Campbell, JD Kotloff, KL Sow, SO Tapia, M Keita, MM Keita, T Diallo, S Hormazabal, JC Murray, P Levine, MM AF Campbell, JD Kotloff, KL Sow, SO Tapia, M Keita, MM Keita, T Diallo, S Hormazabal, JC Murray, P Levine, MM TI Invasive pneumococcal infections among hospitalized children in Bamako, Mali SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE Streptococcus pneumoniae; pneumococcus; children; Africa; vaccines ID PAPUA-NEW-GUINEA; STREPTOCOCCUS-PNEUMONIAE INFECTIONS; IMMUNODEFICIENCY-VIRUS INFECTION; RESPIRATORY-TRACT INFECTIONS; SOUTH-AFRICAN CHILDREN; CONJUGATE VACCINE; SEROTYPE DISTRIBUTION; UNITED-STATES; ANTIMICROBIAL RESISTANCE; POLYSACCHARIDE VACCINE AB Background: Prevention of invasive pneumococcal disease (IPD) in children is a global public health priority, and determination of the most common serotypes is crucial for vaccine development and implementation. Methods: We performed prospective surveillance for IPD in hospitalized children in Bamako, Mali. All febrile children and others suspected to have invasive bacterial disease had an admission blood culture and cultures of additional anatomic sites when indicated. Standard microbiologic methods were used to identify, serotype and determine antibiograms for pneumococcal isolates. Results: Of 2049 children enrolled, 106 (5%) had an IPD, including 47 cases of meningitis and 44 bacteremic pneumonias. The incidence was highest in infants (84/100,000/year). The overall IPD case fatality rate was 24%. Only 2 of 96 isolates were nonsusceptible to penicillin. The serotypes isolated were 5 (54%), 2 (14%), 7F (10%), 19F (8%), 6A/B (3%), 9V (3%), 1 (2%) and 14 (1%). Conclusions: IPD is common and frequently fatal among hospitalized children in Mali, but surprisingly little resistance has occurred. Notably, 91% of the serotypes causing IPD in Bamako children are found in the 11-valent pneumococcal conjugate vaccine. C1 Univ Maryland, Ctr Vaccine Dev, Sch Med, Baltimore, MD 21201 USA. Minist Sante, Hop Gabriel Toure, CNAM, CVD Mali, Bamako, Mali. Dept Pediat, Bamako, Mali. Dept Lab Med, Bamako, Mali. Inst Salud Publ Chile, Bacteriol Sect, Santiago, Chile. NIH, Clin Microbiol Lab, Bethesda, MD 20892 USA. RP Campbell, JD (reprint author), Univ Maryland, Ctr Vaccine Dev, Sch Med, HSF 480,685 W Baltimore St, Baltimore, MD 21201 USA. EM jcampbel@medicine.umaryland.edu RI kotloff, karen/E-7768-2012 OI kotloff, karen/0000-0003-1808-6431 NR 52 TC 54 Z9 57 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD JUL PY 2004 VL 23 IS 7 BP 642 EP 649 DI 10.1097/01.inf.0000130951.85974.79 PG 8 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 840FG UT WOS:000222842000009 PM 15247603 ER PT J AU Higgins, RD Yan, Y Geng, YX Zasloff, M Williams, JI AF Higgins, RD Yan, Y Geng, YX Zasloff, M Williams, JI TI Regression of retinopathy by squalamine in a mouse model SO PEDIATRIC RESEARCH LA English DT Article ID OXYGEN-INDUCED RETINOPATHY; RETINAL NEOVASCULARIZATION; ANGIOGENESIS; AMINOSTEROL; GROWTH AB The goal of this study was to determine whether an antiangiogenic agent, squalamine, given late during the evolution of oxygen-induced retinopathy (OIR) in the mouse, could improve retinal neovascularization. OIR was induced in neonatal C57BL6 mice and the neonates were treated s.c. with squalamine doses begun at various times after OIR induction. A system of retinal whole mounts and assessment of neovascular nuclei extending beyond the inner limiting membrane from animals reared under room air or OIR conditions and killed periodically from d 12 to 21 were used to assess retinopathy in squalamine-treated and untreated animals. OIR evolved after 75% oxygen exposure in neonatal mice with florid retinal neovascularization developing by d 14. Squalamine (single dose, 25 mg/kg s.c.) given on d 15 or 16, but not d 17, substantially improved retinal neovascularization in the mouse model of OIR. There was improvement seen in the degree of blood vessel tuft formation, blood vessel tortuosity, and central vasoconstriction with squalamine treatment at d 15 or 16. Single-dose squalamine at d 12 was effective at reducing subsequent development of retinal neovascularization at doses as low as 1 mg/kg. Squalamine is a very active inhibitor of OIR in mouse neonates at doses as low as 1 mg/kg given once. Further, squalamine given late in the course of OIR improves retinopathy by inducing regression of retinal neovessels and abrogating invasion of new vessels beyond the inner-limiting membrane of the retina. C1 Georgetown Univ, Dept Pediat, Div Neonatol, Off Dean Tranalat Res, Washington, DC 20007 USA. Genaera Corp, Plymouth Meeting, PA 19462 USA. RP Higgins, RD (reprint author), NICHHD, Pregnancy & Perinatol Branch, Ctr Dev Biol & Perinatal Med, Natl Inst Hlth, 6100 Execut Blvd,Room 4B03B,MSC 7510, Bethesda, MD 20892 USA. EM higginsr@mail.nih.gov NR 10 TC 12 Z9 12 U1 1 U2 4 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD JUL PY 2004 VL 56 IS 1 BP 144 EP 149 DI 10.1203/01.PDR.0000128977.55799.34 PG 6 WC Pediatrics SC Pediatrics GA 831WE UT WOS:000222226400024 PM 15128931 ER PT J AU Dietrich, KN Ware, JH Salganik, M Radcliffe, J Rogan, WJ Rhoads, GG Fay, ME Davoli, CT Denckla, MB Bornschein, RL Schwarz, D Dockery, DW Adubato, S Jones, RL AF Dietrich, KN Ware, JH Salganik, M Radcliffe, J Rogan, WJ Rhoads, GG Fay, ME Davoli, CT Denckla, MB Bornschein, RL Schwarz, D Dockery, DW Adubato, S Jones, RL CA Treatment Lead-Exposed Children Cl TI Effect of chelation therapy on the neuropsychological and behavioral development of lead-exposed children after school entry SO PEDIATRICS LA English DT Article DE child; lead; environmental exposure; chelation therapy; succimer; cognition; clinical trials ID SUCCIMER CHELATION; BRAIN LEAD; EFFICACY; PREVENTION; TODDLERS; GROWTH; MODEL AB Objective. Some children in the United States continue to be exposed to levels of lead that increase their risk for lowered intellectual functioning and behavior problems. It is unclear whether chelation therapy can prevent or reverse the neurodevelopmental sequelae of lead toxicity. The objective of this study was to determine whether chelation therapy with succimer ( dimercaptosuccinic acid) in children with referral blood lead levels between 20 and 44 mug/dL (0.96-2.12 mumol/L) at 12 to 33 months of age has neurodevelopmental benefits at age 7 years. Methods. The Treatment of Lead-Exposed Children (TLC) study is a randomized, double-blind, placebo-controlled trial that was conducted between September 1994 and June 2003 in Philadelphia, PA; Newark, NJ; Cincinnati, OH; and Baltimore, MD. Of 1854 referred children who were between the ages of 12 to 33 months and screened for eligibility, 780 were randomized to the active drug and placebo groups stratified by clinical center, body surface area, blood lead level, and language spoken at home. At 7 years of age, 647 subjects remained in the study. Participants were randomly assigned to receive oral succimer or placebo. Up to 3 26-day courses of succimer or placebo therapy were administered depending on response to treatment in those who were given active drug. Eighty-nine percent had finished treatment by 6 months, with all children finishing by 13 months after randomization. All participants received residential lead hazard control measures before treatment. TLC subjects also received a daily multivitamin supplement before and after treatment(s) with succimer or placebo. Scores on standardized neuropsychological measures that tap cognition, behavior, learning and memory, attention, and neuromotor skills were measured. Results. Chelation therapy with succimer lowered average blood lead levels for similar to 6 months but resulted in no benefit in cognitive, behavioral, and neuromotor endpoints. Conclusion. These new follow-up data confirm our previous finding that the TLC regimen of chelation therapy is not associated with neurodevelopmental benefits in children with blood lead levels between 20 and 44 mug/dL (0.96 - 2.17 mumol/L). These results emphasize the importance of taking environmental measures to prevent exposure to lead. Chelation therapy with succimer cannot be recommended for children with blood lead levels between 20 and 44 mug/dL ( 0.96 - 2.12 mumol/L). C1 Univ Cincinnati, Coll Med, Dept Environm Hlth, Div Epidemiol & Biostat, Cincinnati, OH 45267 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Childrens Hosp Philadelphia, Dept Psychol, Philadelphia, PA 19104 USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Univ Med & Dent New Jersey, Environm & Occupat Hlth Sci Inst, Piscataway, NJ 08854 USA. Kennedy Krieger Inst, Baltimore, MD USA. Childrens Hosp Philadelphia, Dept Adolescent Med, Philadelphia, PA 19104 USA. Univ Med & Dent New Jersey, Dept Pediat, Newark, NJ 07103 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Pediat, Newark, NJ 07103 USA. Ctr Dis Control & Prevent, Nutr Biochem Branch, Atlanta, GA USA. RP Dietrich, KN (reprint author), Univ Cincinnati, Coll Med, Dept Environm Hlth, Div Epidemiol & Biostat, Cincinnati, OH 45267 USA. EM kim.dietrich@uc.edu RI Rogan, Walter/I-6034-2012 OI Rogan, Walter/0000-0002-9302-0160 NR 39 TC 99 Z9 108 U1 2 U2 3 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 2004 VL 114 IS 1 BP 19 EP 26 DI 10.1542/peds.114.1.19 PG 8 WC Pediatrics SC Pediatrics GA 834VO UT WOS:000222439200025 PM 15231903 ER PT J AU Milner, JD Stein, DM McCarter, R Moon, RY AF Milner, JD Stein, DM McCarter, R Moon, RY TI Early infant multivitamin supplementation is associated with increased risk for food allergy and asthma SO PEDIATRICS LA English DT Article DE multivitamins; asthma; allergy; infants ID VITAMIN-D; CHILDHOOD ASTHMA; BRONCHIAL-ASTHMA; IMMUNE-SYSTEM; RESPONSES; EXPRESSION; DIAGNOSIS; CYTOKINES; CHILDREN; CELLS AB Objective. Dietary vitamins have potent immunomodulating effects in vitro. Individual vitamins have been shown to skew T cells toward either T-helper 1 or T-helper 2 phenotypic classes, suggesting that they may participate in inflammatory or allergic disease. With the exception of antioxidant protection, there has been little study on the effect of early vitamin supplementation on the subsequent risk for asthma and allergic disease. The objective of this study was to determine whether early vitamin supplementation during infancy affects the risk for asthma and allergic disease during early childhood. Methods. Cohort data were analyzed from the National Center for Health Statistics 1988 National Maternal-Infant Health Survey, which followed pregnant women and their newborns, and the 1991 Longitudinal Follow-up of the same patients, which measured health and disease outcomes. Patients were stratified by race and breastfeeding status. Factors that are known to be associated with alteration of risk for asthma or food allergies were identified using univariate logistic regression. Those factors were then analyzed in multivariate logistic regression models. Early vitamin supplementation was defined as vitamin use within the first 6 months. Results. There were > 8000 total patients in the study. The overall incidence of asthma was 10.5% and of food allergy was 4.9%. In univariate analysis, male gender, smoker in the household, child care, prematurity (< 37 weeks), being black, no history of breastfeeding, lower income, and lower education were associated with higher risk for asthma. Child care, higher levels of education, income, and history of breastfeeding were associated with a higher risk for food allergies. In multivariate logistic analyses, a history of vitamin use within the first 6 months of life was associated with a higher risk for asthma in black infants ( odds ratio [ OR]: 1.27; 95% confidence interval [CI]: 1.04 - 1.56). Early vitamin use was also associated with a higher risk for food allergies in the exclusively formula-fed population ( OR: 1.63; 95% CI: 1.21 - 2.20). Vitamin use at 3 years of age was associated with increased risk for food allergies but not asthma in both breastfed ( OR: 1.62; 95% CI: 1.19 - 2.21) and exclusively formula-fed infants ( OR: 1.39; 95% CI: 1.03 - 1.88). Conclusions. Early vitamin supplementation is associated with increased risk for asthma in black children and food allergies in exclusively formula-fed children. Additional study is warranted to examine which components most strongly contribute to this risk. C1 Childrens Natl Med Ctr, Dept Pediat, Washington, DC 20010 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth Dis Control & Prevent, Baltimore, MD USA. Childrens Natl Med Ctr, Ctr Hlth Serv & Community Res, Washington, DC 20010 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. RP Milner, JD (reprint author), NIAID, NIH, Bldg 10-11S242, Bethesda, MD 20892 USA. EM jdmilner@niaid.nih.gov RI Osborne, Nicholas/N-4915-2015 OI Osborne, Nicholas/0000-0002-6700-2284 NR 29 TC 93 Z9 102 U1 0 U2 7 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 2004 VL 114 IS 1 BP 27 EP 32 DI 10.1542/peds.114.1.27 PG 6 WC Pediatrics SC Pediatrics GA 834VO UT WOS:000222439200026 PM 15231904 ER PT J AU Cheng, TL Brenner, RA Wright, JL Sachs, HC Moyer, P Rao, MR AF Cheng, TL Brenner, RA Wright, JL Sachs, HC Moyer, P Rao, MR TI Children's violent television viewing: Are parents monitoring? SO PEDIATRICS LA English DT Article DE media violence; television viewing; violence prevention; anticipatory guidance; parental norms ID MEDIA VIOLENCE; AGGRESSIVE-BEHAVIOR; VIDEO GAMES; ADOLESCENTS; PEDIATRICIAN; ISSUES; HEALTH; YOUTH; LIFE; TIME AB Objective. Violent media exposure has been associated with aggressive behavior, and it has been suggested that child health professionals counsel families on limiting exposure. Effective violence prevention counseling requires an understanding of norms regarding parental attitudes, practices, and influencing factors. Both theories of reasoned action and planned behavior emphasize that subjective norms and attitudes affect people's perceptions and intended behavior. Few data exist on violent television viewing and monitoring from a cross-section of families. By understanding the spectrum of parental attitudes, community-sensitive interventions for violence prevention can be developed. The objective of this study was to assess attitudes about and monitoring of violent television viewing from the perspective of parents. Methods. An anonymous self-report assisted survey was administered to a convenience sample of parents/guardians who visited child health providers at 3 sites: an urban children's hospital clinic, an urban managed care clinic, and a suburban private practice. The parent questionnaire included questions on child-rearing attitudes and practices and sociodemographic information. Results. A total of 1004 adults who accompanied children for health visits were recruited for the study; 922 surveys were completed (participation rate: 92%). A total of 830 (90%) respondents were parents and had complete child data. Of the 830 respondents, 677 had questions on television viewing included in the survey and were the focus of this analysis. Seventy-five percent of families reported that their youngest child watched television. Of these, 53% reported always limiting violent television viewing, although 73% believed that their children viewed television violence at least 1 time a week. Among television viewers, 81% reported usually or always limiting viewing of sexual content on television and 45% reported usually or always watching television with their youngest child. Among children who watched television, parents reported that they spent an average of 2.6 hours per day watching television. Limitation of television violence was associated with female parents and younger children. Conclusions. There was variability in attitudes and practices regarding television violence viewing and monitoring among parents. Attitudes and practices varied on the basis of the age of the child and the gender of the parent. C1 Childrens Natl Med Ctr, Dept Gen Pediat & Adolescent Med, Washington, DC 20010 USA. Childrens Res Inst, Washington, DC USA. George Washington Univ, Sch Med, Washington, DC USA. NICHHD, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Dept Emergency Med, Washington, DC 20010 USA. Coleman Sachs & Thillairajah Pediat, Rockville, MD USA. RP Cheng, TL (reprint author), Johns Hopkins Univ, 600 N Wolfe St,Pk 392, Baltimore, MD 21287 USA. EM tcheng2@jhmi.edu RI Alrebh, Abdullah/A-3363-2012 NR 37 TC 15 Z9 16 U1 5 U2 17 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 2004 VL 114 IS 1 BP 94 EP 99 DI 10.1542/peds.114.1.94 PG 6 WC Pediatrics SC Pediatrics GA 834VO UT WOS:000222439200035 PM 15231913 ER PT J AU Blackmon, LR Fanaroff, AA Raju, TNK AF Blackmon, LR Fanaroff, AA Raju, TNK TI Research on prevention of Bilirubin-Induced Brain Injury and Kernicterus: National Institute of Child Health and Human Development conference executive summary SO PEDIATRICS LA English DT Article DE bilirubin; kernicterus; jaundice; brain injury; infant; cerebral palsy; chorioathetosis ID MANAGEMENT; HYPERBILIRUBINEMIA; PHOTOTHERAPY; DEFICIENCY; EFFICACY; JAUNDICE; NEWBORN AB In July 2003, the National Institute of Child Health and Human Development convened a conference, "Research on Prevention of Bilirubin-Induced Brain Injury and Kernicterus: Bench-to-Bedside." This article will provide a summary of presentations and discussions from this conference. The summary will focus on the identified knowledge gaps in 5 areas related to bilirubin-induced brain injury and kernicterus: 1) neurobiology and neuroimaging; 2) epidemiology and issues of clinical management; 3) methodologies for assessing clinical jaundice and direct and noninvasive measurement of serum bilirubin and hemolysis; 4) therapies for management of neonatal hyperbilirubinemia; and 5) public health surveillance and systems-based approaches to prevention. C1 NICHHD, Pregnancy & Perinatol Branch, NIH, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. Case Western Reserve Univ, Sch Med, Cleveland, OH USA. Rainbow Babies & Childrens Hosp, Cleveland, OH 44106 USA. RP Raju, TNK (reprint author), NICHHD, Pregnancy & Perinatol Branch, NIH, 6100 Execut Blvd,Room 4B03, Bethesda, MD 20892 USA. EM rajut@mail.nih.gov NR 10 TC 21 Z9 22 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 2004 VL 114 IS 1 BP 229 EP 233 DI 10.1542/peds.114.1.229 PG 5 WC Pediatrics SC Pediatrics GA 834VO UT WOS:000222439200055 PM 15231933 ER PT J AU Olah, Z Trier, U Sauer, B Schafer-Korting, M Kleuser, B AF Olah, Z Trier, U Sauer, B Schafer-Korting, M Kleuser, B TI New chimera proteins for fluorescence correlation spectroscopy SO PHARMAZIE LA English DT Article ID NF-KAPPA-B; ESCHERICHIA-COLI; GENE-EXPRESSION; ACTIVATION; P65; DNA; FRAGMENTS; MOLECULES; SUBUNIT; COMPLEX AB A new class of chimera proteins has been developed. They are ideally suited for detection by fluorescence correlation spectroscopy (FCS), a new technology to analyze molecular interactions. The molecular structure of these chimera proteins consists of four domains: a N-terminal (His)(6)-tag for affinity chromatography followed by an eight amino acid epitope for immunodetection, a polypeptide affinity domain (ADF) for target specific interaction and a C-terminal Green Fluorescent Protein (GFPuv) for reporting of interaction with the target by FCS. We designed, prepared and characterized a prototype of ADF-GFP proteins capable of specific interaction with DNA fragments bearing nuclear factor (NF)-kappaB sites. ADF NF-kappaB p50 and a non-DNA-binding deletion mutant (p35) combined with GFPuv were inserted in a procaryotic vector and expressed in E coli. Following affinity purification the fluoroproteins p50-GFPuv and p35-GFPuv were employed in specific protein-protein and protein-DNA interaction studies. FCS analysis as well as EMSA showed that p50-GFPuv revealed a fully functional ADF. We present a model for the preparation of GFP fusion proteins capable of specific interaction with proteins, lipids or nucleic acids. The rational design allows any polypeptide fragment to be incorporated into the chimeric protein. So a new series of bio-molecules with different binding specificities and assays can be developed. C1 Free Univ Berlin, Inst Pharm, D-14195 Berlin, Germany. Natl Inst Dent & Craniofacial Res, Pain & Neurosensory Mech Branch, NIH, Bethesda, MD USA. RP Olah, Z (reprint author), Free Univ Berlin, Inst Pharm Pharmakol & Toxikol, Konigin Luise Str 2, D-14195 Berlin, Germany. NR 20 TC 0 Z9 0 U1 0 U2 0 PU GOVI-VERLAG GMBH PI ESCHBORN PA PHARMAZEUTISCHER VERLAG GINNHEIMER STRASSE 26, D-65760 ESCHBORN, GERMANY SN 0031-7144 J9 PHARMAZIE JI Pharmazie PD JUL PY 2004 VL 59 IS 7 BP 516 EP 523 PG 8 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 838EE UT WOS:000222695500005 PM 15296087 ER PT J AU DaSilva, LLP Snapp, EL Denecke, J Lippincott-Schwartz, J Hawes, C Brandizzi, F AF DaSilva, LLP Snapp, EL Denecke, J Lippincott-Schwartz, J Hawes, C Brandizzi, F TI Endoplasmic reticulum export sites and golgi bodies behave as single mobile secretory units in plant cells SO PLANT CELL LA English DT Article ID GREEN FLUORESCENT PROTEIN; ARABIDOPSIS CULTURED-CELLS; COPII-DEPENDENT TRANSPORT; ADP-RIBOSYLATION FACTOR-1; BINDING SAR1 PROTEIN; BREFELDIN-A; VESICLE FORMATION; COATED VESICLES; CARGO SELECTION; TOBACCO-LEAVES AB In contrast with animals, plant cells contain multiple mobile Golgi stacks distributed over the entire cytoplasm. However, the distribution and dynamics of protein export sites on the plant endoplasmic reticulum (ER) surface have yet to be characterized. A widely accepted model for ER-to-Golgi transport is based on the sequential action of COPII and COPI coat complexes. The COPII complex assembles by the ordered recruitment of cytosolic components on the ER membrane. Here, we have visualized two early components of the COPII machinery, the small GTPase Sar1p and its GTP exchanging factor Sec12p in live tobacco (Nicotiana tabacum) leaf epidermal cells. By in vivo confocal laser scanning microscopy and fluorescence recovery after photobleaching experiments, we show that Sar1p cycles on mobile punctate structures that track with the Golgi bodies in close proximity but contain regions that are physically separated from the Golgi bodies. By contrast, Sec12p is uniformly distributed along the ER network and does not accumulate in these structures, consistent with the fact that Sec12p does not become part of a COPII vesicle. We propose that punctate accumulation of Sar1p represents ER export sites (ERES). The sites may represent a combination of Sar1p-coated ER membranes, nascent COPII membranes, and COPII vectors in transit, which have yet to lose their coats. ERES can be induced by overproducing Golgi membrane proteins but not soluble bulk-flow cargos. Few punctate Sar1p loci were observed that are independent of Golgi bodies, and these may be nascent ERES. The vast majority of ERES form secretory units that move along the surface of the ER together with the Golgi bodies, but movement does not influence the rate of cargo transport between these two organelles. Moreover, we could demonstrate using the drug brefeldin A that formation of ERES is strictly dependent on a functional retrograde transport route from the Golgi apparatus. C1 Univ Leeds, Ctr Plant Sci, Leeds LS2 9JT, W Yorkshire, England. NICHHD, Cell Biol & Metab Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. Oxford Brookes Univ, Res Sch Biol & Mol Sci, Oxford OX3 0BP, England. RP Brandizzi, F (reprint author), Univ Saskatchewan, Dept Biol, Saskatoon, SK S7N 5E2, Canada. EM federica.brandizzi@usask.ca RI LP daSilva, Luis/A-9949-2010 OI LP daSilva, Luis/0000-0003-3558-0087 NR 68 TC 182 Z9 187 U1 0 U2 12 PU AMER SOC PLANT BIOLOGISTS PI ROCKVILLE PA 15501 MONONA DRIVE, ROCKVILLE, MD 20855 USA SN 1040-4651 J9 PLANT CELL JI Plant Cell PD JUL PY 2004 VL 16 IS 7 BP 1753 EP 1771 DI 10.1105/tpc.022673 PG 19 WC Biochemistry & Molecular Biology; Plant Sciences; Cell Biology SC Biochemistry & Molecular Biology; Plant Sciences; Cell Biology GA 837GZ UT WOS:000222618000012 PM 15208385 ER PT J AU Morrison, PF Chattoraj, DK AF Morrison, PF Chattoraj, DK TI Replication of a unit-copy plasmid F in the bacterial cell cycle: a replication rate function analysis SO PLASMID LA English DT Article ID ESCHERICHIA-COLI; INITIATOR PROTEIN; DNA-REPLICATION; DIVISION CYCLE; ITERONS; NUMBER; SEQUESTRATION; ORIGIN; SWITCH; REPE AB For stability.. the replication of unit-copy plasmids ought to occur by a highly controlled process. We have characterized the replication dynamics of a unit-copy plasmid F by a replication rate function defined as the probability per unit age interval of the cell cycle that a plasmid will initiate replication. Analysis of baby-machine data [J. Bacteriol. 170 (1988) 1380 - J. Bacteriol. 179 (1997) 1393] by stochastics that make no detailed reference to underlying mechanism revealed that this rate function increased monotonically over the cell cycle with rapid increase near cell division. This feature is highly suggestive of a replication control mechanism that is designed to force most plasmids to replicate before cells undergo division. The replication rate function is developed anew from a mechanistic model incorporating the hypotheses that initiators are limiting and that steric hindrance of origins by handcuffing control initiation of replication. The model is based on correctly folded initiator protein monomers arising from an inactive dimer pool via chaperones in limiting amounts, their random distribution to high affinity sites (iterons) at the origin (ori) and an outside focus (incC), the statistical mechanics of bound monomer participation in pairing the two loci (cis-handcuffing), and initiation probability as proportional to the number of non-handcuffed ori-saturated plasmids. Provided cis-handcuffing is present, this model closely accounts for the shape of the replication rate function derived from experiment, and reproduces the observation that replication occurs throughout the cell cycle. Present concepts of iteron-based molecular mechanisms thus appear capable of yielding a quantitative description of unit-copy-number plasmid replication dynamics. Published by Elsevier Inc. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NIH, Div Bioengn & Phys Sci, ORS, Bethesda, MD 20892 USA. RP Chattoraj, DK (reprint author), NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. EM chattord@dc37a.nci.nih.gov NR 26 TC 6 Z9 7 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 0147-619X J9 PLASMID JI Plasmid PD JUL PY 2004 VL 52 IS 1 BP 13 EP 30 DI 10.1016/j.plasmid.2004.04.001 PG 18 WC Genetics & Heredity; Microbiology SC Genetics & Heredity; Microbiology GA 836CW UT WOS:000222533900002 PM 15212889 ER PT J AU Rakowski, W Breen, N Meissner, H Rimer, BK Vernon, SW Clark, MA Freedman, AN AF Rakowski, W Breen, N Meissner, H Rimer, BK Vernon, SW Clark, MA Freedman, AN TI Prevalence and correlates of repeat mammography among women aged 55-79 in the Year 2000 National Health Interview Survey SO PREVENTIVE MEDICINE LA English DT Article DE mammography; behavioral sciences; women's health; preventive health services ID BREAST-CANCER; UNITED-STATES; PARTICIPATION; PREDICTORS; VALIDATION; PROMOTION; SMOKING; OLDER; WHITE; RISK AB Background. Utilization of mammography has increased steadily since the early 1990s. It is now important to expand the attention given to obtaining repeat examination. This study examines the prevalence and cross-sectional correlates of repeat mammography, among women aged 55 - 79, using a 12-month (N = 3,502) and a 24-month interval (N = 3,491). Methods. Data were from the Year 2000 Cancer Control Module of the National Health Interview Survey (NHIS-CCM). The NHIS-CCM asked about the most recent mammogram and the total number of mammograms over the prior 6 years. An algorithm estimated repeat mammography for the two intervals. Results. Prevalence estimates were 49% for the 12-month interval, and 64.1% for the 24-month interval. Correlates of lower likelihood of repeat mammography for both indicators were: no regular source of care, having public or no health insurance, less than a college education, household income less than $45K, not being married, current or never smoking, age 65-79, and lower absolute risk of breast cancer (Gail Model score). Conclusions. A substantial percentage of women do not receive repeat mammography. The correlates of repeat mammography were similar to those often found for ever-had and recent mammography. There is probably some imprecision in the prevalence estimates due to the nature of NHIS-CCM questions. Issues pertinent to the definition of repeat examination are addressed. (C) 2004 The Institute For Cancer Prevention and Elsevier Inc. All rights reserved. C1 Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. Brown Univ, Ctr Gerontol & Hlth Care Res, Providence, RI 02912 USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Univ N Carolina, Dept Hlth Behav & Hlth Educ, Sch Publ Hlth, Chapel Hill, NC 27599 USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. Univ Texas, Sch Publ Hlth, Ctr Hlth Promot & Prevent Res, Houston, TX 77225 USA. RP Rakowski, W (reprint author), Brown Univ, Dept Community Hlth, 167 Angell St,Box G-H1, Providence, RI 02912 USA. EM William_Rakowski@brown.edu FU NCI NIH HHS [K05-CA90485, R01-CA76330] NR 40 TC 64 Z9 64 U1 2 U2 5 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 2004 VL 39 IS 1 BP 1 EP 10 DI 10.1016/j.ypmed.2003.12.032 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 834FR UT WOS:000222397500001 PM 15207980 ER PT J AU O'Malley, AS Beaton, E Yabroff, KR Abramson, R Mandelblatt, J AF O'Malley, AS Beaton, E Yabroff, KR Abramson, R Mandelblatt, J TI Patient and provider barriers to colorectal cancer screening in the primary care safety-net SO PREVENTIVE MEDICINE LA English DT Article DE neoplasm; colorectal; prevention and control [MeSH]; low income; screening; Black/African-American; primary health care ID AFRICAN-AMERICANS; MINORITY POPULATION; RISK; INTERVENTIONS; PERCEPTIONS; RATIONALE; SERVICES; WOMEN; STAGE; TIME AB Objectives. This study examines patient and provider barriers to screening for colorectal cancer among low-income uninsured African-Americans aged 50 years or older in an urban safety-net primary care clinic, with the goal of informing a future intervention. Methods. Four focus groups were conducted among 40 patients from, or living in the immediate neighborhood of, a primary care clinic for uninsured residents of Washington, DC. An additional focus group was conducted among primary care providers from the same clinic. Using semistructured open-ended questions, moderators elicited perceptions of barriers and promoters of colorectal cancer screening and suggestions to improve adherence to screening guidelines. The focus groups were audio-taped and transcribed verbatim. The transcripts were independently coded by two reviewers using established qualitative methodology. Results. Patient and provider comments from the five focus groups fell into one of eight content areas: primary care characteristics (36% of comments), procedural issues related to screening (16% of comments), knowledge (14% of comments), cost/insurance coverage (13%), ordering of priorities (12%), attitudes (5%), information sources (2%), and perceptions of discrimination (2%). Involving various members of the primary care team in colorectal cancer screening processes, and using reminders with feedback, were identified as promising avenues for future interventions in the safety-net setting. Patients and providers cited the lack of referral sources for colonoscopy for follow-up of abnormal fecal occult blood tests (FOBT), and lack of treatment sources as major barriers to the initiation of colorectal cancer screening in uninsured populations. Conclusions. Organizational level interventions, such as a team approach to colorectal cancer screening, are important areas identified for future colorectal cancer screening interventions in the safety-net primary care setting. Larger policy efforts to provide coverage for screening, diagnosis, and treatment among the uninsured are critical to implementing adequate colorectal cancer screening for this population. (C) 2004 The Institute For Cancer Prevention and Elsevier Inc. All rights reserved. C1 Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Dept Med Oncol, Washington, DC 20007 USA. NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Bread City Med Clin, Washington, DC 20001 USA. RP O'Malley, AS (reprint author), Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Dept Med Oncol, 2233 Wisconsin Ave,NW Suite 440, Washington, DC 20007 USA. EM omalleya@georgetown.edu OI Yabroff, K. Robin/0000-0003-0644-5572 FU NCI NIH HHS [5K07 CA 91848] NR 41 TC 89 Z9 89 U1 0 U2 8 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 2004 VL 39 IS 1 BP 56 EP 63 DI 10.1016/j.ypmed.2004.02.022 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 834FR UT WOS:000222397500007 PM 15207986 ER PT J AU Davis, S Stewart, S Bloom, J AF Davis, S Stewart, S Bloom, J TI Increasing the accuracy of perceived breast cancer risk: results from a randomized trial with cancer information service callers SO PREVENTIVE MEDICINE LA English DT Article DE cancer prevention and control; risk notification; telephone information services; health education; Gail model ID FAMILY-HISTORY; WOMEN; MAMMOGRAPHY; NOTIFICATION; PERCEPTION; PROGRAM; IMPACT AB Background. Results are reported from a randomized trial designed to increase the accuracy of perceived breast cancer risk among callers to the NCI's Cancer Information Service (CIS) (n = 392). Methods. CIS callers assigned to the intervention group (n = 200) received a brief educational intervention and an estimate of breast cancer risk over the telephone at the end of usual service. Follow-up inter-views were completed by telephone at 1 month (n = 367). Results. On average, women overestimated their risk by 25 percentage points. Eighty percent of the respondents rated their risk of breast cancer higher than did the assessment tool. Women rated their risk higher if they were under age 50 (P = 0.025) or had a first-degree family history of breast cancer (P = 0.0001), and rated their risk lower if they were Latina (P = 0.050) or Asian/other race/ethnicity (P = 0.013). Women with a first-degree family history of breast cancer in the intervention group significantly reduced their risk overestimate compared to those in the control group (-12.5 vs. 2.8 percentage points, P = 0.006). Conclusions. This intervention was unique because it was delivered in an ongoing service setting. It should be further tested in diverse populations. (C) 2004 The Institute For Cancer Prevention and Elsevier Inc. All rights reserved. C1 No Calif Canc Ctr, Canc Informat Serv, Natl Canc Inst, Union City, CA 94587 USA. Univ Calif Berkeley, Berkeley, CA 94720 USA. RP Davis, S (reprint author), No Calif Canc Ctr, Canc Informat Serv, Natl Canc Inst, 32960 Alvarado Niles Rd, Union City, CA 94587 USA. EM sdavis@nccc.org NR 38 TC 11 Z9 11 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 0091-7435 J9 PREV MED JI Prev. Med. PD JUL PY 2004 VL 39 IS 1 BP 64 EP 73 DI 10.1016/j.ypmed.2004.02.043 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 834FR UT WOS:000222397500008 PM 15207987 ER PT J AU Pan, PY Lu, PH Sheng, ZH AF Pan, PY Lu, PH Sheng, ZH TI The structural and molecular mechanism of neuronal presynaptic plasticity SO PROGRESS IN BIOCHEMISTRY AND BIOPHYSICS LA Chinese DT Article DE presynaptic plasticity; synaptic strength; quantal size; active zone; probability of transmitter release ID LONG-TERM POTENTIATION; NEUROTRANSMITTER RELEASE; SYNAPTIC-TRANSMISSION; QUANTAL RELEASE; PROTEIN; PHOSPHORYLATION; EXOCYTOSIS; FUSION; ENDOCYTOSIS; SYNTAPHILIN AB Synaptic plasticity is a physiologically important mechanism underlying neuronal information processing. In terms of expression site, synaptic plasticity can be divided into presynaptic and postsynaptic. Presynaptic plasticity is implicated in the modulation of the neurotransmitter release machinery and consequently in synaptic strength. From a physiological perspective, this type of plasticity could be derived from a change in quantal size, active zone structure, probability of transmitter release, especially, synaptic vesicle dynamics: from synaptic vesicle trafficking to the nerve terminal, docking at or fusion with the presynaptic plasma membrane, and finally, reconstitution following endocytosis. Each of these steps is mediated by the concerted activities of multiple proteins and protein complexes,, thus presenting numerous points at which the cascades leading to effective neurotransmitter release could be modulated. Potential mechanisms by which the synaptic vesicle release could be modulated and synaptic activity could be silenced or enhanced at the presynaptic terminal are reviewed. C1 Shanghai Med Univ 2, Dept Neurobiol, Shanghai 200025, Peoples R China. Synapt Funct Univ, NINDS, NIH, Bethesda, MD 20892 USA. RP Sheng, ZH (reprint author), Shanghai Med Univ 2, Dept Neurobiol, Shanghai 200025, Peoples R China. EM ShengZ@ninds.nih.gov NR 30 TC 0 Z9 0 U1 0 U2 1 PU SCIENCE CHINA PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1000-3282 J9 PROG BIOCHEM BIOPHYS JI Prog. Biochem. Biophys. PD JUL PY 2004 VL 31 IS 7 BP 584 EP 589 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 841FJ UT WOS:000222914400002 ER PT J AU Shatsky, M Nussinov, R Wolfson, HJ AF Shatsky, M Nussinov, R Wolfson, HJ TI A method for simultaneous alignment of multiple protein structures SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE simultaneous multiple structure alignment; protein structural comparison; structural core; protein interfaces; order independent structural comparison; multiple structure alignment of binding sites ID COMPUTER VISION; MOTIFS; DATABASE; SEQUENCES; EFFICIENT; DOCKING AB Here, we present MultiProt, a fully automated highly efficient technique to detect multiple structural alignments of protein structures. MultiProt finds the common geometrical cores between input molecules. To date, most methods for multiple alignment start from the pairwise alignment solutions. This may lead to a small overall alignment. In contrast, our method derives multiple alignments from simultaneous superpositions of input molecules. Further, our method does not require that all input molecules participate in the alignment. Actually, it efficiently detects high scoring partial multiple alignments for all possible number of molecules in the input. To demonstrate the power of MultiProt, we provide a number of case studies. First, we demonstrate known multiple alignments of protein structures to illustrate the performance of MultiProt. Next, we present various biological applications. These include: (1) a partial alignment of hinge-bent domains; (2) identification of functional groups of G-proteins; (3) analysis of binding sites; and (4) protein-protein interface alignment. Some applications preserve the sequence order of the residues in the alignment, whereas others are order-independent. It is their residue sequence order-independence that allows application of MultiProt to derive multiple alignments of binding sites and of protein-protein interfaces, making MultiProt an extremely useful structural tool. (C) 2004 Wiley-Liss, Inc. C1 Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Sch Comp Sci, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Sackler Fac Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. SAIC Frederick Inc, Basic Res Program, NCI, Lab Expt & Computat Biol, Frederick, MD 21701 USA. RP Shatsky, M (reprint author), Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Sch Comp Sci, IL-69978 Tel Aviv, Israel. EM maxshats@post.tau.ac.il RI Wolfson, Haim/A-1837-2011 FU NCI NIH HHS [N01-CO-12400] NR 36 TC 254 Z9 261 U1 1 U2 9 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-3585 J9 PROTEINS JI Proteins PD JUL 1 PY 2004 VL 56 IS 1 BP 143 EP 156 DI 10.1002/prot.10628 PG 14 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 829AP UT WOS:000222015500014 PM 15162494 ER PT J AU Gladen, BC Rogan, WJ AF Gladen, BC Rogan, WJ TI Relationship of perinatal PCB exposure to neurodevelopmental outcomes: Reply to appraisal SO PSYCHOLOGY IN THE SCHOOLS LA English DT Article ID POLYCHLORINATED-BIPHENYLS; DICHLORODIPHENYL DICHLOROETHENE; MULTIPLE COMPARISONS; HUMAN-MILK; DDE; LACTATION; RATS AB D.V.. Cicchetti, A.S. Kaufman, and S.S. Sparrow (this issue) examine various technical issues related to six studies of perinatal PCB exposure and neurodevelopment and one study of adult PCB exposure and motor function. They raise questions about possible imperfections of the studies, but many of their assertions are unsupported or frankly incorrect, and they do little to assess the potential impact of the issues that they raise; we find none of their arguments about flaws in our study compelling. Their stated purpose is to scientifically evaluate the body of literature, but their narrow focus does not allow a genuine evaluation of the scientific evidence. (C) 2004 Wiley Periodicals, Inc. C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Gladen, BC (reprint author), NIEHS, Biostat Branch, POB 12233,Mail Drop A3-03, Res Triangle Pk, NC 27709 USA. EM gladen@niehs.nih.gov RI Rogan, Walter/I-6034-2012 OI Rogan, Walter/0000-0002-9302-0160 NR 18 TC 1 Z9 1 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0033-3085 J9 PSYCHOL SCHOOLS JI Psychol. Schools PD JUL PY 2004 VL 41 IS 6 BP 687 EP 691 DI 10.1002/pits.20010 PG 5 WC Psychology, Educational SC Psychology GA 834ER UT WOS:000222394900008 ER PT J AU Gasior, M Kaminski, R Witkin, JM AF Gasior, M Kaminski, R Witkin, JM TI Pharmacological modulation of GABA(B) receptors affects cocaine-induced seizures in mice SO PSYCHOPHARMACOLOGY LA English DT Article DE cocaine; baclofen; GABA; seizures; kindling; anticonvulsant ID GAMMA-AMINOBUTYRIC-ACID; ANTIEPILEPTIC DRUGS; KINDLED-SEIZURES; INDUCED CONVULSIONS; NEUROACTIVE STEROIDS; LOCAL-ANESTHETICS; MOUSE-BRAIN; RAT-BRAIN; ANTICONVULSANT; BACLOFEN AB Rationale. Previous data have demonstrated that the convulsant effects of cocaine can be modulated by compounds that increase levels of endogenous gamma-aminobutyric acid (GABA) or that directly stimulate GABA(A) receptors. Objectives. To determine whether the convulsant effects of cocaine can be modulated by ligands selective for GABA(B) receptors in mice. Methods. Effects of the GABA(B) receptor agonist ((+/-)-baclofen), antagonist (phaclofen), and their combination were tested against clonic seizures induced by cocaine (75 mg/kg). Enantiomers of baclofen were used to confirm stereospecificity of (+/-)-baclofen's effects. Pharmacological specificity of (+/-)-baclofen's effects was tested by comparison against seizures induced by GBR 12909 (monoamine transporter inhibitor), pentylenetetrazole (GABA(A) antagonist), N-methyl-D-aspartate (NMDA agonist), and aminophylline (A(1)/A(2) adenosine antagonist). Additionally, effects of (+/-)-baclofen on kindled seizures induced by repeated administration of cocaine (60 mg/kg every 24 h for 6 days) were evaluated. The inverted screen test was used to assess behavioral side effects of baclofen. Results. (+/-)-Baclofen dose-dependently inhibited acute (ED50=4.1 mg/kg) and kindled (6.4 mg/kg) seizures induced by cocaine at doses somewhat lower than those producing behavioral side effects (11.5 mg/kg), and these effects were stereospecific. (+/-)-Baclofen suppressed seizures induced by GBR 12909 but not by pentylenetetrazole, NMDA, and aminophylline, suggesting selectivity of its anticonvulsant effects for monoamine-related mechanisms. Finally, phaclofen dose-dependently enhanced the convulsant effects of a threshold dose of cocaine (60 mg/kg). Conclusions. Modulation of GABA(B) receptors can affect seizures induced by cocaine. This molecular mechanism may be involved in seizures induced by cocaine or, alternatively, may function as an independent inhibitory mechanism against seizures arising from blockade of monoamine uptake. C1 NINDS, Epilepsy Res Sect, NIH, Bethesda, MD 20892 USA. NIDA, Drug Dev Grp, Behav Neurosci Branch, NIH, Baltimore, MD 21224 USA. Lilly Corp Ctr, Lilly Res Labs, Neurosci Discovery Res, Indianapolis, IN 46285 USA. RP Gasior, M (reprint author), NINDS, Epilepsy Res Sect, NIH, 10 Ctr Dr,MSC 1408,Bldg 10,Room 5N250, Bethesda, MD 20892 USA. EM GasiorM@ninds.nih.gov NR 48 TC 14 Z9 14 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2004 VL 174 IS 2 BP 211 EP 219 DI 10.1007/s00213-003-1743-0 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 831SR UT WOS:000222216900006 PM 14985936 ER PT J AU Carney, RM Blumenthal, JA Freedland, KE Youngblood, M Veith, RC Burg, MM Cornell, C Saab, PG Kaufmann, PG Czajkowski, SM Jaffe, AS AF Carney, RM Blumenthal, JA Freedland, KE Youngblood, M Veith, RC Burg, MM Cornell, C Saab, PG Kaufmann, PG Czajkowski, SM Jaffe, AS CA ENRICHD Investigators TI Depression and late mortality after myocardial infarction in the Enhancing Recovery in Coronary Heart Disease (ENRICHD) study SO PSYCHOSOMATIC MEDICINE LA English DT Article DE depression; depressive disorder; myocardial infarction; mortality; cognitive therapy ID RISK; RATIONALE; DISORDER; SURVIVAL; DEATH AB Objective: The Enhancing Recovery in Coronary Heart Disease study was a multicenter clinical trial in which patients with depression and/or low perceived social support after an acute myocardial infarction were randomly assigned to an intervention consisting of cognitive behavior therapy and, in some cases, sertraline, or to usual care. There was no difference in survival between the groups. A possible reason why the intervention failed to affect survival is that too many patients with mild, transient depression were enrolled. Another is that some patients died too soon to complete the intervention. This analysis evaluates whether there was a difference in late (ie, greater than or equal to6 months after the myocardial infarction) mortality among initially depressed patients who had a Beck Depression Inventory score greater than or equal to10 and a past history of major depression, and who completed the 6-month post-treatment assessment. It also examines the relationship between change in depression and late mortality. Methods: Out of the 1,165 (47%) of the Enhancing Recovery in Coronary Heart Disease study participants who met our criteria, 57 died in the first 6 months, and 858 (409 usual care, 449 intervention) completed the 6-month assessment. Cox regression was used to analyze survival. Results: The intervention did not affect late mortality. However, intervention patients whose depression did not improve were at higher risk for late mortality than were patients who responded to treatment. Conclusions: Patients whose depression is refractory to cognitive behavior therapy and sertraline, two standard treatments for depression, are at high risk for late mortality after myocardial infarction. C1 Washington Univ, Sch Med, Behav Med Ctr, Dept Psychiat, St Louis, MO 63108 USA. Mayo Clin, Dept Med, Rochester, MN USA. NHLBI, Bethesda, MD 20892 USA. Univ Miami, Dept Psychiat, Miami, FL 33152 USA. Univ Alabama, Dept Psychiat, Birmingham, AL USA. Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. Univ Washington, Dept Psychiat, Seattle, WA 98195 USA. Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. Duke Univ, Med Ctr, Dept Psychiat, Durham, NC 27710 USA. RP Carney, RM (reprint author), Washington Univ, Sch Med, Behav Med Ctr, Dept Psychiat, 4625 Lindell Ave,Suite 420, St Louis, MO 63108 USA. EM carneyr@bmc.wustl.edu FU NHLBI NIH HHS [N01-HC-55140, N01-HC-55141, N01-HC-55142, N01-HC-55143, N01-HC-55144, N01-HC-55145, N01-HC-55146, N01-HC-55147, N01-HC-55148] NR 27 TC 144 Z9 150 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0033-3174 J9 PSYCHOSOM MED JI Psychosom. Med. PD JUL-AUG PY 2004 VL 66 IS 4 BP 466 EP 474 DI 10.1097/01.psy.0000133362.75075.a6 PG 9 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 840KX UT WOS:000222858600002 PM 15272090 ER PT J AU Paltoo, DN Chu, KC AF Paltoo, DN Chu, KC TI Patterns in cancer incidence among American Indians/Alaska natives, United States, 1992-1999 SO PUBLIC HEALTH REPORTS LA English DT Article ID ALASKA NATIVES; HEALTH AB Objective. Cancer is a major public health concern in American Indian and Alaska Native (AI/AN) communities. However, information on the incidence of cancer is lacking for this group. The purpose of this study is to report cancer incidence patterns for the U.S. AI/AN population. Methods. Age-adjusted annual cancer incidence rates for 1992 through 1999 were calculated for 12 Surveillance, Epidemiology and End Results (SEER) areas, representing a sample (42%) of the U.S. AI/AN population. Trends in cancer incidence rates for the AI/AN sample were determined using standard linear regression of log-transformed rates and were compared to those of the U.S. white population. Results. The top five incident cancers (from highest to lowest) among AI/AN males were prostate, lung and bronchus, colon and rectum, kidney and renal pelvis, and stomach cancers. Among AI/AN women, cancers of the breast, colon and rectum, lung and bronchus, endometrium, and ovary ranked highest. Four sites where cancer incidence rates are greater for AI/ANs than for whites include gallbladder (the AI/AN rate was 4.1 times the rate for white males and 2.6 times the rate for white females), liver and intrahepatic bile duct cancers (1.3 times for males and 2.3 times for females), stomach (1.2 times for males and 1.5 times for females), and kidney and renal pelvis (1.03 times for males and 1.07 times for females). The data show increasing trends for AI/AN males and females and declining trends for white males and females for colorectal, stomach, and pancreatic cancers and leukemia. Similar differences between AI/AN rates and white rates were found for urinary bladder cancers in males and gallbladder cancer in females. Conclusions. Analysis of SEER data allowed for the determination of disparities in cancer incidence between a sample of the U.S. AI/AN population and the white population. The findings of this study provide baseline information necessary for developing cancer prevention and intervention strategies specific to the AI/AN population to address these cancer disparities. C1 NCI, Ctr Canc Res, Canc Prevent Studies Branch, NIH, Bethesda, MD 20892 USA. RP Paltoo, DN (reprint author), NHLBI, Div Heart & Vasc Dis, NIH, 6701 Rocklege Blvd,Suite 9180, Bethesda, MD 20892 USA. EM paltood@mail.nih.gov NR 17 TC 45 Z9 45 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0033-3549 J9 PUBLIC HEALTH REP JI Public Health Rep. PD JUL-AUG PY 2004 VL 119 IS 4 BP 443 EP 451 DI 10.1016/j.phr.2004.05.009 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 860BB UT WOS:000224311100010 PM 15219802 ER PT J AU Jamis-Dow, CA Turner, J Biesecker, LG Choyke, PL AF Jamis-Dow, CA Turner, J Biesecker, LG Choyke, PL TI Radiologic manifestations of Proteus syndrome SO RADIOGRAPHICS LA English DT Article DE bones, abnormalities; bones, hypertrophy; extremities, abnormalities; liver, abnormalities; neoplasms, diagnosis; Proteus syndrome; soft tissues, neoplasms ID PULMONARY THROMBOEMBOLISM; HEMIHYPERTROPHY; MOSAICISM; MUTATIONS; PTEN; ASYMMETRY; GERMLINE; PATIENT; DEATH AB Proteus syndrome is a sporadic disorder named for its highly variable manifestations. The disease causes tissue overgrowth in a mosaic pattern and may affect tissues derived from any germinal layer. The disease process is not usually apparent at birth but develops rapidly in childhood. Common manifestations include macrodactyly, vertebral abnormalities, asymmetric limb overgrowth and length discrepancy, hyperostosis, abnormal and asymmetric fat distribution, asymmetric muscle development, connective-tissue nevi, and vascular malformations. The features of Proteus syndrome indicate that the condition may be caused by a somatic alteration in a gene, but no specific genetic mutation has yet been identified. Therefore, the diagnosis and management of the disease depend heavily on clinical evaluation and imaging. Although the manifestations of Proteus syndrome are highly variable, accurate diagnosis is possible if standard diagnostic criteria are followed and if disease features are assessed in comparison with those found in similar syndromes. (C) RSNA, 2004. C1 NIH, Ctr Clin, Dept Radiol, Bethesda, MD 20892 USA. Georgetown Univ Hosp, Dept Radiol, Washington, DC 20007 USA. NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Choyke, PL (reprint author), NIH, Ctr Clin, Dept Radiol, Bldg 10,Room 1C-660,MSC 1182, Bethesda, MD 20892 USA. EM pchoyke@cc.nih.gov NR 25 TC 43 Z9 45 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0271-5333 J9 RADIOGRAPHICS JI Radiographics PD JUL-AUG PY 2004 VL 24 IS 4 BP 1051 EP 1068 DI 10.1148/rg.244035726 PG 18 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 834UJ UT WOS:000222436100011 PM 15256628 ER PT J AU Tarlow, BJ Wisniewski, SR Belle, SH Rubert, M Ory, MG Gallagher-Thompson, D AF Tarlow, BJ Wisniewski, SR Belle, SH Rubert, M Ory, MG Gallagher-Thompson, D TI Positive aspects of caregiving - Contributions of the REACH project to the development of new measures for Alzheimer's caregiving SO RESEARCH ON AGING LA English DT Article DE psychometric analysis; Alzheimer's disease; research measures; care-giving satisfaction ID FAMILY CAREGIVERS; DISEASE; STRESS; DEMENTIA; OUTCOMES; IMPACT; APPRAISAL; BURDEN; CARE AB The aim of this study was to assess a newly developed measure for the positive aspects of caregiving using a sample of dementia caregivers. The measure was developed and administered to 1,229 participants in a national collaborative Alzheimer's disease caregiver study and evaluated for validity and reliability using standard psychometric analyses. Factor analysis identified two components in this nine-item measure: Self-Affirmation and Outlook on Life. Cronbach's alphas for the components were .86 and .80, respectively. For the entire scale, Cronbach's alpha was .89. The Positive Aspects of Caregiving measure, tested with a large, diverse, and well-characterized sample shows promise as a valid and reliable instrument. With additional implementation and testing, the measure has the potential to substantially increase our understanding of basic caregiving research and the outcomes of intervention efforts. C1 Hebrew Rehabil Ctr Aged, Boston, MA 02131 USA. Univ Pittsburgh, Epidemiol Data Ctr, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. NIH, Bethesda, MD 20892 USA. Stanford Univ, Stanford, CA 94305 USA. RP Tarlow, BJ (reprint author), Hebrew Rehabil Ctr Aged, Boston, MA 02131 USA. OI Wisniewski, Stephen/0000-0002-3877-9860 NR 42 TC 118 Z9 132 U1 1 U2 11 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 2004 VL 26 IS 4 BP 429 EP 453 DI 10.1177/0164027504264493 PG 25 WC Gerontology SC Geriatrics & Gerontology GA 827KN UT WOS:000221898500003 ER PT J AU Sayre, MR Travers, AH Daya, M Greene, HL Salive, ME Vijayaraghavan, K Craven, RA Groh, WJ Hallstrom, AP AF Sayre, MR Travers, AH Daya, M Greene, HL Salive, ME Vijayaraghavan, K Craven, RA Groh, WJ Hallstrom, AP CA The PAD Investigators TI Measuring survival rates from sudden cardiac arrest: the elusive definition SO RESUSCITATION LA English DT Article DE sudden cardiac arrest; heart arrest; emergency medical services; epidemiology; ventricular fibrillation; defibrillation; cardiopulmonary resuscitation ID HOSPITAL VENTRICULAR-FIBRILLATION; UTSTEIN-STYLE; DEFIBRILLATION; RESUSCITATION; GUIDELINES; CARE; TALE; CPR AB Background: Measuring survival from sudden out-of-hospital cardiac arrest (OOH-CA) is often used as a benchmark of the quality of a community's emergency medical service (EMS) system. The definition of OOH-CA survival rates depends both upon the numerator (surviving cases) and the denominator (all cases). Purpose: The purpose of the public access defibrillation (PAD) trial was to measure the impact on survival of adding an automated external defibrillator (AED) to a volunteer response system trained in CPR. This paper reports the definition of OOH-CA developed by the PAD trial investigators, and it evaluates alternative statistical methods used to assess differences in reported "survival." Methods: Case surveillance was limited to the prospectively determined geographic boundaries of the participating trial units. The numerator in calculating a survival rate should include only those patients who survived an event but who otherwise would have died except for the application of some facet of emergency medical care-in this trial a defibrillatory shock. Among denominators considered were: total population of the study unit, all deaths within the study unit, and documented ventricular fibrillation cardiac arrests. The PAD classification focused upon cases that might have benefited from the early use of an AED, in addition to the likely benefit from early recognition of OOH-CA, early access of EMS, and early cardiopulmonary resuscitation (CPR). Results of this classification system were used to evaluate the impact of the PAD definition on the distribution of cardiac arrest case types between CPR only and CPR + AED units. Results: Potential OOH-CA episodes were classified into one of four groups: definite, probable, uncertain, or not an OOH-CA. About half of cardiac arrests in the PAD units were judged to be definite OOH-CA events and therefore potentially treatable with an AED. However, events that occurred in CPR-only units were less likely to be classified as definite or probable OOH-CA events than those in CPR + AED units (43% versus 55%, odds ratio 0.78, 95% confidence interval 0.57-1.07). The study retained sufficient power to permit a statistical analysis of the alternative hypothesis that the CPR + AED method results in twice as many survivors as a CPR-only approach. The result is critically dependent on the denominator used for calculating survival rates; but the analysis does not require a denominator as the numerators will have identical Poisson distributions (counts for rare events) under the null hypothesis since randomization distributes the risk of cardiac arrest evenly between the two arms. Conclusion: Reported OOH-CA rates and survival rates vary widely, depending upon the definitions applied to events. Rigorous assessment of treatments applied to improve survival can be obscured by inappropriate definitions. Large-scale randomized interventions designed to improve survival from OOH-CA can be evaluated based upon the absolute numbers of patients surviving, rather than a change in the proportion surviving. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 Ohio State Univ, Dept Emergency Med, Columbus, OH 43210 USA. Univ Alberta, Div Emergency Med, Edmonton, AB T6G 2M7, Canada. Oregon Hlth Sci Univ, Ctr Policy & Res Emergency Med, Portland, OR 97201 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. NHLBI, Bethesda, MD 20892 USA. Arizona Heart Inst, Dept Cardiol, Phoenix, AZ USA. Eastern Virginia Med Sch, LLC, Virginia, VA USA. Eastern Virginia Med Sch, Dept Family & Community Med, Virginia, VA USA. Indiana Univ, Dept Med, Indianapolis, IN 46204 USA. RP Sayre, MR (reprint author), Ohio State Univ, Dept Emergency Med, 150 Means Hall,1654 Upham Dr, Columbus, OH 43210 USA. EM sayre.84@osu.edu RI Sayre, Michael/E-8383-2017 OI Sayre, Michael/0000-0003-0322-3181 FU NHLBI NIH HHS [N01-HC-95177] NR 19 TC 12 Z9 13 U1 1 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0300-9572 J9 RESUSCITATION JI Resuscitation PD JUL PY 2004 VL 62 IS 1 BP 25 EP 34 DI 10.1016/j.resuscitation.2004.02.007 PG 10 WC Critical Care Medicine; Emergency Medicine SC General & Internal Medicine; Emergency Medicine GA 840TD UT WOS:000222881800002 PM 15246580 ER PT J AU Jeronimo, SMB Duggal, P Braz, RFS Cheng, C Monteiro, GRG Nascimento, ET Martins, DRA Karplus, TM Ximenes, MFFM Oliveira, CCG Pinheiro, VG Pereira, W Peralta, JM Sousa, JMA Medeiros, IM Pearson, RD Burns, TL Pugh, EW Wilson, ME AF Jeronimo, SMB Duggal, P Braz, RFS Cheng, C Monteiro, GRG Nascimento, ET Martins, DRA Karplus, TM Ximenes, MFFM Oliveira, CCG Pinheiro, VG Pereira, W Peralta, JM Sousa, JMA Medeiros, IM Pearson, RD Burns, TL Pugh, EW Wilson, ME TI An emerging peri-urban pattern of infection with Leishmania chagasi, the protozoan causing visceral leishmaniasis in northeast Brazil SO SCANDINAVIAN JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CUTANEOUS LEISHMANIASIS; SUBCLINICAL INFECTION; NATURAL-HISTORY; FOLLOW-UP; ANTIGEN; SUSCEPTIBILITY; TRANSMISSION; EPIDEMIC; SUDAN AB Peri-urban visceral leishmaniasis (VL) caused by Leishmania chagasi is emerging in a new epidemiologic pattern in Brazilian cities. We studied peri-urban VL in endemic neighborhoods surrounding Natal, Brazil, identified through hospitalized individuals with VL. Clinical and environmental information obtained for 1106 members of 216 families living in endemic neighborhoods enabled us to identify 4 groups: VL: individuals with current or prior symptomatic visceral leishmaniasis (n = 135); DTH +: individuals with positive delayed-type hypersensitivity response with no history of VL (n = 390); Ab +: individuals with negative DTH response and seropositive (n = 21); DTH-: individuals with negative DTH and seronegative (n = 560). The mean+/-SD age of VL was 9.3+/-12.3 y. The gender distribution was nearly equal below age 5, but skewed toward males at higher ages. Acutely infected VL subjects had significantly lower hematocrits, neutrophils, and eosinophils than other categories. AB+ subjects also had lower eosinophil counts than others, a possible immune marker of early infection. VL was not associated with ownership of dogs or other animals, raising the question whether the reservoir differs in peri-urban settings. This new pattern of L. chagasi infection enables us to identify epidemiological and host factors underlying this emerging infectious disease. C1 Univ Fed Rio Grande Norte, Dept Bioquim, BR-59072970 Natal, RN, Brazil. Univ Fed Rio Grande Norte, Dept Infect Dis, BR-59072970 Natal, RN, Brazil. Univ Fed Rio Grande Norte, Dept Microbiol & Parasitol, BR-59072970 Natal, RN, Brazil. NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD USA. Univ Fed Rio de Janeiro, Inst Microbiol, BR-21941 Rio De Janeiro, Brazil. Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA. Univ Iowa, Dept Biostat, Iowa City, IA 52242 USA. Univ Iowa, Dept Epidemiol, Iowa City, IA 52242 USA. Univ Iowa, Dept Microbiol, Iowa City, IA 52242 USA. VA Med Ctr, Iowa City, IA USA. Univ Virginia, Dept Internal Med, Charlottesville, VA USA. Univ Virginia, Dept Pathol, Charlottesville, VA 22903 USA. Ctr Inherited Dis Res, Baltimore, MD USA. Johns Hopkins Univ, Baltimore, MD USA. RP Jeronimo, SMB (reprint author), Univ Fed Rio Grande Norte, Dept Bioquim, CP 1624, BR-59072970 Natal, RN, Brazil. EM smbj@cb.ufrn.br RI Jeronimo, Selma/M-8672-2014 FU FIC NIH HHS [TW01369]; NIAID NIH HHS [AI-30639, AI45540, AI48822, T32 AI07511]; NIDDK NIH HHS [DK/AI2550] NR 30 TC 50 Z9 50 U1 0 U2 5 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0036-5548 J9 SCAND J INFECT DIS JI Scand. J. Infect. Dis. PD JUL PY 2004 VL 36 IS 6-7 BP 443 EP 449 DI 10.1080/00365540410020451 PG 7 WC Infectious Diseases SC Infectious Diseases GA 833PS UT WOS:000222351100008 PM 15307565 ER PT J AU Caporaso, N Marti, GE Goldin, L AF Caporaso, N Marti, GE Goldin, L TI Perspectives on familial chronic lymphocytic leukemia: Genes and the environment SO SEMINARS IN HEMATOLOGY LA English DT Article ID B-CLL; WALDENSTROMS-MACROGLOBULINEMIA; PERIPHERAL-BLOOD; CANCER INCIDENCE; LINKAGE ANALYSIS; ATM MUTATIONS; ANTICIPATION; EXPRESSION; LYMPHOMA; EXPOSURE C1 NCI, Div Canc epidemiol & Genet, Genet Epidemiol Branch, Bethesda, MD 20892 USA. Fed Drug Adm, Div Cell & Gene Therapies, Lab Med & Mol Genet, Flow & Image Cytometry Sect, Bethesda, MD USA. RP Caporaso, N (reprint author), NCI, Div Canc epidemiol & Genet, Genet Epidemiol Branch, EPS 7116,6120 Execut Blvd, Bethesda, MD 20892 USA. NR 62 TC 17 Z9 19 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 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD JUL PY 2004 VL 41 IS 3 BP 201 EP 206 DI 10.1053/j.seminhematol.2004.05.002 PG 6 WC Hematology SC Hematology GA 841BG UT WOS:000222903700004 PM 15269880 ER PT J AU Cook, JA Gius, D Wink, DA Krishna, MC Russo, A Mitchell, JB AF Cook, JA Gius, D Wink, DA Krishna, MC Russo, A Mitchell, JB TI Oxidative stress, redox, and the tumor microenvironment SO SEMINARS IN RADIATION ONCOLOGY LA English DT Article ID NF-KAPPA-B; PERFORMANCE LIQUID-CHROMATOGRAPHY; NITRIC-OXIDE; IN-VIVO; CELL RADIOSENSITIZATION; THIOREDOXIN REDUCTASE; SUPEROXIDE-DISMUTASE; TRANSCRIPTION FACTOR; IONIZING-RADIATION; GLUTATHIONE LEVELS C1 NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, Radiat Oncol Branch, Bethesda, MD 20892 USA. RP Mitchell, JB (reprint author), NCI, Radiat Biol Branch, Bldg 10,Room B3-B69, Bethesda, MD 20892 USA. NR 40 TC 138 Z9 143 U1 1 U2 14 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 2004 VL 14 IS 3 BP 259 EP 266 DI 10.1016/j.semradonc.2004.04.001 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 843MO UT WOS:000223088200009 PM 15254869 ER PT J AU Walter-Ginzburg, A Blumstein, T Guralnik, JM AF Walter-Ginzburg, A Blumstein, T Guralnik, JM TI The Israeli kibbutz as a venue for reduced disability in old age: lessons from the Cross-sectional And Longitudinal Aging Study (CALAS) SO SOCIAL SCIENCE & MEDICINE LA English DT Review DE disability; ADL; old-old; kibbutz; Israel ID SOCIAL NETWORK CHARACTERISTICS; LABOR-FORCE PARTICIPATION; ACTIVE LIFE EXPECTANCY; GENDER-DIFFERENCES; PHYSICAL-ACTIVITY; HEALTH-STATUS; SOCIOECONOMIC-STATUS; FUNCTIONAL STATUS; PREDICTIVE VALUE; WOMENS HEALTH AB It is important to identify ways to moderate disability in old age. We assessed whether the kibbutz way of life results in reduced disability by examining risk factors for disability in three comparable populations: kibbutz members (lifetime kibbutz exposure); parents of kibbutz members who came to live on the kibbutz in old age due to health and social needs (old age exposure); and comparable Israelis in the general population (no exposure). Kibbutz members were less disabled, defined as needing help with at least one of five activities of daily living, than the other groups. Kibbutz members had 30% lower risk of disability, after controlling for sociodemographics and social networks, health and health behaviors, and life history and background. Introducing length of residence in current home and death of a child to the analysis reduced this finding to non-significance. Overall, risk of disability was significantly higher for older age groups, women, homemakers, people with more comorbid conditions, those with more children, and those with a child that had died, while risk of disability was significantly lower for those with larger social networks, those who had engaged in physical activity at midlife, and those who had lived in their homes longer. Since occupations on the kibbutz (primarily agricultural and blue collar) have equal pay, and kibbutz members have complete economic security, our results suggest that it is not such occupations themselves but their association with low incomes that have contributed to previous associations of blue collar and agricultural occupations with poor health and high disability. Lower disability among kibbutz members may be due to the social, economic, and instrumental support provided on the kibbutz, as well as to an active life style, suggesting features of kibbutz life that can be replicated elsewhere to reduce disability. (C) 2003 Elsevier Ltd. All rights reserved. C1 Tel Aviv Univ, Herczeg Inst Aging, IL-69978 Tel Aviv, Israel. Chaim Sheba Med Ctr, Gertner Inst Epidemiol & Hlth Policy Res, IL-52621 Tel Hashomer, Israel. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Walter-Ginzburg, A (reprint author), Tel Aviv Univ, Herczeg Inst Aging, IL-69978 Tel Aviv, Israel. EM adrianwg@alum.mit.edu FU NIA NIH HHS [AGO5885] NR 127 TC 4 Z9 4 U1 1 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD JUL PY 2004 VL 59 IS 2 BP 389 EP 403 DI 10.1016/j.socscimed.2003.10.026 PG 15 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 820EI UT WOS:000221369600014 PM 15110428 ER PT J AU Marron, JS Muller, HG Rice, J Wang, JL Wang, NY Wang, YD Davidian, M Diggle, P Follmann, D Louis, TA Taylor, J Zeger, S Goetghebeur, E Carroll, RJ AF Marron, JS Muller, HG Rice, J Wang, JL Wang, NY Wang, YD Davidian, M Diggle, P Follmann, D Louis, TA Taylor, J Zeger, S Goetghebeur, E Carroll, RJ TI Discussion of nonparametric and semiparametric regression SO STATISTICA SINICA LA English DT Editorial Material ID CAUSAL INFERENCE; MODELS; COUNTERFACTUALS; CURVES C1 Univ N Carolina, Chapel Hill, NC 27515 USA. Univ Calif Davis, Davis, CA 95616 USA. Univ Calif Berkeley, Berkeley, CA 94720 USA. Texas A&M Univ, College Stn, TX 77843 USA. Univ Calif Santa Barbara, Santa Barbara, CA 93106 USA. N Carolina State Univ, Raleigh, NC 27695 USA. Univ Lancaster, Lancaster LA1 4YW, England. NIAID, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD 21218 USA. Univ Michigan, Ann Arbor, MI 48109 USA. State Univ Ghent, Ghent, Belgium. RP Marron, JS (reprint author), Univ N Carolina, Chapel Hill, NC 27515 USA. RI Diggle, Peter/A-3025-2009 NR 14 TC 5 Z9 5 U1 0 U2 0 PU STATISTICA SINICA PI TAIPEI PA C/O DR H C HO, INST STATISTICAL SCIENCE, ACADEMIA SINICA, TAIPEI 115, TAIWAN SN 1017-0405 J9 STAT SINICA JI Stat. Sin. PD JUL PY 2004 VL 14 IS 3 BP 615 EP 629 PG 15 WC Statistics & Probability SC Mathematics GA 850ZE UT WOS:000223652100002 ER PT J AU Huang, JHZ Wu, CO Zhou, L AF Huang, JHZ Wu, CO Zhou, L TI Polynomial spline estimation and inference for varying coefficient models with longitudinal data SO STATISTICA SINICA LA English DT Article; Proceedings Paper CT Joint Summer Research Conference on Emerging Issues in Longitudinal Analysis CY JUL 28-AUG 01, 2002 CL Mt Holyoke Coll, S Hadley, MA HO Mt Holyoke Coll DE asymptotic normality; confidence intervals; nonparametric regression; repeated measurements; varying coefficient models ID COVARIANCE STRUCTURE; CONFIDENCE BANDS; LINEAR-MODELS; REGRESSION; CURVES AB We consider nonparametric estimation of coefficient functions in a varying coefficient model of the form Y-ij = X-i(T)(t(ij))beta(t(ij)) + epsilon(i)(t(ij)) based on longitudinal observations {(Y-ij, X-i (t(ij)), t(ij)), i = 1,...,n, j = 1,...,n(i)}, where t(ij) and n(i) are the time of the jth measurement and the number of repeated measurements for the ith subject, and Y-ij and X-i(t(ij)) = (X-i0(tij),..., X-iL(t(ij)))(T) for L greater than or equal to 0 are the ith subject's observed outcome and covariates at t(ij). We approximate each coefficient function by a polynomial spline and employ the least squares method to do the estimation. An asymptotic theory for the resulting estimates is established, including consistency, rate of convergence and asymptotic distribution. The asymptotic distribution results are used as a guideline to construct approximate confidence intervals and confidence bands for components of beta(t). We also propose a polynomial spline estimate of the covariance structure of epsilon(t), which is used to estimate the variance of the spline estimate beta(t). A data example in epidemiology and a simulation study are used to demonstrate our methods. C1 Univ Penn, Wharton Sch, Dept Stat, Philadelphia, PA 19104 USA. NHLBI, Off Biostat Res, DECA, Rockledge Ctr 2, Bethesda, MD 20892 USA. Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. RP Huang, JHZ (reprint author), Univ Penn, Wharton Sch, Dept Stat, 400 Jon M Huntsman Hall,3730 Walnut St, Philadelphia, PA 19104 USA. EM jianhua@wharton.upenn.edu; wuc@nhlbi.nih.gov; lzhou@cceb.upenn.edu NR 43 TC 141 Z9 152 U1 0 U2 2 PU STATISTICA SINICA PI TAIPEI PA C/O DR H C HO, INST STATISTICAL SCIENCE, ACADEMIA SINICA, TAIPEI 115, TAIWAN SN 1017-0405 J9 STAT SINICA JI Stat. Sin. PD JUL PY 2004 VL 14 IS 3 BP 763 EP 788 PG 26 WC Statistics & Probability SC Mathematics GA 850ZE UT WOS:000223652100009 ER PT J AU Modarres, R Zheng, G AF Modarres, R Zheng, G TI Maximum likelihood estimation of dependence parameter using ranked set sampling SO STATISTICS & PROBABILITY LETTERS LA English DT Article DE bivariate distribution; correlation; Fisher information; imperfect ranking; parametric bootstrap ID FISHER INFORMATION; CONCOMITANT; STATISTICS AB We study the maximum likelihood estimation of the dependence parameter of a general bivariate distribution using ranked set sampling. We compare the Fisher information about the dependence parameter in ranked set samples and simple random samples. Results are applied to the bivariate normal and bivariate extreme value distributions. In ranked set sampling with unequal allocations, we select samples using maximal Fisher information in order statistics. We study the performance of the parametric bootstrap for bivariate ranked set samples. (C) 2004 Elsevier B.V. All rights reserved. C1 George Washington Univ, Dept Stat, Washington, DC 20052 USA. NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. RP Modarres, R (reprint author), George Washington Univ, Dept Stat, 2201 G St NW, Washington, DC 20052 USA. EM reza@gwu.edu; zhengg@nhlbi.nih.gov NR 15 TC 5 Z9 5 U1 2 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-7152 J9 STAT PROBABIL LETT JI Stat. Probab. Lett. PD JUL 1 PY 2004 VL 68 IS 3 BP 315 EP 323 DI 10.1016/j.spl.2004.04.003 PG 9 WC Statistics & Probability SC Mathematics GA 836IA UT WOS:000222547900011 ER PT J AU Schramm, P Schellinger, PD Klotz, E Kallenberg, K Fiebach, JB Kulkens, S Heiland, S Knauth, M Sartor, K AF Schramm, P Schellinger, PD Klotz, E Kallenberg, K Fiebach, JB Kulkens, S Heiland, S Knauth, M Sartor, K TI Comparison of perfusion computed tomography and computed tomography angiography source images with perfusion-weighted imaging and diffusion-weighted Imaging in patients with acute stroke of less than 6 hours' duration SO STROKE LA English DT Article DE stroke, acute; perfusion; computed tomography; angiography; magnetic resonance imaging ID ACUTE HEMISPHERIC STROKE; ISCHEMIC-STROKE; CT ANGIOGRAPHY; THROMBOLYTIC THERAPY; CEREBRAL-ISCHEMIA; DYNAMIC CT; PREDICTION; BRAIN; DIAGNOSIS; ONSET AB Background and Purpose - We aimed to determine the diagnostic value of perfusion computed tomography (PCT) and CT angiography (CTA) including CTA source images (CTA-SI) in comparison with perfusion-weighted magnetic resonance imaging (MRI) (PWI) and diffusion-weighted MRI (DWI) in acute stroke <6 hours. Methods - Noncontrast-enhanced CT, PCT, CTA, stroke MRI, including PWI and DWI, and MR angiography (MRA), were performed in patients with symptoms of acute stroke lasting <6 hours. We analyzed ischemic lesion volumes on patients' arrival as shown on NECT, PCT, CTA-SI, DWI, and PWI ( Wilcoxon, Spearman, Bland - Altman) and compared them to the infarct extent as shown on day 5 NECT. Results - Twenty-two stroke patients underwent CT and MRI scanning within 6 hours. PCT time to peak (PCT-TTP) volumes did not differ from PWI-TTP ( P = 0.686 for patients who did not undergo thrombolysis/P = 0.328 for patients who underwent thrombolysis), nor did PCT cerebral blood volume (PCT-CBV) differ from PWI-CBV ( P = 0.893/ P = 0.169). CTA-SI volumes did not differ from DWI volumes ( P = 0.465/ P = 0.086). Lesion volumes measured in PCT maps significantly correlated with lesion volumes on PWI ( P = 0.0047, r = 1.0/ P = 0.0019, r = 0.897 for TTP; P = 0.0054, r = 0.983/P = 0.0026, r = 0.871 for CBV). Also, PCT-CBV lesion volumes significantly correlated with follow-up CT lesion volumes ( P = 0.0047, r = 1.0/ P = 0.0046, r = 0.819). Conclusions - In hyperacute stroke, the combination of PCT and CTA can render important diagnostic information regarding the infarct extent and the perfusion deficit. Lesions on PCT-TTP and PCT-CBV do not differ from lesions on PWI-TTP and PWI-CBV; lesions on CTA source images do not differ from lesions on DWI. The combination of noncontrast-enhanced CT ( NECT), perfusion CT ( PCT), and CT angiography ( CTA) can render additional information within <15 minutes and may help in therapeutic decision-making if PWI and DWI are not available or cannot be performed on specific patients. C1 Univ Heidelberg, Sch Med, Dept Neuroradiol, D-69120 Heidelberg, Germany. Univ Heidelberg, Sch Med, Dept Neurol, D-69120 Heidelberg, Germany. NINDS, NIH, Bethesda, MD 20892 USA. Siemens Med Solut, Forchheim, Germany. Univ Gottingen, Sch Med, Dept Neuroradiol, D-3400 Gottingen, Germany. RP Schramm, P (reprint author), Univ Heidelberg, Sch Med, Dept Neuroradiol, Neuenheimer Feld 400, D-69120 Heidelberg, Germany. EM peter_schramm@med.uni-heidelberg.de OI Fiebach, Jochen B./0000-0002-7936-6958 NR 19 TC 185 Z9 194 U1 0 U2 5 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 2004 VL 35 IS 7 BP 1652 EP 1657 DI 10.1161/01.STR.0000131271.54098.22 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 832HE UT WOS:000222257300025 PM 15155964 ER PT J AU Ando, H Zhou, J Macova, M Imboden, H Saavedra, JM AF Ando, H Zhou, J Macova, M Imboden, H Saavedra, JM TI Angiotensin II AT(1) receptor blockade reverses pathological hypertrophy and inflammation in brain microvessels of spontaneously hypertensive rats SO STROKE LA English DT Article DE cerebral arteries; inflammation; intercellular adhesion molecule-1; middle cerebral artery; cerebrovascular disorders ID INTERCELLULAR-ADHESION MOLECULE-1; NITRIC-OXIDE SYNTHASE; ENDOTHELIAL-CELLS; PERIVASCULAR CELLS; ICAM-1 EXPRESSION; CEREBRAL-ISCHEMIA; TYPE-1 RECEPTOR; PATHOGENESIS; MACROPHAGES; ANTAGONISM AB Background and Purpose-The spontaneously hypertensive rat (SHR) is vulnerable to brain ischemia and stress and exhibits a chronically stimulated brain angiotensin II system, cerebrovascular hypertrophy, and inflammation. Pretreatment with angiotensin II type 1 (AT(1)) receptor antagonists protects from brain ischemia and from stress and prevents the development of stress-induced gastric ulcers in part by reducing inflammation in the gastric mucosa. We studied whether AT(1) receptor antagonists could exert antiinflammatory effects in the brain vasculature as a mechanism for their protective effects against ischemia. Methods-Ten-week-old SHR and normotensive Wistar-Kyoto male rats received the AT(1) receptor antagonist candesartan (0.3 mg/kg per day) or vehicle for 28 days via osmotic minipumps. We studied AT(1) receptors, intercellular adhesion molecule-1 (ICAM-1), endothelial nitric oxide synthase (eNOS), and number of macrophages by immunohistochemistry and Western blots. Results-We found increased endothelial AT(1) receptor expression of brain microvessels and middle cerebral artery of SHR. Brain AT(1) receptor inhibition reversed the pathological vascular hypertrophy, increased and normalized eNOS expression, and decreased ICAM-1 expression and the number of adherent and infiltrating macrophages in cerebral vessels of SHR. Conclusions-The antiinflammatory effects of AT(1) receptor antagonists may be an important mechanism in protecting against ischemia. C1 NIMH, Pharmacol Sect, Div Intramural Res Programs, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Bern, Inst Cell Biol, Bern, Switzerland. RP Saavedra, JM (reprint author), NIMH, Pharmacol Sect, Div Intramural Res Programs, NIH,Dept Hlth & Human Serv, 10 Ctr Dr,Bldg 10,Room 2D-57, Bethesda, MD 20892 USA. EM Saavedrj@intra.nimh.nih.gov NR 34 TC 99 Z9 104 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUL PY 2004 VL 35 IS 7 BP 1726 EP 1731 DI 10.1161/01.STR.0000129788.26346.18 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 832HE UT WOS:000222257300039 PM 15143297 ER PT J AU Wlodawer, A AF Wlodawer, A TI How to kill an enzyme - (In more ways than one) SO STRUCTURE LA English DT Editorial Material ID NEURONAL CEROID-LIPOFUSCINOSIS; CRYSTAL-STRUCTURE; CARBOXYL PROTEINASE; PEPTIDASE-I; COMPLEX; SEDOLISIN; FAMILY AB The crystal structures of a zymogen and two mutants of the serine-carboxyl protease kumamolisin beautifully describe the mode of inhibition and activation of the proenzyme, while reminding us that our understanding of the enzymatic mechanisms is far from complete. C1 NCI, Macromol Crystallog Lab, Prot Struct Sect, Frederick, MD 21702 USA. RP Wlodawer, A (reprint author), NCI, Macromol Crystallog Lab, Prot Struct Sect, Frederick, MD 21702 USA. NR 12 TC 4 Z9 4 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD JUL PY 2004 VL 12 IS 7 BP 1117 EP 1119 DI 10.1016/j.str.2004.06.009 PG 3 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 840NP UT WOS:000222866100001 PM 15242582 ER PT J AU Hickenbottom, SJ Kimmel, AR Londos, C Hurley, JH AF Hickenbottom, SJ Kimmel, AR Londos, C Hurley, JH TI Structure of a lipid droplet protein: The PAT family member TIP47 SO STRUCTURE LA English DT Article ID DIFFERENTIATION-RELATED PROTEIN; HORMONE-SENSITIVE LIPASE; HIGH-DENSITY-LIPOPROTEIN; A-MEDIATED LIPOLYSIS; PERILIPIN-A; CYTOPLASMIC DOMAIN; ALPHA-SYNUCLEIN; BINDING; EXPRESSION; STORAGE AB The perilipin/ADRP/TIP47 (PAT) proteins localize to the surface of intracellular neutral lipid droplets. Perilipin is essential for lipid storage and hormone regulated lipolysis in adipocytes, and perilipin null mice exhibit a dramatic reduction in adipocyte lipid stores. A significant fraction of the similar to200 amino acid N-terminal region of the PAT proteins consists of 11-mer helical repeats that are also found in apolipoproteins and other lipid-associated proteins. The C-terminal 60% of TIP47, a representative PAT protein, comprises a monomeric and independently folded unit. The crystal structure of the C-terminal portion of TIP47 was determined and refined at 2.8 Angstrom resolution. The structure consists of an alpha/beta domain of novel topology and a four-helix bundle resembling the LDL receptor binding domain of apolipoprotein E. The structure suggests an analogy between PAT proteins and apolipoproteins in which helical repeats interact with lipid while the ordered C-terminal region is involved in protein:protein interactions. C1 NIDDKD, Cellular & Dev Biol Lab, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIDDKD, Mol Biol Lab, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDKD, Cellular & Dev Biol Lab, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM hurley@helix.nih.gov NR 51 TC 110 Z9 113 U1 2 U2 8 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD JUL PY 2004 VL 12 IS 7 BP 1199 EP 1207 DI 10.1016/j.str.2004.04.021 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 840NP UT WOS:000222866100015 PM 15242596 ER PT J AU Tang, JR Stern-Nezer, S Liu, PC Matyakhina, L Riordan, M Luban, NLC Steinbach, PJ Kaler, SG AF Tang, JR Stern-Nezer, S Liu, PC Matyakhina, L Riordan, M Luban, NLC Steinbach, PJ Kaler, SG TI Mutation in the leucine-rich repeat C-flanking region of platelet glycoprotein Ib beta impairs assembly of von Willebrand factor receptor SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE genetic diseases; platelets; structural biology ID BERNARD-SOULIER-SYNDROME; IX-V COMPLEX; MISSENSE MUTATION; GIANT PLATELETS; TERMINAL DOMAIN; GPIB-BETA; PROTEIN; ALPHA; IDENTIFICATION; ABNORMALITIES AB We describe a syndrome of thrombocytopenia, bleeding episodes, congenital heart disease and facial dysmorphism in a newborn infant, and trace the cause to mutations on chromosome 22 that involve the gene for platelet glycoprotein lbbeta (GPlbbeta, Human Genome Organisation gene symbol GPIBB), a critical component of the von Willebrand factor (vWF) receptor. Fluorescence in situ hybridization in transformed lymphoblasts revealed hemizygous microdeletion of 22q11.2 containing the GP I BB locus. DNA sequencing revealed a C to T transition in the patient's remaining GP I BB allele, predicting a novel proline to serine substitution (Pro96Ser) in the carboxyterminal flanking domain of a leucine-rich repeat. We characterized the mutant GPIBB allele by expression in a cell line (CHOalphaIX) that stably expresses two other components of the vWF receptor, GPlbalpha and GPIX Flow cytometry and confocal imaging of transfected CHOalphaIX cells demonstrated that P96S GPlbbeta abrogates surface assembly of the complex, consistent with platelet flow cytometry studies in the patient. Based on sequence homology to the known crystal structures of two other leucine-rich repeat proteins, the human Nogo receptor and GPlbalpha, we propose a new structural model of GPlbbeta. The model refutes earlier assumptions about cysteine-cysteine interactions in the amino-terminal region of GPlbbeta, and predicts a hydrophobic patch the burial of which may contribute to proper conformation of the fully assembled vWF receptor complex. C1 NIH, Unit Pediat Genet, Lab Clin Genom, Bethesda, MD 20892 USA. NIH, Sect Endocrinol & Genet, Dev Endocrinol Branch, NICHHD, Bethesda, MD 20892 USA. NIH, Dept Lab Med, Bethesda, MD 20892 USA. NIH, Ctr Mol Modeling, Ctr Informat Technol, Bethesda, MD 20892 USA. George Washington Univ, Childrens Natl Med Ctr, Dept Lab Med, Sch Med, Washington, DC USA. George Washington Univ, Childrens Natl Med Ctr, Lab Hematol Oncol, Sch Med, Washington, DC USA. RP Kaler, SG (reprint author), NIH, Unit Pediat Genet, Lab Clin Genom, Bldg 10,Room 9S-261,10 Ctr Dr MSC 1834, Bethesda, MD 20892 USA. EM sgk@box-s.nih.gov NR 45 TC 10 Z9 10 U1 2 U2 3 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD JUL PY 2004 VL 92 IS 1 BP 75 EP 88 DI 10.1160/th-04-02-0071 PG 14 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 838KC UT WOS:000222711200011 PM 15213848 ER PT J AU Moreno, M Silva, EL Ramirez, LE Palacio, LG Rivera, D Arcos-Burgos, M AF Moreno, M Silva, EL Ramirez, LE Palacio, LG Rivera, D Arcos-Burgos, M TI Chagas' disease susceptibility/resistance: linkage disequilibrium analysis suggests epistasis between major histocompatibility complex and interleukin-10 SO TISSUE ANTIGENS LA English DT Article DE Chagas; genetics; HLA; IL-2; IL-2R beta; IL-4; IL-10; interleukins; linkage disequilibrium; MALD; MHC; NRAMP1; Trypanosoma cruzi ID TRYPANOSOMA-CRUZI INFECTION; HLA ANTIGENS; TISSUE PARASITISM; CARDIOMYOPATHY; POLYMORPHISMS; POPULATIONS; GAMMA; HEART; CHILE; BLOOD AB Association between the major histocompatibility complex (MHC) and the susceptibility/resistance to acquire Chagas' disease has been largely demonstrated. To study the role of candidate genes in this susceptibility/resistance to Chagas, we designed a population-genetic-based case-control approach (chagasic n = 104 and controls n = 60) and tested the presence of genotype and linkage disequilibrium on microsatellite loci establishing specific landmarks for the MHC, interleukin (IL)-2, IL-2Rbeta chain, IL-4, IL-10, and natural resistance-associated mactophage protein 1 (NRAMP1). After demonstrating no genetic stratification among cases and controls (F-st were not different from 0), we found significant allelic differences among chagasic patients and controls at microsatellite locus D6S291 (MHC) and at the microsatellite pointing out the IL-10. At the MHC, we found significant differences between patients and controls in Hardy-Weinberg equilibrium-expected genotype proportions. Additionally, MHC II-locus-inferred haplotypes in chagasic patients exhibited strong significant departures from the expected proportions predicted by the second Mendelian law. The linkage disequilibrium pattern at MHC involves a region of approximately 10 cM. These results replicate previous analyses and suggest that presence of epistasis between MHC with humoral systems, such as IL-10, could be underlying the susceptibility/resistance to Chagas' disease. C1 Univ Anioquia, Populat Genet Mutacarcinogenesis & Genet Epidemio, Inst Biol, Medellin, Colombia. Triangulo Mineiro, Sch Med, Uberlandia, MG, Brazil. RP Arcos-Burgos, M (reprint author), NHGRI, Med Genet Branch, NIH, 10 Ctr Dr,MSC 1852,Bldg 10,Room 10C107, Bethesda, MD 20892 USA. EM marcosbu@nhgri.nih.gov NR 27 TC 13 Z9 14 U1 0 U2 2 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD JUL PY 2004 VL 64 IS 1 BP 18 EP 24 DI 10.1111/j.1399-0039.2004.00260.x PG 7 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 828ND UT WOS:000221979100003 PM 15191519 ER PT J AU Tuli, R Nandi, S Li, WJ Tuli, S Huang, XX Manner, PA Laquerriere, P Noth, U Hall, DJ Tuan, RS AF Tuli, R Nandi, S Li, WJ Tuli, S Huang, XX Manner, PA Laquerriere, P Noth, U Hall, DJ Tuan, RS TI Human mesenchymal progenitor cell-based tissue engineering of a single-unit osteochondral construct SO TISSUE ENGINEERING LA English DT Article ID BONE MORPHOGENETIC PROTEIN-2; HUMAN TRABECULAR BONE; STEM-CELLS; CHONDROGENIC DIFFERENTIATION; BIODEGRADABLE POLYMER; ARTICULAR-CARTILAGE; MARROW; REPAIR; CHONDROCYTES; COMPOSITES AB A desirable strategy for articular cartilage repair is to surgically replace the damaged area with an in vitro-engineered osteochondral plug. We report here the development of a novel osteochondral construct using human trabecular bone-derived mesenchymal progenitor cells and a biodegradable poly-D,L-lactic acid scaffold. The cartilage layer was fabricated by press-coating a chondrifying high-density cell pellet onto the scaffold, which was then loaded with cells previously initiated to undergo osteogenesis. The composite was then cultured in a cocktail medium formulated to maintain both chondrogenesis and osteogenesis. Macroscopically, the construct consisted of a cartilage-like layer adherent to, and overlying, a dense bone-like component. RT-PCR, immunohistochemistry, and histology revealed hyaline-like cartilage and bone with an interface resembling the native osteochondral junction. All parameters, including mechanical properties, improved with increased culture time. The single-cell source nature of the construct, which minimizes handling while maximizing biocompatibility, suggests applicability for articular cartilage repair. C1 NIAMSD, Cartilage Biol & Orthoped Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Grad Program Cell & Tissue Engn, Philadelphia, PA USA. George Washington Univ, Med Ctr, Dept Orthoped Surg, Washington, DC 20037 USA. NIH, Div Bioengn & Phys Sci, Off Res Serv, Bethesda, MD 20892 USA. Univ Wurzburg, Dept Orthoped Surg, Wurzburg, Germany. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthoped Branch, NIH, US Dept HHS, Bldg 50,Room 1503,50 South Dr,MSC 8022, Bethesda, MD 20892 USA. EM tuanr@mail.nih.gov RI Li, Wan-Ju/A-7002-2008; Laquerriere, Patrice/P-1025-2016 OI Laquerriere, Patrice/0000-0001-7637-9094 FU NIAMS NIH HHS [AR Z041113] NR 35 TC 77 Z9 81 U1 1 U2 11 PU MARY ANN LIEBERT INC PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1076-3279 J9 TISSUE ENG JI Tissue Eng. PD JUL-AUG PY 2004 VL 10 IS 7-8 BP 1169 EP 1179 DI 10.1089/ten.2004.10.1169 PG 11 WC Cell & Tissue Engineering SC Cell Biology GA 853TG UT WOS:000223851200020 PM 15363173 ER PT J AU Allen, DG Pearse, G Haseman, JK Maronpot, RR AF Allen, DG Pearse, G Haseman, JK Maronpot, RR TI Prediction of rodent carcinogenesis: An evaluation of prechronic liver lesions as forecasters of liver tumors in NTP carcinogenicity studies SO TOXICOLOGIC PATHOLOGY LA English DT Article DE rat; mouse; prechronic toxicity; liver tumors; carcinogenicity; bioassay ID TERM BIOASSAYS; IDENTIFICATION AB The National Toxicology Program (NTP) developed the chronic 2-year bioassay as a mechanism for predicting the carcinogenic potential of chemicals in humans. The cost and duration of these studies has limited their use to small numbers of selected chemicals. Many different short-term methods aimed at increasing predictive accuracy and the number of chemicals evaluated have been developed in attempts to successfully correlate their results with evidence of carcinogenicity ( or lack of carcinogenicity). Using NTP studies, the effectiveness of correlating prechronic liver lesions with liver cancer encompassing multiple studies using mice ( 83 compounds) and rats (87 compounds) was assessed. These lesions include hepatocellular necrosis, hepatocellular hypertrophy, hepatocellular cytomegaly, bile duct hyperplasia, and hepatocellular degeneration, along with increased liver weight. Our results indicate that pooling 3 of these prechronic data points ( hepatocellular necrosis, hepatocellular hypertrophy, and hepatocellular cytomegaly) can be very predictive of carcinogenicity in the 2-year study (p < 0.05). The inclusion of increased liver weight as an endpoint in the pool of data points increases the number of rodent liver carcinogens that are successfully predicted ( p < 0.05), but also results in the prediction of increased numbers of noncarcinogenic chemicals as carcinogens. The use of multiple prechronic study endpoints provides supplementary information that enhances the predictivity of identifying chemicals with carcinogenic potential. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Pathol Associates Inc, Raleigh, NC USA. Natl Toxicol Program, Res Triangle Pk, NC USA. RP Pearse, G (reprint author), NIEHS, POB 12233,MD B3-06,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM pearse@niehs.nih.gov NR 11 TC 56 Z9 56 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL-AUG PY 2004 VL 32 IS 4 BP 393 EP 401 DI 10.1080/01926230490440934 PG 9 WC Pathology; Toxicology SC Pathology; Toxicology GA 842YO UT WOS:000223040800004 PM 15307212 ER PT J AU Mozzachio, K Linder, K Dixon, D AF Mozzachio, K Linder, K Dixon, D TI Uterine smooth muscle tumors in potbellied pigs (Sus scrofa) resemble human fibroids: A potential animal model SO TOXICOLOGIC PATHOLOGY LA English DT Article DE uterus; leiomyoma; potbellied pig; fibroids; porcine; animal model ID REPRODUCTIVE-TRACT LEIOMYOMATA; RODENT MODEL; FREQUENCY; GENITALIA; ETIOLOGY AB Uterine leiomyomas, commonly termed fibroids, clinically affect approximately 25% of women of reproductive age in the United States, with a subclinical incidence as high as 77%. The pathogenesis of fibroid formation remains poorly understood, due in large part to the lack of a suitable animal model. This retrospective study characterizes the clinical, gross, and histopathologic features of similar, spontaneously occurring uterine tumors in potbellied pigs. Medical records available through a local Potbellied Pig Spay/Neuter Program, pig sanctuaries, and the Duchess Fund database were reviewed for evidence of reproductive disease or surgery. One-hundred and six female potbellied pigs were evaluated and uterine neoplasia was identified in 17 animals; tissues were available for 13 of these. Uterine leiomyoma was diagnosed in 11 of 13 cases, leiomyosarcoma in 1 of 13 cases, and undifferentiated sarcoma in 1 case. Pigs presented with clinical signs including abdominal distension or vaginal bleeding or were subclinical and identified during ovariohysterectomy. Tumors ranged from microscopic to 45 kg, were often multiple, and primarily involved the uterine horns. Hematoxylin and eosin and trichrome-stained sections were evaluated for morphological features of human and animal leiomyomas; immunohistochemistry to detect smooth muscle actin was also performed. The cellular pattern/morphology and variable degree of fibroplasia of the leiomyomas were similar to that reported for human fibroids. These results support further investigation of uterine leiomyomas in potbellied pigs as a potentially valuable animal model for studying human fibroids. C1 NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. N Carolina State Univ, Coll Vet Med, Dept Populat Hlth & Pathobiol, Raleigh, NC 27606 USA. RP Dixon, D (reprint author), NIEHS, Lab Expt Pathol, POB 12233,MDC2-09, Res Triangle Pk, NC 27709 USA. EM dixon@niehs.nih.gov NR 27 TC 21 Z9 22 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL-AUG PY 2004 VL 32 IS 4 BP 402 EP 407 DI 10.1080/01926230490440880 PG 6 WC Pathology; Toxicology SC Pathology; Toxicology GA 842YO UT WOS:000223040800005 PM 15307213 ER PT J AU Martin, KR Jokinen, MP Honeycutt, HP Quinn, A Kari, FW Barrett, JC French, JE AF Martin, KR Jokinen, MP Honeycutt, HP Quinn, A Kari, FW Barrett, JC French, JE TI Tumor spectrum in the p53 heterozygous zeta globin-promoted Tg.AC (v-Ha-ras) bitransgenic mouse model SO TOXICOLOGIC PATHOLOGY LA English DT Article DE p53 heterozygote; Tg.AC; v-Ha-ras; bitransgenic; zeta globin; benzo(a)pyrene ID TRANSGENIC MOUSE; MICE; CARCINOGENICITY; MAMMARY; CANCER; TUMORIGENESIS; MUTATIONS; PROLIFERATION; APOPTOSIS; LESIONS AB The use of a bitransgenic mouse model for cancer is an effective approach for studying the impact of specific carcinogens and the occurrence of tissue-specific lesions. We studied the novel p53 heterozygous zeta globin-promoted Tg. AC (v-Ha-ras) mouse model because these mice contain a carcinogen-inducible ras oncogene and one functional p53 tumor suppressor allele, both of which occur frequently in human cancers. Our aim was to characterize the short-term control and chemically induced tumor spectrum in this novel model. Mice were placed on basal semipurified diet containing 20% soy protein for 2 weeks prior to random allocation to groups. Subsequently, 15 male and 15 female mice were administered corn oil vehicle alone or containing benzo(a) pyrene (20 mg/kg body weight) via oral gavage 2 times per week for 10 weeks with subsequent observation for 18 weeks. Mice exhibited lesions characteristic of FVB/N, p53 heterozygous and Tg. AC mouse models. However, an array of unique, novel lesions were observed including uterine leiomyosarcomas, mammary gland carcinomas, mammary squamous cell carcinomas, and parotid salivary gland carcinomas suggesting tissue-specific interactions of the 2 genotypes. Thus, this bitransgenic model may provide further insight into the mechanistic interaction of 2 genes commonly mutated in neoplasia. C1 NIEHS, Lab Environm Carcinogenesis & Mutagenesis, Res Triangle Pk, NC 27709 USA. Pathol Associates Int, Durham, NC USA. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Martin, KR (reprint author), Penn State Univ, Nutr & Canc Lab, 126 Henderson Bldg S, University Pk, PA 16802 USA. EM krm12@psu.edu NR 33 TC 1 Z9 1 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL-AUG PY 2004 VL 32 IS 4 BP 418 EP 425 DI 10.1080/01926230490462129 PG 8 WC Pathology; Toxicology SC Pathology; Toxicology GA 842YO UT WOS:000223040800008 PM 15204965 ER PT J AU Lobenhofer, EK Cui, XG Bennett, L Cable, PL Merrick, BA Churchill, GA Afshari, CA AF Lobenhofer, EK Cui, XG Bennett, L Cable, PL Merrick, BA Churchill, GA Afshari, CA TI Exploration of low-dose estrogen effects: Identification of No Observed Transcriptional Effect Level (NOTEL) SO TOXICOLOGIC PATHOLOGY LA English DT Article DE estrogen; transcription; microarray; low dose; gene expression; dose response ID HUMAN-BREAST-CANCER; GENE-EXPRESSION PATTERNS; CDNA MICROARRAY; CELL-LINE; MCF-7; ANTIESTROGEN; PROLIFERATION; STIMULATION; ACTIVATION; CULTURE AB Identifying a minimal dose capable of eliciting a biological response is a fundamental issue in a number of scientific fields, including: drug development, signal transduction research, and environmental toxicology. Frequently, proliferation, viability, and other assays based on the cellular response to a treatment are used to assess the threshold dose for minimal activity. Here we propose a novel approach for identifying the effects of low dose treatments and pinpointing the threshold dose. Using microarrays, we examined the transcriptional response of a hormone responsive breast cancer cell line (MCF-7) stimulated with various concentrations of estrogen. Previous studies have focused on transcriptional responses to physiologically relevant concentrations of estrogen. However, relatively few studies have examined the transcriptional effects of concentrations below normal physiologic levels. These doses may not stimulate the expression of any genes or, alternatively, may regulate a different subset of genes that had not been previously characterized as estrogen responsive. We used gene expression profiling, coupled with a detailed analysis of replicates, to measure estrogen effects on many transcriptional targets and found that only physiologically relevant doses of estrogen (1 x 10(-10) M and higher) were capable of inducing a transcriptional response. This study demonstrates the utility of gene expression profiling as a means to identify concentrations that do not elicit a change in gene expression, or simply a No Observed Transcriptional Effect Level (NOTEL). The identification of a NOTEL for a given compound may be beneficial in several different scientific disciplines. For example, in the development of therapeutic drugs, a NOTEL could be used to identify doses of pharmaceutical compounds that are no longer effective at modulating the expression of biomarkers of efficacy. C1 NIEHS, Natl Ctr Toxicogenom, Res Triangle Pk, NC 27709 USA. NIEHS, Gene Regulat Grp, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. Jackson Lab, Bar Harbor, ME 04609 USA. RP Lobenhofer, EK (reprint author), Paradigm Genet Inc, POB 14528, Res Triangle Pk, NC 27709 USA. EM elobenhofer@paragen.com OI Cui, Xiangqin/0000-0003-0621-9313 NR 36 TC 33 Z9 33 U1 2 U2 6 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL-AUG PY 2004 VL 32 IS 4 BP 482 EP 492 DI 10.1080/01926230490483324 PG 11 WC Pathology; Toxicology SC Pathology; Toxicology GA 842YO UT WOS:000223040800014 PM 15223774 ER PT J AU Mueller, SO Simon, S Chae, K Metzler, M Korach, KS AF Mueller, SO Simon, S Chae, K Metzler, M Korach, KS TI Phytoestrogens and their human metabolites show distinct agonistic and antagonistic properties on estrogen receptor alpha (ER alpha) and ER beta in human cells SO TOXICOLOGICAL SCIENCES LA English DT Article DE ER alpha; ER beta; xenoestrogen; endocrine disruptors; Ishikawa; coactivator recruitment ID MAMMALIAN LIGNANS ENTEROLACTONE; BREAST-CANCER; ANTIESTROGENIC PROPERTIES; TRANSCRIPTIONAL ACTIVITY; COACTIVATOR RECRUITMENT; MAMMARY TUMORIGENESIS; GENISTEIN EXPOSURE; RESPONSE ELEMENTS; HORMONE-RECEPTOR; HUMAN HEALTH AB Phytoestrogens exert pleiotropic effects on cellular signaling and show some beneficial effects on estrogen-dependent diseases. However, due to activation/inhibition of the estrogen receptors ERalpha or ERbeta, these compounds may induce or inhibit estrogen action and, therefore, have the potential to disrupt estrogen signaling. We performed a comprehensive analysis and potency comparison of phytoestrogens and their human metabolites for ER binding, induction/suppression of ERalpha and ERbeta transactivation, and coactivator recruitment in human cells. The soy-derived genistein, coumestrol, and equol displayed a preference for transactivation of ERbeta compared to ERalpha and were 10- to 100-fold less potent than diethylstilbestrol. In contrast, zearalenone was the most potent phytoestrogen tested and activated preferentially ERalpha. All other phytoestrogens tested, including resveratrol and human metabolites of daidzein and enterolactone, were weak ER agonists. Interestingly, the daidzein metabolites 3',4',7-isoflavone and 4',6,7-isoflavone were superagonists on ERalpha and ERbeta. All phytoestrogens tested showed reduced potencies to activate ERalpha and ERbeta compared to diethylstilbestrol on the estrogen-responsive C3 promoter compared to a consensus estrogen response element indicating a degree of promoter dependency. Zearalenone and resveratrol were antagonistic on both ERalpha and ERbeta at high doses. The phytoestrogens enhanced preferentially recruitment of GRIP1 to ERalpha similar to 17beta-estradiol. In contrast, for ERbeta no distinct preference for one coactivator (GRIP1 or SRC-1) was apparent and the overall coactivator association was less pronounced than for ERalpha. Due to their abundance and (anti)-estrogenic potencies, the soy-derived isoflavones, coumestrol, resveratrol, and zearalenone would appear to have the potential for effectively functioning as endocrine disruptors. C1 Merck KGaA, Inst Toxicol, Mol Toxicol, D-64293 Darmstadt, Germany. NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. Univ Karlsruhe, Inst Food Chem & Toxicol, Karlsruhe, Germany. RP Mueller, SO (reprint author), Merck KGaA, Inst Toxicol, Mol Toxicol, Frankfurter Str 250, D-64293 Darmstadt, Germany. EM stefan.o.mueller@merck.de OI Korach, Kenneth/0000-0002-7765-418X NR 52 TC 304 Z9 315 U1 4 U2 37 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 2004 VL 80 IS 1 BP 14 EP 25 DI 10.1093/toxsci/kfh147 PG 12 WC Toxicology SC Toxicology GA 830IT UT WOS:000222116300003 PM 15084758 ER PT J AU Heinloth, AN Irwin, RD Boorman, GA Nettesheim, P Fannin, RD Sieber, SO Snell, ML Tucker, CJ Li, LP Travlos, GS Vansant, G Blackshear, PE Tennant, RW Cunningham, ML Paules, RS AF Heinloth, AN Irwin, RD Boorman, GA Nettesheim, P Fannin, RD Sieber, SO Snell, ML Tucker, CJ Li, LP Travlos, GS Vansant, G Blackshear, PE Tennant, RW Cunningham, ML Paules, RS TI Gene expression profiling of rat livers reveals indicators of potential adverse effects SO TOXICOLOGICAL SCIENCES LA English DT Article DE toxicogenomics; mitochondrial toxicity; hepatotoxicity; acetaminophen ID ACETAMINOPHEN HEPATOTOXICITY; PROTEIN-KINASE; GLUTATHIONE; INDUCTION; TOXICITY; INJURY; METALLOTHIONEIN; PHOSPHORYLATION; PROTECTION; PROTEOMICS AB This study tested the hypothesis that gene expression profiling can reveal indicators of subtle injury to the liver induced by a low dose of a substance that does not cause overt toxicity as defined by conventional criteria of toxicology (e.g., abnormal clinical chemistry and histopathology). For the purpose of this study we defined this low dose as subtoxic, i.e., a dose that elicits effects which are below the detection of conventional toxicological parameters. Acetaminophen (APAP) was selected as a model hepatotoxicant because (1) considerable information exists concerning the mechanism of APAP hepatotoxicity that can occur following high doses, (2) intoxication with APAP is the leading cause of emergency room visits involving acute liver failure within the United States, and (3) conventional clinical markers have poor predictive value. Rats treated with a single dose of 0, 50, 150, or 1500 mg/kg APAP were examined at 6, 24, or 48 h after exposure for conventional toxicological parameters and for gene expression alterations. Patterns of gene expression were found which indicated cellular energy loss as a consequence of APAP toxicity. Elements of these patterns were apparent even after exposure to subtoxic doses. With increasing dose, the magnitude of changes increased and additional members of the same biological pathways were differentially expressed. The energy loss suggested by gene expression changes was confirmed at the 1500 mg/kg dose exposure by measuring ATP levels. Only by ultrastructural examination could any indication of toxicity be identified after exposure to a subtoxic dose of APAP and that was occasional mitochondrial damage. In conclusion, this study provides evidence that supports the hypothesis that gene expression profiling may be a sensitive means of identifying indicators of potential adverse effects in the absence of the occurrence of overt toxicity. C1 NIEHS, Natl Ctr Toxicogenom, Res Triangle Pk, NC 27709 USA. NIEHS, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. Althea Technol Inc, San Diego, CA USA. Integrated Lab Syst Inc, Res Triangle Pk, NC USA. RP Paules, RS (reprint author), NIEHS, Natl Ctr Toxicogenom, 111 Alexander Dr,Mail Drop D2-03,POB 12233, Res Triangle Pk, NC 27709 USA. EM paules@niehs.nih.gov FU NIEHS NIH HHS [N01-ES-95446, 2-R44-ES10514-02] NR 36 TC 133 Z9 145 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 2004 VL 80 IS 1 BP 193 EP 202 DI 10.1093/toxsci/kfh145 PG 10 WC Toxicology SC Toxicology GA 830IT UT WOS:000222116300021 PM 15084756 ER PT J AU Rigden, DJ Mello, LV Galperin, MY AF Rigden, DJ Mello, LV Galperin, MY TI The PA14 domain, a conserved all-beta domain in bacterial toxins, enzymes, adhesins and signaling molecules SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Article ID POLYCYSTIC KIDNEY-DISEASE; GLUCOSIDASE GENE; ANTHRAX TOXIN; PROTEIN; ENCODES; CLONING; EXPRESSION; SEQUENCE; DATABASE; TRANSCRIPTION AB yIterative database searches starting from a domain insert sequence in bacterial beta-glucosidases reveals the presence of a conserved domain shared by a wide variety of bacterial and eukaryotic proteins. These include other glycosidases, glycosyltransferases, proteases, amidases, adhesins, and bacterial toxins such as anthrax protective antigen (PA). The domain also occurs in the mammalian protein fibrocystin, mutation of which leads to autosomal-recessive polycystic kidney and hepatic disease. The crystal structure of PA shows that this domain (named PA14 after its location in the PA(20) pro-peptide) has a beta-barrel architecture. A PA14 sequence alignment suggests a binding function, rather than a catalytic role, whereas the PA14 domain distribution is compatible with carbohydrate binding. C1 Univ Liverpool, Sch Biol Sci, Liverpool L69 7ZB, Merseyside, England. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EMBRAPA, Cenargen, Natl Ctr Genet Resources & Biotechnol, BR-70770900 Brasilia, DF, Brazil. RP Rigden, DJ (reprint author), Univ Liverpool, Sch Biol Sci, Crown St, Liverpool L69 7ZB, Merseyside, England. EM drigden@liverpool.ac.uk RI Galperin, Michael/B-5859-2013; OI Galperin, Michael/0000-0002-2265-5572; Rigden, Daniel/0000-0002-7565-8937 NR 31 TC 57 Z9 57 U1 1 U2 7 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD JUL PY 2004 VL 29 IS 7 BP 335 EP 339 DI 10.1016/j.tibs.2004.05.002 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 844GS UT WOS:000223146700002 PM 15236739 ER PT J AU Goldberg, TE Weinberger, DR AF Goldberg, TE Weinberger, DR TI Genes and the parsing of cognitive processes SO TRENDS IN COGNITIVE SCIENCES LA English DT Review ID DEFICIT HYPERACTIVITY DISORDER; CARD SORTING TEST; PREFRONTAL CORTEX; NEUROPHYSIOLOGICAL DEFICIT; SUSCEPTIBILITY LOCUS; ALZHEIMERS-DISEASE; 7-REPEAT ALLELE; WORKING-MEMORY; POLYMORPHISM; ASSOCIATION AB Now that the human genome has been sequenced there exists the possibility of identifying specific genes that affect human cognition. In this article, recent studies that have found associations between common gene variants and specific cognitive processes are reviewed. Several principles for evaluating this new field are also discussed. The interpretation of results is far from simple because a single gene can affect multiple processes, multiple genes can impact on a single process, and multiple cognitive processes are intercorrelated. In general, functional neuroimaging has been a more sensitive assay of cognitive processing than behavioral measures used alone, although there are important caveats regarding its use. Replicated findings so far involve associations between a COMT polymorphism and prefrontally-based executive functions and neurophysiology, and a BDNF polymorphism and medial-temporal-cortex based declarative memory processes. Implicit in this review is a concern that many of the cognitive paradigms used evolved for purposes well outside those described here. As such it may be necessary to view cognition in novel ways, based on constraints imposed by genomics and neurobiology, in order to increase the effect size of genotypic influences on cognition. C1 NIMH, IRP, GCAPP, Clin Brain Disorders Branch,NIH, Bethesda, MD 20892 USA. RP Goldberg, TE (reprint author), NIMH, IRP, GCAPP, Clin Brain Disorders Branch,NIH, Bethesda, MD 20892 USA. EM goldbert@intra.nimh.nih.gov NR 56 TC 224 Z9 231 U1 10 U2 22 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1364-6613 J9 TRENDS COGN SCI JI TRENDS COGN. SCI. PD JUL PY 2004 VL 8 IS 7 BP 325 EP 335 DI 10.1016/j.tics.2004.05.011 PG 11 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 840MJ UT WOS:000222862500010 PM 15242692 ER PT J AU Hardikar, AA AF Hardikar, AA TI Generating new pancreas from old SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID EMBRYONIC STEM-CELLS; REGENERATING RAT PANCREAS; PARTIAL PANCREATECTOMY; ISLET NEOGENESIS; BONE-MARROW; BETA-CELLS; 90-PERCENT PANCREATECTOMY; ENDOCRINE PANCREAS; DIABETES-MELLITUS; TRANSGENIC MICE AB Pancreas regeneration after tissue damage is a key response to pancreatic injury, involving pancreatic duct progenitor cells and intra-islet precursor cells. Surgical removal of the pancreas, duct obstruction by cellophane wrapping and bone marrow-derived stem cell transplantation act as inductive stimuli, leading to pancreas regeneration. The exact role of growth and differentiation factors regulating pancreatic P-cell mass remains unknown. Here, I will attempt to integrate recent findings and speculate on the factors that trigger this fascinating response, wherein the pancreas responds to a deficit in cell mass and undergoes new islet formation, leading to restoration of normal P-cell mass. I will also discuss recent advances in regenerating endocrine pancreatic cells, which could affect stem cell-based approaches to treating diabetes mellitus. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. RP Hardikar, AA (reprint author), NIDDKD, NIH, Bldg 50,Room 4128, Bethesda, MD 20892 USA. EM anand_hardikar@nih.gov NR 64 TC 22 Z9 22 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD JUL PY 2004 VL 15 IS 5 BP 198 EP 203 DI 10.1016/j.tem.2004.05.001 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 841VI UT WOS:000222959300004 PM 15223048 ER PT J AU Kondrashov, FA Koonin, EV AF Kondrashov, FA Koonin, EV TI A common framework for understanding the origin of genetic dominance and evolutionary fates of gene duplications SO TRENDS IN GENETICS LA English DT Article ID HUMAN-DISEASE GENES; HAPLOINSUFFICIENCY; DOSAGE; YEAST AB The dominance of wild-type alleles and the concomitant recessivity of deleterious mutant alleles might have evolved by natural selection or could be a by-product of the molecular and physiological mechanisms of gene action. We compared the properties of human haplosufficient genes, whose wild-type alleles are dominant over loss-of-function alleles, with haploinsufficient (recessive wild-type) genes, which produce an abnormal phenotype when heterozygous for a loss-of-function allele. The fraction of haplosufficient genes is the highest among the genes that encode enzymes, which is best compatible with the physiological theory. Haploinsufficient genes, on average, have more paralogs than haplosufficient genes, supporting the idea that gene dosage could be important for the initial fixation of duplications. Thus, haplo(in)sufficiency of a gene and its propensity for duplication might have a common evolutionary basis. C1 Univ Calif Davis, Sect Evolut & Ecol, Davis, CA 95616 USA. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. RP Kondrashov, FA (reprint author), Univ Calif Davis, Sect Evolut & Ecol, Davis, CA 95616 USA. EM kondrashov@ucdavis.edu RI Kondrashov, Fyodor Alexeevich/H-6331-2015 OI Kondrashov, Fyodor Alexeevich/0000-0001-8243-4694 NR 24 TC 112 Z9 112 U1 1 U2 16 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD JUL PY 2004 VL 20 IS 7 BP 287 EP 291 DI 10.1016/j.tig.2004.05.001 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 838JW UT WOS:000222710500005 PM 15219392 ER PT J AU Iyer, LM Aravind, L Coon, SL Klein, DC Koonin, EV AF Iyer, LM Aravind, L Coon, SL Klein, DC Koonin, EV TI Evolution of cell-cell signaling in animals: did late horizontal gene transfer from bacteria have a role? SO TRENDS IN GENETICS LA English DT Editorial Material ID SEROTONIN N-ACETYLTRANSFERASE; UNIVERSAL COMMON ANCESTOR; PHYLOGENETIC ANALYSES; ORGANELLAR GENES; NUCLEAR GENOMES; NERVOUS-SYSTEM; ORIGIN; PERSPECTIVE; PROKARYOTES; VERTEBRATES AB Cell-cell signaling is essential for the functioning of the nervous, neuroendocrine and immune systems. Crucial for these processes are small, rapidly diffusible messengers including catecholamines (epinephrine, norepinephrine and dopamine), indoles (serotonin and melatonin), histamine, acetylcholine and nitric oxide. In this article, we show that the evolutionary history of most genes encoding enzymes involved in the metabolism of these messengers is best described by scenarios that include horizontal gene transfer (HGT) from bacteria, with some transfers occurring after the divergence of animals from fungi. The acquisition of bacterial genes via HGT seems to have had the essential role of extending existing biochemical pathways to yield the messengers. The possible relatively late HGT of some signaling enzymes contrasts with the apparent acquisition of central metabolic pathway enzymes early in eukaryotic evolution from the proto-mitochondrial endosymbiont. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. Natl Inst Child Hlth & Dev, Sect Neuroendocrinol, Dev Neurobiol Lab, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov NR 38 TC 77 Z9 82 U1 1 U2 15 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD JUL PY 2004 VL 20 IS 7 BP 292 EP 299 DI 10.1016/j.tig2004.05.007 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 838JW UT WOS:000222710500007 PM 15219393 ER PT J AU Rugeles, MT Shearer, GM AF Rugeles, MT Shearer, GM TI Alloantigen recognition in utero: dual advantage for the fetus? SO TRENDS IN IMMUNOLOGY LA English DT Article ID HUMAN CHORIONIC-GONADOTROPIN; IMMUNODEFICIENCY-VIRUS TYPE-1; LEUKEMIA INHIBITORY FACTOR; ANTI-HIV ACTIVITY; CORD BLOOD; INFECTED INDIVIDUALS; T-HELPER; TRANSMISSION; CELLS; RIBONUCLEASE AB The relatively low frequency of vertical transmission of HIV-1 suggests that natural protective mechanisms block viral infection during gestation and at parturition. Findings of independent observations raise the possibility that HLA alloantigen recognition in utero between the maternal and fetal immune systems can activate or enhance soluble factors, such as leukemia inhibitory factor, human chorionic gonadotropin, stromal cell-derived factor-1 and ribonucleases (RNases), all of which have all been reported to inhibit HIV-1 replication. We propose that these factors, which can be activated by MHC allorecognition, promote survival of the fetus and neonate by reducing the incidence of vertical transmission of certain pathogenic viruses. It might be relevant that some of these factors are also important for embryo implantation and fetal development, and might therefore have a dual role at this crucial point in the survival of mammalian species. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. AA 1226 Univ Antioquia, Immunovirol Grp, Medellin, Colombia. RP Shearer, GM (reprint author), NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. EM gene_shearer@nih.gov NR 48 TC 13 Z9 14 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD JUL PY 2004 VL 25 IS 7 BP 348 EP 352 DI 10.1016/j.it.2004.04.007 PG 5 WC Immunology SC Immunology GA 838KY UT WOS:000222713400004 PM 15207501 ER PT J AU Piccirillo, CA Thornton, AM AF Piccirillo, CA Thornton, AM TI Cornerstone of peripheral tolerance: naturally occurring CD4(+)CD25(+) regulatory T cells SO TRENDS IN IMMUNOLOGY LA English DT Review ID IMMUNOLOGICAL SELF-TOLERANCE; VERSUS-HOST-DISEASE; CUTTING EDGE; IN-VITRO; DENDRITIC CELLS; SUPPRESSOR FUNCTION; AUTOIMMUNE-DISEASE; ANTIGEN 4; EX-VIVO; INDUCTION AB Immunological tolerance involves maintaining a state of unresponsiveness to autoantigens while generating protective immunity against invading pathogens. Recently, a surprising resurgence in research on regulatory T cells has been noted, and few areas have enthralled immunologists and generated so many ardent debates. Naturally occurring CD4(+)CD25(+) regulatory T cells have become the cornerstone T-cell population mediating peripheral tolerance to autoantigens, as well as regulation of T-cell responses directed at foreign antigens. However, several fundamental questions concerning CD4(+)CD25(+) T cells remain unanswered. Here, we propose to critically re-evaluate some recent conclusions and provide a consensus overview. C1 McGill Univ, Dept Microbiol & Immunol, Host Resistance Lab, Montreal, PQ H3A 2B4, Canada. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Piccirillo, CA (reprint author), McGill Univ, Dept Microbiol & Immunol, Host Resistance Lab, 3775 Univ St, Montreal, PQ H3A 2B4, Canada. EM ciro.piccirillo@mcgill.ca NR 66 TC 119 Z9 126 U1 2 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD JUL PY 2004 VL 25 IS 7 BP 374 EP 380 DI 10.1016/j.it.2004.04.009 PG 7 WC Immunology SC Immunology GA 838KY UT WOS:000222713400008 PM 15207505 ER PT J AU Xiao, RP Zhu, WZ Zheng, M Chakir, K Bond, R Lakatta, EG Cheng, HP AF Xiao, RP Zhu, WZ Zheng, M Chakir, K Bond, R Lakatta, EG Cheng, HP TI Subtype-specific beta-adrenoceptor signaling pathways in the heart and their potential clinical implications SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID RAT VENTRICULAR MYOCYTES; ADRENERGIC-RECEPTOR KINASE; CARDIAC G(S-ALPHA) OVEREXPRESSION; HUMAN BETA(1)-ADRENERGIC RECEPTOR; ACUTE MYOCARDIAL-INFARCTION; FACTOR GENE-EXPRESSION; TREATED GUINEA-PIGS; FAILING HUMAN HEART; BETA(2)-ADRENERGIC RECEPTOR; G-PROTEIN AB beta-Adrenoceptor stimulation serves as the most powerful means to increase cardiac output in response to stress or exercise. However, sustained beta(2)-adrenoceptor stimulation promotes pathological cardiac remodeling such as myocyte hypertrophy and apoptosis, thus contributing to heart failure. Coexisting cardiac beta-adrenoceptor subtypes, mainly beta(1)-adrenoceptors and beta(2)-adrenoceptors, activate different signaling cascades with beta(1)-adrenoceptors coupling to G(s) and beta(2)-adrenoceptors coupling to G(s) and G(i) pathways. As a result, sustained beta(2)-adrenoceptor stimulation protects cardiomyocytes against apoptosis via a G(1)-phosphatidylinositol 3-kinaseprotein kinase B pathway, whereas chronic beta(1)-adrenoceptor stimulation induces myocyte hypertrophy and apoptosis by protein kinase A-independent activation of calmodullin kinase II signaling. These advances in our understanding of beta-adrenoceptor subtype signaling identify the mechanisms that underlie the beneficial effects of beta-adrenoceptor antagonists and delineate the rationale for combining beta(1)-adrenoceptor blockade with beta(2)-adrenoceptor activation as a potential therapy for heart failure. C1 NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. Peking Univ, Minist Educ, Inst Cardiovasc Sci, Key Lab Mol & Cardiovasc Sci, Beijing, Peoples R China. Peking Univ, Minist Educ, Inst Mol Med, Key Lab Mol & Cardiovasc Sci, Beijing, Peoples R China. Univ Houston, Dept Pharmacol & Pharmaceut Sci, Houston, TX 77204 USA. Peking Univ, Coll Life Sci, Natl Lab Biomembrane & Membrane Biotechnol, Beijing, Peoples R China. RP Xiao, RP (reprint author), NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. EM xiaor@grc.nia.nih.gov NR 80 TC 95 Z9 98 U1 0 U2 7 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 2004 VL 25 IS 7 BP 358 EP 365 DI 10.1016/j.tips.2004.05.007 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 839NE UT WOS:000222791000008 PM 15219978 ER PT J AU Leapman, RD Kocsis, E Zhang, G Talbot, TL Laquerriere, P AF Leapman, RD Kocsis, E Zhang, G Talbot, TL Laquerriere, P TI Three-dimensional distributions of elements in biological samples by energy-filtered electron tomography SO ULTRAMICROSCOPY LA English DT Article DE electron tomography; energy-filtered imaging; core excitation; phosphorus distributions; ribosomes; three-dimensional reconstruction; hyperbaric freezing ID CRYOELECTRON TOMOGRAPHY; LOSS SPECTROSCOPY; MICROSCOPY; TRANSCRIPTION; VISUALIZATION; RESOLUTION; SPECIMENS; SECTIONS; ELEGANS; REGION AB By combining electron tomography with energy-filtered electron microscopy, we have shown the feasibility of determining the three-dimensional distributions of phosphorus in biological specimens. Thin sections of the nematode, Caenorhabditis elegans were prepared by high-pressure freezing,. freeze-substitution and plastic embedding. Images were recorded at energy losses above and below the phosphorus L-2,L-3 edge using a post-column imaging filter operating at a beam energy of 120 keV. The unstained specimens exhibited minimal contrast in bright-field images. After it was determined that the specimen was sufficiently thin to allow two-window ratio imaging of phosphorus, pairs of pre-edge and post-edge images were acquired in series over a tilt range of +/-55degrees at 5degrees increments for two orthogonal tilt axes. The projected phosphorus distributions were aligned using the pre-edge images that contained inelastic contrast from colloidal gold particles deposited on the specimen surface. A reconstruction and surface rendering of the phosphorus distribution clearly revealed features 15-20 nm in diameter, which were identified as ribosomes distributed along the stacked membranes of endoplasmic reticulum and in the cytoplasm. The sensitivity of the technique was estimated at <35 phosphorus atoms per voxel based on the known total ribosomal phosphorus content of approximately 7000 atoms. Although a high electron dose of approximately 10(7) e/nm(2) was required to record two-axis tilt series, specimens were sufficiently stable to allow image alignment and tomographic reconstruction. Published by Elsevier B.V. C1 NIH, ORS, Div Bioengn & Phys Sci, Bethesda, MD 20892 USA. RP Leapman, RD (reprint author), NIH, ORS, Div Bioengn & Phys Sci, Bldg 13,3N17, Bethesda, MD 20892 USA. EM leapman@helix.nih.gov RI Laquerriere, Patrice/P-1025-2016 OI Laquerriere, Patrice/0000-0001-7637-9094 NR 42 TC 55 Z9 57 U1 2 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3991 J9 ULTRAMICROSCOPY JI Ultramicroscopy PD JUL PY 2004 VL 100 IS 1-2 BP 115 EP 125 DI 10.1016/j.ultramic.2004.03.002 PG 11 WC Microscopy SC Microscopy GA 838MD UT WOS:000222716500010 PM 15219696 ER PT J AU Petricoin, EF Ornstein, DK Liotta, LA AF Petricoin, EF Ornstein, DK Liotta, LA TI Clinical proteomics: applications for prostate cancer biomarker discovery and detection SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article; Proceedings Paper CT Seminar on Chemoprevention of Prostate Cancer CY MAR 05, 2004 CL Reston, VA DE protein microarray; mass spectrometry; diagnostics; biomarkers; proteomics; pattern recognition ID MOLECULAR WEIGHT PROTEINS; MASS-SPECTROMETRY; OVARIAN-CANCER; SERUM; IDENTIFICATION; PATTERNS; ANTIGEN; DISEASE; TRIAL AB The science of proteomics comprises much more than simply generating lists of proteins that change in expression as a cause of or consequence of pathophysiology. The goal of proteomics should be to characterize the information flow through the intercellular protein circuitry that communicates with the extracellular microenvironment and then ultimately to the serum/plasma macroenvironment. Serum proteomic pattern diagnostics is a new type of proteomic concept in which patterns of ion signatures generated from high dimensional mass spectrometry data are used as diagnostic classifiers. This recent approach has exciting potential for clinical utility of diagnostic patterns because low molecular weight metabolites, peptides, and protein fragments may have higher accuracy than traditional biomarkers of cancer detection. Intriguingly, we now have discovered that this diagnostic information exists in a bound state, complexed with circulating highly abundant carrier proteins. These diagnostic fragments may one day be harvested by circulating nanoparticles, designed to absorb, enrich, and amplify the repertoire of diagnostic biomarkers generated-even at the critical, initial stages of carcinogenesis. (C) 2004 Elsevier Inc. All rights reserved. C1 US FDA, Ctr Biol Evaluat & Res, NCI Clin Proteom Program, Off Cell & Gene Therapies, Bethesda, MD 20892 USA. Univ Calif Irvine, Dept Urol, Irvine, CA USA. US FDA, Pathol Lab, Clin Proteom Program, Ctr Canc Res,NCI,NIH, Bethesda, MD 20892 USA. RP Petricoin, EF (reprint author), US FDA, Ctr Biol Evaluat & Res, NCI Clin Proteom Program, Off Cell & Gene Therapies, Bldg 29A,Room 2D12,8800 Rockville Pike, Bethesda, MD 20892 USA. EM petricoin@cber.fda.gov NR 33 TC 48 Z9 56 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD JUL-AUG PY 2004 VL 22 IS 4 BP 322 EP 328 DI 10.1016/j.urolonc.2004.04.011 PG 7 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 847MB UT WOS:000223395800009 PM 15283891 ER PT J AU Grizzle, WE Semmes, OJ Basler, J Izbicka, E Feng, ZD Kagan, J Adam, BL Troyer, D Srivastava, S Thornquist, M Zhang, Z Thompson, IM AF Grizzle, WE Semmes, OJ Basler, J Izbicka, E Feng, ZD Kagan, J Adam, BL Troyer, D Srivastava, S Thornquist, M Zhang, Z Thompson, IM TI The Early Detection Research Network surface-enhanced laser desorption and ionization prostate cancer detection study: a study in biomarker validation in genitourinary oncology SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article; Proceedings Paper CT Seminar on Chemoprevention of Prostate Cancer CY MAR 05, 2004 CL Reston, VA DE prostate cancer; biomarkers; proteomics; SELDI; cancer detection ID PROTEOMIC PATTERNS; MASS-SPECTROMETRY; REFERENCE RANGES; OVARIAN-CANCER; ANTIGEN; SERUM; IDENTIFICATION; MANAGEMENT; BENIGN; TRIAL AB Prostate-specific antigen (PSA) screening has led to a dramatic increase in prostate cancer detection with a concurrent stage migration. Although the test has revolutionized prostate cancer detection by identifying disease that is potentially curable in the majority of men, only 25% of men receiving test results of PSA >4 ng/ml will have prostate cancer and many men receiving a normal PSA will have disease, including high-grade disease. There is a need for improved biomarkers for detecting prostate cancer. One such method of cancer detection is surface-enhanced laser desorption and ionization (SELDI). The Early Detection Research Network (EDRN) validation study for SELDI for prostate cancer is described. In a three-stage study, the portability and reproducibility of the technique will be determined; the predictive algorithm will be refined in a multi-institutional case-control population; followed by ultimate validation in the context of a prospective trial with complete disease ascertainment. The unique aspect of the EDRN SELDI validation study is the novel use of two groups of cancer cases: those cases with higher-risk disease (Gleason greater than or equal to 7) and those cases with lower-risk disease (Gleason less than or equal to 6). This study will allow the first evaluation of a predictive algorithm that includes prognosis in disease screening. The EDRN SELDI prostate cancer biomarker validation study is a rigorous evaluation of a new detection method for prostate cancer. The methodologies used for this evaluation will prove useful for guiding future biomarker studies in this challenging disease. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Texas, Hlth Sci Ctr, Div Urol, San Antonio, TX 78285 USA. Univ Alabama, Birmingham, AL USA. Eastern Virginia Med Sch, Norfolk, VA 23501 USA. Inst Drug Dev, San Antonio, TX USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. Med Coll Georgia, Augusta, GA 30912 USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. RP Thompson, IM (reprint author), Univ Texas, Hlth Sci Ctr, Div Urol, 7703 Floyd Curl Dr, San Antonio, TX 78285 USA. EM thompsoni@uthscsa.edu FU NCI NIH HHS [U01 CA085067] NR 24 TC 29 Z9 43 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD JUL-AUG PY 2004 VL 22 IS 4 BP 337 EP 343 DI 10.1016/j.urolonc.2004.04.008 PG 7 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 847MB UT WOS:000223395800011 PM 15283893 ER PT J AU Kramer, BS AF Kramer, BS TI The science of early detection SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article; Proceedings Paper CT Seminar on Chemoprevention of Prostate Cancer CY MAR 05, 2004 CL Reston, VA DE cancer screening; selection bias; lead-time bias; length-biased sampling; overdiagnosis ID PROSTATE-CANCER; NEUROBLASTOMA; MORTALITY; IMPACT; TRENDS; RATES; TIME AB Most clinical judgment and clinical intuition derives from observations made on patients who suffer from a disease or medical condition. However, the target population for cancer screening is healthy people who would not seek out a health professional unless convinced to do so by advertising or public messages. Extrapolation of clinical observations to the target population for screening can be very misleading and even harmful. This is because powerful screening biases and confounding effects-such as selection bias, lead-time bias, length-bias sampling, and overdiagnosis-can mislead even the most astute clinician. This article will discuss those biases, review methods to avoid them, and provide useful resources to the clinician or health scientist. (C) 2004 Elsevier Inc. All rights reserved. C1 NIH, Dept Hlth & Human Serv, Off Dis Prevent, OD, Bethesda, MD 20892 USA. RP Kramer, BS (reprint author), NIH, Dept Hlth & Human Serv, Off Dis Prevent, OD, 6100 Execut Blvd,Room 2B03, Bethesda, MD 20892 USA. EM bk76p@nih.gov NR 16 TC 16 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 1078-1439 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD JUL-AUG PY 2004 VL 22 IS 4 BP 344 EP 347 DI 10.1016/j.urolonc.2003.04.001 PG 4 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 847MB UT WOS:000223395800012 PM 15283894 ER PT J AU Andriole, GL Reding, D Hayes, RB Prorok, PC Gohagan, JK AF Andriole, GL Reding, D Hayes, RB Prorok, PC Gohagan, JK CA PLCO Steering Comm TI The Prostate, Lung, Colon, and Ovarian (PLCO) cancer screening trial: status and promise SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article; Proceedings Paper CT Seminar on Chemoprevention of Prostate Cancer CY MAR 05, 2004 CL Reston, VA DE cancer screening; prevention; biorepository AB The Prostate, Lung, Cancer, and Ovarian Cancer Screening Trial is a randomized, multicenter, study evaluating whether screening for prostate, lung, colon, and ovarian cancer will reduce cancer-specific mortality. More than 155,000 participants have been identified and will be monitored through 2015. A biorepository of screened individuals and control participants has been created. Together, the data derived from the intervention and control arms and material in the biorepository provide a valuable resource to allow identification and testing of novel biomarkers for human disease. (C) 2004 Elsevier Inc. All rights reserved. C1 Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. Marshfield Med Res & Educ Fdn, Marshfield, WI USA. NCI, Bethesda, MD 20892 USA. RP Andriole, GL (reprint author), Washington Univ, Sch Med, Div Urol Surg, 4960 Childrens Pl,Campus Box 8242, St Louis, MO 63110 USA. EM andrioleg@wustl.edu OI Hayes, Richard/0000-0002-0918-661X NR 4 TC 27 Z9 27 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD JUL-AUG PY 2004 VL 22 IS 4 BP 358 EP 361 DI 10.1016/j.urolonc.2004.04.013 PG 4 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 847MB UT WOS:000223395800015 PM 15283897 ER PT J AU Croker, KS Ryan, A Morzenti, T Cave, L Maze-Gallman, T Ford, L AF Croker, KS Ryan, A Morzenti, T Cave, L Maze-Gallman, T Ford, L TI Delivering prostate cancer prevention messages to the public: how the National Cancer Institute (NCI) effectively spread the word about the Prostate Cancer Prevention Trial (PCPT) results SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article; Proceedings Paper CT Seminar on Chemoprevention of Prostate Cancer CY MAR 05, 2004 CL Reston, VA DE PCPT; public health message; media; diffusion of innovations theory; consumer information processing; finasteride; prostate cancer prevention AB The Prostate Cancer Prevention Trial was the first clinical trial to show that a direct intervention (5 mg of finasteride daily for 7 years) could reduce a man's risk of developing prostate cancer. Initial results also suggested that men taking finasteride had an increased risk of developing what appeared to be higher-grade disease (Gleason score 7-10). The National Cancer Institute has a congressional mandate to communicate health information to the public and has established methods to reach the public directly and to reach information intermediaries in the media, professional societies, and advocacy groups. The groundbreaking yet complicated results of the Prostate Cancer Prevention Trial were widely disseminated by National Cancer Institute using the social marketing and public-relations strategies and tactics detailed here. (C) 2004 Elsevier Inc. All rights reserved. C1 NCI, Div Canc Prevent, Bethesda, MD 20892 USA. NCI, Off Commun, Bethesda, MD 20892 USA. RP Croker, KS (reprint author), NCI, Div Canc Prevent, 6130 Execut Blvd,MSC 7315, Bethesda, MD 20892 USA. EM smigelk@mail.nih.gov NR 14 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD JUL-AUG PY 2004 VL 22 IS 4 BP 369 EP 376 DI 10.1016/j.urolonc.2004.04.015 PG 8 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 847MB UT WOS:000223395800017 PM 15283899 ER PT J AU Ou, W Xiong, Y Silver, J AF Ou, W Xiong, Y Silver, J TI Quantification of virus-envelope-mediated cell fusion using a tetracycline transcriptional transactivator: fusion does not correlate with syncytium formation SO VIROLOGY LA English DT Article DE cell fusion; quantitative fusion assay; tTA; luciferase; murine leukemia virus; syncytium ID LONG TERMINAL REPEAT; ECOTROPIC MURINE RETROVIRUSES; N-LINKED GLYCOSYLATION; GENE-EXPRESSION; CYTOPLASMIC DOMAIN; EUKARYOTIC CELLS; LEUKEMIA VIRUSES; GIANT-CELLS; R-PEPTIDE; RECEPTOR AB Cell fusion occurs in many cellular processes and viral infections. We developed a new, quantitative cell fusion assay based on the tetracycline-controlled transactivator (tTA)-induced expression of a luciferase reporter gene. The assay is objective, sensitive, linear over 2-3 orders of magnitude, amenable to microtiter-plate format, and generalizable to study fusion mediated by a variety of genes. Applied to HIV and MLV, cell fusion paralleled virus entry in terms of co-receptor requirements, need for post-translational processing of envelope, and complementation of SU mutations by soluble receptor-binding domain. However, biochemically measured fusion did not correlate with syncytia detected by standard light microscopy. When the assay indicated cell fusion occurred but overt syncytia were not observed, confocal microscopy using fluorescent protein markers showed that fusion was limited mainly to pairs of cells. Such nonprogressive cell fusion suggests that post-translational processing of envelope may be altered in heterokaryons co-expressing envelope and receptor. Published by Elsevier Inc. C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Silver, J (reprint author), NIAID, Mol Microbiol Lab, NIH, Bldg 4,Room 336,4 Ctr Dr,MSC 0460, Bethesda, MD 20892 USA. EM wou@niaid.nih.gov; jsilver@nih.gov OI Silver, Jonathan/0000-0001-9231-6368 NR 47 TC 12 Z9 12 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 0042-6822 J9 VIROLOGY JI Virology PD JUL 1 PY 2004 VL 324 IS 2 BP 263 EP 272 DI 10.1016/j.virol.2004.02.032 PG 10 WC Virology SC Virology GA 833YE UT WOS:000222376800003 PM 15207614 ER PT J AU Matzinger, P AF Matzinger, P TI The Danger model SO VOX SANGUINIS LA English DT Article C1 NIAID, Ghost Lab, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Matzinger, P (reprint author), NIAID, Ghost Lab, Cellular & Mol Immunol Lab, NIH, Bldg 4,Room 111, Bethesda, MD 20892 USA. EM pmatzinger@niaid.nih.gov NR 0 TC 5 Z9 5 U1 1 U2 9 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0042-9007 J9 VOX SANG JI Vox Sang. PD JUL PY 2004 VL 87 SU 2 BP 18 EP 18 DI 10.1111/j.1741-6892.2004.00508.x PG 1 WC Hematology SC Hematology GA 831RD UT WOS:000222212900007 ER PT J AU Hill, JM Finkel, T Quyyumi, AA AF Hill, JM Finkel, T Quyyumi, AA TI Endothelial progenitor cells and endothelial dysfunction SO VOX SANGUINIS LA English DT Article ID CORONARY-ARTERY DISEASE; BONE-MARROW; RISK-FACTORS; POSTNATAL NEOVASCULARIZATION; PRECURSOR CELLS; NITRIC-OXIDE; ATHEROSCLEROSIS; MOBILIZATION; POPULATION; KINETICS C1 NHLBI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. Emory Univ Hosp, Atlanta, GA 30322 USA. RP Hill, JM (reprint author), London Chest Hosp, Dept Cardiol, Bonner Rd,Bethnal Green, London E2 9JX, England. EM hillj@nhlbi.nih.gov NR 31 TC 8 Z9 8 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0042-9007 J9 VOX SANG JI Vox Sang. PD JUL PY 2004 VL 87 SU 2 BP 31 EP 37 DI 10.1111/j.1741-6892.2004.00451.x PG 7 WC Hematology SC Hematology GA 831RD UT WOS:000222212900012 PM 15209875 ER PT J AU Alter, HJ AF Alter, HJ TI Emerging, re-emerging and submerging infectious threats to the blood supply SO VOX SANGUINIS LA English DT Article ID GB-VIRUS-C; POSTTRANSFUSION HEPATITIS; MOLECULAR-CLONING; UNKNOWN ETIOLOGY; SEN VIRUS; NON-A; TRANSFUSION; AGENT; IDENTIFICATION; TRANSMISSION C1 NIH, Dept Transfus Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Alter, HJ (reprint author), NIH, Dept Transfus Med, Warren Grant Magnuson Clin Ctr, Bldg 10,Rm 1C-711,10 Ctr Dr, Bethesda, MD 20892 USA. EM halter@dtm.cc.nih.gov NR 14 TC 12 Z9 11 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0042-9007 J9 VOX SANG JI Vox Sang. PD JUL PY 2004 VL 87 SU 2 BP 56 EP 61 DI 10.1111/j.1741-6892.2004.00496.x PG 6 WC Hematology SC Hematology GA 831RD UT WOS:000222212900017 PM 15209880 ER PT J AU Stroncek, D AF Stroncek, D TI Granulocyte gene polymorphisms and mutations: effects on immune response and neutrophil proliferation SO VOX SANGUINIS LA English DT Article ID FC-GAMMA-RIIA; MOLECULAR-BASIS; RECEPTOR-III; CD177; NB1; EXPRESSION; ELASTASE C1 NIH, Warren Grant Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. RP Stroncek, D (reprint author), NIH, Warren Grant Magnuson Clin Ctr, Dept Transfus Med, 10 Ctr Dr,MSC 1184,Bldg 10,Room 1C711, Bethesda, MD 20892 USA. EM dstroncek@mail.cc.nih.gov NR 19 TC 2 Z9 2 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0042-9007 J9 VOX SANG JI Vox Sang. PD JUL PY 2004 VL 87 SU 2 BP 101 EP 104 DI 10.1111/j.1741-6892.2004.00463.x PG 4 WC Hematology SC Hematology GA 831RD UT WOS:000222212900028 PM 15209891 ER PT J AU Shibata, T Solo-Gabriele, HM Fleming, LE Elmir, S AF Shibata, T Solo-Gabriele, HM Fleming, LE Elmir, S TI Monitoring marine recreational water quality using multiple microbial indicators in an urban tropical environment SO WATER RESEARCH LA English DT Article DE indicator microbes; coliform; marine recreational water quality ID ESCHERICHIA-COLI; ENTEROCOCCI; STREAM AB The microbial water quality at two beaches, Hobie Beach and Crandon Beach, in Miami-Dade County, Florida, USA was measured using multiple microbial indicators for the purpose of evaluating correlations between microbes and for identifying possible sources of contamination. The indicator microbes chosen for this study (enterococci, Escherichia coli, fecal coliform, total coliform and C. perfringens) were evaluated through three different sampling efforts. These efforts included daily measurements at four locations during a wet season month and a dry season month, spatially intensive water sampling during low- and high-tide periods, and a sand sampling effort. Results indicated that concentrations did not vary in a consistent fashion between one indicator microbe and another. Daily water quality frequently exceeded guideline levels at Hobie Beach for all indicator microbes except for fecal coliform, which never exceeded the guideline. Except for total coliform, the concentrations of microbes did not change significantly between seasons in spite of the fact that the physical-chemical parameters (rainfall, temperature, pH, and salinity) changed significantly between the two monitoring periods. Spatially intense water sampling showed that the concentrations of microbes were significantly different with distance from the shoreline. The highest concentrations were observed at shoreline points and decreased at offshore points. Furthermore, the highest concentrations of indicator microbe concentrations were observed at high tide, when the wash zone area of the beach was submerged. Beach sands within the wash zone tested positive for all indicator microbes, thereby suggesting that this zone may serve as the source of indicator microbes. Ultimate sources of indicator microbes to this zone may include humans, animals, and possibly the survival and regrowth of indicator microbes due to the unique environmental conditions found within this zone. Overall, the results of this study indicated that the concentrations of indicator microbes do not necessarily correlate with one another. Exceedence of water quality guidelines, and thus the frequency of beach advisories, depends upon which indicator microbe is chosen. (C) 2004 Elsevier Ltd. All rights reserved. C1 Univ Miami, Dept Civil Environm & Architectural Engn, Coral Gables, FL 33124 USA. Univ Miami, NIEHS, Marine & Freshwater Biomed Sci Ctr, Rosenstiel Sch Marine & Atmospher Sci, Virginia Key, FL 33149 USA. Miami Dade Cty Hlth Dept, Miami, FL 33056 USA. RP Solo-Gabriele, HM (reprint author), Univ Miami, Dept Civil Environm & Architectural Engn, POB 248294, Coral Gables, FL 33124 USA. EM hmsolo@miami.edu FU NIEHS NIH HHS [P30 ES005705, P30ES05705, P50 ES012736, P50 ES012736-02] NR 29 TC 109 Z9 113 U1 4 U2 28 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0043-1354 J9 WATER RES JI Water Res. PD JUL PY 2004 VL 38 IS 13 BP 3119 EP 3131 DI 10.1016/j.watres.2004.04.044 PG 13 WC Engineering, Environmental; Environmental Sciences; Water Resources SC Engineering; Environmental Sciences & Ecology; Water Resources GA 842KL UT WOS:000223002900018 PM 15261551 ER PT J AU Dong, ZJ Wei, HM Sun, R Gao, B Tian, ZG AF Dong, Zhong-Jun Wei, Hai-Ming Sun, Rui Gao, Bin Tian, Zhi-Gang TI Isolation of murine hepatic lymphocytes using mechanical dissection for phenotypic and functional analysis of NK1.1(+) cells SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article AB AIM: To choose an appropriate methods for the isolation of hepatic lymphocytes between the mechanical dissection and the enzymatic digestion and investigate the effects of two methods on phenotype and function of hepatic lymphocytes. METHODS: Hepatic lymphocytes were isolated from untreated, poly (I:C)-stimulated or ConA-stimulated mice using the two methods, respectively. The cell yield per liver was evaluated by direct counting under microscope. Effects of digestive enzymes on the surface markers involved in hepatic lymphocytes were represented by relative change rate [(percentage of post-digestion - percentage of pre-digestion)/percentage of pre-digestion]. Phenotypic analyses of the subpopulations of hepatic lymphocytes and intracellular cytokines were detected by flow cytometry. The cytotoxicity of NK cells from wild C57BL/6 or poly (I:C)-stimulated C57BL/6 mice was analyzed with a 4-h (51)Cr release assay. RESULTS: NK1.1(+) cell markers, NK1.1 and DX5, were significantly down-expressed after enzymatic digestion and their relative change rates were about 28% and 32%, respectively. Compared with the enzymatic digestion, the cell yield isolated from unstimulated, poly (I:C)-treated or ConA-treated mice by mechanical dissection was not significantly decreased. Hepatic lymphocytes isolated by the mechanical dissection comprised more innate immune cells like NK, NKT and gamma delta cells in normal C57BL/6 mice. After poly (I:C) stimulation, hepatic NK cells rose to about 35%, while NKT cells simultaneously decreased. Following ConA injection, the number of hepatic NKT cells was remarkably reduced to 3.67%. Higher ratio of intracellular IFN-gamma(+)(68%) or TNF-alpha(+)(15%) NK1.1(+) cells from poly (I:C)-treated mice was obtained using mechanical dissection method than control mice. There was no difference in viability between the mechanical dissection and the enzymatic digestion, and hepatic lymphocytes obtained with the two methods had similar cytotoxicity against YAC-1 cells. CONCLUSION: There is no difference in the cell yield and viability of the hepatic lymphocyte isolated with the two methods. The mechanical dissection, but not the enzymatic digestion, may be suitable for the phenotypic analysis of hepatic NK1.1(+) cell. C1 [Sun, Rui; Tian, Zhi-Gang] Shandong Acad Med Sci, Shandong Canc Biotherapy Ctr, Jinan 250062, Shandong, Peoples R China. [Dong, Zhong-Jun; Wei, Hai-Ming; Sun, Rui; Tian, Zhi-Gang] Univ Sci & Technol China, Inst Immunol, Hefei 230027, Anhui, Peoples R China. [Gao, Bin] NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. RP Tian, ZG (reprint author), Univ Sci & Technol China, Sch Life Sci, 443 Huangshan Rd, Hefei 230027, Anhui, Peoples R China. EM ustctzg@yahoo.com.cn RI Tian, Zhigang/J-3512-2013 FU National Science Fund for Distinguished Young Scholars [30125038]; National Natural Science Foundation of China [30230340]; National High Technology Research and Development Program of China (863 Program) [2002AA216151]; Chinese Academy of Sciences [KSCX2-2-08] FX Supported by the National Science Fund for Distinguished Young Scholars, No. 30125038 and the Key Project of National Natural Science Foundation of China, No. 30230340 and the National High Technology Research and Development Program of China (863 Program), No. 2002AA216151 and Chinese Academy of Sciences, No. KSCX2-2-08 NR 35 TC 21 Z9 23 U1 1 U2 3 PU BAISHIDENG PUBL GRP CO LTD PI BEIJING PA RM 903, BLDG D, OCEAN INTERNATIONAL CTR, NO 62 DONGSIHUAN ZHONGLU, BEIJING, CHAOYANG DISTRICT 100025, PEOPLES R CHINA SN 1007-9327 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD JUL 1 PY 2004 VL 10 IS 13 BP 1928 EP 1933 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA V19UO UT WOS:000208097500019 PM 15222039 ER PT J AU Lim, M Jackson, TA Anfinrud, PA AF Lim, M Jackson, TA Anfinrud, PA TI Orientational distribution of CO before and after photolysis of MbCO and HbCO: A determination using time-resolved polarized mid-IR spectroscopy SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID VIBRATIONAL STARK SPECTROSCOPY; X-RAY-STRUCTURE; CARBON-MONOXIDE; HEME-PROTEINS; MOLECULAR-DYNAMICS; GEMINATE RECOMBINATION; LIGAND-BINDING; CONFORMATIONAL-CHANGES; INFRARED-SPECTROSCOPY; CRYSTAL-STRUCTURE AB The technique of time-resolved polarized mid-IR spectroscopy was used to probe the orientational distribution of carbon monoxide (CO) bound to and docked within horse myoglobin, sperm whale myoglobin, and human hemoglobin A in neutral pH solution at 283 K. An accurate determination of the orientation required that the experimentally measured polarization anisotropy be corrected for the effects of fractional photolysis in an optically thick sample. The experimental method measures the direction of the transition dipole, which is parallel to the CO bond axis when docked and nearly parallel when bound to the heme. The polarization anisotropy of bound CO is virtually the same for all protein systems investigated and is unchanging across its inhomogeneously broadened mid-IR absorption spectrum. From these results, it was concluded that the transition dipole moment of bound CO is oriented :570 from the heme plane normal. The polarized absorbance spectra of docked CO are similar for all protein systems investigated, but in stark contrast to bound CO, the polarization anisotropy is strongly correlated with vibrational frequency. The frequency-dependent anisotropy imposes severe constraints on the orientational probability distribution function of the transition dipole, which is well described as a dipole bathed in a Stark field whose out-of-plane motion is constrained by a simple double-well potential. The orientational and spatial constraints imposed on docked CO by the surrounding highly conserved amino acids serve to mediate ligand transport to and from the binding site and thereby control the rates and pathways for geminate ligand rebinding and ligand escape. C1 Pusan Natl Univ, Dept Chem, Pusan 609735, South Korea. Harvard Univ, Sch Med, MIT, Div Hlth Sci & Technol, Boston, MA 02115 USA. NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Anfinrud, PA (reprint author), Pusan Natl Univ, Dept Chem, Pusan 609735, South Korea. EM anfinrud@nih.gov NR 71 TC 50 Z9 50 U1 0 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUN 30 PY 2004 VL 126 IS 25 BP 7946 EP 7957 DI 10.1021/ja035475f PG 12 WC Chemistry, Multidisciplinary SC Chemistry GA 831SY UT WOS:000222217600052 PM 15212544 ER PT J AU Li, H Webb, SP Ivanic, J Jensen, JH AF Li, H Webb, SP Ivanic, J Jensen, JH TI Determinants of the relative reduction potentials of type-1 copper sites in proteins SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID PSEUDOMONAS-AERUGINOSA AZURIN; POLARIZABLE CONTINUUM MODEL; FOCK PERTURBATION-THEORY; EXTREME ACID STABILITY; X-RAY-ABSORPTION; REDOX POTENTIALS; CRYSTAL-STRUCTURE; BLUE PROTEINS; AXIAL LIGAND; SPECTROSCOPIC CHARACTERIZATION AB The relative Cu(2+)/Cu(+) reduction potentials of six type-1 copper sites (cucumber stellacyanin, P. aeruginosa azurin, poplar plastocyanin, C. cinereus laccase, T. ferrooxidans rusticyanin, and human ceruloplasmin), which lie in a reduction potential range from 260 mV to over 1000 mV, have been studied by quantum mechanical calculations. The range and relative orderings of the reduction potentials are reproduced very well compared to experimental values. The study suggests that the main structural determinants of the relative reduction potentials of the blue copper sites are located within 6 Angstrom of the Cu atoms. Further analysis suggests that the reduction potential differences of type-1 copper sites are caused by axial ligand interactions, hydrogen bonding to the S(Cys), and protein constraint on the inner sphere ligand orientations. The low reduction potential of cucumber stellacyanin is due mainly to a glutamine ligand at the axial position, rather than a methionine or a hydrophobic residue as in the other proteins. A stronger interaction with a backbone carbonyl group is a prime contributor to the lower reduction potential of P. aeruginosa azurin as compared to poplar plastocyanin, whereas the reverse is true for C. cinereus laccase and T. ferrooxidans rusticyanin. The lack of an axial methonine ligand also contributes significantly to the increased reduction potentials of C. cinereus laccase and human ceruloplasmin. However, in the case of C. cinereus laccase, this increase is attenuated by the presence of only one amide NH hydrogen bond to the S(Cys) rather than two in the other proteins. In human ceruloplasmin the reduction potential is further increased by the structural distortion of the equatorial ligand orientation. C1 Univ Iowa, Dept Chem, Iowa City, IA 52242 USA. NCI, Adv Biomed Comp Ctr, SAIC Frederick, Frederick, MD 21702 USA. RP Jensen, JH (reprint author), Univ Iowa, Dept Chem, Iowa City, IA 52242 USA. EM Jan-Jensen@uiowa.edu RI Jensen, Jan/G-4338-2010 OI Jensen, Jan/0000-0002-1465-1010 FU NCI NIH HHS [N01-CO-12400] NR 90 TC 99 Z9 100 U1 2 U2 17 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 30 PY 2004 VL 126 IS 25 BP 8010 EP 8019 DI 10.1021/ja049345y PG 10 WC Chemistry, Multidisciplinary SC Chemistry GA 831SY UT WOS:000222217600059 PM 15212551 ER PT J AU Heineman, TC Pesnicak, L Ali, MA Krogmann, T Krudwig, N Cohen, JI AF Heineman, TC Pesnicak, L Ali, MA Krogmann, T Krudwig, N Cohen, JI TI Varicella-zoster virus expressing HSV-2 glycoproteins B and D induces protection against HSV-2 challenge SO VACCINE LA English DT Article DE varicella-zoster virus; herpes simplex virus; glycoprotein B; glycoprotein D ID HERPES-SIMPLEX-VIRUS; RECURRENT GENITAL HERPES; PRIME-BOOST IMMUNIZATION; GUINEA-PIGS; DNA VACCINE; HUMAN-CELLS; INFECTION; MICE; TYPE-2; DISEASE AB A recombinant Oka (ROka) varicella-zoster virus (VZV) vaccine was constructed that expresses herpes simplex virus type 2 (HSV-2) glycoproteins B (gB) and D (gD). Guinea pigs received one of four inocula: (a) uninfected cells, (b) recombinant Oka VZV infected cells, (c) recombinant Oka VZV expressing HSV-2 gB/gD (ROka-gB2/gD2) infected cells, or (d) heat-inactivated ROka-gB2/gD2 infected cells. Only animals inoculated with ROka-gB2/gD2 developed high titers of neutralizing antibodies to HSV-2. Animals immunized with ROka-gB2/gD2 had reduced mortality after intravaginal challenge with HSV-2 compared with animals that received ROka or heat-in activated ROka-gB2/gD2. Animals immunized with ROka-gB2/gD2 had reduced lesions scores for the first 2 weeks after challenge, and reduced shedding of HSV-2 on Days 5 and 7 after challenge, compared to the other two groups. These data show that recombinant VZV expressing HSV-2 antigens must be infectious to offer significant protection against challenge with HSV-2, and that ROka-gB2/gD2 has promise as a candidate HSV-2 vaccine. (C) 2004 Elsevier Ltd. All rights reserved. C1 NIH, Med Virol Sect, Clin Invest Lab, Bethesda, MD 20892 USA. St Louis Univ, Sch Med, Div Infect Dis & Immunol, St Louis, MO 63103 USA. RP Cohen, JI (reprint author), NIH, Med Virol Sect, Clin Invest Lab, Bldg 10,Room 11N228,10 Ctr Dr MSC 1888, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov NR 38 TC 14 Z9 17 U1 2 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 30 PY 2004 VL 22 IS 20 BP 2558 EP 2565 DI 10.1016/j.vaccine.2003.02.010 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 834LQ UT WOS:000222413000008 PM 15193381 ER PT J AU Zhou, YH Purcell, RH Emerson, SU AF Zhou, YH Purcell, RH Emerson, SU TI An ELISA for putative neutralizing antibodies to hepatitis E virus detects antibodies to genotypes 1, 2, 3, and 4 SO VACCINE LA English DT Article DE hepatitis E virus; neutralizing anti-HEV; enzyme immunoassay ID ACUTE VIRAL-HEPATITIS; MONOCLONAL-ANTIBODIES; CAPSID PROTEIN; RECOMBINANT VACCINE; ENZYME-IMMUNOASSAY; INSECT CELLS; IDENTIFICATION; HEV; IMMUNODOMINANT; DISEASE AB Two monoclonal antibodies that neutralize hepatitis E virus (HEV) were used to identify a subregion of ORF2 capsid protein spanning amino acids 459-607 as the shortest peptide to form the corresponding neutralization epitopes. An enzyme-linked immunosorbent assay (ELISA) based on a purified recombinant protein covering amino acids 458-607 in ORF2 of the Sar-55 strain (genotype 1) efficiently detected anti-HEV in non-human primates which had been experimentally infected with the four known mammalian genotypes of HEV, respectively. However, anti-HEV in these animals did not react with a shorter ORF2 peptide spanning amino acids 475-607. The ELISA was highly specific and sensitive when human or non-human primate sera were tested in parallel with a previously established ELISA based on amino acids 112-607 in ORF2. The antibody titer to peptides 458-607 in two ORF2-vaccinated rhesus monkeys which had different HEV challenge outcomes differed at the time of challenge. Since the ELISA appeared to be specific for neutralizing antibodies against HEV, it should be especially useful for quantifying the humoral immune response in hepatitis E vaccine trials. Published by Elsevier Ltd. 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. RP Emerson, SU (reprint author), NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, 50 S Dr,MSC-8009, Bethesda, MD 20892 USA. EM semerson@niaid.nih.gov NR 38 TC 58 Z9 66 U1 1 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 30 PY 2004 VL 22 IS 20 BP 2578 EP 2585 DI 10.1016/j.vaccine.2003.12.017 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 834LQ UT WOS:000222413000010 PM 15193383 ER PT J AU Evans, TG Frey, S Israel, H Chiu, J El-Habib, R Gilbert, P Gaitan, A Montefiori, DC AF Evans, TG Frey, S Israel, H Chiu, J El-Habib, R Gilbert, P Gaitan, A Montefiori, DC CA HIV Vaccine Trials Network TI Long-term memory B-cell responses in recipients of candidate human immunodeficiency virus type 1 vaccines SO VACCINE LA English DT Article DE antibodies; vaccines; HIV-1 ID HIV-1/SIV CHIMERIC VIRUS; NEUTRALIZING ANTIBODIES; CANARYPOX VACCINE; PHASE-II; INFECTION; IMMUNOGENICITY; VOLUNTEERS; SAFETY; IMMUNIZATION; PROTECTION AB The efficacy and practical application of human immunodeficiency virus type I (HIV-1) vaccines may depend in part on the longevity of the immune responses generated, particularly those in the memory compartment. Candidate vaccines based on the HIV-1 envelope glycoproteins generate binding and neutralizing antibodies in humans but there have been no prior studies on the long-term persistence and recall of those responses. We evaluated six healthy, HIV non-infected adults who had received a combination of recombinant canarypox HIV-1 vaccines boosted by gp120 and who had achieved a high serum titer of neutralizing antibody to HIV-1 MN. These individuals were administered a gp160 boost 4-5 years after their last vaccination. Four volunteers had detectable binding and neutralizing antibodies at the time of boosting and all six volunteers exhibited a recall binding and neutralizing antibody response. The antibodies neutralized multiple T cell line-adapted (TCLA) strains of virus, including the vaccine strain, but not primary isolates. These results demonstrate that memory B-cell responses can last for many years following HIV-1 envelope glycoprotein immunization. In principle, similar long-term memory may be possible with improved immunogens that generate broadly cross-reactive neutralizing antibodies. (C) 2004 Elsevier Ltd. All rights reserved. C1 Univ Calif Davis, Div Infect Dis, San Diego, CA 92121 USA. St Louis Univ, Div Infect Dis, St Louis, MO USA. NIAID, Div Aids, Vaccine & Prevent Res Program, NIH, Bethesda, MD USA. Aventis Pasteur, Lyon, France. Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. RP Evans, TG (reprint author), Vical Inc, 10390 Pacific Ctr Court, San Diego, CA 92121 USA. EM tevans@vical.com FU NIAID NIH HHS [AI46703, AI46705, AI46725, AI48021] NR 26 TC 9 Z9 9 U1 1 U2 1 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 30 PY 2004 VL 22 IS 20 BP 2626 EP 2630 DI 10.1016/j.vaccine.2003.12.011 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 834LQ UT WOS:000222413000015 PM 15193388 ER PT J AU Stroncek, D Read, EJ AF Stroncek, D Read, EJ TI Cell processing: Current status and future directions SO YONSEI MEDICAL JOURNAL LA English DT Article; Proceedings Paper CT Yonsei Biomedical Symposium on Current Perspectives in Cell Based Therapy CY FEB 20-21, 2004 CL Yonsei Univ, Seoul, SOUTH KOREA HO Yonsei Univ DE cell processing; periphral blood progenitor cells; CD34+cells; dendritic cells; immune therapy ID TRANSPLANTATION; GENERATION; TRIAL; GVHD AB Specialized clinical cell processing began in the Department of Transfusion Medicine at the National Institutes of Health in 1984. The number and complexity of procedures performed increased quickly and in 1997 a highly specialized cell processing laboratory was opened. The laboratory has approximately 3,000 square feet, specialized air handing, a highly trained staff, and written laboratory procedures. In addition to standard laboratory equipment, the laboratory has numerous cell isolation instruments, flow cytometers, and automated cell counting instruments. The laboratory supports blood and bone marrow transplant protocols by isolating CD34+ stem cells, removing T lymphocytes, culturing lymphocytes to eliminate donor lymphocytes that are reactive with recipient alloantigens, and stimulating lymphocytes to induce Th2 type cells to reduce graft versus host disease. The laboratory has also been preparing dendritic cells to support protocols using immune therapy to treat cancer. In addition, pancreatic islet cells are isolated from organ donors for transplantation to treat type I diabetes mellitus. C1 NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Stroncek, D (reprint author), NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, 10 Ctr Dr,MSC-1184,Bldg 10,Room 1C711, Bethesda, MD 20892 USA. EM dstroncek@cc.nih.gov NR 11 TC 1 Z9 1 U1 0 U2 1 PU YONSEI UNIV COLLEGE MEDICINE PI SEOUL PA C/O KYUN0-IL IM, M.D., PH.D, SHINCHON DONG 134, SEODAEMOON KU, SEOUL 120-752, SOUTH KOREA SN 0513-5796 J9 YONSEI MED J JI Yonsei Med. J. PD JUN 30 PY 2004 VL 45 SU S BP 1 EP 4 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 838YF UT WOS:000222748700001 PM 15250041 ER PT J AU Panelli, MC Nagorsen, D Wang, E Monsurro, V Jin, P Katia, Z Smith, K Ngalame, Y Marincola, FM AF Panelli, MC Nagorsen, D Wang, E Monsurro, V Jin, P Katia, Z Smith, K Ngalame, Y Marincola, FM TI Mechanism of immune response during immunotherapy SO YONSEI MEDICAL JOURNAL LA English DT Article; Proceedings Paper CT Yonsei Biomedical Symposium on Current Perspectives in Cell Based Therapy CY FEB 20-21, 2004 CL Yonsei Univ, Seoul, SOUTH KOREA HO Yonsei Univ DE immunization; immunotherapy; interleukin-2; melanoma ID METASTATIC MELANOMA; INTERLEUKIN-2 AB Tumor immunology embraces an extensive array of biological phenomena that include interactions between neoplastic cells and the innate and adaptive immune response. Among immune cells, T cells have taken the center stage because they can be easily demonstrated to specifically recognize autologous cancer cells. However, their role is limited and other components of the immune response are likely necessary for the completion of cancer rejection. Metastatic melanoma and renal cell carcinoma (RCC) are malignancies strongly predisposed to regress in response to the systemic administration of high-dose interleukin (IL)-2. Several clinical Studies in extensive cohorts of patients have shown that this treatment can induce complete or partial clinical regressions of metastatic disease in 15 to 20% of patients who receive this treatment.(1-6) Although IL-2 has direct pluti-potent effects on cells with immune and inflammatory function, it remains unexplained which cell subset is implicated in mediating tumor regression. In a quest to characterize the mechanism of action of IL-2 during the course of immunotherapy, we have investigated the early changes in transcriptional profiles of circulating mononuclear cells and microenvironment of melanoma metastases following high dose IL-2 administration (720,000 IU/kg) by serial sampling of blood cells and tumors in the form of fine needle aspirate (FNA).(7) Furthermore, studies are currently on going to characterize the proteomic profiling of RCC patients undergoing the same treatment using protein arrays (manuscript in preparation). The predominant activation of genes related to inflammation and activation of mononuclear phagocytes lead us to further characterize this cell subset in the context of stimulation with a panel of soluble factors potentially present in the circulation and tumor microenvironment. C1 NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Panelli, MC (reprint author), NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bldg 10,R-1C711, Bethesda, MD 20892 USA. EM MPanelli@mail.cc.nih.gov NR 9 TC 0 Z9 0 U1 0 U2 3 PU YONSEI UNIV COLLEGE MEDICINE PI SEOUL PA C/O KYUN0-IL IM, M.D., PH.D, SHINCHON DONG 134, SEODAEMOON KU, SEOUL 120-752, SOUTH KOREA SN 0513-5796 J9 YONSEI MED J JI Yonsei Med. J. PD JUN 30 PY 2004 VL 45 SU S BP 15 EP 17 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 838YF UT WOS:000222748700004 PM 15250044 ER PT J AU Lim, JB Kwon, OH Kim, HS Kim, HO Choi, JR Provenzano, M Stroncek, D AF Lim, JB Kwon, OH Kim, HS Kim, HO Choi, JR Provenzano, M Stroncek, D TI Adoptive immunotherapy for cytomegalovirus (CMV) disease in immunocompromised patients SO YONSEI MEDICAL JOURNAL LA English DT Article; Proceedings Paper CT Yonsei Biomedical Symposium on Current Perspectives in Cell Based Therapy CY FEB 20-21, 2004 CL Yonsei Univ, Seoul, SOUTH KOREA HO Yonsei Univ DE cytomegalovirus; immunotherapy; cytotoxic T lymphocytes; CMV pp65 ID CYTOTOXIC T-LYMPHOCYTES; IMMEDIATE-EARLY PROTEIN; CELL EPITOPES; INFECTION; VIRUS; TRANSPLANTATION; PP65; IDENTIFICATION; ANTIGEN; VIVO AB Cytomegalovirus (CMV) reactivation in immune compromised patients such as those undergoing hematopoietic progenitor cell transplantation (HPCT) and those with HIV infections can cause severe morbidity and mortality despite treatment with appropriate antiviral agents. The recovery of Cytomegalovirus (CMV) specific cytotoxic T lymphocytes (CTL) plays an important role in the reconstitution of CMV specific immunity in immunocompromised patients. Recent studies have reported that CMV reactivation can be successfully treated by adoptive transfer of CMV-specific T cell clones from CMV seropositive donors expanded in vitro with CMV infected fibroblasts or lysates of CMV infected cells. Other studies have used immune dominant CMV proteins or peptides to expand CMV-specific cytotoxic T lymphocytes. This review describes the clinical manifestations of CMV disease in immunocompromised patients, recent advances of antiviral therapy for CMV disease, the principals of the induction of cellular immune response to CMV, and the clinical application of CMV immunotherapy. C1 NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Yonsei Univ, Coll Med, Dept Lab Med, Seoul, South Korea. RP Stroncek, D (reprint author), NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, 10 Ctr Dr,MSC-1184,Bldg 10,Room 1C711, Bethesda, MD 20892 USA. EM dstroncek@mail.cc.nih.gov NR 43 TC 5 Z9 6 U1 0 U2 1 PU YONSEI UNIV COLLEGE MEDICINE PI SEOUL PA C/O KYUN0-IL IM, M.D., PH.D, SHINCHON DONG 134, SEODAEMOON KU, SEOUL 120-752, SOUTH KOREA SN 0513-5796 J9 YONSEI MED J JI Yonsei Med. J. PD JUN 30 PY 2004 VL 45 SU S BP 18 EP 22 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 838YF UT WOS:000222748700005 PM 15250045 ER PT J AU Gallo, SA Clore, GM Louis, JA Bewley, CA Blumenthal, R AF Gallo, SA Clore, GM Louis, JA Bewley, CA Blumenthal, R TI Temperature-dependent intermediates in HIV-1 envelope glycoprotein-mediated fusion revealed by inhibitors that target N- and C-terminal helical regions of HIV-1 gp41 SO BIOCHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CELL-CELL FUSION; TRIMERIC COILED-COIL; TRANSMEMBRANE GLYCOPROTEIN; PEPTIDE INHIBITOR; SYNTHETIC PEPTIDE; ATOMIC-STRUCTURE; 6-HELIX BUNDLE; ENTRY; ECTODOMAIN AB Peptides derived from the N- (N-HR) and C- (C-HR) terminal heptad repeat regions adjacent to the fusion peptide and transmembrane domains, respectively, of human immunodeficiency virus (HIV)-1 gp41 inhibit HIV-1 viral envelope glycoproteins (Env)-mediated cell fusion specifically. The mechanism of HIV-1 Env-mediated cell fusion and its inhibition by agents that target the N- and C-HR regions was investigated. Priming experiments with Env-expressing cells indicate that the N-HR region but not the C-HR region is exposed by treatment with sCD4 at 31 degreesC, whereas both the N- and C-HR regions are exposed at 37 degreesC. C1 NCI, Lab Expt & Computat Biol, Frederick, MD 21702 USA. RP Blumenthal, R (reprint author), NCI, Lab Expt & Computat Biol, Frederick, MD 21702 USA. EM blumen@helix.nih.gov RI Clore, G. Marius/A-3511-2008; OI Clore, G. Marius/0000-0003-3809-1027; Gallo, Stephen/0000-0001-6043-2153 NR 30 TC 17 Z9 17 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 29 PY 2004 VL 43 IS 25 BP 8230 EP 8233 DI 10.1021/bi049957v PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 831TC UT WOS:000222218000027 PM 15209519 ER PT J AU Hultgren, A Rau, DC AF Hultgren, A Rau, DC TI Exclusion of alcohols from spermidine-DNA assemblies: Probing the physical basis of preferential hydration SO BIOCHEMISTRY LA English DT Article ID X-RAY-DIFFRACTION; OSMOTIC-STRESS; DOUBLE HELICES; INTERMOLECULAR FORCES; DIELECTRIC-CONSTANT; PROTEIN STABILITY; CONDENSATION; POLYAMINES; PRECIPITATION; TRANSITION AB The interaction of the alcohols 2-methyl-2,4-pentanediol (MPD) and 2-propanol and of glycerol with condensed spermidine(3+)-DNA arrays are investigated with direct force measurements using osmotic stress coupled with X-ray scattering. Thermodynamic forces between DNA helices are measured from the dependence of helical interaxial spacings on the osmotic pressure applied by poly(ethylene glycol) solutions in equilibrium with the DNA phase. The sensitivity of these forces to solute concentration can be transformed into a change in the number of excess or deficit solutes or waters in the DNA phase by applying the Gibbs-Duhem equation. The alcohols examined are excluded from the condensed DNA array and strongly affect the osmotic stress force curves. DNA is preferentially hydrated. MPD is significantly more excluded than 2-propanol. The exclusion of these alcohols, however, is not due to a steric repulsion since glycerol that is intermediate in size between MPD and 2-propanol does not observably affect DNA force curves. As the distance between DNA helices varies, the change in the number of excess waters is independent of alcohol concentration for each alcohol. These solutes are acting osmotically on the condensed array. The distance dependence of exclusion indicates that repulsive water structuring forces dominate the interaction of alcohols with the DNA surface. The exclusion measured for these condensed arrays can quantitatively account for the effect of these alcohols on the precipitation of DNA from dilute solution by spermidine(3+). C1 NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. RP Rau, DC (reprint author), NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. EM raud@mail.nih.gov NR 53 TC 37 Z9 37 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 29 PY 2004 VL 43 IS 25 BP 8272 EP 8280 DI 10.1021/bi049559s PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 831TC UT WOS:000222218000032 PM 15209524 ER PT J AU Campia, U Cardillo, C Panza, JA AF Campia, U Cardillo, C Panza, JA TI Ethnic differences in the vasoconstrictor activity of endogenous endothelin-1 in hypertensive patients SO CIRCULATION LA English DT Article DE hypertension; endothelin; endothelium ID RACIAL-DIFFERENCES; VASCULAR-TONE; ETA-RECEPTOR; VASODILATION; EXPRESSION; RESISTANCE; ARTERIES; BLOCKADE; DISEASE; HEALTH AB Background-The pathogenesis of essential hypertension in blacks may differ from that in whites. In particular, black patients usually present with a salt-sensitive, low-renin form, which in animal models is associated with enhanced activity of endothelin-1 (ET-1). This study aimed to assess whether ethnic differences exist in the vascular activity of ET-1 in normotensive and hypertensive blacks and whites. Methods and Results-Forearm blood flow (FBF) responses to intraarterial infusion of an ETA receptor blocker (BQ-123) were analyzed by plethysmography in 37 normotensive patients and 27 hypertensive patients according to race. BQ-123 did not affect FBF in normotensive subjects (P=0.30), whereas it produced significant vasodilation in hypertensive subjects (P<0.001). In normotensives, FBF response to BQ-123 was similar in white (n = 22) and black (n = 15) patients (P = 0.85). In contrast, in hypertensive patients, the vasodilator effect of ETA receptor blockade was significantly higher in blacks (n = 13) than in whites (n = 14) (P = 0.01). To rule out differences in smooth muscle reactivity, the effects of race on FBF responses to exogenous ET-1 were analyzed in the hypertensive subgroups. Endothelin-1 induced a significant vasoconstriction in both white (n = 7) and black patients (n = 5) (both P<0.001), without differences between them (P = 0.46). In 8 black hypertensives, the response to selective ETA blockade was not modified by nonselective blockade of ET-1 receptors by co-infusion of BQ-123 and BQ-788 (P = 0.66). Conclusions-Hypertensive blacks have enhanced ETA-dependent vasoconstrictor tone, probably related to increased production of ET-1. Given the negative vascular effects of ET-1, this abnormality may contribute to the pathogenesis of hypertension and its complications in black patients. C1 Washington Hosp Ctr, Washington, DC 20010 USA. NHLBI, Bethesda, MD 20892 USA. Univ Cattolica Sacro Cuore, Rome, Italy. RP Panza, JA (reprint author), Washington Hosp Ctr, 110 Irving St NW,Suite 2A 74, Washington, DC 20010 USA. EM julio.a.panza@medstar.net NR 29 TC 37 Z9 38 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 29 PY 2004 VL 109 IS 25 BP 3191 EP 3195 DI 10.1161/01.CIR.0000130590.24107.D3 PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 833GY UT WOS:000222326300022 PM 15148269 ER PT J AU Kantorow, M Hawse, JR Cowell, TL Benhamed, S Pizarro, GO Reddy, VN Hejtmancik, JF AF Kantorow, M Hawse, JR Cowell, TL Benhamed, S Pizarro, GO Reddy, VN Hejtmancik, JF TI Methionine sulfoxide reductase A is important for lens cell viability and resistance to oxidative stress SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HYDROGEN-PEROXIDE; EPITHELIAL-CELLS; ESCHERICHIA-COLI; GLUTATHIONE-PEROXIDASE; MOLECULAR CHAPERONE; NUCLEAR CATARACT; GENE-EXPRESSION; PROTEINS; CRYSTALLINS; DAMAGE AB Age-related cataract, an opacity of the eye lens, is the leading cause of visual impairment in the elderly, the etiology of which is related to oxidative stress damage. Oxidation of methionine to methionine sulfoxide is a major oxidative stress product that reaches levels as high as 60% in cataract while being essentially absent from clear lenses. Methionine oxidation results in loss of protein function that can be reversed through the action of methionine sulfoxide reductase A (MsrA), which is implicated in oxidative stress protection and is an essential regulator of longevity in species ranging from Escherichia coli to mice. To establish a role for MsrA in lens protection against oxidative stress, we have examined the levels and spatial expression patterns of MsrA in the human lens and have tested the ability of MsrA to protect lens cells directly against oxidative stress. In the present report, we establish that MsrA is present throughout the human lens, where it is likely to defend lens cells and their components against methionine oxidation. We demonstrate that overexpression of MsrA protects lens cells against oxidative stress damage, whereas silencing of the MsrA gene renders lens cells more sensitive to oxidative stress damage. We also provide evidence that MsrA is important for lens cell function in the absence of exogenous stress. Collectively, these data implicate MsrA as a key player in lens cell viability and resistance to oxidative stress, a major factor in the etiology of age-related cataract. C1 Florida Atlantic Univ, Boca Raton, FL 33431 USA. NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. Univ Michigan, WK Kellogg Eye Ctr, Dept Ophthalmol, Ann Arbor, MI 48105 USA. RP Kantorow, M (reprint author), Florida Atlantic Univ, 777 Glades Rd,POB 3091, Boca Raton, FL 33431 USA. EM mkantoro@fau.edu FU NEI NIH HHS [EY13022, R01 EY013022] NR 62 TC 108 Z9 111 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 29 PY 2004 VL 101 IS 26 BP 9654 EP 9659 DI 10.1073/pnas.0403532101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834IU UT WOS:000222405600026 PM 15199188 ER PT J AU Johnson, BR Nitta, RT Frock, RL Mounkes, L Barbie, DA Stewart, CL Harlow, E Kennedy, BK AF Johnson, BR Nitta, RT Frock, RL Mounkes, L Barbie, DA Stewart, CL Harlow, E Kennedy, BK TI A-type lamins regulate retinoblastoma protein function by promoting subnuclear localization and preventing proteasomal degradation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MUSCULAR-DYSTROPHY; NUCLEAR-ENVELOPE; GENE-PRODUCT; COMPLEX-FORMATION; MAMMALIAN-CELLS; IN-VITRO; PRB; RB; TRANSCRIPTION; EXPRESSION AB The retinoblastoma protein (pRB) is a critical regulator of cell proliferation and differentiation and an important tumor suppressor. In the G(1) phase of the cell cycle, pRB localizes to perinucleolar sites associated with lamin A/C intranuclear foci. Here, we examine pRB function in cells lacking lamin A/C, finding that pRB levels are dramatically decreased and that the remaining pRB is mislocalized. We demonstrate that A-type lamins protect pRB from proteasomal degradation. Both pRB levels and localization are restored upon reintroduction of lamin A. Lmna(-/-) cells resemble Rb-/- cells, exhibiting altered cell-cycle properties and reduced capacity to undergo cell-cycle arrest in response to DNA damage. These findings establish a functional link between a core nuclear structural component and an important cell-cycle regulator. They further raise the possibility that altered pRB function may be a contributing factor in dystrophic syndromes arising from LMNA mutation. C1 Univ Washington, Dept Biochem, Sch Med, Seattle, WA 98195 USA. Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. NCI, Frederick Canc Res & Dev Ctr, Lab Canc & Dev Biol, Frederick, MD 21702 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Kennedy, BK (reprint author), Univ Washington, Dept Biochem, Sch Med, Box 357350, Seattle, WA 98195 USA. EM bkenn@u.washington.edu OI Frock, Richard/0000-0001-6963-4931 NR 39 TC 184 Z9 187 U1 1 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 29 PY 2004 VL 101 IS 26 BP 9677 EP 9682 DI 10.1073/pnas.0403250101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834IU UT WOS:000222405600030 PM 15210943 ER PT J AU Liu, CG Calin, GA Meloon, B Gamliel, N Sevignani, C Ferracin, M Dumitru, CD Shimizu, M Zupo, S Dono, M Alder, H Bullrich, F Negrini, M Croce, CM AF Liu, CG Calin, GA Meloon, B Gamliel, N Sevignani, C Ferracin, M Dumitru, CD Shimizu, M Zupo, S Dono, M Alder, H Bullrich, F Negrini, M Croce, CM TI An oligonucleotide microchip for genome-wide microRNA profiling in human and mouse tissues SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GENES; IDENTIFICATION; RNA AB MicroRNAs (miRNAs) are a class of small noncoding RNA genes recently found to be abnormally expressed in several types of cancer. Here, we describe a recently developed methodology for miRNA gene expression profiling based on the development of a microchip containing oligonucleotides corresponding to 245 miRNAs from human and mouse genomes. We used these microarrays to obtain highly reproducible results that revealed tissue-specific miRNA expression signatures, data that were confirmed by assessment of expression by Northern blots, real-time RT-PCR, and literature search. The microchip oligolibrary can be expanded to include an increasing number of miRNAs discovered in various species and is useful for the analysis of normal and disease states. C1 Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. Compugen USA Inc, Jamesburg, NJ 08831 USA. Univ Ferrara, Dept Expt & Diagnost Med, I-44700 Ferrara, Italy. Univ Ferrara, Interdept Ctr Canc Res, I-44700 Ferrara, Italy. Natl Canc Inst, I-16123 Genoa, Italy. Osped Civile La Spezia, Lab Anal Clin, I-19126 La Spezia, Italy. RP Croce, CM (reprint author), Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. EM c-croce@mail.jci.tju.edu RI Negrini, Massimo/J-2377-2016; Ferracin, Manuela/K-2097-2016 OI Negrini, Massimo/0000-0002-0007-1920; Ferracin, Manuela/0000-0002-1595-6887 FU NCI NIH HHS [P01 CA081534, P01-CA81534] NR 18 TC 644 Z9 712 U1 5 U2 43 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 29 PY 2004 VL 101 IS 26 BP 9740 EP 9744 DI 10.1073/pnas.0403293101 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834IU UT WOS:000222405600041 PM 15210942 ER PT J AU Wilderman, PJ Sowa, NA FitzGerald, DJ FitzGerald, PC Gottesman, S Ochsner, UA Vasil, ML AF Wilderman, PJ Sowa, NA FitzGerald, DJ FitzGerald, PC Gottesman, S Ochsner, UA Vasil, ML TI Identification of tandem duplicate regulatory small RNAs in Pseudomonas aeruginosa involved in iron homeostasis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID FERRIC UPTAKE REGULATOR; ESCHERICHIA-COLI; SUPEROXIDE-DISMUTASE; OXIDATIVE STRESS; FLUORESCENS CHA0; ENCODING GENES; EXOTOXIN-A; HFQ; EXPRESSION; GENETICS AB In many bacteria, iron homeostasis is controlled primarily by the ferric uptake regulator (Fur), a transcriptional repressor. However, some genes, including those involved in iron storage, are positively regulated by Fur. A Fur-repressed regulatory small RNA (sRNA), RyhB, has been identified in Escherichia coli, and it has been demonstrated that negative regulation of genes by this sRNA is responsible for the positive regulation of some genes by Fur. No RyhB sequence homologs were found in Pseudomonas aeruginosa, despite the identification of genes positively regulated by its Fur homolog. A bioinformatics approach identified two tandem sRNAs in P. aeruginosa that were candidates for functional homologs of RyhB. These sRNAs (PrrF1 and PrrF2) are >95% identical to each other, and a functional Fur box precedes each. Their expression is induced under iron limitation. Deletion of both sRNAs is required to affect the iron-dependent regulation of an array of genes, including those involved in resistance to oxidative stress, iron storage, and intermediary metabolism. As in E. coli, induction of the PrrF sRNAs leads to the rapid loss of mRNAs for sodB (superoxide dismutase), sdh (succinate dehydrogenase), and a gene encoding a bacterioferritin. Thus, the PrrF sRNAs are the functional homologs of RyhB sRNA. At least one gene, bfrB, is positively regulated by Fur and Fe2+, even in the absence of the PrrF sRNAs. This work suggests that the role of sRNAs in bacterial iron homeostasis may be broad, and approaches similar to those described here may identify these sRNAs in other organisms. C1 Univ Colorado, Hlth Sci Ctr, Dept Microbiol, Denver, CO 80262 USA. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Genome Anal Unit, NIH, Bethesda, MD 20892 USA. RP FitzGerald, DJ (reprint author), Univ Colorado, Hlth Sci Ctr, Dept Microbiol, 4200 E 9th Ave, Denver, CO 80262 USA. EM djpf@helix.nih.gov; mike.vasil@uchsc.edu RI Ducey, Thomas/A-6493-2011; Luan, Gan/B-3211-2015 FU NIAID NIH HHS [AI15940, R01 AI015940, R37 AI015940] NR 43 TC 252 Z9 266 U1 5 U2 22 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 29 PY 2004 VL 101 IS 26 BP 9792 EP 9797 DI 10.1073/pnas.0403423101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834IU UT WOS:000222405600050 PM 15210934 ER PT J AU Buchholz, UJ Bukreyev, A Yang, LJ Lamirande, EW Murphy, BR Subbarao, K Collins, PL AF Buchholz, UJ Bukreyev, A Yang, LJ Lamirande, EW Murphy, BR Subbarao, K Collins, PL TI Contributions of the structural proteins of severe acute respiratory syndrome coronavirus to protective immunity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID FELINE INFECTIOUS PERITONITIS; PARAINFLUENZA VIRUS TYPE-3; SYNCYTIAL VIRUS; HEMAGGLUTININ-NEURAMINIDASE; BRONCHITIS-VIRUS; CYTOPLASMIC TAILS; ENVELOPE PROTEIN; REPLICATION; RESISTANCE; PARTICLES AB We investigated the contributions of the structural proteins of severe acute respiratory syndrome (SARS) coronavirus (CoV) to protective immunity by expressing them individually and in combinations from a recombinant parainfluenza virus (PIV) type 3 vector called BHPIV3. This vector provided direct immunization of the respiratory tract, the major site of SARS transmission, replication, and disease. The BHPIV3/SARS recombinants were evaluated for immunogenicity and protective efficacy in hamsters, which support a high level of pulmonary SARS-CoV replication. A single intranasal administration of BHPIV3 expressing the SARS-CoV spike protein (S) induced a high titer of SARS-CoV-neutralizing serum antibodies, only 2-fold less than that induced by SARS-CoV infection. The expression of S with the two other putative virion envelope proteins, the matrix M and small envelope E proteins, did not augment the neutralizing antibody response. In absence of 5, expression of M and E or the nucleocapsid protein N did not induce a detectable serum SARS-CoV-neutralizing antibody response. Immunization with BHPIV3 expressing S provided complete protection against SARS-CoV challenge in the lower respiratory tract and partial protection in the upper respiratory tract. This was augmented slightly by coexpression with M and E. Expression of M, E, or N in the absence of S did not confer detectable protection. These results identify S among the structural proteins as the only significant SARS-CoV neutralization antigen and protective antigen and show that a single mucosal immunization is highly protective in an experimental animal that supports efficient replication of SARS-CoV. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Buchholz, UJ (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM ubuchholz@niaid.nih.gov NR 31 TC 139 Z9 154 U1 1 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 29 PY 2004 VL 101 IS 26 BP 9804 EP 9809 DI 10.1073/pnas.0403492101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834IU UT WOS:000222405600052 PM 15210961 ER PT J AU Ishai, A Pessoa, L Bikle, PC Ungerleider, LG AF Ishai, A Pessoa, L Bikle, PC Ungerleider, LG TI Repetition suppression of faces is modulated by emotion SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE face perception; functional MRI ID EVENT-RELATED FMRI; HAPPY FACIAL EXPRESSIONS; INFERIOR TEMPORAL CORTEX; HUMAN NEURAL SYSTEM; HUMAN AMYGDALA; VISUAL-CORTEX; MACACA-FASCICULARIS; RECOGNITION MEMORY; WORKING-MEMORY; SHORT-TERM AB Single-unit recordings and functional brain imaging studies have shown reduced neural responses to repeated stimuli in the visual cortex. By using event-related functional MRI, we compared the activation evoked by repetitions of neutral and fearful faces,which were either task relevant (targets) or irrelevant (distracters). We found that within the inferior occipital gyri, lateral fusiform gyri, superior temporal sulci, amygdala, and the inferior frontal gyri/insula, targets evoked stronger responses than distracters and their repetition was associated with significantly reduced responses. Repetition suppression, as manifested by the difference in response amplitude between the first and third repetitions of a target, was stronger for fearful than neutral faces. Distracter faces, regardless of their repetition or valence, evoked negligible activation, indicating top-down attenuation of behaviorally irrelevant stimuli. Our findings demonstrate a three-way interaction between emotional valence, repetition, and task relevance and suggest that repetition suppression is influenced by high-level cognitive processes in the human brain. C1 Natl Inst Mental Hlth, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Ishai, A (reprint author), Univ Zurich, Brain Res Inst, Winterthurerstr 190, CH-8057 Zurich, Switzerland. EM ishai@hifo.unizh.ch NR 62 TC 178 Z9 182 U1 3 U2 16 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 29 PY 2004 VL 101 IS 26 BP 9827 EP 9832 DI 10.1073/pnas.0403559101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834IU UT WOS:000222405600056 PM 15210952 ER PT J AU Lopez-Lopez, C LeRoith, D Torres-Aleman, I AF Lopez-Lopez, C LeRoith, D Torres-Aleman, I TI Insulin-like growth factor I is required for vessel remodeling in the adult brain SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IGF-I; ENDOTHELIAL-CELLS; BINDING-PROTEINS; ANGIOGENESIS; EXERCISE; SERUM; HYPOXIA; CULTURE; HIF-1 AB Although vascular dysfunction is a major suspect in the etiology of several important neurodegenerative diseases, the signals involved in vessel homeostasis in the brain are still poorly understood. We have determined whether insulin-like growth factor I (IGF-I), a wide-spectrum growth factor with angiogenic actions, participates in vascular remodeling in the adult brain. IGF-I induces the growth of cultured brain endothelial cells through hypoxia-inducible factor 1alpha and vascular endothelial growth factor, a canonical angiogenic pathway. Furthermore, the systemic injection of IGF-I in adult mice increases brain vessel density. Physical exercise that stimulates widespread brain vessel growth in normal mice fails to do so in mice with low serum IGF-I. Brain injury that stimulates angiogenesis at the injury site also requires IGF-I to promote perilesion vessel growth, because blockade of IGF-I input by an anti-IGF-I abrogates vascular growth at the injury site. Thus, IGF-I participates in vessel remodeling in the adult brain. Low serum/brain IGF-I levels that are associated with old age and with several neurodegenerative diseases may be related to an increased risk of vascular dysfunction. C1 Consejo Super Invest Cientificas, Cajal Inst, Lab Neuroendocrinol, Madrid 28002, Spain. Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Torres-Aleman, I (reprint author), Consejo Super Invest Cientificas, Cajal Inst, Lab Neuroendocrinol, Madrid 28002, Spain. EM torres@cajal.csic.es NR 34 TC 179 Z9 194 U1 1 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 29 PY 2004 VL 101 IS 26 BP 9833 EP 9838 DI 10.1073/pnas.0400337101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834IU UT WOS:000222405600057 PM 15210967 ER PT J AU Brovelli, A Ding, MZ Ledberg, A Chen, YH Nakamura, R Bressler, SL AF Brovelli, A Ding, MZ Ledberg, A Chen, YH Nakamura, R Bressler, SL TI Beta oscillations in a large-scale sensorimotor cortical network: Directional influences revealed by Granger causality SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cerebral cortex; motor maintenance; parietal; local field potential; coherence ID FIELD POTENTIAL OSCILLATIONS; MULTIPLE TIME-SERIES; PRIMATE MOTOR CORTEX; VOLUNTARY MOVEMENTS; LINEAR-DEPENDENCE; BEHAVING MONKEYS; PARIETAL CORTEX; AWAKE MONKEYS; SYNCHRONIZATION; MUSCLE AB Previous studies have shown that synchronized beta frequency (14-30 Hz) oscillations in the primary motor cortex are involved in maintaining steady contractions of contralateral arm and hand muscles. However, little is known about the role of postcentral cortical areas in motor maintenance and their patterns of interaction with motor cortex. We investigated the functional relations of beta-synchronized neuronal assemblies in pre- and postcentral areas of two monkeys as they pressed a hand lever during the wait period of a visual discrimination task. By using power and coherence spectral analysis, we identified a beta-synchronized large-scale network linking pre- and postcentral areas. We then used Granger causality spectra to measure directional influences among recording sites. In both monkeys, strong Granger causal influences were observed from primary somatosensory cortex to both motor cortex and inferior posterior parietal cortex, with the latter area also exerting Granger causal influences on motor cortex. Granger causal influences from motor cortex to postcentral sites, however, were weak in one monkey and not observed in the other. These results are the first, to our knowledge, to demonstrate in awake monkeys that synchronized beta oscillations bind multiple sensorimotor areas into a large-scale network during motor maintenance behavior and carry Granger causal influences from primary somatosensory and inferior posterior parietal cortices to motor cortex. C1 Florida Atlantic Univ, Ctr Complex Syst & Brain Sci, Boca Raton, FL 33431 USA. Lab Neuropsychol, NIH, Bethesda, MD 20892 USA. RP Bressler, SL (reprint author), Florida Atlantic Univ, Ctr Complex Syst & Brain Sci, 777 Glades Rd, Boca Raton, FL 33431 USA. EM bressler@fau.edu RI Brovelli, Andrea/H-6036-2012; OI Brovelli, Andrea/0000-0002-5342-1330; Ledberg, Anders/0000-0003-3827-8721 FU NIMH NIH HHS [MH64204, MH42900, R01 MH042900, R01 MH064204, R37 MH042900] NR 47 TC 488 Z9 502 U1 6 U2 41 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 29 PY 2004 VL 101 IS 26 BP 9849 EP 9854 DI 10.1073/pnas.0308538101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834IU UT WOS:000222405600060 PM 15210971 ER PT J AU Gasior, M Witkin, JM Goldberg, SR Munzar, P AF Gasior, M Witkin, JM Goldberg, SR Munzar, P TI Chlormethiazole potentiates the discriminative stimulus effects of methamphetamine in rats SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE chlormethiazole; methamphetamine; drug-discrimination; (rat) ID RHESUS-MONKEYS; D-AMPHETAMINE; COCAINE; NEUROTOXICITY; ECSTASY; PHARMACOLOGY; DIZOCILPINE; AGONISTS; ABUSE; MDMA AB Chlormethiazole is a positive modulator of gamma-aminobutyric acid (GABA)(A) receptors used in the treatment of alcohol withdrawal seizures. It recently has been reported to attenuate seizures engendered by acute and repeated exposure to cocaine in mice and neurotoxic effects of methamphetamine in rats. The aim of the present study was to determine whether chlormethiazole could also attenuate the discriminative stimulus effects of methamphetarnine, a behavior predictive of the subjective effects of methamphetamine in humans. In Sprague-Dawley rats trained to discriminate 1.0 mg/kg methamphetamine [intraperitoneally (i.p.)] from saline under a fixed-ratio schedule of food delivery, the ability of chlormethiazole (i.p.) to (1) substitute for methamphetamine, (2) antagonize effects of methamphetamine and to (3) shift the methamphetamine dose-effect function was investigated. Chlormethiazole (18 and 30 mg/kg, i.p.) partially substituted for the discriminative stimulus effects of methamphetarnine when administered alone (maximum group average, 60% responses on the methamphetamine-appropriate lever). Chlormethiazole did not attenuate effects of methamphetamine when coadministered with the training dose of methamphetamine. Instead, chlormethiazole potentiated the discriminative stimulus effects of methamphetamine as demonstrated by a significant (about 2.5-fold) leftward and upward shift in the methamphetamine dose-effect function in the presence of chlormethiazole (10 mg/kg). In conclusion, the present findings suggest that there is a behavioral interaction between methamphetamine and chlormethiazole. The profile of this interaction is qualitatively different from that of methamphetamine and classical GABAergic drugs (i.e., benzodiazepines and barbiturates), suggesting the involvement of non-GABAergic mechanisms in the effects produced by chlormethiazole. (C) 2004 Elsevier B.V. All rights reserved. C1 NINDS, Epilepsy Res Sect, NIH, Bethesda, MD 20892 USA. Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Neurosci Discovery Res, Indianapolis, IN 46285 USA. Natl Inst Drug Abuse, Preclin Pharmacol Sect, Behav Neurosci Branch, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. Alexza MDC, Palo Alto, CA 94303 USA. RP Gasior, M (reprint author), NINDS, Epilepsy Res Sect, NIH, 10 Ctr Dr,MSC 1408,Bldg 10,Room 5N250, Bethesda, MD 20892 USA. EM gasiorm@ninds.nih.gov NR 36 TC 9 Z9 9 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD JUN 28 PY 2004 VL 494 IS 2-3 BP 183 EP 189 DI 10.1016/j.ejphar.2004.05.011 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 834GC UT WOS:000222398600013 PM 15212973 ER PT J AU Kirke, PN Mills, JI Molloy, AM Brody, LC O'Leary, VB Daly, L Murray, S Conley, M Mayne, PD Smith, O Scott, JM AF Kirke, PN Mills, JI Molloy, AM Brody, LC O'Leary, VB Daly, L Murray, S Conley, M Mayne, PD Smith, O Scott, JM TI Impact of the MHFR C677T polymorphism on risk of neural tube defects: case-control study SO BRITISH MEDICAL JOURNAL LA English DT Article ID 5,10-METHYLENETETRAHYDROFOLATE REDUCTASE; HOMOCYSTEINE C1 Hlth Res Board, Child Hlth Epidemiol Div, Dublin 2, Ireland. NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Epidemiol Sect, Bethesda, MD 20892 USA. Univ Ireland Trinity Coll, St James Hosp, Dept Clin Med, Dublin 8, Ireland. NHGRI, Mol Pathogenesis Sect, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Univ Dublin Trinity Coll, Dept Biochem, Dublin 2, Ireland. Natl Univ Ireland Univ Coll Dublin, Dept Epidemiol & Publ Hlth Med, Dublin 2, Ireland. Childrens Univ Hosp, Dublin 1, Ireland. Natl Ctr Hereditary Coagulat Disorders, Dublin 8, Ireland. RP Kirke, PN (reprint author), Hlth Res Board, Child Hlth Epidemiol Div, Dublin 2, Ireland. EM pkirke@hrb.ie FU NICHD NIH HHS [N0IHD 23163] NR 5 TC 79 Z9 81 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD JUN 26 PY 2004 VL 328 IS 7455 BP 1535 EP 1536 DI 10.1136/bmj.38036.646030.EE PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 834DV UT WOS:000222392700019 PM 15155469 ER PT J AU Bukreyev, A Lamirande, EW Buchholz, UJ Vogel, LN Elkins, WR St Claire, M Murphy, BR Subbarao, K Collins, PL AF Bukreyev, A Lamirande, EW Buchholz, UJ Vogel, LN Elkins, WR St Claire, M Murphy, BR Subbarao, K Collins, PL TI Mucosal immunisation of African green monkeys (Cercopithecus aethiops) with an attenuated parainfluenza virus expressing the SARS coronavirus spike protein for the prevention of SARS SO LANCET LA English DT Article ID ACUTE RESPIRATORY SYNDROME; HEMAGGLUTININ-NEURAMINIDASE; FUSION GLYCOPROTEINS; TYPE-3 PIV3; IMMUNOGENICITY; REPLICATION; INFECTION; VACCINE; BOVINE; IDENTIFICATION AB Background The outbreak of severe acute respiratory syndrome (SARS) in 2002 was caused by a previously unknown coronavirus-SARS coronavirus (SARS-CoV). We have developed an experimental SARS vaccine for direct immunisation of the respiratory tract, the major site of SARS-coronavirus transmission and disease. Methods We expressed the complete SARS coronavirus envelope spike (S) protein from a recombinant attenuated parainfluenza virus (BHPIV3) that is being developed as a live attenuated, intranasal paediatric vaccine against human parainfluenza virus type 3 (HPIV3). We immunised eight African green monkeys, four with a single dose of BHPIV3/SARS-S and four with a control, BHPIV3/Ctrl, administered via the respiratory tract. A SARS-coronavirus challenge was given to all monkeys 28 days after immunisation. Findings Immunisation of animals with BHPIV3/SARS-S induced the production of SARS-coronavirus-neutralising serum antibodies, indicating that a systemic immune response resulted from mucosal immunisation. After challenge with SARS coronavirus, all monkeys in the control group shed SARS coronavirus, with shedding lasting 5-8 days. No viral shedding occurred in the group immunised with BHPIV3/SARS-S. Interpretation A vectored mucosal vaccine expressing the SARS-coronavirus S protein alone may be highly effective in a single-dose format for the prevention of SARS. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Bioqual, Rockville, MD 20850 USA. RP Bukreyev, A (reprint author), NIAID, Infect Dis Lab, NIH, Bldg 50,Room 6505, Bethesda, MD 20892 USA. EM AB176v@nih.gov NR 29 TC 155 Z9 168 U1 1 U2 5 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUN 26 PY 2004 VL 363 IS 9427 BP 2122 EP 2127 DI 10.1016/S0140-6736(04)16501-X PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 832LF UT WOS:000222268300008 PM 15220033 ER PT J AU Fruchart-Najib, J Bauge, E Niculescu, LS Pham, T Thomas, B Rommens, C Majd, Z Brewer, B Pennacchio, LA Fruchart, JC AF Fruchart-Najib, J Bauge, E Niculescu, LS Pham, T Thomas, B Rommens, C Majd, Z Brewer, B Pennacchio, LA Fruchart, JC TI Mechanism of triglyceride lowering in mice expressing human apolipoprotein A5 SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE apolipoprotein AV; apolipoprotein CIII; lipoprotein lipasc; VLDL clearance and postprandial hyperlipemia ID LIPOPROTEIN-LIPASE ACTIVITY; ACTIVATED RECEPTOR-ALPHA; LOW-DENSITY LIPOPROTEINS; CORONARY-ARTERY DISEASE; APOA5 GENE VARIANTS; RICH LIPOPROTEINS; C-III; AV GENE; PLASMA TRIGLYCERIDES; TRANSGENIC MICE AB Overexpression of human APOA5 in mice results in dramatically decreased plasma triglyceride levels. In this study we explored the mechanism underlying this hypotriglyceridemic effect. Initially we found that triglyceride turnover was faster in hAPOA5 transgenic mice compared to controls, and this strongly correlated with increased LPL activity in postheparin plasma. Furthermore, we show that in vitro recombinant apoAV interacts physically with lipoprotein lipase and significantly increased its activity. We show that both apoB and apoCIII are decreased in hAPOA5 transgenic mice indicating a decrease in VLDL number. To further investigate the mechanism of hAPOA5 in a hyperlipidemic background, we inter-crossed hAPOA5 and hAPOC-3 transgenic mice. We found a marked decrease in VLDL triglyceride and cholesterol, as well as apolipoprotein B and CIII levels. These data indicated that apoAV induces a decrease in VLDL size by activating lipolysis and an increase of VLDL clearance. In a postprandial state, the normal triglyceride response found in wild-type mice was significantly reduced in hAPOA5 transgenics. In addition, we demonstrated that in response to this fat load in hAPOA5 x hAPOC3 mice, apoAV, but not apoCIII, was redistributed from primarily HDL to VLDL. This shift of apoAV in VLDL appears to limit the increase of triglyceride by activating the lipoprotein lipase. (C) 2004 Elsevier Inc. All rights reserved. C1 Inst Pasteur, INSERM, UR 545, Dept Atherosclerose, F-59019 Lille, France. Univ Lille 2, F-59019 Lille, France. Genfit SA, F-59120 Loos, France. NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. Lawrence Berkeley Lab, Genome Sci Dept, Berkeley, CA 94720 USA. Lawrence Berkeley Lab, Joint Genome Inst, Berkeley, CA 94720 USA. Inst Cellular Biol N Simionescu, Bucharest, Romania. RP Fruchart-Najib, J (reprint author), Inst Pasteur, INSERM, UR 545, Dept Atherosclerose, Rue Pr Calmette BP 245, F-59019 Lille, France. EM jamila.fruchart@pasteur-lille.fr RI Niculescu, Loredan Stefan/F-2591-2010 OI Niculescu, Loredan Stefan/0000-0002-1394-9085 FU NHLBI NIH HHS [HL071954A, HL66681] NR 36 TC 150 Z9 161 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 25 PY 2004 VL 319 IS 2 BP 397 EP 404 DI 10.1016/j.bbrc.2004.05.003 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 829PS UT WOS:000222062700016 PM 15178420 ER PT J AU Kadas, J Weber, IT Bagossi, P Miklossy, G Boross, P Oroszlan, S Tozser, J AF Kadas, J Weber, IT Bagossi, P Miklossy, G Boross, P Oroszlan, S Tozser, J TI Narrow substrate specificity and sensitivity toward ligand-binding site mutations of human T-cell leukemia virus type 1 protease SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; DRUG-RESISTANT MUTANTS; ROUS-SARCOMA-VIRUS; HIV-1 PROTEASE; ESCHERICHIA-COLI; ANEMIA VIRUS; KINETIC CHARACTERIZATION; INHIBITOR COMPLEX; IN-VIVO; PROTEINASE AB Human T-cell leukemia virus type 1 (HTLV-1) is associated with a number of human diseases; therefore, its protease is a potential target for chemotherapy. To compare the specificity of HTLV-1 protease with that of human immunodeficiency virus type 1 (HIV-1) protease, oligopeptides representing naturally occurring cleavage sites in various retroviruses were tested. The number of hydrolyzed peptides as well as the specificity constants suggested a substantially broader specificity of the HIV protease. Amino acid residues of HTLV-1 protease substrate-binding sites were replaced by equivalent ones of HIV-1 protease. Most of the single and multiple mutants had altered specificity and a dramatically reduced folding and catalytic capability, suggesting that mutations are not well tolerated in HTLV-1 protease. The catalytically most efficient mutant was that with the flap residues of HIV-1 protease. The inhibition profile of the mutants was also determined for five inhibitors used in clinical practice and inhibitor analogs of HTLV-1 cleavage sites. Except for indinavir, the HIV-1 protease inhibitors did not inhibit wild type and most of the mutant HTLV-1 proteases. The wild type HTLV-1 protease was inhibited by the reduced peptide bond-containing substrate analogs, whereas the mutants showed various degrees of weakened binding capability. Most interesting, the enzyme with HIV-1-like residues in the flap region was the most sensitive to the HIV-1 protease inhibitors and least sensitive to the HTLV-1 protease inhibitors, indicating that the flap plays an important role in defining the specificity differences of retroviral proteases. C1 Univ Debrecen, Med & Hlth Sci Ctr, Dept Biochem & Mol Biol, Res Ctr Mol Med, H-4012 Debrecen, Hungary. Georgia State Univ, Dept Biol, Atlanta, GA 30303 USA. NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. RP Tozser, J (reprint author), Univ Debrecen, Med & Hlth Sci Ctr, Dept Biochem & Mol Biol, Res Ctr Mol Med, POB 6, H-4012 Debrecen, Hungary. EM tozser@indi.biochem.dote.hu RI Tozser, Jozsef/A-7840-2008; OI Tozser, Jozsef/0000-0003-0274-0056; Tozser, Jozsef/0000-0001-5076-8729 FU FIC NIH HHS [TW01001]; NIGMS NIH HHS [R01 GM062920, GM62920] NR 58 TC 34 Z9 37 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 25 PY 2004 VL 279 IS 26 BP 27148 EP 27157 DI 10.1074/jbc.M401868200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 830KH UT WOS:000222120400041 PM 15102858 ER PT J AU Jeromin, A Muralidhar, D Parameswaran, MN Roder, J Fairwell, T Scarlata, S Dowal, L Mustafi, SM Chary, KVR Sharma, Y AF Jeromin, A Muralidhar, D Parameswaran, MN Roder, J Fairwell, T Scarlata, S Dowal, L Mustafi, SM Chary, KVR Sharma, Y TI N-terminal myristoylation regulates calcium-induced conformational changes in neuronal calcium sensor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CA2+ SIGNAL-TRANSDUCTION; BINDING-PROTEINS; FREQUENIN; RECOVERIN; CELLS; SWITCH; CHROMAFFIN; EXPRESSION; FAMILY; VILIP AB Neuronal calcium sensor-1 (NCS-1), a Ca2+-binding protein, plays an important role in the modulation of neurotransmitter release and phosphatidylinositol signaling pathway. It is known that the physiological activity of NCS-1 is governed by its myristoylation. Here, we present the role of myristoylation of NSC-1 in governing Ca2+ binding and Ca2+-induced conformational changes in NCS-1 as compared with the role in the nonmyristoylated protein. The Ca-45 binding and isothermal titration calorimetric data show that myristoylation increases the degree of cooperativity; thus, the myristoylated NCS-1 binds Ca2+ more strongly ( with three Ca2+ binding sites) than the non-myristoylated one ( with two Ca2+ binding sites). Both forms of protein show different conformational features in far-UV CD when titrated with Ca2+. Large conformational changes were seen in the near-UV CD with more changes in the case of nonmyristoylated protein than the myristoylated one. Although the changes in the far-UV CD upon Ca2+ binding were not seen in E120Q mutant ( disabling EF-hand 3), the near-UV CD changes in conformation also were not influenced by this mutation. The difference in the binding affinity of myristoylated and non-myristoylated proteins to Ca2+ also was reflected by Trp fluorescence. Collisional quenching by iodide showed more inaccessibility of the fluorophore in the myristoylated protein. Mg2+-induced changes in near-UV CD are different from Ca2+-induced changes, indicating ion selectivity. 8-Anilino-1-naphthalene sulfonic acid binding data showed solvation of the myristoyl group in the presence of Ca2+, which could be attributed to the myristoyl-dependent conformational changes in NCS-1. These results suggest that myristoylation influences the protein conformation and Ca2+ binding, which might be crucial for its physiological functions. C1 Ctr Cellular & Mol Biol, Hyderabad 500007, Andhra Pradesh, India. Baylor Coll Med, Houston, TX 77030 USA. Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. NHLBI, NIH, Bethesda, MD 20892 USA. SUNY Stony Brook, Basic Hlth Sci Ctr, Dept Physiol & Biophys, Stony Brook, NY 11794 USA. Tata Inst Fundamental Res, Dept Chem Sci, Bombay 400005, Maharashtra, India. RP Sharma, Y (reprint author), Ctr Cellular & Mol Biol, Uppal Rd, Hyderabad 500007, Andhra Pradesh, India. EM yogendra@ccmb.res.in RI Roder, John/G-6468-2013 NR 39 TC 34 Z9 34 U1 0 U2 5 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 25 PY 2004 VL 279 IS 26 BP 27158 EP 27167 DI 10.1074/jbc.M312172200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 830KH UT WOS:000222120400042 PM 15102861 ER PT J AU Pai, HV Kommaddi, RP Chinta, SJ Mori, T Boyd, MR Ravindranath, V AF Pai, HV Kommaddi, RP Chinta, SJ Mori, T Boyd, MR Ravindranath, V TI A frameshift mutation and alternate splicing in human brain generate a functional form of the pseudogene cytochrome P4502D7 that demethylates codeine to morphine SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RAT-BRAIN; XENOBIOTIC METABOLISM; CONSTITUTIVE EXPRESSION; MULTIPLE FORMS; MONOOXYGENASE; SYSTEM; IDENTIFICATION; INDUCIBILITY; LOCALIZATION; ACTIVATION AB A frameshift mutation 138delT generates an open reading frame in the pseudogene, cytochrome P4502D7 (CYP2D7), and an alternate spliced functional transcript of CYP2D7 containing partial inclusion of intron 6 was identified in human brain but not in liver or kidney from the same individual. mRNA and protein of the brain variant CYP2D7 were detected in 6 of 12 human autopsy brains. Genotyping revealed the presence of the frameshift mutation 138delT only in those human subjects who expressed the brain variant CYP2D7. Genomic DNA analysis in normal volunteers revealed the presence of functional CYP2D7 in 4 of 8 individuals. In liver, the major organ involved in drug metabolism, a minor metabolic pathway mediated by CYP2D6 metabolizes codeine (pro-drug) to morphine ( active drug), whereas norcodeine is the major metabolite. In contrast, when expressed in Neuro2a cells, brain variant CYP2D7 metabolized codeine to morphine with greater efficiency compared with the corresponding activity in cells expressing CYP2D6. Morphine binds to mu-opioid receptors in certain regions of the central nervous system, such as periaqueductal gray, and produces pain relief. The brain variant CYP2D7 and mu-opioid receptor colocalize in neurons of the periaqueductal gray area in human brain, indicating that metabolism of codeine to morphine could occur at the site of opioid action. Histiospecific isoforms of P450 generated by alternate splicing, which mediate selective metabolism of pro- drugs within tissues, particularly the brain, to generate active drugs may play an important role in drug action and provide newer insights into the genetics of metabolism. C1 Natl Brain Res Inst, Manesar 122050, Haryana, India. NCI, Mol Targets Dev Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. Univ S Alabama, Canc Res Inst, Mobile, AL 36688 USA. RP Ravindranath, V (reprint author), Natl Brain Res Inst, Manesar 122050, Haryana, India. EM vijir@nbrc.ac.in FU NIMH NIH HHS [MH55494] NR 40 TC 51 Z9 56 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 25 PY 2004 VL 279 IS 26 BP 27383 EP 27389 DI 10.1074/jbc.M402337200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 830KH UT WOS:000222120400069 PM 15051713 ER PT J AU Mishina, Y Starbuck, MW Gentile, MA Fukuda, T Kasparcova, V Seedor, JG Hanks, MC Amling, M Pinero, GJ Harada, S Behringer, RR AF Mishina, Y Starbuck, MW Gentile, MA Fukuda, T Kasparcova, V Seedor, JG Hanks, MC Amling, M Pinero, GJ Harada, S Behringer, RR TI Bone morphogenetic protein type IA receptor signaling regulates postnatal osteoblast function and bone remodeling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TGF-BETA-SUPERFAMILY; MOUSE OSTEOCALCIN GENE; OSTEOCLAST FORMATION; CRE RECOMBINASE; EXPRESSION; MICE; DIFFERENTIATION; CELLS; LIMB; MEMBER AB Bone morphogenetic proteins (BMPs) function during various aspects of embryonic development including skeletogenesis. However, their biological functions after birth are less understood. To investigate the role of BMPs during bone remodeling, we generated a postnatal osteoblast-specific disruption of Bmpr1a that encodes the type IA receptor for BMPs in mice. Mutant mice were smaller than controls up to 6 months after birth. Irregular calcification and low bone mass were observed, but there were normal numbers of osteoblasts. The ability of the mutant osteoblasts to form mineralized nodules in culture was severely reduced. Interestingly, bone mass was increased in aged mutant mice due to reduced bone resorption evidenced by reduced bone turnover. The mutant mice lost more bone after ovariectomy likely resulting from decreased osteoblast function which could not overcome ovariectomy-induced bone resorption. In organ culture of bones from aged mice, ablation of the Bmpr1a gene by adenoviral Cre recombinase abolished the stimulatory effects of BMP4 on the expression of lysosomal enzymes essential for osteoclastic bone resorption. These results demonstrate essential and age-dependent roles for BMP signaling mediated by BMPRIA ( a type IA receptor for BMP) in osteoblasts for bone remodeling. C1 NIEHS, LRDT, NIH, Res Triangle Pk, NC 27709 USA. Univ Texas, MD Anderson Canc Ctr, Dept Mol Genet, Houston, TX 77030 USA. Merck Res Labs, Dept Mol Endocrinol Bone Biol, West Point, PA 19486 USA. Procter & Gamble Pharmaceut, Hlth Care Res Ctr, Mason, OH USA. Univ Hamburg, Dept Trauma Surg, Hamburg, Germany. Univ Texas, Dent Branch, Dept Basic Sci, Houston, TX 77030 USA. RP Mishina, Y (reprint author), NIEHS, LRDT, NIH, 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM mishina@niehs.nih.gov FU NIAMS NIH HHS [AR42919] NR 43 TC 99 Z9 105 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 25 PY 2004 VL 279 IS 26 BP 27560 EP 27566 DI 10.1074/jbc.M404222200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 830KH UT WOS:000222120400089 PM 15090551 ER PT J AU Kageyama, A Oka, M Okada, T Nakamura, S Ueyama, T Saito, N Hearing, VJ Ichihashi, M Nishigori, C AF Kageyama, A Oka, M Okada, T Nakamura, S Ueyama, T Saito, N Hearing, VJ Ichihashi, M Nishigori, C TI Down-regulation of melanogenesis by phospholipase D2 through ubiquitin proteasome-mediated degradation of tyrosinase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; ADP-RIBOSYLATION FACTOR; MESSENGER-RNA LEVELS; GTP-BINDING PROTEIN; B16 MELANOMA-CELLS; MAMMALIAN-CELLS; D ACTIVATION; D1; PIGMENTATION; MELANOCYTES AB The involvement of phospholipase D (PLD) in the regulation of melanogenesis was examined. Treatment of B16 mouse melanoma cells with 12-O-tetradecanoylphorbol-13- acetate (TPA) resulted in the activation of PLD and a decrease in melanin content. 1-Butanol, but not 2-butanol, completely blocked the TPA-induced inhibition of melanogenesis, suggesting the involvement of PLD in this event. Reverse transcription-PCR and immunoblot analyses revealed the existence of both PLD isozymes, PLD1 and PLD2, in B16 cells. When PLD1 or PLD2 was introduced into those cells by an adenoviral gene-transfer technique, both PLD1 and PLD2 were activated by TPA. When PLD1 and PLD2 were overexpressed, PLD2 potently caused a decrease in melanin content, whereas the effect of PLD1 expression on melanin content was minimal. Over-expression of PLD2 itself did not affect protein kinase C activity, as assessed by the intracellular distribution and levels of expression of each isoform expressed in B16 cells. The effects of TPA on the down-regulation of basal or alpha-melanocyte-stimulating hormone-enhanced melanogenesis were almost completely blocked by expressing a lipase activity-negative mutant, LN-PLD2, but not by LN-PLD1. Further, the PLD2-induced decrease in melanin content was accompanied by a decrease in the amount and activity of tyrosinase, a key enzyme in melanogenesis, whereas the mRNA level of tyrosinase was unchanged by the over-expression of PLD2. Moreover, treatment with proteasome inhibitors completely blocked the PLD2-induced down-regulation of melanogenesis. Taken together, the present results indicate that the TPA-induced down-regulation of melanogenesis is mediated by PLD2 but not by PLD1 through the ubiquitin proteasome-mediated degradation of tyrosinase. This suggests that PLD2 may play an important role in regulating pigmentation in vivo. C1 Kobe Univ, Grad Sch Med, Dept Mol & Cellular Biol, Div Dermatol, Kobe, Hyogo 6500017, Japan. Kobe Univ, Grad Sch Med, Dept Mol & Cellular Biol, Div Clin Mol Med, Kobe, Hyogo 6500017, Japan. Kobe Univ, Grad Sch Med, Dept Mol & Cellular Biol, Div Biochem, Kobe, Hyogo 6500017, Japan. Kobe Univ, Biosignal Res Ctr, Mol Pharmacol Lab, Kobe, Hyogo 6578501, Japan. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Oka, M (reprint author), Kobe Univ, Grad Sch Med, Dept Mol & Cellular Biol, Div Dermatol, Kobe, Hyogo 6500017, Japan. EM oka@med.kobe-u.ac.jp NR 49 TC 38 Z9 40 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 25 PY 2004 VL 279 IS 26 BP 27774 EP 27780 DI 10.1074/jbc.M401786200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 830KH UT WOS:000222120400112 PM 15067002 ER PT J AU Gallo, SA Sackett, K Rawat, SS Shai, YC Blumenthal, R AF Gallo, SA Sackett, K Rawat, SS Shai, YC Blumenthal, R TI The stability of the intact envelope glycoproteins is a major determinant of sensitivity of HIV/SIV to peptidic fusion inhibitors SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE HIV; SIV; membrane fusion; entry inhibitors; gp41 ID IMMUNODEFICIENCY-VIRUS TYPE-1; HIV-1 GP41; SIV GP41; SYNTHETIC PEPTIDE; MEMBRANE-FUSION; 6-HELIX BUNDLE; HELICAL DOMAIN; RECEPTOR; CORE; ENTRY AB C-peptides derived from the HIV envelope glycoprotein transmembrane subunit gp41 C-terminal heptad repeat (C-HR) region are potent HIV fusion inhibitors. These peptides interact with the gp41 N-terminal heptad repeat (N-HR) region and block the gp41 six-helix bundle formation that is required for fusion. However, the parameters that govern this inhibition have yet to be elucidated. We address this issue by comparing the ability of C34, derived from HIV-1, HIV-2 and SIV gp41, to inhibit HIVA, HIV-2 and SIV envelope-mediated fusion and the ability of these peptides to form stable six-helix bundles with N36 peptides derived from gp41 of these three viruses. The ability to form six-helix bundles was examined by circular dichroism spectroscopy, and HIV/SIV Env-mediated membrane fusion was monitored by a dye transfer assay. HIV-1 N36 formed stable helix bundles with HIV-1, HIV-2 and SIV C34, which all inhibited HIV-1 Env-mediated fusion at IC50 < 10 nM. The three C34 peptides were poor inhibitors of HIV-2 and SIV fusion (IC50 > 100 nM), although HIV-2 and SIV N36 formed stable helix bundles with SIV C34. Priming experiments with sCD4 indicate that, in contrast to HIV-1, HIV-2 and SIV Env do not expose their N-HR region to SIV C34 following CD4 binding, but rapidly proceed to co-receptor engagement and six-helix bundle formation resulting in fusion. Our results suggest that several factors, including six-helix bundle stability and the ability of CD4 to destabilize the envelope glycoprotein, serve as determinants of sensitivity to entry inhibitors. (C) 2004 Elsevier Ltd. All rights reserved. C1 NCI, Membrane Struct & Funct Sect, LECB, CCR,NIH, Frederick, MD 21702 USA. Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. RP Blumenthal, R (reprint author), NCI, Membrane Struct & Funct Sect, LECB, CCR,NIH, Frederick, MD 21702 USA. EM blumen@helix.nih.gov OI Gallo, Stephen/0000-0001-6043-2153 NR 31 TC 35 Z9 35 U1 1 U2 2 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 25 PY 2004 VL 340 IS 1 BP 9 EP 14 DI 10.1016/j.jmb.2004.04.027 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 831UR UT WOS:000222222300002 PM 15184018 ER PT J AU Mucke, N Wedig, T Burer, A Marekov, LN Steinert, PM Langowski, J Aebi, U Herrmann, H AF Mucke, N Wedig, T Burer, A Marekov, LN Steinert, PM Langowski, J Aebi, U Herrmann, H TI Molecular and biophysical characterization of assembly-starter units of human vimentin SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE assembly; chemical cross-linking; intermediate filament; analytical ultracentrifugation; vimentin ID INTERMEDIATE-FILAMENT PROTEINS; TRANSIENT ELECTRIC BIREFRINGENCE; MICROTUBULE TRACKS; DE-NOVO; DESMIN; SUBUNITS; DYNAMICS; INVITRO; DIMER; CELLS AB We have developed an assembly protocol for the intermediate filament (IF) protein vimentin based on a phosphate buffer system, which enables the dynamic formation of authentic IFs. The advantage of this physiological buffer is that analysis of the subunit interactions by chemical crosslinking of internal lysine residues becomes feasible. By this system, we have analyzed the potential interactions of the coiled-coil rod domains with one another, which are assumed to make a crucial contribution to IF formation and stability. We show that headless vimentin, which dimerizes under low salt conditions, associates into tetramers of the A(22)-type configuration under assembly conditions, indicating that one of the effects of increasing the ionic strength is to favor coil 2-coil 2 interactions. Furthermore, in order to obtain insight into the molecular interactions that occur during the first phase of assembly of full-length vimentin, we employed a temperature-sensitive variant of human vimentin, which is arrested at the "unit-length filament" (ULF) state at room temperature, but starts to elongate upon raising the temperature to 37 degreesC. Most importantly, we demonstrate by cross-linking analysis that ULF formation of A(22) and A(12) cross-linking products in mature IFs, however, indicates that major rearrangements do occur during the longitudinal annealing and radial compaction steps of IF assembly. (C) 2004 Elsevier Ltd. All rights reserved. C1 German Canc Res Ctr, Div Cell Biol, D-69120 Heidelberg, Germany. German Canc Res Ctr, Div Biophys Macromol, D-69120 Heidelberg, Germany. Univ Basel, Bioctr, Maurice E Muller Inst Struct Biol, CH-4056 Basel, Switzerland. NIAMS, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. RP Herrmann, H (reprint author), German Canc Res Ctr, Div Cell Biol, Neuenheimer Feld 280, D-69120 Heidelberg, Germany. EM h.herrmann@dkfz.de RI Langowski, Jorg/A-1843-2011 OI Langowski, Jorg/0000-0001-8600-0666 NR 50 TC 87 Z9 87 U1 1 U2 4 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 25 PY 2004 VL 340 IS 1 BP 97 EP 114 DI 10.1016/j.jmb.2004.04.039 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 831UR UT WOS:000222222300009 PM 15184025 ER PT J AU Jia, ST Noma, K Grewal, SIS AF Jia, ST Noma, K Grewal, SIS TI RNAi-independent heterochromatin nucleation by the stress-activated ATF/CREB family proteins SO SCIENCE LA English DT Article ID ATF1 TRANSCRIPTION FACTOR; FISSION YEAST; SCHIZOSACCHAROMYCES-POMBE; HISTONE H3; SEXUAL DEVELOPMENT; METHYLATION; GENOME; LOCALIZATION; EXPRESSION; ENCODES AB At the silent mating-type interval of fission yeast, the RNA interference (RNAi) machinery cooperates with cenH, a DNA element homologous to centromeric repeats, to initiate heterochromatin formation. However, in RNAi mutants, heterochromatin assembly can still occur at low efficiency. Here, we report that Atf1 and Pcr1, two ATF/CREB family proteins, act in a parallel mechanism to the RNAi pathway for heterochromatin nucleation. Deletion of atf1 or pcr1 alone has little effect on silencing at the mating-type region, but when combined with RNAi mutants, double mutants fail to nucleate heterochromatin assembly. Moreover, deletion of atf1 or pcr1 in combination with cenH deletion causes loss of silencing and heterochromatin formation. Furthermore, Atf1 and Pcr1 bind to the mating-type region and target histone H3 lysine-9 methylation and the Swi6 protein essential for heterochromatin assembly. These analyses link ATF/CREB family proteins, involved in cellular response to environmental stresses, to nucleation of constitutive heterochromatin. C1 NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Grewal, SIS (reprint author), NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM grewals@mail.nih.gov NR 23 TC 173 Z9 179 U1 2 U2 8 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUN 25 PY 2004 VL 304 IS 5679 BP 1971 EP 1976 DI 10.1126/science.1099035 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 832BG UT WOS:000222241600047 PM 15218150 ER PT J AU Fairhurst, RM Casella, JF AF Fairhurst, RM Casella, JF TI Homozygous hemoglobin C disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 NIAID, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. RP Fairhurst, RM (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 5 Z9 5 U1 1 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 24 PY 2004 VL 350 IS 26 BP E24 EP E24 DI 10.1056/NEJMicm030486 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 831MR UT WOS:000222199000012 PM 15215497 ER PT J AU Park, HU Jeong, JH Chung, JH Brady, JN AF Park, HU Jeong, JH Chung, JH Brady, JN TI Human T-cell leukemia virus type 1 Tax interacts with Chk1 and attenuates DNA-damage induced G(2) arrest mediated by Chk1 SO ONCOGENE LA English DT Article DE HTLV-1 Tax; Chk1; interaction; attenuation; G(2) checkpoint ID TELANGIECTASIA-MUTATED ATM; PRIMARY HUMAN-LYMPHOCYTES; S-PHASE CHECKPOINT; HTLV-I; IONIZING-RADIATION; TRANSACTIVATION FUNCTION; TUMOR-SUPPRESSOR; GENE-EXPRESSION; PROTEIN-KINASE; CANCER-CELLS AB Checkpoint kinase 1 (Chk1) mediates diverse cellular responses to genotoxic stress, regulating the network of genome-surveillance pathways that coordinate cell cycle progression with DNA repair. Chk1 is essential for mammalian development and viability, and has been shown to be important for both S and G(2) checkpoints. We now present evidence that the HTLV-1 Tax protein interacts directly with Chk1 and impairs its kinase activities in vitro and in vivo. The direct and physical interaction of Chk1 and Tax was observed in HTLV-1-infected T cells (C81, HuT 102 and MT-2) and transfected fibroblasts (293 T) by coimmunoprecipitation and by in vitro GST pull-down assays. Interestingly, Tax inhibited the kinase activity of Chk1 protein in in vitro and in vivo kinase assays. Consistent with these results, Tax inhibited the phosphorylation-dependent degradation of Cdc25A and G(2) arrest in response to gamma-irradiation (IR) in a dose-dependent manner in vivo. The G(2) arrest did not require Chk2 or p53. These studies provide the first example of a viral transforming protein targeting Chk1 and provide important insights into checkpoint pathway regulation. C1 NCI, Virus Tumor Biol Sect, Cellular Oncol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Brady, JN (reprint author), NCI, Virus Tumor Biol Sect, Cellular Oncol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM bradyj@exchange.nih.gov NR 73 TC 43 Z9 44 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 24 PY 2004 VL 23 IS 29 BP 4966 EP 4974 DI 10.1038/sj.onc.1207644 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 831ZX UT WOS:000222237300002 PM 15107832 ER PT J AU Zeeberg, BR Riss, J Kane, DW Bussey, KJ Uchio, E Linehan, WM Barrett, JC Weinstein, JN AF Zeeberg, BR Riss, J Kane, DW Bussey, KJ Uchio, E Linehan, WM Barrett, JC Weinstein, JN TI Mistaken identifiers: Gene name errors can be introduced inadvertently when using Excel in bioinformatics SO BMC BIOINFORMATICS LA English DT Article AB Background: When processing microarray data sets, we recently noticed that some gene names were being changed inadvertently to non-gene names. Results: A little detective work traced the problem to default date format conversions and floating-point format conversions in the very useful Excel program package. The date conversions affect at least 30 gene names; the floating-point conversions affect at least 2,000 if Riken identifiers are included. These conversions are irreversible; the original gene names cannot be recovered. Conclusions: Users of Excel for analyses involving gene names should be aware of this problem, which can cause genes, including medically important ones, to be lost from view and which has contaminated even carefully curated public databases. We provide work-arounds and scripts for circumventing the problem. C1 NCI, Genom & Bioinformat Grp, Mol Pharmacol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. CCR, Lab Biosyst & Canc, Bethesda, MD 20892 USA. SRA Int, Fairfax, VA 22033 USA. NIH, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Zeeberg, BR (reprint author), NCI, Genom & Bioinformat Grp, Mol Pharmacol Lab, Ctr Canc Res,NIH, Bldg 37,Rm 5041,9000 Rockville Pike, Bethesda, MD 20892 USA. EM barry@discover.nci.nih.gov; rissj@helix.nih.gov; david_kane@sra.com; busseyk@mail.nih.gov; eu8v@nih.gov; linehanm@mail.nih.gov; barrett@mail.nih.gov; weinstein@dtpvx2.ncifcrf.gov NR 5 TC 25 Z9 27 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD JUN 23 PY 2004 VL 5 AR 80 DI 10.1186/1471-2105-5-80 PG 6 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 837GS UT WOS:000222617300001 PM 15214961 ER PT J AU Iyer, LM Koonin, EV Aravind, L AF Iyer, LM Koonin, EV Aravind, L TI Evolution of bacterial RNA polymerase: implications for large-scale bacterial phylogeny, domain accretion, and horizontal gene transfer SO GENE LA English DT Article DE DNA-dependent RNA polymerases; bacterial evolution; domain architecture; synapomorphy; phylogenetic analysis ID STRUCTURAL BASIS; ANGSTROM RESOLUTION; TRANSCRIPTION INITIATION; HOLOENZYME; SEQUENCE; PROTEIN; SUBUNITS; ALIGNMENT; DISTANCE; AQUIFEX AB Comparative analysis of the domain architectures of the, beta, beta', and sigma(70) subunits of bacterial DNA-dependent RNA polymerases (DdRp), combined with sequence-based phylogenetic analysis, revealed a fundamental split among bacteria. DNA-dependent RNA polymerase subunits of Group I, which includes Proteobacteria, Aquifex, Chlamydia, Spirochaetes, Cytophaga-Chlorobium, and Planctomycetes, are characterized by three distinct inserts, namely a Sandwich Barrel Hybrid Motif domain in the beta subunit, a beta - beta' module (BBM) I domain in the beta' subunit, and a distinct helical module in the sigma subunit. The DdRp subunits of remaining bacteria, which comprise Group 11, lack these inserts, although some additional inserted domains are present in individual lineages. The separation of bacteria into Group I and Group 11 is generally compatible with the topologies of phylogenetic trees of the conserved regions of DdRp subunits and concatenated ribosomal proteins and might represent the primary bifurcation in bacterial evolution. A striking deviation from this evolutionary pattern is Aquifex whose DdRp subunits cluster within Group 1, whereas phylogenetic analysis of ribosomal proteins identifies Aquifex as grouping with Thermotoga another bacterial hyperthemophile belonging to Group II. The inferred evolutionary scenario for the DdRp subunits includes domain accretion and rearrangement, with some likely horizontal transfer events. Although evolution of bacterial DdRp appeared to be generally dominated by vertical inheritance, horizontal transfer of complete genes for all or some of the,subunits, resulting in displacement of the ancestral genes, might have played a role in several lineages, such as Aquifex, Thermotoga, and Fusobacterium. (C) 2004 Elsevier B.V. All rights reserved. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM koonin@ncbi.nlin.nih.gov NR 40 TC 70 Z9 73 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD JUN 23 PY 2004 VL 335 BP 73 EP 88 DI 10.1016/j.gene.2004.03.017 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA 834TR UT WOS:000222434300007 PM 15194191 ER PT J AU Newton-Cheh, C O'Donnell, CJ AF Newton-Cheh, C O'Donnell, CJ TI Sex differences and genetic associations with myocardial infarction SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID CORONARY-ARTERY-DISEASE; RECEPTOR-ALPHA GENE; RANDOMIZED CONTROLLED-TRIAL; HEART-DISEASE; POPULATION STRATIFICATION; LINKAGE DISEQUILIBRIUM; CARDIOVASCULAR-DISEASE; POSTMENOPAUSAL WOMEN; COMMON DISEASE; BLOOD-PRESSURE C1 NHLBI Framingham Heart Study, Framingham, MA USA. Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. MIT, Cambridge, MA 02139 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP O'Donnell, CJ (reprint author), 73 Mt Wayte Ave 2, Framingham, MA 01702 USA. EM codonnell@nih.gov NR 30 TC 13 Z9 13 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 23 PY 2004 VL 291 IS 24 BP 3008 EP 3010 DI 10.1001/jama.291.24.3008 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 831HD UT WOS:000222184600033 PM 15213215 ER PT J AU Ikemoto, S Witkin, BM Zangen, A Wise, RA AF Ikemoto, S Witkin, BM Zangen, A Wise, RA TI Rewarding effects of AMPA administration into the supramammillary or posterior hypothalamic nuclei but not the ventral tegmental area SO JOURNAL OF NEUROSCIENCE LA English DT Article DE reinforcement; intracranial self-administration; conditioned place preference; microdialysis; nucleus accumbens; dopamine D-1 receptor antagonist; SCH 23390; excitatory amino acid; glutamate ID PHA-L ANALYSIS; DOPAMINE NEURONS; NMDA RECEPTORS; MOTIVATED BEHAVIOR; ACCUMBENS DOPAMINE; SELF-STIMULATION; ADJACENT REGIONS; PLEASURE CENTERS; RAT; BRAIN AB We examined whether injections of the excitatory amino acid AMPA are rewarding when injected into the posterior hypothalamus and ventral tegmental area. Rats quickly learned to lever-press for infusions of AMPA into the supramammillary or posterior hypothalamic nuclei but failed to learn to lever-press for similar injections into the ventral tegmental areas. AMPA injections into the supramammillary nucleus, but not the ventral tegmental area, induced conditioned place preference. The rewarding effects of AMPA appear to be mediated by AMPA receptors, because coadministration of the AMPA antagonist CNQX blocked the rewarding effects of AMPA, and administration of the enantiomer R-AMPA did not mimic the rewarding effects. AMPA injections into the supramammillary nucleus, but not the ventral tegmental area, also increased extracellular dopamine concentrations in the nucleus accumbens. Pretreatment with the D-1 dopamine antagonist SCH 23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine] led to extinction of AMPA self-administration. These findings implicate posterior hypothalamic regions in reward function and suggest that reward mechanisms localized around the ventral tegmental area are more complex than has been assumed recently. C1 NIDA, Behav Neurosci Branch, NIH, US Dept HHS, Baltimore, MD 21224 USA. RP Ikemoto, S (reprint author), NIDA, Behav Neurosci Branch, NIH, US Dept HHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM sikemoto@intra.nida.nih.gov RI Wise, Roy/A-6465-2012; OI Ikemoto, Satoshi/0000-0002-0732-7386 NR 44 TC 30 Z9 30 U1 1 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 23 PY 2004 VL 24 IS 25 BP 5758 EP 5765 DI 10.1523/JNEUROSCI.5367-04.2004 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 832AC UT WOS:000222237900012 PM 15215298 ER PT J AU Assadi, M Sharpe, JC Snell, C Loh, YP AF Assadi, M Sharpe, JC Snell, C Loh, YP TI The C-terminus of prohormone convertase 2 is sufficient and necessary for raft association and sorting to the regulated secretory pathway SO BIOCHEMISTRY LA English DT Article ID CARBOXYPEPTIDASE-E; CPE(FAT)/CPE(FAT) MICE; TRANSMEMBRANE DOMAIN; CHROMAFFIN GRANULES; CELL-SURFACE; PC2; RECEPTOR; PROTEIN; IDENTIFICATION; MATURATION AB Prohormone convertase 2 (PC2) is a member of the subtilisin family of proteases involved in prohormone maturation in the granules of the regulated secretory pathway (RSP). It has been suggested that targeting of this enzyme to the RSP is dependent on its association with lipid rafts in membranes at the trans-Golgi network. Here, we investigate the orientation of PC2 in granule membranes and the role of the C-terminus in sorting of the enzyme to the RSP. Molecular modeling and circular dichroism showed that this domain of PC2 forms an alpha-helix and inserts into artificial membranes. Furthermore, we show that the C-terminus of PC2 can be biotinylated at the C-terminus in Intact chromaffin granules, indicating that it is a transmembrane protein. To determine if the PC2 C-terminus is necessary for raft association and sorting, we transfected a chimera of CPEDelta15 (carboxypeptidase E without the last 15 residues) and the last 25 residues of PC2 (CPEDelta15-PC2), and a truncated PC2 mutant with the last 6 residues deleted (PC2Delta6) into Neuro2a cells. Whereas CPEDelta15 was not raft-associated or sorted to the RSP, addition of the 25 residues of PC2 C-terminus to CPEDelta15 restored raft association and localization to the RSP granules, as determined by immunocytochemistry. Deletion of the last 6 residues of PC2 eliminated lipid raft association and sorting of PC2Delta6 to the RSP. These results showed that the PC2 C-terminus confers raft association and is sufficient and necessary for sorting PC2 to the RSP. C1 NICHHD, Dev Neurobiol Lab, Cellular Neurobiol Sect, NIH, Bethesda, MD 20892 USA. NINDS, Biochem Sect, Surg Neurol Branch, NIGMS,NIH, Bethesda, MD 20892 USA. Medvir UK Ltd, Cambridge CB1 9T, England. RP Loh, YP (reprint author), NICHHD, Dev Neurobiol Lab, Cellular Neurobiol Sect, NIH, Bldg 49,Rm 5A-38,49 Convent Dr,MSC 4480, Bethesda, MD 20892 USA. EM lohp@mail.nih.gov NR 26 TC 28 Z9 28 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 22 PY 2004 VL 43 IS 24 BP 7798 EP 7807 DI 10.1021/bi036331g PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 829QE UT WOS:000222063900016 PM 15196022 ER PT J AU Newman, JH Fanburg, BL Archer, SL Badesch, DB Barst, RJ Garcia, JGN Kao, PN Knowles, JA Loyd, JE McGoon, MD Morse, JH Nichols, WC Rabinovitch, M Rodman, DM Stevens, T Tuder, RM Voelkel, NF Gail, DB AF Newman, JH Fanburg, BL Archer, SL Badesch, DB Barst, RJ Garcia, JGN Kao, PN Knowles, JA Loyd, JE McGoon, MD Morse, JH Nichols, WC Rabinovitch, M Rodman, DM Stevens, T Tuder, RM Voelkel, NF Gail, DB TI Pulmonary arterial hypertension - Future directions - Report of a National Heart, Lung and Blood Institute/Office of Rare Diseases workshop SO CIRCULATION LA English DT Review DE circulation; hypertension, pulmonary; pulmonary heart disease; vasculature ID SMOOTH-MUSCLE-CELLS; REDUCTASE INHIBITOR SIMVASTATIN; PLACEBO-CONTROLLED TRIAL; NITRIC-OXIDE SYNTHASE; PROTEIN-RECEPTOR-II; PROSTACYCLIN ANALOG; GERMLINE MUTATIONS; GROWTH-FACTOR; DOUBLE-BLIND; RATS C1 Nashville VA Med Ctr, Dept Med, Nashville, TN USA. Vanderbilt Univ, Dept Med, Nashville, TN USA. Tufts Univ New England Med Ctr, Dept Med, Boston, MA 02111 USA. Univ Alberta Hosp, Div Cardiol, Edmonton, AB T6G 2B7, Canada. Univ Colorado, Hlth Sci Ctr, Dept Med, Denver, CO 80262 USA. Columbia Univ Coll Phys & Surg, Pulm Hypertens Ctr, New York, NY 10032 USA. Columbia Univ Coll Phys & Surg, Dept Med, New York, NY 10032 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. Stanford Univ, Med Ctr, Dept Med, Stanford, CA 94305 USA. Stanford Univ, Med Ctr, Dept Pulm & Crit Care, Stanford, CA 94305 USA. Stanford Univ, Med Ctr, Dept Pediat, Stanford, CA 94305 USA. Mayo Clin, Div Cardiovasc Dis, Rochester, MN USA. Cincinnati Childrens Hosp, Div Human Genet, Program Human Genet, Med Ctr, Cincinnati, OH USA. Univ Alabama, Dept Pharmacol, Ctr Lung Biol, Coll Med, Mobile, AL USA. NHLBI, Lung Biol & Dis Program, Div Lung Dis, Bethesda, MD 20892 USA. RP Gail, DB (reprint author), NHLBI, Lung Biol & Dis Program, Div Lung Dis, 6701 Rockledge Dr,Suite 10018, Bethesda, MD 20892 USA. EM gaild@nhlbi.nih.gov RI Garcia, Joe/E-8862-2010; Archer, Stephen/C-3621-2013 NR 56 TC 69 Z9 70 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 22 PY 2004 VL 109 IS 24 BP 2947 EP 2952 DI 10.1161/01.CIR.0000132476.87231.6F PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 831FH UT WOS:000222178800007 PM 15210611 ER PT J AU Buzas, B Max, MB AF Buzas, B Max, MB TI Pain in Parkinson disease SO NEUROLOGY LA English DT Editorial Material ID ROSTRAL VENTROMEDIAL MEDULLA; NEURONS; NOCICEPTION; MODULATION; RAT C1 Natl Inst Dent & Craniofacial Res, Pain & Neurosensory Mech Branch, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. RP Buzas, B (reprint author), Natl Inst Dent & Craniofacial Res, Pain & Neurosensory Mech Branch, NIH, Dept Hlth & Human Serv, Pk 5 Bldg,Room 431,12420 Parklawn Dr, Rockville, MD 20852 USA. EM bbuzas@mail.nih.gov FU NIDCR NIH HHS [Z01 DE00366] NR 13 TC 18 Z9 19 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUN 22 PY 2004 VL 62 IS 12 BP 2156 EP 2157 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 831FF UT WOS:000222178600002 PM 15210873 ER PT J AU Zhuang, Z Lee, YS Zeng, W Furuta, M Valyi-Nagy, T Johnson, MD Vnencak-Jones, CL Woltjer, RL Weil, RJ AF Zhuang, Z Lee, YS Zeng, W Furuta, M Valyi-Nagy, T Johnson, MD Vnencak-Jones, CL Woltjer, RL Weil, RJ TI Molecular genetic and proteomic analysis of synchronous malignant gliomas SO NEUROLOGY LA English DT Article ID PLEOMORPHIC XANTHOASTROCYTOMA; GLIOBLASTOMA; P53 AB Described is a patient with concurrent discrete gliomas: a pleomorphic xanthoastrocytoma with anaplastic features and an anaplastic oligoastrocytoma. The distinct and morphologically dissimilar tumors demonstrated similar genetic abnormalities by loss of heterozygosity and comparative genome hybridization. Clonality and proteomic analyses highlighted an independent origin for the two tumors. Proteomic methods may prove useful in cases where the differential diagnosis and pathogenetic origin of tumors are uncertain, as well as more globally for its ability to provide insight into specific expression of proteins that may serve as unique markers of tumorigenesis or as novel targets of therapy. C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Univ Illinois, Coll Med, Dept Pathol, Chicago, IL 60612 USA. Vanderbilt Univ, Dept Pathol, Nashville, TN USA. Vanderbilt Univ, Dept Neurosurg, Nashville, TN USA. Univ Washington, Dept Pathol, Seattle, WA 98195 USA. RP Weil, RJ (reprint author), NINDS, Surg Neurol Branch, NIH, 9000 Rockville Pike,Bldg 10,Rm 5D37, Bethesda, MD 20892 USA. EM weilr@ninds.nih.gov NR 10 TC 14 Z9 14 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUN 22 PY 2004 VL 62 IS 12 BP 2316 EP 2319 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 831FF UT WOS:000222178600035 PM 15210906 ER PT J AU Shill, HA Bushara, KO Mari, Z Reich, M Hallett, M AF Shill, HA Bushara, KO Mari, Z Reich, M Hallett, M TI Open-label dose-escalation study of oral 1-octanol in patients with essential tremor SO NEUROLOGY LA English DT Article ID HARMALINE-INDUCED TREMOR AB Twenty-one single oral doses of 1-octanol were given to patients with essential tremor ( ET) in an open-label dose-escalation study. The drug was well tolerated up to 64 mg/kg. The main side effect was an unusual taste. No overt intoxication was seen. There was evidence for efficacy, with a significant reduction in tremor amplitude as measured by accelerometry and handwriting that was maximal at 2 hours. Higher doses may produce more sustained benefit. C1 NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. Minneapolis Vet Affairs Med Ctr, Minneapolis, MN USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10,Rm 5N226,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov NR 10 TC 27 Z9 27 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 22 PY 2004 VL 62 IS 12 BP 2320 EP 2322 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 831FF UT WOS:000222178600036 PM 15210907 ER PT J AU Wang, Y Chan, SL Miele, L Yao, PJ Mackes, J Ingram, DK Mattson, MP Furukawa, K AF Wang, Y Chan, SL Miele, L Yao, PJ Mackes, J Ingram, DK Mattson, MP Furukawa, K TI Involvement of Notch signaling in hippocampal synaptic plasticity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE long-term potentiation; long-term depression; Alzheimer's disease; NF-kappa B; learning and memory ID NF-KAPPA-B; POSITIVE FEEDBACK LOOP; LONG-TERM POTENTIATION; POSTNATAL MOUSE-BRAIN; PRESENILIN-1 MUTATIONS; PROTEOLYTIC RELEASE; ALZHEIMERS-DISEASE; MUTANT MICE; CELL-DEATH; DIFFERENTIATION AB During development of the nervous system, the fate of stem cells is regulated by a cell surface receptor called Notch. Notch is also present in the adult mammalian brain; however, because Notch null mice die during embryonic development, it has proven difficult to determine the functions of Notch. Here, we used Notch antisense transgenic mice that develop and reproduce normally, but exhibit reduced levels of Notch, to demonstrate a role for Notch signaling in synaptic plasticity. Mice with reduced Notch levels exhibit impaired long-term potentiation (LTP) at hippocampal CA1 synapses. A Notch ligand enhances LTP in normal mice and corrects the defect in LTP in Notch antisense transgenic mice. Levels of basal and stimulation-induced NF-kappaB activity were significantly decreased in mice with reduced Notch levels. These findings suggest an important role for Notch signaling in a form of synaptic plasticity known to be associated with learning and memory processes. C1 NIA, Gerontol Res Ctr, Neurosci Lab, Baltimore, MD 21224 USA. NIA, Labs Expt Gerontol, Baltimore, MD 21224 USA. Univ Illinois, Dept Biopharmaceut Sci, Chicago, IL 60612 USA. Univ Illinois, Ctr Canc, Chicago, IL 60612 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Furukawa, K (reprint author), NIA, Gerontol Res Ctr, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM furukawaka@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 NR 41 TC 144 Z9 148 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 22 PY 2004 VL 101 IS 25 BP 9458 EP 9462 DI 10.1073/pnas.0308126101 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 832PE UT WOS:000222278600053 PM 15190179 ER PT J AU Zhang, Z Dmitrieva, NI Park, JH Levine, RL Burg, MB AF Zhang, Z Dmitrieva, NI Park, JH Levine, RL Burg, MB TI High urea and NaCl carbonylate proteins in renal cells in culture and in vivo, and high urea causes 8-oxoguanine lesions in their DNA SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DUCT MIMCD3 CELLS; OXIDATION; TRANSCRIPTION; MEDULLA; DISEASE; STRESS; KINASE; KIDNEY; DAMAGE; EGR-1 AB Urea and NaCl are elevated in the renal inner medulla. We now find that a high concentration of urea or NaCl increases reactive oxygen species (ROS) in mouse renal inner medullary (mlMCD3) cells in culture. Previously, high NaCl, but not high urea, was found to cause DNA double-strand breaks. We now tested whether high urea or NaCl causes oxidative damage to DNA or cellular proteins. We find that high urea increases mlMCD3 cell DNA single-strand breaks and 8-oxoguanine lesions. High NaCl does not cause detectable 8-oxoguanine lesions. High urea or NaCl also greatly increases carbonylation of proteins in mlMCD3 cells. Carbonylation occurs within 5 min and with as little as 5 mM urea, a normal plasma level. It increases as urea is raised over the range in uremia. A high raffinose level increases ROS and carbonylation. High sorbitol and glycerol levels do not increase ROS or carbonylation. Carbonyl content is high in mouse renal inner medullas where interstitial NaCl and urea concentrations are normally high. There, numerous proteins are carbonylated, and carbonylation occurs in both collecting ducts and thin limbs. Conclusions: (i) Oxidative stress, associated with high urea, causes 8-oxoguanine DNA lesions in mlMCD3 cell DNA. (it) High urea or NaCl carbonylates proteins in mlMCD3 cells and in renal inner medullary cells in vivo. (iii) In mlMCD3 cells a normal plasma concentration of urea causes carbonylation, and carbonylation increases over the uremic range of urea concentration, indicating that urea can contribute directly to the carbonylation found in uremia. C1 NHLBI, Kidney & Electrolyte Metab Lab, Bethesda, MD 20892 USA. NHLBI, Biochem Lab, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. RP Zhang, Z (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, Bethesda, MD 20892 USA. EM zhangz@nhlbi.nih.gov RI Dmitrieva, Natalia/A-2924-2013; Levine, Rodney/D-9885-2011 OI Dmitrieva, Natalia/0000-0001-8074-6950; NR 29 TC 87 Z9 91 U1 1 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 22 PY 2004 VL 101 IS 25 BP 9491 EP 9496 DI 10.1073/pnas.0402961101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 832PE UT WOS:000222278600059 PM 15190183 ER PT J AU Song, YL Roller, PP Long, YQ AF Song, YL Roller, PP Long, YQ TI Development of L-3-aminotyrosine suitably protected for the synthesis of a novel nonphosphorylated hexapeptide with low-nanomolar Grb2-SH2 domain-binding affinity SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE aminotyrosine; Grb2-SH2 domain; nonphosphorylated ligand; cyclic peptide; sulfoxide; SPR assay ID CYCLIC PEPTIDE ANTAGONISTS; STRUCTURE-BASED DESIGN; SH2 DOMAIN; SIGNAL-TRANSDUCTION; STRUCTURAL BASIS; INHIBITOR; RECOGNITION; AGENTS; AMIDES AB Synthesis of orthogonally protected (2S)-2-amino-3-(3 -amino-4-hydroxy-phenyl)-propionic acid (10) suitable for solid phase peptide synthesis and its first use for the preparation of nonphosphorylated Grb2-SH2 domain antagonists (4a-c) are reported. The 3-aminotyrosine containing sulfoxide-cyclized hexapeptide (4b) exhibited potent Grb2-SH2 domain binding affinity with IC50 = 50 nM which represents the highest affinity yet reported for a peptide inhibitor against Grb2-SH2 domain with only six residues free of phosphotyrosine or phosphotyrosine mimics. This potent small peptidomimetic 4b may be representative of a new class of therapeutically relevant Grb2-SH2 domain-directed agents, and acts as a chemotherapeutic lead for the treatment of erbB2-related cancers. (C) 2004 Elsevier Ltd. All rights reserved. C1 CAS, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China. NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. RP Long, YQ (reprint author), CAS, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China. EM yqlong@mail.shcnc.ac.cn NR 27 TC 13 Z9 13 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JUN 21 PY 2004 VL 14 IS 12 BP 3205 EP 3208 DI 10.1016/j.bmcl.2004.03.103 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 825RU UT WOS:000221776800041 PM 15149676 ER PT J AU Grundt, P Kopajtic, TA Katz, JL Newman, AH AF Grundt, P Kopajtic, TA Katz, JL Newman, AH TI The effect of 6-substituted-4 ',4 ''-difluorobenztropines on monoamine transporters and the muscarinic M1 receptor SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE monoamine transporters; muscarinic M1 receptor; benztropine; ligand binding ID DOPAMINE UPTAKE INHIBITORS; COCAINE; ANALOGS; BINDING; LIGANDS; DISCOVERY; DRUGS; 6-AND AB A series of racemic 6-hydroxy and carboalkoxy substituted-4',4"-difluorobenztropines was synthesized and evaluated for binding at the dopamine (DAT), the serotonin (SERT), the norepinephrine (NET) transporters, and the muscarinic M1 receptor. Each of the analogues displaced [H-3]WIN 35,428 (DAT) with a range of affinities from 5.81 to 175 nM and [H-3]pirenzepine (M1), with a range of affinities (K-i = 27.0-8430 nM). Binding affinities at the SERT and the NET were generally low. Published by Elsevier Ltd. C1 NIDA, Intramural Res Program, NIH, Psychobiol Sect, Baltimore, MD 21224 USA. RP Grundt, P (reprint author), NIDA, Intramural Res Program, NIH, Psychobiol Sect, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM pgrundt@intra.nida.nih.gov; anewman@intra.nida.nih.gov OI Katz, Jonathan/0000-0002-1068-1159 NR 18 TC 7 Z9 7 U1 3 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JUN 21 PY 2004 VL 14 IS 12 BP 3295 EP 3298 DI 10.1016/j.bmcl.2004.03.075 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 825RU UT WOS:000221776800058 PM 15149693 ER PT J AU Tycko, R AF Tycko, R TI Sensitivity enhancement in two-dimensional solid-state NMR spectroscopy by transverse mixing SO CHEMPHYSCHEM LA English DT Article DE dipolar recoupling; magic-angle spinning; NMR spectroscopy; protein structures; solid-state structures ID SHIFT CORRELATION SPECTROSCOPY; ANGLE-SPINNING NMR; ROTATING SOLIDS; DISTANCE MEASUREMENTS; STRUCTURAL CONSTRAINTS; AMYLOID FIBRILS; PAIRING DOMAIN; RECA PROTEIN; DNA-BINDING; IMPROVEMENT AB The sensitivity of two-dimensional (2D) C-13-C-13 solid-state NMR spectroscopy under magic-angle spinning (MAS) is shown to be enhanced by the use of transverse polarization transfer in place of the conventional longitudinal polarization transfer. Experimental results are reported for 2D spectroscopy of a 20-residue, filament-forming peptide derived from the E. coli RecA protein, containing five uniformly C-13-labeled residues, performed at 14.1 T with high-speed MAS and with finite pulse ratio-frequency-driven recoupling of dipolar interactions in the mixing period. Significant sensitivity enhancements observed at short mixing periods results from a more rapid build-up of cross-peaks under transverse mixing than under longitudinal mixing and from the root2 gain inherent in 2D measurements in which both orthogonal transverse polarization components in the t(1) period contribute to each free-induction decay signal detected in the t(2) period. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. EM robertt@niddk.nih.gov NR 36 TC 14 Z9 14 U1 0 U2 2 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1439-4235 J9 CHEMPHYSCHEM JI ChemPhysChem PD JUN 21 PY 2004 VL 5 IS 6 BP 863 EP 868 DI 10.1002/cphc.200301208 PG 6 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 833CP UT WOS:000222314300011 PM 15253312 ER PT J AU Bocek, P Foucras, G Paul, WE AF Bocek, P Foucras, G Paul, WE TI Interferon gamma enhances both in vitro and in vivo priming of CD4(+) T cells for IL-4 production SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE T cell activation; cell differentiation; T lymphocyte subsets; cytokine; T-bet ID IFN-GAMMA; LEISHMANIA-MAJOR; TRANSCRIPTION FACTOR; INTERLEUKIN (IL)-4; GENE-EXPRESSION; TH2 CELLS; MICE; RESPONSES; INFECTION; RECEPTOR AB Classical studies have demonstrated that in vitro priming of naive CD4 T cells to become T helper (Th)2 cells is strikingly dependent on interleukin (IL)-4, whereas pruning for interferon (IFN)gamma production is IL-12/IFNgamma-dependent. Therefore, it was quite surprising when we noted that pruning of naive C57BL/6 CD4(+) cells to become IL-4 producers was substantially inhibited by the addition of anti-IFNgamma antibodies. This was true using immobilized anti-CD3 and anti-CD28 antibodies or soluble anti-CD3/anti-CD28 and antigen-presenting cells in the presence or absence of added IL-4. Priming of CD4 T cells from IFNgamma(-/-) C57BL/6 mice with immobilized anti-CD3 and anti-CD28 resulted in limited production of IL-4, even with the addition of 1,000 U/ml of IL-4. Titrating IFNgamma into such cultures showed a striking increase in the proportion of T cells that secreted IL-4 upon challenge; this effect was completely IL-4-dependent in that it was blocked with anti-IL-4 antibody. Thus, IFNgamma plays an unanticipated but substantial role in Th2 printing, although it is an important Th1 cytokine, and under certain circumstances a Th1 inducer. C1 NIAID, Div Allergy Immunol & Transplantat, Immunol Lab, NIH, Bethesda, MD 20892 USA. Natl Vet Sch, ENVT, INRA, UMR, F-31076 Toulouse 03, France. RP Bocek, P (reprint author), NIAID, Div Allergy Immunol & Transplantat, Immunol Lab, NIH, 6610 Rockledge Dr,Rm 3060, Bethesda, MD 20892 USA. EM pbocek@niaid.nih.gov NR 36 TC 44 Z9 45 U1 0 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUN 21 PY 2004 VL 199 IS 12 BP 1619 EP 1630 DI 10.1084/jem.20032014 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 831TJ UT WOS:000222218700002 PM 15210741 ER PT J AU Fernandez-Capetillo, O Allis, CD Nussenzweig, A AF Fernandez-Capetillo, O Allis, CD Nussenzweig, A TI Phosphorylation of histone H2B at DNA double-strand breaks SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE DNA damage; epigenetics; histone H2B; chromatin; histone code ID H2AX PHOSPHORYLATION; GENOMIC INSTABILITY; IONIZING-RADIATION; DAMAGE RESPONSE; NUCLEAR FOCI; SERINE 139; SENSITIVITY; GAMMA-H2AX; COMPLEX; REPAIR AB Posttranslational modifications of histone tails regulate numerous biological processes including transcription, DNA repair, and apoptosis. Although recent studies suggest that structural alterations in chromatin are critical for triggering the DNA damage response, very little is known about the nature of DNA damage-induced chromatin perturbations. Here we show that the serine 14 residue in the NH2-terminal tail of histone H2B is rapidly phosphorylated at sites of DNA double-strand breaks. At late time points after irradiation, the phosphorylated form of H2B, H2B-(Ser14P), accumulates into irradiation-induced foci. H2B-(Ser14P) foci formation is not associated with the apoptotic phosphorylation of H2B but is strictly dependent on the phosphorylated isoform of H2AX. Our results broaden the spectrum of histone modifications that constitute the DNA damage "histone code" and suggest a model for the underlying chromatin structure within damage-induced foci. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Rockefeller Univ, Lab Chromatin Biol, New York, NY 10021 USA. RP Nussenzweig, A (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,4B04,10 Ctr Dr, Bethesda, MD 20892 USA. EM andre_nussenzweig@nih.gov RI Fernandez-Capetillo, Oscar/H-3508-2015 OI Fernandez-Capetillo, Oscar/0000-0002-2690-6885 NR 27 TC 99 Z9 104 U1 1 U2 6 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 21 PY 2004 VL 199 IS 12 BP 1671 EP 1677 DI 10.1084/jem.20032247 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 831TJ UT WOS:000222218700007 PM 15197225 ER PT J AU Erman, B Guinter, TI Singer, A AF Erman, B Guinter, TI Singer, A TI Defined alpha beta T cell receptors with distinct ligand specificities do not require those ligands to signal double negative thymocyte differentiation SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE DN to DP transition; alpha beta TCR transgene; ligand-independent signaling; pre-TCR/alpha gamma TCR ID ANTIGEN RECEPTOR; LYMPHOCYTE DEVELOPMENT; POSITIVE SELECTION; TRANSGENIC MICE; PT-ALPHA; B-CELLS; TCR; EXPRESSION; GENE; REARRANGEMENT AB During T cell development in the thymus, pre-T cell receptor (TCR,) complexes signal CD4(-)CD8(-) (double negative [DN]) thymocytes to differentiate into CD4(+) CD8(+) (double positive [DP]) thymocytes, and they generate such signals without apparent ligand engagements. Although ligand-independent signaling is unusual and might be unique to the pre-TCR, it is possible that other TCR complexes such as alphabeta TCR or alphagamma TCR might also be able to signal the DN to DP transition in the absence of ligand engagement if they were expressed on DN thymocytes. Although alphagamma TCR complexes efficiently signal DN thymocyte differentiation, it is not yet certain if alphabeta TCR complexes are also capable of signaling DN thymocyte differentiation, nor is it certain if such signaling is dependent upon ligand engagement. This study has addressed these questions by expressing defined alphabeta TCR transgenes in recombination activating gene 2(-/-) pre-Talpha(-/-) double deficient mice. In such double deficient mice, the only antigen receptors that can be expressed are those encoded by the alphabeta TCR transgenes. In this way, this study definitively demonstrates that alphabeta TCR can in fact signal the DN to DP transition. In addition, this study demonstrates that transgenic alphabeta TCRs signal the DN to DP transition even in the absence of their specific MHC-peptide ligands. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Room 4B36, Bethesda, MD 20892 USA. EM SingerA@nih.gov NR 29 TC 7 Z9 7 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUN 21 PY 2004 VL 199 IS 12 BP 1719 EP 1724 DI 10.1084/jem.20032204 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 831TJ UT WOS:000222218700012 PM 15210747 ER PT J AU Desper, R Khan, J Schaffer, AA AF Desper, R Khan, J Schaffer, AA TI Tumor classification using phylogenetic methods on expression data SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE tumor classification; gene expression data; microarrays; phylogenetic trees; small round blue cell tumors; breast cancer ID GENE-EXPRESSION; MOLECULAR CLASSIFICATION; CLASS PREDICTION; CANCER; TREES; RECONSTRUCTION; PATTERNS; PROFILES; MAPS AB Tumor classification is a well-studied problem in the field of bioinformatics. Developments in the field of DNA chip design have now made it possible to measure the expression levels of thousands of genes in sample tissue from healthy cell lines or tumors. A number of studies have examined the problems of tumor classification: class discovery, the problem of defining a number of classes of tumors using the data from a DNA chip, and class prediction, the problem of accurately classifying an unknown tumor, given expression data from the unknown tumor and from a learning set. The current work has applied phylogenetic methods to both problems. To solve the class discovery problem, we impose a metric on a set of tumors as a function of their gene expression levels, and impose a tree structure on this metric, using standard tree fitting methods borrowed from the field of phylogenctics. Phylogenetic methods provide a simple way of imposing a clear hierarchical relationship on the data, with branch lengths in the classification tree representing the degree of separation witnessed. We tested our method for class discovery on two data sets: a data set of 87 tissues, comprised mostly of small, round, blue-cell tumors (SRBCTs), and a data set of 22 breast tumors. We fit the 87 samples of the first set to a classification tree, which neatly separated into four major clusters corresponding exactly to the four groups of tumors, namely neuroblastomas, rhabdomyosarcomas, Burkitt's lymphomas, and the Ewing's family of tumors. The classification tree built using the breast cancer data separated tumors with BRCA1 mutations from those with BRCA2 mutations, with sporadic tumors separated from both groups and from each other. We also demonstrate the flexibility of the class discovery method with regard to standard resampling methodology such as jackknifing and noise perturbation. To solve the class prediction problem, we built a classification tree on the learning set, and then sought the optimal placement of each test sample within the classification tree. We tested this method on the SRBCT data set, and classified each tumor successfully. (C) 2004 Elsevier Ltd. All rights reserved. C1 Natl Lib Med, Computat Biol Branch, Natl Ctr Biotechnol Informat, NIH,Dept Hlth & Human Serv, Bethesda, MD 20894 USA. NCI, Pediat Oncol Branch, NIH, Dept Hlth & Human Serv, Gaithersburg, MD USA. RP Desper, R (reprint author), Natl Lib Med, Computat Biol Branch, Natl Ctr Biotechnol Informat, NIH,Dept Hlth & Human Serv, Bldg 38A,Room 8N805,8600 Rockville Pike, Bethesda, MD 20894 USA. EM desper@ncbi.nlm.nih.gov RI Schaffer, Alejandro/F-2902-2012; Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 NR 26 TC 23 Z9 23 U1 1 U2 3 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 J9 J THEOR BIOL JI J. Theor. Biol. PD JUN 21 PY 2004 VL 228 IS 4 BP 477 EP 496 DI 10.1016/j.jtbi.2004.02.021 PG 20 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 830XL UT WOS:000222157400005 PM 15178197 ER PT J AU Szymanska, K Lesi, OA Kirk, GD Sam, O Taniere, P Scoazec, JY Mendy, M Friesen, MD Whittle, H Montesano, R Hainaut, P AF Szymanska, K Lesi, OA Kirk, GD Sam, O Taniere, P Scoazec, JY Mendy, M Friesen, MD Whittle, H Montesano, R Hainaut, P TI Ser-249 TP53 mutation in tumour and plasma DNA of hepatocellular carcinoma patients from a high incidence area in the Gambia, West Africa SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE Ser-249 TP53; hepatocellular carcinoma; plasma; circulating free DNA; the Gambia; aflatoxin ID SQUAMOUS-CELL CARCINOMA; LIVER-CANCER PATIENTS; P53 MUTATIONS; AFLATOXIN B-1; CODON 249; GENE; EXPOSURE; SERUM; CARCINOGENESIS; SPECTROMETRY AB Hepatocellular carcinoma (HCC) is frequent in areas of high exposure to aflatoxin and high prevalence of HBV infection, such as western Africa and south-east China. A selective mutation in TP53 (AGG --> AGT at codon 249, Arg --> Ser) has been identified as a hotspot in HCCs from such areas, reflecting DNA damage caused by aflatoxin metabolites. Recent studies have shown that circulating free DNA can be retrieved from human plasma, and it is hypothesised that plasma DNA may serve as a source for biomarkers of tumorigenic processes. In our study, we have determined the prevalence of Ser-249 mutation, using a PCR-restriction digestion method, with selective use of short oligonucleotide mass spectrometry analysis (SOMA), in a series of 29 biopsy specimens of HCC from The Gambia in West Africa. Overall, we identified the Ser-249 mutation in 35% (10/29) of the tumours. In parallel, we tested 17 plasma samples from HCC patients with matching tumour tissue. The 249 status concordance between tumour tissues and matched plasma was 88.5%. These results indicate that the Ser-249 mutation is common in HCC in The Gambia (35%), although a higher prevalence has been reported in other regions with high population exposure to aflatoxin (e.g., eastern China: >50%). Moreover, our studies indicate that plasma is a convenient source of liver tumour-derived DNA, thus holding promise for earlier detection and diagnosis of cancer. (C) 2004 Wiley-Liss, Inc. C1 Int Agcy Res Canc, F-69008 Lyon 08, France. Gambia Hepatitis Intervent Study, Lyon, France. NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. Royal Victoria Hosp, Banjul, Gambia. Hop Edouard Herriot, Anat Pathol Lab, Lyon, France. MRC Labs, IARC, Gambia Hepatitis Intervent Study, Fajara, Gambia. RP Hainaut, P (reprint author), Int Agcy Res Canc, 150 Cours Albert Thomas, F-69008 Lyon 08, France. EM hainaut@iarc.fr RI Kirk, Gregory/A-8484-2009; Friesen, Marlin/D-7328-2012; Hainaut, Pierre /B-6018-2012 OI Hainaut, Pierre /0000-0002-1303-1610 FU NCI NIH HHS [N02CP40521] NR 37 TC 41 Z9 46 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUN 20 PY 2004 VL 110 IS 3 BP 374 EP 379 DI 10.1002/ijc.20103 PG 6 WC Oncology SC Oncology GA 820GD UT WOS:000221374600009 PM 15095302 ER PT J AU Castelao, JE Yuan, JM Gago-Dominguez, M Skipper, PL Tannenbaum, SR Chan, KK Watson, MA Bell, DA Coetzee, GA Ross, RK Yu, MC AF Castelao, JE Yuan, JM Gago-Dominguez, M Skipper, PL Tannenbaum, SR Chan, KK Watson, MA Bell, DA Coetzee, GA Ross, RK Yu, MC TI Carotenoids/vitamin C and smoking-related bladder cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE bladder cancer; diet; cartenoids; vitimin C; 3-and 4-aminobiphenyl adducts; arylamine-metabolizing enzymes ID PERMANENT HAIR-DYES; DIETARY FACTORS; UROTHELIAL CANCER; URINARY-BLADDER; RISK; VEGETABLES; FRUITS; SUPPLEMENTS; COHORT; MEN AB Previous epidemiological studies of fruit and vegetable intake and bladder cancer risk have yielded inconsistent results, especially with respect to the role of cigarette smoking as a possible modifier of the diet-bladder cancer association. A population-based case-control study was conducted in nonAsians of Los Angeles, California, which included 1,592 bladder cancer patients and an equal number of neighborhood controls matched to the index cases by sex, date of birth (within 5 years) and race between January 1, 1987 and April 30, 1996. Information on smoking, medical and medication history, and intake frequencies of food groups rich in preformed nitrosamines, vitamins A and C and various, carotenoids, were collected through in-person, structured interviews. Beginning in January 1992, all case patients and their matched control subjects were asked for a blood sample donation at the end of the in-person interviews for measurements of 3- and 4-aminobiphenyl (ABP) hemoglobin adducts, and glutathione S-transferases M1/T1/P1 (GSTM1/T1/P1) and N-acetyltransferase-1 (NAT1) genotypes. Seven hundred seventy-one (74%) case patients and 775 (79%) control subjects consented to the blood donation requests. In addition, all case patients and matched control subjects were asked to donate an overnight urine specimen following caffeine consumption for measurements of cytochrome P4501A2 (CYPIA2) and N-acetyltransferase-2 (NAT2) phenotypes. Urine specimens were collected from 724 (69%) case patients and 689 (70%) control subjects. After adjustment for nondietary risk factors including cigarette smoking, there were strong inverse associations between bladder cancer risk and intake of dark-green vegetables [p value for linear trend (p) = 0.01], yellow-orange vegetables (p = 0.01), citrus fruits/juices (p = 0.002) and tomato products (p = 0.03). In terms of nutrients, bladder cancer risk was inversely associated with intake of both total carotenoids (p = 0.004) and vitamin C (p = 0.02). There was a close correlation (r = 0.58, p = 0.0001) between intakes of total carotenoids and vitamin C in study subjects. When both nutrients were included in a multivariate logistic regression model, only total carotenoids exhibited a residual effect that was of borderline statistical significance (p = 0.07 and p = 0.40 for total carotenoids and vitamin C, respectively). Cigarette smoking was a strong modifier of the observed dietary effects; these protective effects were confined largely to ever smokers and were stronger in current than ex-smokers. Smokers showed a statistically significant or borderline statistically significant decrease in 3- and 4-aminobiphenyl (ABP)-hemoglobin adduct level with increasing intake of carotenoids (p = 0.04 and 0.05, respectively). The protective effect of carotenoids on bladder cancer seemed to be influenced by NAT1 genotype, NAT2 phenotype and CYP1A2 phenotype; the association was mainly confined to subjects possessing the putative NAT1-rapid, NAT2-rapid and CYP1A2-rapid genotype/phenotype. The carotenoid-bladder cancer association was not affected by the GSTM1, GSTT1 and GSTP1 genotypes. (C) 2004 Wiley-Liss, Inc. C1 Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Los Angeles, CA 90089 USA. MIT, Dept Chem, Cambridge, MA 02139 USA. MIT, Div Toxicol, Cambridge, MA 02139 USA. Ohio State Univ, Coll Pharm, Columbus, OH 43210 USA. NIEHS, Lab Computat Biol & Risk Anal, Res Triangle Pk, NC 27709 USA. RP Castelao, JE (reprint author), Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, 1441 Eastlake Ave, Los Angeles, CA 90089 USA. EM castelao@usc.edu OI Yuan, Jian-Min/0000-0002-4620-3108 FU NCI NIH HHS [R01 CA65726, R35 CA53890, P01 CA17054]; NIEHS NIH HHS [P30 ES07048, P01 ES05622] NR 37 TC 47 Z9 47 U1 0 U2 6 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUN 20 PY 2004 VL 110 IS 3 BP 417 EP 423 DI 10.1002/ijc.20104 PG 7 WC Oncology SC Oncology GA 820GD UT WOS:000221374600015 PM 15095308 ER PT J AU Joffe, S Harrington, DP George, SL Emanuel, EJ Budzinski, LA Weeks, JC AF Joffe, S Harrington, DP George, SL Emanuel, EJ Budzinski, LA Weeks, JC TI Satisfaction of the uncertainty principle in cancer clinical trials: retrospective cohort analysis SO BRITISH MEDICAL JOURNAL LA English DT Article ID BREAST-CANCER; EQUIPOISE; ETHICS; PERSPECTIVE; ONCOLOGY; THERAPY; REASONS; SURGERY AB Objective To assess whether publicly funded adult cancer trials satisfy the uncertainty principle, which states that physicians should enrol a patient in a trial only if they are substantially uncertain which of the treatments in the trial is most appropriate for the patient. This principle is violated if trials systematically favour either the experimental or the standard treatment. Design Retrospective cohort study of completed cancer trials, with randomisation as the unit of analysis. Setting Two cooperative research groups in the United States. Studies included 93 phase III randomised trials (103 randomisations) that completed recruitment of patients between 1981 and 1995. Main outcome measures Whether the randomisation favoured the experimental treatment, the standard treatment, or neither treatment; effect size (outcome of the experimental treatment compared with outcome of the standard treatment) for each randomisation. Results Three randomisations (3%) favoured the standard treatment, 70 (68%) found no significant difference between treatments, and 30 (29%) favoured the experimental treatment. The average effect size was 1.20 (95% confidence interval 1.13 to 1.28), reflecting a slight advantage for the experimental treatment. Conclusions In cooperative group trials in adults with cancer, there is a measurable average improvement in disease control associated with assignment to the experimental rather than the standard arm. However, the heterogeneity of outcomes and the small magnitude of the advantage suggest that, as a group, these trials satisfy the uncertainty principle. C1 Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Biostat Sci, Boston, MA 02115 USA. NIH, Dept Clin Bioeth, Warren G Magnuson Clin Ctr, Durham, NC 27710 USA. Lesley Coll, Cambridge, MA 02138 USA. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Ctr Stat, Canc & Leukemia Grp B, Durham, NC 27710 USA. RP Joffe, S (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. EM steven_joffe@dfci.harvard.edu OI Joffe, Steven/0000-0002-0667-7384 FU NCI NIH HHS [CA23318, CA33601, CA96872] NR 24 TC 14 Z9 14 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD JUN 19 PY 2004 VL 328 IS 7454 BP 1463 EP 1466 DI 10.1136/bmj.38118.685289.55 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 832CK UT WOS:000222244600014 PM 15163611 ER PT J AU Belsky, L Richardson, HS AF Belsky, L Richardson, HS TI Medical researchers' ancillary clinical care responsibilities SO BRITISH MEDICAL JOURNAL LA English DT Article C1 NIH, Dept Clin Bioeth, Bethesda, MD 20898 USA. RP Belsky, L (reprint author), NIH, Dept Clin Bioeth, 10 Ctr Dr, Bethesda, MD 20898 USA. EM lbelsky@mail.cc.nih.gov NR 8 TC 90 Z9 90 U1 0 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD JUN 19 PY 2004 VL 328 IS 7454 BP 1494 EP 1496 DI 10.1136/bmj.328.7454.1494 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 832CK UT WOS:000222244600025 PM 15205296 ER PT J AU Priola, SA Vorberg, I AF Priola, SA Vorberg, I TI Identification of possible animal origins of prion disease in human beings SO LANCET LA English DT Editorial Material ID CREUTZFELDT-JAKOB-DISEASE; SINGLE AMINO-ACID; SPONGIFORM ENCEPHALOPATHY; VARIANT CJD; INCUBATION-TIME; BSE AGENT; SCRAPIE; PROTEIN; MICE; PHENOTYPES C1 NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Tech Univ Munich, Inst Virol, D-8000 Munich, Germany. RP Priola, SA (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM spriola@niaid.nih.gov NR 17 TC 7 Z9 7 U1 0 U2 3 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUN 19 PY 2004 VL 363 IS 9426 BP 2013 EP 2014 DI 10.1016/S0140-6736(04)16487-8 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 830YJ UT WOS:000222159800005 PM 15207949 ER PT J AU Lodde, BM Delporte, C Goldsmith, CM Tak, PP Baum, BJ AF Lodde, BM Delporte, C Goldsmith, CM Tak, PP Baum, BJ TI A recombinant adenoviral vector encoding functional vasoactive intestinal peptide SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE vasoactive intestinal peptide; gene transfer; adenovirus; autoimmune disease ID IN-VIVO; POLYPEPTIDE; CELLS; GENE; VIP; AUTOIMMUNE; EXPRESSION; ARTHRITIS; SECRETION; RECEPTOR AB Vasoactive intestinal peptide (VIP) is a small neuropeptide, which exerts pleiotropic functions. Based on its immunomodulatory, secretory, and possibly trophic effects, VIP is a valuable candidate molecule for the management of autoimmune disease. The purpose of this study was to develop a recombinant viral vector capable of directing the expression of functional VIP. The vector rAd5CMVhVIP was constructed and used to infect 293 cells. VIP expression was measured by an ELISA and function was evaluated by measurement of intracellular cAMP formation. rAd5CMVhVIP directed VIP expression and the transgenic VIP elicited a dose-dependent increase of intracellular cAMP, mediated through the VIP receptor VPAC(1). This is the first report showing the construction of a recombinant viral vector encoding biologically active VIP. (C) 2004 Elsevier Inc. All rights reserved. C1 Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, DHHS, Bethesda, MD 20892 USA. Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. Free Univ Brussels, Fac Med, Dept Biochem & Nutr, Brussels, Belgium. RP Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, DHHS, Bethesda, MD 20892 USA. EM blodde@dir.nidcr.nih.gov NR 27 TC 6 Z9 10 U1 2 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 18 PY 2004 VL 319 IS 1 BP 189 EP 192 DI 10.1016/j.bbrc.2004.04.171 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 828TX UT WOS:000221997300027 PM 15158460 ER PT J AU Maceyka, M Nava, VE Milstien, S Spiegel, S AF Maceyka, M Nava, VE Milstien, S Spiegel, S TI Aminoacylase 1 is a sphingosine kinase 1-interacting protein SO FEBS LETTERS LA English DT Article DE aminoacylase 1; sphingosine kinase; sphingosine; sphingosine-1-phosphate; yeast two-hybrid ID KINASE; SPHINGOSINE-1-PHOSPHATE; ACTIVATION; CELLS; 1-PHOSPHATE; APOPTOSIS; GROWTH; LOCALIZATION; RECEPTORS; SURVIVAL AB Sphingosine kinase type 1 (SphK1) and its product sphingosine-1-phosphate have been shown to promote cell growth and inhibit apoptosis of tumor cells. In an effort to further understand the regulation of SphK1, we used a yeast two-hybrid screen to find SphK1-interacting proteins. One of these was identified as aminoacylase 1 (Acyl), a metalloenzyme that removes amide-linked acyl groups from amino acids and may play a role in regulating responses to oxidative stress. Both the C-terminal fragment found in the two-hybrid screen and full-length Acyl co-immunoprecipitate with SphK1. Though both C-terminal and full-length proteins slightly reduce SphK1 activity measured in vitro, the C-terminal fragment inhibits while full-length Acyl potentiates the effects of SphK1 on proliferation and apoptosis. Interestingly, Acyl induces redistribution of SphK1 as observed by immunocytochemistry and subcellular fractionation. Collectively, our data suggest that Acyl physically interacts with SphK1 and may influence its physiological functions. (C) 2004 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 Virginia Commonwealth Univ, Sch Med, Dept Biochem, Richmond, VA 23298 USA. NCI, Pathol Lab, Bethesda, MD USA. NIMH, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Virginia Commonwealth Univ, Sch Med, Dept Biochem, Med Coll Virginia Campus, Richmond, VA 23298 USA. EM sspiegel@vcu.edu RI Maceyka, Michael/B-9277-2008 FU NCI NIH HHS [R01CA61774] NR 32 TC 42 Z9 44 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUN 18 PY 2004 VL 568 IS 1-3 BP 30 EP 34 DI 10.1016/j.febslet.2004.04.093 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 831OX UT WOS:000222205200007 PM 15196915 ER PT J AU Karsten, V Hegde, RS Sinai, AP Yang, M Joiner, KA AF Karsten, V Hegde, RS Sinai, AP Yang, M Joiner, KA TI Transmembrane domain modulates sorting of membrane proteins in Toxoplasma gondii SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DENSE GRANULE ANTIGEN; PARASITOPHOROUS VACUOLE MEMBRANE; ENDOPLASMIC-RETICULUM; MOLECULAR CHARACTERIZATION; SECRETORY PROTEINS; CYTOCHROME B(5); RETENTION; BIOGENESIS; SEQUENCE; DEGRADATION AB Overlapping mechanisms that function simultaneously in the intracellular sorting of mammalian membrane proteins often confound delineation of individual sorting pathways. By analyzing sorting in the evolutionarily simpler organism Toxoplasma gondii, we demonstrate a role for transmembrane domain (TMD) length in modulating the signal-dependent segregation of membrane proteins to distinct intracellular organelles. The dense granule localization of the single pass transmembrane protein GRA4 could be completely rerouted to the Golgi and cell surface simply by replacement of its TMD with that from either vesicular stomatitis virus G or the low density lipoprotein (LDL) receptor. Mutational and biochemical analyses suggested that this effect was not caused by any specific sequence motif or strength of membrane association of the GRA4 TMD. Instead, a property imparted by the vesicular stomatitis virus G or LDL receptor TMDs, both of which are longer than the GRA4 TMD, appeared to be a decisive factor. Indeed, shortening the LDL receptor TMD to a length similar to that of GRA4 resulted in dense granule localization, whereas lengthening the GRA4 TMD resulted in rerouting to the Golgi. From these data, we conclude that although the TMD may not necessarily be a sole determinant in membrane protein sorting, its properties can markedly modulate the utilization of more conventional signal-mediated sorting pathways. C1 Yale Univ, Sch Med, Dept Internal Med, Infect Dis Sect, New Haven, CT 06520 USA. NICHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Joiner, KA (reprint author), Univ Arizona, Hlth Sci Ctr, Coll Med, 1501 N Campbell Ave,Rm 2205, Tucson, AZ 85724 USA. EM kjoiner@u.arizona.edu OI Hegde, Ramanujan/0000-0001-8338-852X NR 43 TC 22 Z9 24 U1 3 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 18 PY 2004 VL 279 IS 25 BP 26052 EP 26057 DI 10.1074/jbc.M400480200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 828VY UT WOS:000222003000017 PM 15056659 ER PT J AU Shieh, JJ Pan, CJ Mansfield, BC Chou, JY AF Shieh, JJ Pan, CJ Mansfield, BC Chou, JY TI A potential new role for muscle in blood glucose homeostasis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GLYCOGEN-STORAGE-DISEASE; PHOSPHOHISTIDINE-ENZYME INTERMEDIATE; GLUCOSE-6-PHOSPHATE TRANSPORTER; MURINE GLUCOSE-6-PHOSPHATASE; SKELETAL-MUSCLE; GENE; TYPE-1A; IDENTIFICATION; CATALYSIS; PROTEIN AB The breakdown of tissue glycogen into glucose is critical for blood glucose homeostasis between meals. In the final steps of glycogenolysis, intracellular glucose 6-phosphate (Glc-6-P) is transported into the endoplasmic reticulum where it is hydrolyzed to glucose by glucose-6-phosphatase (Glc-6-Pase). Although the majority of body glycogen is stored in the muscle, the current dogma holds that Glc-6-Pase (now named Glc-6-Pase-alpha) is expressed only in the liver, kidney, and intestine, implying that muscle glycogen cannot contribute to interprandial blood glucose homeostasis. Recently we reported a second Glc-6-P hydrolase, Glc-6-Pase-beta. Glc-6-Pase-alpha shares kinetic and structural similarities to Glc-6-Pase-alpha and couples with the Glc-6-P transporter to form an active Glc-6-Pase complex (Shieh, J.-J., Pan, C.-J., Mansfield, B. C., and Chou, J. Y. (2003) J. Biol. Chem. 278, 47098-47103). Here we demonstrate that muscle expresses both Glc-6-Pase-beta and Glc-6-P transporter and that they can couple to form an active Glc-6-Pase complex. Our data suggest that muscle may have a previously unrecognized role in interprandial glucose homeostasis. C1 NICHD, Sect Cellular Differentat, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Chou, JY (reprint author), NICHD, Sect Cellular Differentat, Heritable Disorders Branch, NIH, Bldg 10,Rm 9S241,9000 Rockville Pike, Bethesda, MD 20892 USA. EM chouja@mail.nih.gov OI Mansfield, Brian/0000-0002-8533-2789 NR 31 TC 16 Z9 17 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 18 PY 2004 VL 279 IS 25 BP 26215 EP 26219 DI 10.1074/jbc.M402036200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 828VY UT WOS:000222003000037 PM 15087461 ER PT J AU Brar, SS Watson, M Diaz, M AF Brar, SS Watson, M Diaz, M TI Activation-induced cytosine deaminase (AID) is actively exported out of the nucleus but retained by the induction of DNA breaks SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CLASS-SWITCH RECOMBINATION; DOUBLE-STRAND BREAKS; IMMUNOGLOBULIN VARIABLE GENES; B MESSENGER-RNA; SOMATIC HYPERMUTATION; POLYMERASE-ETA; ANTIBODY DIVERSIFICATION; CYTIDINE; REPAIR; MICE AB Activation-induced cytosine deaminase (AID) is a cytosine deaminase that is critical to immunoglobulin hypermutation, class switch recombination, and gene conversion. In the context of hypermutating B cells, AID deaminates cytosine in the DNA of immunoglobulin genes, leading to the accumulation of mutations in the variable regions. However, when AID is expressed ectopically, it is a generalized mutator of G: C base pairs. Therefore, we asked whether AID may be partially regulated by an active system of nuclear export. We found that removal of a highly conserved nuclear export signal in the C terminus of AID causes accumulation of AID in the nucleus. However, a putative nuclear localization signal in the N terminus does not appear to be functional. Finally, we found that agents that induce DNA breaks caused retention of AID in the nucleus, suggesting that DNA breaks or the repair patches initiated as a result are a substrate for AID binding. C1 NIEHS, Genet Mol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Diaz, M (reprint author), NIEHS, Genet Mol Lab, NIH, 111 TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM diaz@niehs.nih.gov NR 60 TC 97 Z9 99 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 18 PY 2004 VL 279 IS 25 BP 26395 EP 26401 DI 10.1074/jbc.M403503200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 828VY UT WOS:000222003000060 PM 15087440 ER PT J AU Leikina, E Mittal, A Cho, MS Melikov, K Kozlov, MM Chernomordik, LV AF Leikina, E Mittal, A Cho, MS Melikov, K Kozlov, MM Chernomordik, LV TI Influenza hemagglutinins outside of the contact zone are necessary for fusion pore expansion SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MEDIATED MEMBRANE-FUSION; VIRUS HEMAGGLUTININ; BIOLOGICAL-MEMBRANES; LATERAL MOBILITY; HEMIFUSION; CELL; FISSION; PATHWAY; PH; CONFORMATION AB Current models for membrane fusion in diverse biological processes are focused on the local action of fusion proteins present in the contact zone where the proteins anchored in one membrane might interact directly with the other membrane. Are the fusion proteins outside of the contact zone just bystanders? Here we assess the role of these "outsider" proteins in influenza virus hemagglutinin-mediated fusion between red blood cells and either hemagglutinin-expressing cells or viral particles. To selectively inhibit or enhance the actions of hemagglutinin outsiders, the antibodies that bind to hemagglutinin and proteases that cleave it were conjugated to polystyrene microspheres too large to enter the contact zone. We also involved hemagglutinin outsiders into interactions with additional red blood cells. We find the hemagglutinin outsiders to be necessary and sufficient for fusion. Interfering with the activity of the hemagglutinin outsiders inhibited fusion. Selective conversion of hemagglutinin outsiders alone into fusion-competent conformation was sufficient to achieve fusion. The discovered functional role of fusion proteins located outside of the contact zone suggests a tempting analogy to mechanisms by which proteins mediate membrane fission from outside of the fission site. C1 NICHD, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, IL-69978 Tel Aviv, Israel. RP Chernomordik, LV (reprint author), NICHD, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, Bldg 10,Rm 10D04,10 Ctr Dr, Bethesda, MD 20892 USA. EM lchern@helix.nih.gov RI Melikov, Kamran/A-6604-2009; Mittal, Aditya/E-3087-2010 OI Mittal, Aditya/0000-0002-4030-0951 NR 33 TC 35 Z9 36 U1 1 U2 6 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 18 PY 2004 VL 279 IS 25 BP 26526 EP 26532 DI 10.1074/jbc.M401883200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 828VY UT WOS:000222003000076 PM 15078874 ER PT J AU Sedelies, KA Sayers, TJ Edwards, KM Chen, WS Pellicci, DG Godfrey, DI Trapani, JA AF Sedelies, KA Sayers, TJ Edwards, KM Chen, WS Pellicci, DG Godfrey, DI Trapani, JA TI Discordant regulation of granzyme H and granzyme B expression in human lymphocytes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SERINE ESTERASE GENE; CATHEPSIN-G GENE; CYTOTOXIC LYMPHOCYTES; CELL-DEATH; CASPASE ACTIVATION; CYTOSOLIC DELIVERY; TARGET-CELLS; T-CELLS; APOPTOSIS; PERFORIN AB We analyzed the expression of granzyme H in human blood leukocytes, using a novel monoclonal antibody raised against recombinant granzyme H. 33-kDa granzyme H was easily detected in unfractionated peripheral blood mononuclear cells, due to its high constitutive expression in CD3(-)CD56(+) natural killer (NK) cells, whereas granzyme B was less abundant. The NK lymphoma cell lines, YT and Lopez, also expressed high granzyme H levels. Unstimulated CD4(+) and particularly CD8(+) T cells expressed far lower levels of granzyme H than NK cells, and various agents that classically induce T cell activation, proliferation, and enhanced granzyme B expression failed to induce granzyme H expression in T cells. Also, granzyme H was not detected in NK T cells, monocytes, or neutrophils. There was a good correlation between mRNA and protein expression in cells that synthesize both granzymes B and H, suggesting that gzmH gene transcription is regulated similarly to gzmB. Overall, our data indicate that although the gzmB and gzmH genes are tightly linked, expression of the proteins is quite discordant in T and NK cells. The finding that granzyme H is frequently more abundant than granzyme B in NK cells is consistent with a role for granzyme H in complementing the pro-apoptotic function of granzyme B in human NK cells. C1 Peter MacCallum Canc Ctr, Canc Immunol Lab, Melbourne 8006, Australia. NCI, Basic Res Program, SAIC Frederick Inc, NIH, Frederick, MD 21702 USA. Austin & Repatriat Med Ctr, Ludwig Inst Canc Res, Heidelberg, Vic 3084, Australia. Monash Univ, Sch Med, Dept Pathol & Immunol, Melbourne, Vic 3181, Australia. RP Trapani, JA (reprint author), Peter MacCallum Canc Ctr, Canc Immunol Lab, Locked Bag 1,ABeckett St, Melbourne 8006, Australia. EM joe.trapani@petermac.org RI Chen, Weisan/E-7828-2012; Sayers, Thomas/G-4859-2015 FU NCI NIH HHS [N01-CO-56000] NR 38 TC 52 Z9 52 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 18 PY 2004 VL 279 IS 25 BP 26581 EP 26587 DI 10.1074/jbc.M312481200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 828VY UT WOS:000222003000083 PM 15069086 ER PT J AU Lee, IH You, JO Ha, KS Bae, DS Suh, PG Rhee, SG Bae, YS AF Lee, IH You, JO Ha, KS Bae, DS Suh, PG Rhee, SG Bae, YS TI AHNAK-mediated activation of phospholipase C-gamma 1 through protein kinase C SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ARACHIDONIC-ACID RELEASE; A(2); CA2+; PHOSPHORYLATION; BRADYKININ; CALCIUM; GAMMA; CELLS; PLC-GAMMA-1; FIBROBLASTS AB We have recently shown that phospholipase C-gamma (PLC-gamma) is activated by the central repeated units ( CRUs) of the AHNAK protein in the presence of arachidonic acid. Here we demonstrate that four central repeated units ( 4 CRUs) of AHNAK act as a scaffolding motif networking PLC-gamma and PKC-alpha. Specifically, 4 CRUs of AHNAK bind and activate PKC-alpha, which in turn stimulates the release of arachidonic acid near where PLC-gamma1 is localized. Moreover, 4 CRUs of AHNAK interacted with PLC-gamma and the concerted action of 4 CRUs with arachidonic acid stimulated PLC-gamma activity. Stimulation of NIH3T3 cells expressing 4 CRUs of AHNAK with phorbol 12-myristate 13-acetate resulted in the increased generation of total inositol phosphates (IPT) and mobilization of the intracellular calcium. Phorbol 12-myristate 13-acetate-dependent generation of IPT was completely blocked in NIH3T3 cells depleted of PLC-gamma1 by RNA interference. Furthermore, bradykinin, which normally stimulated the PLC-beta isozyme resulting in the generation of a monophasic IPT within 30 s in NIH3T3 cells, led to a biphasic pattern for generation of IPT in NIH3T3 cells expressing 4 CRUs of AHNAK. The secondary activation of PLC is likely because of the scaffolding activity of AHNAK, which is consistent with the role of 4 CRUs as a molecular linker between PLC-gamma and PKC-alpha. C1 Ewha Womans Univ, Ctr Cell Signaling Res, Div Mol Life Sci, Seoul 120750, South Korea. Kangweon Natl Univ, Dept Biochem, Chunchon 200701, Kangwondo, South Korea. SungKyunKwan Univ, Samsung Med Ctr, Dept Obstet & Gynecol, Seoul 135230, South Korea. POSTECH, Dept Life Sci, Pohang 790784, South Korea. NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20852 USA. RP Bae, YS (reprint author), Ewha Womans Univ, Ctr Cell Signaling Res, Div Mol Life Sci, 11-1 Daehyun Dong, Seoul 120750, South Korea. EM baeys@ewha.ac.kr RI Suh, Pann-Ghill/F-3610-2010 NR 43 TC 32 Z9 34 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 18 PY 2004 VL 279 IS 25 BP 26645 EP 26653 DI 10.1074/jbc.M311525200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 828VY UT WOS:000222003000091 PM 15033986 ER PT J AU Johnson, MD Yu, LR Conrads, TP Kinoshita, Y Uo, T Matthews, JD Lee, SW Smith, RD Veenstra, TD Morrison, RS AF Johnson, MD Yu, LR Conrads, TP Kinoshita, Y Uo, T Matthews, JD Lee, SW Smith, RD Veenstra, TD Morrison, RS TI Proteome analysis of DNA damage-induced neuronal death using high throughput mass spectrometry SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RESPONSE MEDIATOR PROTEIN-2; ACTIN DEPOLYMERIZING FACTOR; ALZHEIMERS-DISEASE; CELL-DEATH; PARKINSONS-DISEASE; OXIDATIVE STRESS; NEUROFIBRILLARY TANGLES; TRANSCRIPTIONAL TARGET; LIQUID-CHROMATOGRAPHY; HIPPOCAMPAL-NEURONS AB Isotope-coded affinity tag reagents and high throughput mass spectrometry were used to quantitate changes in the expression of 150 proteins in mouse wild-type (p53(+/+)) cortical neurons undergoing DNA damage-induced death. Immunological techniques confirmed several of the changes in protein expression, but microarray analysis indicated that many of these changes were not accompanied by altered mRNA expression. Proteome analysis revealed perturbations in mitochondrial function, free radical production, and neuritogenesis that were not observed in p53-deficient neurons. Changes in Tau, cofilin, and other proteins recapitulated abnormalities observed in neurodegenerative states in vivo. Additionally, DNA damage caused a p53-dependent decrease in expression of members of the protein kinase A (PKA) signaling pathway. PKA inhibition promoted death in the absence of DNA damage, revealing a novel mechanism by which endogenous down-regulation of PKA signaling may contribute to p53-dependent neuronal death. These data demonstrate the power of high throughput mass spectrometry for quantitative analysis of the neuronal proteome. C1 Univ Washington, Sch Med, Dept Neurol Surg, Seattle, WA 98195 USA. NCI, Biomed Proteom Program, SAIC Frederick, Frederick, MD 21702 USA. Pacific NW Natl Lab, Environm & Mol Sci Lab, Richland, WA 99352 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol Surg, Boston, MA 02115 USA. RP Morrison, RS (reprint author), Univ Washington, Sch Med, Dept Neurol Surg, Box 356470,1959 NE Pacific St, Seattle, WA 98195 USA. EM yael@u.washington.edu RI Smith, Richard/J-3664-2012; Lee, Sang-Won/H-6760-2013 OI Smith, Richard/0000-0002-2381-2349; Lee, Sang-Won/0000-0002-5042-0084 FU NINDS NIH HHS [K08 NS43482-01, NS35533, NS39617, NS41714] NR 48 TC 22 Z9 23 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 18 PY 2004 VL 279 IS 25 BP 26685 EP 26697 DI 10.1074/jbc.M401274200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 828VY UT WOS:000222003000095 PM 15060066 ER PT J AU Ahvazi, B Boeshans, KM Steinert, PM AF Ahvazi, B Boeshans, KM Steinert, PM TI Crystal structure of transglutaminase 3 in complex with GMP - Structural basis for nucleotide specificity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CROSS-LINKING ENZYMES; TISSUE TRANSGLUTAMINASE; EPIDERMAL-KERATINOCYTES; PROTRANSGLUTAMINASE-E; CALCIUM-IONS; PROTEIN; BINDING; ACTIVATION; EXPRESSION; CELLS AB Epidermal-type Transglutaminase 3(TGase3) is a Ca2+-dependent enzyme involved in the cross-linking of structural proteins required in the assembly of the cell envelope. We have recently shown that calcium-activated TGase 3, like TGase 2, can bind, hydrolyze, and is inhibited by GTP despite lacking structural homology with other GTP-binding proteins. Here we report the crystal structure determined at 2.0 Angstrom resolution of TGase 3 in complex with GMP to elucidate the structural features required for nucleotide recognition. Binding affinities for various nucleotides were found by fluorescence displacement to be as follows: guanosine 5'-3-O-( thio) triphosphate (GTPgammaS) (0.4 muM), GTP (0.6 muM), GDP (1.0 muM), GMP (0.4 muM), and ATP (28.0 muM). Furthermore, we found that GMP binds as a reversible, noncompetitive inhibitor of TGase 3 transamidation activity, similar to GTPgammaS and GDP. A genetic algorithm similarity program ( GASP) approach ( virtual ligand screening) identified three compounds from the Lead Quest(TM) data base (Tripos Inc.) based on superimposition of GTPgammaS, GDP, and GMP guanine nucleotides from our crystal structures to generate the minimum align flexible fragment. These three were nucleotide analogs without a phosphate group containing the minimal binding motif for TGase 3 that includes a nucleoside recognition groove. Binding affinities were measured as follows: TP349915 (K-d = 4.1 muM), TP395289 (K-d = 38.5 muM), TP394305 (K-d = 1.0 mM). Remarkably, these compounds do not inhibit but instead activate TGase 3 transamidation by about 10-fold. These results suggest that the nucleotide binding pocket in TGase 3 may be exploited to either enhance or inhibit the enzymatic activity as required for different therapeutic approaches. C1 NIAMS, Xray Crystallog Facil, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. NIAMS, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ahvazi, B (reprint author), NIAMS, Xray Crystallog Facil, Off Sci & Technol, NIH, 50 S Dr,Bldg 1345, Bethesda, MD 20892 USA. EM ahvazib@mail.nih.gov NR 46 TC 14 Z9 14 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 18 PY 2004 VL 279 IS 25 BP 26716 EP 26725 DI 10.1074/jbc.M403481200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 828VY UT WOS:000222003000098 PM 15084592 ER PT J AU Li, SP Wang, XT Klee, CB Krieger, C AF Li, SP Wang, XT Klee, CB Krieger, C TI Overexpressed mutant G93A superoxide dismutase protects calcineurin from inactivation SO MOLECULAR BRAIN RESEARCH LA English DT Article DE amyotrophic lateral sclerosis; calcineurin; protein phosphatase; superoxide dismutase; transgenic ID AMYOTROPHIC-LATERAL-SCLEROSIS; OXIDATIVE INACTIVATION; TRANSGENIC MICE; SPINAL-CORD; DEGENERATION AB Previous studies have claimed that there is a failure of a mutant form of superoxide dismutase (mSOD) to protect the protein phosphatase, calcineurin (CN), against inactivation in the pathogenesis of amyotrophic lateral sclerosis (ALS), as determined in a murine model of ALS resulting from overexpression of mSOD (G93A). In contrast to previous studies, we find that mice overexpressing G93A mSOD have no statistically significant differences in the expression, or activity, of CN. However, CN from G93A mSOD overexpressing mice is significantly more protected against inactivation than non-transgenic mice that do not overexpress SOD. This reduced inactivation of CN is a consequence of increased expression of G93A mSOD. Thus, like wild-type SOD, G93A mSOD protects CN against inactivation. (C) 2004 Elsevier B.V All rights reserved. C1 Simon Fraser Univ, Sch Kinesiol, Burnaby, BC V5A 1S6, Canada. NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. Univ British Columbia, Dept Med, Vancouver, BC V5Z 1M9, Canada. RP Krieger, C (reprint author), Simon Fraser Univ, Sch Kinesiol, 8888 Univ Dr, Burnaby, BC V5A 1S6, Canada. EM ckrieger@sfu.ca NR 19 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD JUN 18 PY 2004 VL 125 IS 1-2 BP 156 EP 161 DI 10.1016/j.molbrainres.2004.02.025 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 832HU UT WOS:000222258900018 ER PT J AU Opresko, PL Otterlei, M Graakjaer, J Bruheim, P Dawut, L Kolvraa, S May, A Seidman, MM Bohr, VA AF Opresko, PL Otterlei, M Graakjaer, J Bruheim, P Dawut, L Kolvraa, S May, A Seidman, MM Bohr, VA TI The Werner syndrome helicase and exonuclease cooperate to resolve telomeric D loops in a manner regulated by TRF1 and TRF2 SO MOLECULAR CELL LA English DT Article ID PROMYELOCYTIC LEUKEMIA BODIES; SYNDROME PROTEIN; SYNDROME CELLS; SYNDROME FIBROBLASTS; MAMMALIAN TELOMERES; DNA-REPAIR; LIFE-SPAN; WRN; RECOMBINATION; INSTABILITY AB Werner syndrome (WS) is characterized by features of premature aging and is caused by loss of the RecO helicase protein WRN. WS fibroblasts display defects associated with telomere dysfunction, including accelerated telomere erosion and premature senescence. In yeast, RecO helicases act in an alternative pathway for telomere lengthening (ALT) via homologous recombination. We found that WRN associates with telomeres when dissociation of telomeric D loops is likely during replication and recombination. In human ALT cells, WRN associates directly with telomeric DNA. The majority of TRF1/PCNA colocalizing foci contained WRN in live S phase ALT cells but not in telomerase-positive HeLa cells. Biochemically, the WRN helicase and 3' to 5' exonuclease act simultaneously and cooperate to release the 3' invading tail from a telomeric D loop in vitro. The telomere binding proteins TRF1 and TRF2 limit digestion by WRN. We propose roles for WRN in dissociating telomeric structures in telomerase-deficient cells. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Norwegian Univ Sci & Technol, Dept Canc Res & Mol Med, N-7489 Trondheim, Norway. Aarhus Univ, Inst Human Genet, DK-8000 Aarhus, Denmark. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. EM vbohr@nih.gov OI Opresko, Patricia/0000-0002-6470-2189 NR 43 TC 212 Z9 220 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JUN 18 PY 2004 VL 14 IS 6 BP 763 EP 774 DI 10.1016/j.molcel.2004.05.023 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 831DQ UT WOS:000222173800009 PM 15200954 ER PT J AU Kulkarni, SS Grundt, P Kopajtic, T Katz, JL Newman, AH AF Kulkarni, SS Grundt, P Kopajtic, T Katz, JL Newman, AH TI Structure-activity relationships at monoamine transporters for a series of N-substituted 3 alpha-(bis[4-fluorophenyl]methoxy)tropanes: Comparative molecular field analysis, synthesis, and pharmacological evaluation SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID DOPAMINE UPTAKE INHIBITORS; LIGAND-BINDING; 3-ALPHA-(DIPHENYLMETHOXY)TROPANE ANALOGS; PHOTOAFFINITY LIGANDS; BENZTROPINE ANALOGS; METHYL-ESTERS; COCAINE; RECEPTORS; POTENT; DISCOVERY AB The development of structure-activity relationships (SAR) with divergent classes of monoamine transporter ligands and comparison of their effects in animal models of cocaine abuse have provided insight into the complex relationship among structure, binding profiles, and behavioral activity. Many 3alpha-(diphenylmethoxy)tropane (benztropine) analogues are potent dopamine uptake inhibitors but exhibit behavioral profiles that differ from those of cocaine and other compounds in this class. One of the most potent and dopamine transporter (DAT) selective N-substituted benztropine analogues (N-(4-phenyl-n-butyl)-3alpha-(bis[4-fluorophenyl]methoxy)-tropane, le) is devoid of cocaine-like behaviors in rodent models but is also highly lipophilic (cLogD = 5.01), which compromises its water solubility and may adversely affect its pharmacokinetic properties. To further explore the SAR in this series and ultimately to design dopamine uptake inhibitors with favorable lipophilicities for drug development, a comparative molecular field analysis (CoMFA) was performed on a set of benztropine analogues previously synthesized in our laboratory. The CoMFA field analysis on the statistically significant (r(cv)(2) = 0.632; r(ncv)(2) = 0.917) models provided valuable insight into the structural features required for optimal binding to the DAT, which was used to design a series of novel benztropine analogues with heteroatom substitutions at the tropane N-8. These compounds were evaluated for binding at DAT, serotonin (SERT) and norepinephrine (NET) transporters, and muscarinic M1 receptors in rat brain. Inhibition of [H-3]DA uptake in synaptosomes was also evaluated. Most of the analogues showed high DAT affinity (12-50 nM), selectivity (10- to 120-fold), potent inhibition of dopamine uptake, and lower lipophilicities as predicted by cLogD values. C1 NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. NIDA, Psychobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Newman, AH (reprint author), NIDA, Med Chem Sect, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM anewman@intra.nida.nih.gov NR 33 TC 32 Z9 32 U1 3 U2 5 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 17 PY 2004 VL 47 IS 13 BP 3388 EP 3398 DI 10.1021/jm030646c PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 828HC UT WOS:000221963400007 PM 15189035 ER PT J AU Stapleton, JT Williams, CF Xiang, JH AF Stapleton, JT Williams, CF Xiang, JH TI GB virus C and survival in persons with HIV infection - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID COINFECTION C1 Univ Iowa, Iowa City, IA 52242 USA. NIH, Bethesda, MD 20892 USA. Iowa City Vet Affairs Med Ctr, Iowa City, IA 52242 USA. RP Stapleton, JT (reprint author), Univ Iowa, Iowa City, IA 52242 USA. EM jack-stapleton@uiowa.edu 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 17 PY 2004 VL 350 IS 25 BP 2618 EP 2618 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 829NE UT WOS:000222054700017 ER PT J AU Bleyer, AJ Hart, TC AF Bleyer, AJ Hart, TC TI Polycystic kidney disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC 27157 USA. Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. RP Bleyer, AJ (reprint author), Wake Forest Univ, Bowman Gray Sch Med, 300 S Hawthorne Rd, Winston Salem, NC 27157 USA. EM ableyer@wfubmc.edu NR 2 TC 5 Z9 10 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 17 PY 2004 VL 350 IS 25 BP 2622 EP 2622 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 829NE UT WOS:000222054700025 PM 15201424 ER PT J AU Gebreselassie, D Bowen, WD AF Gebreselassie, D Bowen, WD TI Sigma-2 receptors are specifically localized to lipid rafts in rat liver membranes SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE sigma receptor; lipid raft; sphingolipid; apoptosis; liver; rat ID TUMOR-CELL-LINES; PLASMA-MEMBRANE; SIGMA(2) RECEPTORS; BINDING-SITES; PROTEINS; DOMAINS; SURFACE; CERAMIDE; ROLES; TRANSPORT AB We have previously shown that sigma-2 receptors are relatively difficult to solubilize (Eur. J. Pharmacol. 304 (1996) 201), suggesting possible localization in detergent-resistant lipid raft domains. Rat liver membranes were treated on ice with 1% Triton X-100 or 20 mM 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), and the extract subjected to centrifugation on a discontinuous gradient of 5%, 38%, and 40% sucrose. Gradient fractions were analyzed for sigma-1 receptors using [3 H](+)-pentazocine and for sigma-2 receptors using [H-3] 1,3-di-o-tolylguanidine ([H-3]DTG), in the presence of dextrallorphan. Flotillin-2 was assessed by immunoblotting as a marker for lipid rafts. Sigma-2 receptors were found to discretely co-localize with flotillin-2 in lipid raft fractions. However, sigma-1 receptors were found throughout the gradient. Rafts prepared in CHAPS had sigma-2 receptors with normal pharmacological characteristics, whereas those in Triton X-100-prepared rafts had about seven-fold lower affinity for [3 H]DTG and other ligands. Thus, sigma-2 receptors are resident in membrane lipid rafts, whereas sigma-1 receptors appear in both raft and non-raft membrane domains. Lipid rafts may play an important role in the mechanism of sigma-2 receptor-induced apoptosis. (C) 2004 Elsevier B.V. All rights reserved. C1 NIDDKD, Unit Receptor Biochem & Pharmacol, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RP Bowen, WD (reprint author), NIDDKD, Unit Receptor Biochem & Pharmacol, Med Chem Lab, NIH, Bldg 8,Km B1-23-8 Ctr DR MSC 0815, Bethesda, MD 20892 USA. EM bowenw@bdg8.niddk.nih.gov NR 43 TC 49 Z9 53 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD JUN 16 PY 2004 VL 493 IS 1-3 BP 19 EP 28 DI 10.1016/j.ejphar.2004.04.005 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 830RZ UT WOS:000222141900002 PM 15189760 ER PT J AU Khurana, S Chacon, I Xie, GF Yamada, M Wess, J Raufman, JP Kennedy, RH AF Khurana, S Chacon, I Xie, GF Yamada, M Wess, J Raufman, JP Kennedy, RH TI Vasodilatory effects of cholinergic agonists are greatly diminished in aorta from M3R(-/-) mice SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE receptor subtype; vascular relaxation; cholinergic agonist; SIN-1; ATP ID MUSCARINIC RECEPTOR SUBTYPES; CEREBRAL BLOOD-VESSELS; MEDIATING VASODILATION; ACETYLCHOLINE-RECEPTOR; NITRIC-OXIDE; RELAXATION; RAT; CONTRACTION; ARTERY AB Acetylcholine interacts with endothelial muscarinic receptors to enhance nitric oxide (NO) release and thereby cause vasodilation. The present study was designed to determine if this effect of acetylcholine is mediated by muscarinic M-3 receptors. Thoracic aortae were isolated from wild-type (WT) and M-3 receptor knock out (M3R-/-) male mice, and endothelium-intact (1) and -denuded (D) aortic rings were bathed in physiological buffer. Preparations were utilized to examine the contractile response to phenylephrine (1 x 10(-8) -3 x 10(-4) M added cumulatively) and the vasodilatory actions of acetylcholine (10(-8) - 10(-4) M), carbachol (10(-9)- 10(-4) M), ATP (3 x 10(-5) M) and the NO donor SIN-1 (10(-4) M), each added in the presence of phenylephrine. Endothelium-dependent vasodilatory effects of acetylcholine and carbachol were obvious in aortae isolated from WT mice (56.3 +/- 9.8% and 49.1 +/- 4.1% reductions, respectively, in phenylephrine-induced contraction; p < 0.05), while acetylcholine and carbachol-associated relaxations observed in endothelium-intact M3R-/- preparations (17.9 +/- 2.6% and 13.5 +/- 4.2% reductions, respectively) did not differ significantly from time-control values. ATP-induced, endothelium-dependent vasodilation was similar in preparations from M3R-/- and WT mice, and SIN-1 elicited similar dilatory effects in intact and denuded WT and M3R-/- segments. Phenylephrine concentration-response curves were shifted leftwards by removal of the endothelium in both groups (EC50 values: WT-I/D-25.59 +/- 6.86/3.13 +/- 1.01 x 10(-7) M; M3R-/-I/D-13.92 +/- 4.21/1.52 +/- 0.46 x 10(-7) M; both p < 0.05); however, the phenylephrine response did not differ significantly when compared between the WT and M3R-/- groups. These results indicate that the attenuated vasodilatory effect of acetylcholine in endothelium-intact aortae from M3R-/- mice is due to the absence of muscarinic M-3 receptors, and thus suggest that in mouse aorta, muscarinic M-3 receptors play a major role in the endothelium-dependent acetylcholine-induced vasodilation. (C) 2004 Elsevier B.V. All rights reserved. C1 Univ Arkansas Med Sci, Dept Pharmacal Sci, Little Rock, AR 72205 USA. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. VA Maryland Hlth Care Syst, Div Gastroenterol & Hepatol, Baltimore, MD 21201 USA. NIDDKD, Lab Bioorgan Chem, Bethesda, MD 20892 USA. Cent Arkansas Vet Hlth Care Syst, Div Gastroenterol & Hepatol, Little Rock, AR 72205 USA. RP Kennedy, RH (reprint author), Univ Arkansas Med Sci, Dept Pharmacal Sci, 4301 W Markham St,Mail Slot 522-3, Little Rock, AR 72205 USA. EM kennedyrichardh@uams.edu NR 19 TC 32 Z9 33 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD JUN 16 PY 2004 VL 493 IS 1-3 BP 127 EP 132 DI 10.1016/j.ejphar.2004.04.012 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 830RZ UT WOS:000222141900015 PM 15189773 ER PT J AU Fox, CS Levy, D Culleton, B AF Fox, CS Levy, D Culleton, B TI Methods for estimating glomerular filtration rate - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID SERUM CREATININE; KIDNEY-DISEASE; EQUATIONS C1 NHLBI, Framingham Heart Study, Framingham, MA 01701 USA. Univ Calgary, Foothills Hosp, Calgary, AB, Canada. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, Framingham, MA 01701 USA. EM foxca@nhlbi.nih.gov NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 16 PY 2004 VL 291 IS 23 BP 2820 EP 2820 DI 10.1001/jama.291.23.2820 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 828GT UT WOS:000221962500025 ER PT J AU Fox, CS Parise, H D'Agostino, RB Lloyd-Jones, DM Vasan, RS Wang, TJ Levy, D Wolf, PA Benjamin, EJ AF Fox, CS Parise, H D'Agostino, RB Lloyd-Jones, DM Vasan, RS Wang, TJ Levy, D Wolf, PA Benjamin, EJ TI Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID FOLLOW-UP; FRAMINGHAM; ARRHYTHMIAS; PREVALENCE; IMPACT; ADULTS; STROKE; LOCUS AB Context Atrial fibrillation (AF) is the most common cardiac dysrhythmia in the United States. Whereas rare cases of familial AF have been reported, it is unknown if AF among unselected individuals is a heritable condition. Objective To determine whether parental AF increases the risk for the development of offspring AF. Design, Setting, and Participants Prospective cohort study (1983-2002) within the Framingham Heart Study, a population-based epidemiologic study. Participants were 2243 offspring (1165 women, 1078 men) at least 30 years of age and free of AF whose parents had both been evaluated in the original cohort. Main Outcome Measures Development of new-onset AF in the offspring was prospectively examined in association with previously documented parental AF. Results Among 2243 offspring participants, 681 (30%) had at least 1 parent with documented AF; 70 offspring participants (23 women; mean age, 62 [range, 40-81] years) developed AF in follow-up. Compared with no parental AF, AF in at least 1 parent increased the risk of offspring AF (multivariable-adjusted odds ratio [OR], 1.85; 95% confidence interval [Cl], 1.12-3.06; P=.02). These results were stronger when age was limited to younger than 75 years in both parents and offspring (multivariable-adjusted OR, 3.23; 95% Cl, 1.87-5.58; P<.001) and when the sample was further limited to those without antecedent myocardial infarction, heart failure, or valve disease (multivariable-adjusted OR, 3.17; 95% Cl, 1.71-5.86; P<.001). Conclusions Parental AF increases the future risk for offspring AF, an observation supporting a genetic susceptibility to developing this dysrhythmia. Further research into the genetic factors predisposing to AF is warranted. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Prevent Med Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Div Cardiol, Chicago, IL 60611 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov RI Lloyd-Jones, Donald/C-5899-2009; OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [K23-HL-04253, K23-HL-074077-01, K24-HL-04334, N01-HC-25195]; NINDS NIH HHS [5R01-NS-17950] NR 28 TC 316 Z9 319 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 16 PY 2004 VL 291 IS 23 BP 2851 EP 2855 DI 10.1001/jama.291.23.2851 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 828GT UT WOS:000221962500031 PM 15199036 ER PT J AU Pivovarova, NB Nguyen, HV Winters, CA Brantner, CA Smith, CL Andrews, SB AF Pivovarova, NB Nguyen, HV Winters, CA Brantner, CA Smith, CL Andrews, SB TI Excitotoxic calcium overload in a subpopulation of mitochondria triggers delayed death in hippocampal neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE excitotoxicity; NMDA; mitochondria; calcium; apoptosis; hippocampus; cytochrome c ID CYTOCHROME-C RELEASE; INTERMEMBRANE JUNCTIONAL COMPLEXES; PERMEABILITY TRANSITION PORE; APOPTOSIS-INDUCING FACTOR; CEREBELLAR GRANULE CELLS; GLUTAMATE NEUROTOXICITY; BRAIN MITOCHONDRIA; CORTICAL-NEURONS; CNS MITOCHONDRIA; STRIATAL NEURONS AB In neurons, excitotoxic stimulation induces mitochondrial calcium overload and the release of pro-apoptotic proteins, which triggers delayed cell death. The precise mechanisms of apoptogen release, however, remain controversial. To characterize the linkage between mitochondrial calcium load and cell vulnerability, and to test the hypothesis that only a subpopulation of mitochondria damaged by calcium overload releases apoptogens, we have measured directly the concentrations of total Ca ( free plus bound) in individual mitochondria and monitored in parallel structural changes and the subcellular localization of pro-apoptotic cytochrome c after NMDA overstimulation in cultured hippocampal neurons. Beyond transient elevation of cytosolic calcium and perturbation of Na+/K+ homeostasis, NMDA stimulation induced dramatic, but mainly reversible, changes in mitochondria, including strong calcium elevation, membrane potential depolarization, and variable swelling. Elevation of matrix Ca in the approximately one-third of mitochondria that were strongly swollen, as well as the absence of swelling when Ca2+ entry was abolished, indicate an essential role for Ca overload. Shortly after NMDA exposure, cytochrome c, normally localized to mitochondria, became diffusely distributed in the cytoplasm, coincident with the appearance of severely swollen mitochondria with ruptured outer membranes; under these conditions, cytochrome c was retained in intact mitochondria, implying that it was released mainly from damaged mitochondria. Consistent with the role of mitochondrial Ca overload, carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone decreased Ca accumulation, prevented cytochrome c release, and was neuroprotective. These results support a mechanism in which delayed excitotoxic death involves apoptogen release from a subpopulation of calcium-overloaded mitochondria, whereas other, undamaged mitochondria maintain normal function. C1 NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. NINDS, Ligt Imaging Facil, NIH, Bethesda, MD 20892 USA. RP Andrews, SB (reprint author), NINDS, Neurobiol Lab, NIH, 36-2A-21,36 Convent Dr, Bethesda, MD 20892 USA. EM sba@helix.nih.gov OI Brantner, Christine/0000-0001-8172-901X NR 72 TC 87 Z9 90 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 16 PY 2004 VL 24 IS 24 BP 5611 EP 5622 DI 10.1523/JNEUROSCI.0531-04.2004 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 829RM UT WOS:000222067300018 PM 15201334 ER PT J AU Morcombe, CR Gaponenko, V Byrd, RA Zilm, KW AF Morcombe, CR Gaponenko, V Byrd, RA Zilm, KW TI Diluting abundant spins by isotope edited radio frequency field assisted diffusion SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID SOLID-STATE NMR; ANGLE-SPINNING NMR; MICROCRYSTALLINE UBIQUITIN; SH3 DOMAIN; SPECTROSCOPY; PROTEINS; ASSIGNMENTS; RESONANCES; DISTANCES; BACKBONE C1 Yale Univ, Dept Chem, New Haven, CT 06520 USA. Natl Canc Inst, Struct Biophys Lab, Frederick, MD 21702 USA. RP Zilm, KW (reprint author), Yale Univ, Dept Chem, POB 208107, New Haven, CT 06520 USA. EM kurt.zilm@yale.edu RI Byrd, R. Andrew/F-8042-2015 OI Byrd, R. Andrew/0000-0003-3625-4232 NR 14 TC 147 Z9 147 U1 4 U2 22 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 16 PY 2004 VL 126 IS 23 BP 7196 EP 7197 DI 10.1021/ja047919t PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 828HE UT WOS:000221963600021 PM 15186155 ER PT J AU Grishaev, A Bax, A AF Grishaev, A Bax, A TI An empirical backbone-backbone hydrogen-bonding potential in proteins and its applications to NMR structure refinement and validation SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID MAGNETIC-RESONANCE SPECTROSCOPY; 3-DIMENSIONAL SOLUTION STRUCTURE; IMMUNOGLOBULIN-BINDING DOMAIN; PANCREATIC TRYPSIN-INHIBITOR; LIQUID-CRYSTALLINE MEDIUM; FIBROBLAST GROWTH-FACTOR; MAIN-CHAIN ATOMS; X-RAY STRUCTURES; MEAN FORCE; STAPHYLOCOCCAL NUCLEASE AB A new multidimensional potential is described that encodes for the relative spatial arrangement of the peptidyl backbone units as observed within a large database of high-resolution X-ray structures. The detailed description afforded by such an analysis provides an opportunity to study the atomic details of hydrogen bonding in proteins. The specification of the corresponding potential of mean force (PMF) is based on a defined set of physical principles and optimized to yield the maximum advantage when applied to protein structure refinement. The observed intricate differences between hydrogen-bonding geometries within various patterns of secondary structure allow application of the PMF to both validation of protein structures and their refinement. A pronounced improvement of several aspects of structural quality is observed following the application of such a potential to a variety of NMR-derived models, including a noticeable decrease in backbone coordinate root-mean-square deviation relative to the X-ray structures and a considerable improvement in the Ramachandran map statistics. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Grishaev, A (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM grishaev@speck.niddk.nih.gov; bax@nih.gov NR 63 TC 74 Z9 76 U1 0 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUN 16 PY 2004 VL 126 IS 23 BP 7281 EP 7292 DI 10.1021/ja0319994 PG 12 WC Chemistry, Multidisciplinary SC Chemistry GA 828HE UT WOS:000221963600031 PM 15186165 ER PT J AU Drazner, MH Rame, JE Marino, EK Gottdiener, JS Kitzman, DW Gardin, JM Manolio, TA Dries, DL Siscovick, DS AF Drazner, MH Rame, JE Marino, EK Gottdiener, JS Kitzman, DW Gardin, JM Manolio, TA Dries, DL Siscovick, DS TI Increased left ventricular mass is a risk factor for the development of a depressed left ventricular ejection fraction within five years SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID CONGESTIVE-HEART-FAILURE; CARDIOVASCULAR HEALTH; SYSTOLIC FUNCTION; PROGNOSTIC IMPLICATIONS; MIDWALL MECHANICS; HYPERTENSION; HYPERTROPHY; DISEASE; DYSFUNCTION; PERFORMANCE AB OBJECTIVES Our aim in this study was to determine whether increased left ventricular mass (LVM) is a risk factor for the development of a reduced left ventricular ejection fraction (LVEF). BACKGROUND Prior studies have shown that increased LVM is a risk factor for heart failure but not whether it is a risk factor for a low LVEF. METHODS As part of the Cardiovascular Health Study, a prospective population-based longitudinal study, we performed echocardiograms upon participant enrollment and again at follow-up of 4.9 +/- 0.14 years. In the present analysis, we identified 3,042 participants who had at baseline a normal LVEF and an assessment of LVM (either by electrocardiogram or echocardiogram), and at follow-up a measurable LVEF. The frequency of the development of a qualitatively depressed LVEF on two-dimensional echocardiography, corresponding approximately to an LVEF <55%, was analyzed by quartiles of baseline LVM. Multivariable regression determined whether LVM was independently associated with the development of depressed LVEF. RESULTS Baseline quartile of echocardiographic LVM indexed to body surface area was associated with development of a depressed LVEF (4.8% in quartile 1, 4.4% in quartile 2, 7.5% in quartile 3, and 14.1% in quartile 4 [p < 0.001]). A similar relationship was seen in the subgroup of participants without myocardial infarction (p < 0.001). In multivariable regression that adjusted for confounders, both baseline echocardiographic: (p < 0.001) and electrocardiographic (p < 0.001) LVM remained associated with development of depressed LVEF. CONCLUSIONS Increased LVM as assessed by electrocardiography or echocardiography is an independent risk factor for the development of depressed LVEF. (C) 2004 by the American College of Cardiology Foundation. C1 Univ Texas, SW Med Ctr,Dept Internal Med, Heart Failure Res Unit,Div Cardiol, Donald W Reynolds Cardiovasc Clin Res Ctr, Dallas, TX USA. St Francis Hosp, Div Cardiol, Roslyn, NY USA. Wake Forest Univ, Sch Med, Dept Med, Cardiol Sect, Winston Salem, NC 27109 USA. St Johns Hosp, Div Cardiol, Detroit, MI USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. RP Drazner, MH (reprint author), 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM mark.drazner@utsouthwestern.edu FU NHLBI NIH HHS [N01-HC-15103, N01-HC-35129, N01-HC-85079, N01-HC-85086] NR 34 TC 158 Z9 164 U1 0 U2 4 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 16 PY 2004 VL 43 IS 12 BP 2207 EP 2215 DI 10.1016/j.jacc.2003.11.064 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 828IJ UT WOS:000221966700009 PM 15193681 ER PT J AU Barzilay, JI Kronmal, RA Gottdiener, JS Smith, NL Burke, GL Tracy, R Savage, PJ Carlson, M AF Barzilay, JI Kronmal, RA Gottdiener, JS Smith, NL Burke, GL Tracy, R Savage, PJ Carlson, M TI The association of fasting glucose levels with congestive heart failure in diabetic adults >= 65 years SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID CARDIOVASCULAR HEALTH; GLYCEMIC CONTROL; SYSTOLIC FUNCTION; MELLITUS; RISK; CARDIOMYOPATHY; COMPLICATIONS; DYSFUNCTION; DISEASE; AGE AB OBJECTIVES The purpose of this study was to determine if fasting glucose levels are an independent risk factor for congestive heart failure (CHF) in elderly individuals with diabetes mellitus (DM) with or without coronary heart disease (CHD). BACKGROUND Diabetes mellitus and CHF frequently coexist in the elderly. It is not clear whether fasting glucose levels in the setting of DM are a risk factor for incident CHF in the elderly. METHODS A cohort of 829 diabetic participants, age greater than or equal to65 years, without prevalent CHF, was followed for five to eight years. The Cox proportional hazards modeling was used to determine the risk of CHF by fasting glucose levels. The cohort was categorized by the presence or absence of prevalent CHD. RESULTS For a I standard deviation (60.6 mg/dl) increase in fasting glucose, the adjusted hazard ratios for incident CHF among participants without CHD at baseline, with or without an incident myocardial infarction (MI) or CHD event on follow-up, was 1.41 (95% confidence interval 1.24 to 1.61; p < 0.0001). Among those with prevalent CHD at baseline, with or without another incident MI or CHD event on follow-up, the corresponding adjusted hazard ratio was 1.27 (95% confidence interval 1.02 to 1.58; p < 0.05). CONCLUSIONS Among older adults with DM, elevated fasting glucose levels are a risk factor for incident CHF. The relationship of fasting glucose to CHF differs somewhat by the presence or absence of prevalent CHD. (C) 2004 by the American College of Cardiology Foundation. C1 Kaiser Permanente, Tucker, GA 30084 USA. Emory Univ, Sch Med, Div Endocrinol, Atlanta, GA USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. St Francis Hosp, Dept Cardiol, Roslyn, NY USA. Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Winston Salem, NC USA. Univ Vermont, Dept Pathol, Coll Med, Colchester, Essex, England. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. Johns Hopkins Sch Publ Hlth, Ctr Aging & Hlth, Baltimore, MD USA. RP Barzilay, JI (reprint author), Kaiser Permanente, 200 Crescent Ctr Pkwy, Tucker, GA 30084 USA. EM joshua.barzilay@kp.org FU NHLBI NIH HHS [N01-HC-15103, N01-HC-35129, N01-HC-85079, N01-HC-85086] NR 30 TC 43 Z9 44 U1 0 U2 0 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 16 PY 2004 VL 43 IS 12 BP 2236 EP 2241 DI 10.1016/j.jacc.2003.10.074 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 828IJ UT WOS:000221966700014 PM 15193686 ER PT J AU Ingkanisorn, WP Rhoads, KL Aletras, AH Kellman, P Arai, AE AF Ingkanisorn, WP Rhoads, KL Aletras, AH Kellman, P Arai, AE TI Gadolinium delayed enhancement cardiovascular magnetic resonance correlates with clinical measures of myocardial infarction SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID CARDIAC TROPONIN-T; FUNCTIONAL RECOVERY; CORONARY-OCCLUSION; TRANSMURAL EXTENT; SIZE; VISUALIZATION; REPERFUSION; INJURY; DEATH AB OBJECTIVES The current study tested the hypothesis that gadolinium delayed enhancement assessment of infarct size correlates with clinical indices of myocardial infarction (MI) in humans. Acute infarct mass by cardiac magnetic resonance (CMR) was compared with peak troponin 1, acute and chronic left ventricular (LV) systolic function, and chronic infarct mass in patients imaged after recent acute MI. BACKGROUND Cardiac magnetic resonance accurately determines myocardial viability in patients with chronic ischemic heart disease but is not well validated for recent MI. METHODS Patients with first acute MI (n = 33) or chronic MI (n = 10) underwent cine CMR followed by gadolinium delayed enhancement imaging. A follow-up CMR scan was performed on 20 of the 33 acute MI patients and all of the chronic MI patients. RESULTS In patients with acute percutaneous coronary intervention, acute MI mass correlated with peak troponin I (r = 0.83, p < 0.001, n = 23). In the 20 acute infarct patients with follow-up CMR scans, the acute infarct size correlated well with the follow-up LV ejection fraction (r = 0.86, p < 0.001). The transmural extent of delayed enhancement imaged acutely correlated inversely with wall thickening measured acutely (p < 0.001) and at follow-up (p < 0.001). Although chronic infarct size was reproducible (11 +/- 4% vs. 12 +/- 7%, p = NS), acute infarct size decreased from 16 +/- 12% to 11 +/- 9% (p < 0.003). CONCLUSION In humans imaged shortly after acute MI, gadolinium delayed enhancement acute CMR infarct size correlates with acute and chronic indices of infarct size but will appear to diminish in size on follow-up. (C) 2004 by the American College of Cardiology Foundation. C1 NHLBI, Dept Hlth & Human Serv, Lab Cardiac Energet, NIH, Bethesda, MD 20892 USA. Sururban Hosp, Bethesda, MD USA. RP Arai, AE (reprint author), NHLBI, Dept Hlth & Human Serv, Lab Cardiac Energet, NIH, 10 Ctr Dr,MSC 1061,Bldg 10,Room B1D-416, Bethesda, MD 20892 USA. EM araia@nih.gov OI Aletras, Anthony/0000-0002-3786-3817 NR 27 TC 188 Z9 197 U1 0 U2 4 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 16 PY 2004 VL 43 IS 12 BP 2253 EP 2259 DI 10.1016/j.jacc.2004.02.046 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 828IJ UT WOS:000221966700017 PM 15193689 ER PT J AU Schatzkin, A Peters, U AF Schatzkin, A Peters, U TI Advancing the calcium-colorectal cancer hypothesis SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID COLON-CANCER; VITAMIN-D; UNITED-STATES; DAIRY-PRODUCTS; RISK; PREVENTION; TRIAL; INTERVENTION; RECURRENCE; NEOPLASIA C1 NCI, Nutrit Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. RP Schatzkin, A (reprint author), NCI, Nutrit Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Execut Plaza S,6120 Execut Blvd, Rockville, MD 20852 USA. EM schatzka@mail.nih.gov NR 21 TC 7 Z9 8 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 16 PY 2004 VL 96 IS 12 BP 893 EP 894 DI 10.1093/jnci/djh190 PG 2 WC Oncology SC Oncology GA 833MG UT WOS:000222340900001 PM 15199101 ER PT J AU Leonard, GD Swain, SM AF Leonard, GD Swain, SM TI Ductal carcinoma in situ, complexities and challenges SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID INTRADUCTAL BREAST-CANCER; SURGICAL ADJUVANT BREAST; TERM-FOLLOW-UP; COMPARATIVE GENOMIC HYBRIDIZATION; ESTROGEN-RECEPTOR EXPRESSION; MAMMOGRAPHIC SCREENING TRIAL; HORMONE REPLACEMENT THERAPY; RANDOMIZED CONTROLLED-TRIAL; MIDDLE-AGED WOMEN; LOCAL RECURRENCE AB The incidence of ductal carcinoma in situ (DCIS), a noninvasive form of breast cancer, has increased markedly in recent decades, and DCIS now accounts for approximately 20% of breast cancers diagnosed by mammography. Laboratory and patient data suggest that DCIS is a precursor lesion for invasive cancer. The appropriate classification of DCIS has provoked much debate; a number of classification systems have been developed, but there is a lack of uniformity in the diagnosis and prognostication of this disease. Further investigation of molecular markers should improve the classification of DCIS and our understanding of its relationship to invasive disease. Controversy also exists with regard to the optimal management of DCIS patients. In the past, mastectomy was the primary treatment for patients with DCIS, but as with invasive cancer, breast-conserving surgery has become the standard approach. Three randomized trials have reported a statistically significant decrease in the risk of recurrence with radiation therapy in combination with lumpectomy compared with lumpectomy alone, but there was no survival advantage with the addition of radiotherapy. Two randomized trials have suggested an additional benefit, in terms of recurrence, with the addition of adjuvant tamoxifen therapy, although in one trial the benefit was not statistically significant. Current data suggest that tamoxifen use should be restricted to patients with estrogen receptor-positive DCIS. Neither trial demonstrated a survival benefit with adjuvant tamoxifen. Ongoing and recently completed studies should provide information on outcomes in patients treated with lumpectomy alone and on the effectiveness of aromatase inhibitors as an alternative to tamoxifen. [J Natl Cancer Inst 2004;96:906-20] C1 NCI, Canc Therapeut Branch, Canc Res Ctr, OHHS,Natl Naval Med Ctr, Bethesda, MD 20889 USA. RP Swain, SM (reprint author), NCI, Canc Therapeut Branch, Canc Res Ctr, OHHS,Natl Naval Med Ctr, Bldg 8,Rm 5101,8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM swains@mail.nih.gov OI Swain, Sandra/0000-0002-1320-3830 NR 226 TC 225 Z9 238 U1 1 U2 10 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 16 PY 2004 VL 96 IS 12 BP 906 EP 920 DI 10.1093/jnci/djh164 PG 15 WC Oncology SC Oncology GA 833MG UT WOS:000222340900010 PM 15199110 ER PT J AU Karadag, A Ogbureke, KUE Fedarko, NS Fisher, LW AF Karadag, A Ogbureke, KUE Fedarko, NS Fisher, LW TI Bone sialoprotein, matrix metalloproteinase 2, and alpha(v)beta(3) integrin in osteotropic cancer cell invasion SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID COMPLEMENT-MEDIATED ATTACK; HUMAN BREAST-CANCER; HUMAN LUNG-CANCER; MATRIX-METALLOPROTEINASE; EPITHELIAL-CELLS; OSTEOPONTIN EXPRESSION; PROTEIN-SEQUENCE; ACID SEQUENCE; TUMOR-CELLS; MIGRATION AB Background: Bone sialoprotein (BSP) interacts separately with both matrix metalloproteinase 2 (MMP-2) and integrin alpha(v)beta(3) and is overexpressed in many metastatic tumors. Its role in tumor biology, however, remains unclear. We investigated whether BSP enhances cancer cell invasiveness by forming a trimolecular complex with MMP-2 and cell-surface integrin alpha(v)beta(3). Methods: Invasiveness of breast, prostate, lung, and thyroid tumor cell lines was measured with a modified Boyden chamber assay. Binding and co-localization of BSP, MMP-2, and integrin alpha(v)beta(3) were investigated with immunoprecipitation and in situ hybridization. All statistical tests were two-sided. Results.. Treatment with BSP increased invasiveness of many breast, prostate, lung, and thyroid cancer cells through Matrigel in a dose-dependent manner. BSP at 50 nM increased the invasiveness of SW-579 thyroid cancer cells (95.2 units, 95% confidence interval [CI] = 90.4 to 100 units) by approximately 10-fold compared with that of untreated control SW-579 cells (9.1 units, 95% CI = 5.7 to 12.5 units) (P<.001). Addition of an inactive mutated BSP, in which BSP's integrin-binding RGD tripeptide was altered, or addition of integrin alpha(v)beta(3)-blocking antibodies resulted in invasiveness equivalent to that of untreated cells. Inhibiting cellular MMP-2 activity with chemical inhibitors or a specific antibody also blocked BSP-enhanced invasiveness. Osteopontin and dentin matrix protein 1, proteins related to BSP that also bind integrin alpha(v)beta(3) and form complexes with other MMPs (but not MMP-2), did not enhance invasiveness. Immunoprecipitation showed that a complex containing BSP, integrin alpha(v)beta(3), and MMP-2 formed in vitro. Addition of BSP increased the amount of MMP-2 bound by cells in an integrin-dependent fashion. Co-expression of BSP, integrin alpha(v)beta(3), and MMP-2 in papillary thyroid carcinoma cells was shown by in situ hybridization. Conclusion: Cancer cells appear to become more invasive when BSP forms a cell-surface trimolecular complex by linking MMP-2 to integrin alpha(v)beta(3). [J Natl Cancer Inst 2004;96:956-65] C1 NIDCR, Craniofacial & Skeletal Dis Branch, US Dept HHS, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Med, Div Geriatr, Baltimore, MD 21205 USA. RP Karadag, A (reprint author), NIDCR, Craniofacial & Skeletal Dis Branch, US Dept HHS, NIH, 9000 Rockville Pike,Bldg 30,Rm 228, Bethesda, MD 20892 USA. EM akaradag@dir.nidcr.nih.gov NR 54 TC 79 Z9 85 U1 0 U2 5 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 16 PY 2004 VL 96 IS 12 BP 956 EP 965 DI 10.1093/jnci/djh169 PG 10 WC Oncology SC Oncology GA 833MG UT WOS:000222340900015 PM 15199115 ER PT J AU Hauptmann, M Lubin, JH Stewart, PA Hayes, RB Blair, A AF Hauptmann, M Lubin, JH Stewart, PA Hayes, RB Blair, A TI Re: Mortality from lymphohematopoietic malignancies among workers in formaldehyde industries - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID EMBALMERS; COHORT C1 NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Hauptmann, M (reprint author), NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, 6120 Execut Blvd,EPS-8050, Bethesda, MD 20892 USA. EM hauptmann@nih.gov NR 7 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 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUN 16 PY 2004 VL 96 IS 12 BP 967 EP 968 DI 10.1093/jnci/djh177 PG 2 WC Oncology SC Oncology GA 833MG UT WOS:000222340900017 ER PT J AU Hauptmann, M Lubin, JH Stewart, PA Hayes, RB Blair, A AF Hauptmann, M Lubin, JH Stewart, PA Hayes, RB Blair, A TI Mortality from solid cancers among workers in formaldehyde industries SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE carcinogens; cohort studies; formaldehyde; lung; mortality; nasopharynx; neoplasms; occupational health ID FIBER PRODUCTION WORKERS; RESPIRATORY SYSTEM CANCER/; NESTED CASE-CONTROL; NASOPHARYNGEAL CARCINOMA; OCCUPATIONAL-EXPOSURE; LUNG-CANCER; HISTORICAL COHORT; INSTITUTE FORMALDEHYDE; EPIDEMIOLOGIC EVIDENCE; WEINKAM ANALYSIS AB In industrial workers, formaldehyde exposure has been associated with cancer of the nasal cavities, nasopharynx, prostate, lung, and pancreas; however, these associations are inconsistent and remain controversial. Animals exposed to formaldehyde show excesses of nasal cancer. In an extended follow-up of a large cohort of formaldehyde-exposed workers, the authors evaluated mortality from solid cancers (1,921 deaths) among 25,619 workers (865,708 person-years) employed in 10 US formaldehyde-producing or -using facilities through 1994. Exposure assessment included quantitative estimates of formaldehyde exposure. Standardized mortality ratios and relative risks were calculated. Compared with that for the US population, mortality from solid cancers was significantly lower than expected among subjects exposed and nonexposed to formaldehyde (standardized mortality ratios = 0.91 and 0.78, respectively). Relative risks for nasopharyngeal cancer (nine deaths) increased with average exposure intensity, cumulative exposure, highest peak exposure, and duration of exposure to formaldehyde (p-trend = 0.066, 0.025, <0.001, and 0.147, respectively). Formaldehyde exposure did not appear to be associated with lung (744 deaths), pancreas (93 deaths), or brain (62 deaths) cancer. Although relative risks for prostate cancer (145 deaths) were elevated for some measures of formaldehyde exposure, the trend was inconsistent. In this cohort of formaldehyde-industry workers, some evidence was found of an exposure-response relation with mortality from nasopharyngeal cancer (based on small numbers) but not for cancers of the pancreas, brain, lung, or prostate. C1 NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Hauptmann, M (reprint author), NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM hauptmann@nih.gov OI Hayes, Richard/0000-0002-0918-661X NR 58 TC 148 Z9 153 U1 3 U2 33 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 2004 VL 159 IS 12 BP 1117 EP 1130 DI 10.1093/aje/kwh174 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 830MJ UT WOS:000222126000002 PM 15191929 ER PT J AU Gold, EB Block, G Crawford, S Lachance, L FitzGerald, G Miracle, H Sherman, S AF Gold, EB Block, G Crawford, S Lachance, L FitzGerald, G Miracle, H Sherman, S TI Lifestyle and demographic factors in relation to vasomotor symptoms: Baseline results from the study of women's health across the nation SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Review DE diet; ethnic groups; menopause; reproductive history; signs and symptoms; smoking; tobacco smoke pollution ID BINDING GLOBULIN PRODUCTION; STANDARDIZED SOY EXTRACT; ESTROGEN PLUS PROGESTIN; BREAST-CANCER SURVIVORS; MENOPAUSAL HOT FLASHES; CORE BODY-TEMPERATURE; UP HERS-II; POSTMENOPAUSAL WOMEN; PREMENOPAUSAL WOMEN; CIGARETTE-SMOKING AB Results of recent trials highlight the risks of hormone therapy, increasing the importance of identifying preventive lifestyle factors related to menopausal symptoms. The authors examined the relation of such factors to vasomotor symptoms in the multiethnic sample of 3,302 women, aged 42-52 years at baseline (1995-1997), in the Study of Women's Health Across the Nation (SWAN). All lifestyle factors and symptoms were self-reported. Serum hormone and gonadotropin concentrations were measured once in days 2-7 of the menstrual cycle. After adjustment for covariates using multiple logistic regression, significantly more African-American and Hispanic and fewer Chinese and Japanese than Caucasian women reported vasomotor symptoms. Fewer women with postgraduate education reported vasomotor symptoms. Passive exposure to smoke, but not active smoking, higher body mass index, premenstrual symptoms, perceived stress, and age were also significantly associated with vasomotor symptoms, although a dose-response relation with hours of smoke exposure was not observed. No dietary nutrients were significantly associated with vasomotor symptoms. These cross-sectional findings require further longitudinal exploration to identify lifestyle changes for women that may help prevent vasomotor symptoms. C1 Univ Calif Davis, Sch Med, Dept Epidemiol & Prevent Med, Davis, CA 95616 USA. Univ Calif Berkeley, Sch Publ Hlth, Div Community Hlth & Human Dev, Berkeley, CA 94720 USA. Univ Massachusetts, Sch Med, Div Prevent & Behav Med, Worcester, MA USA. Univ Michigan, Sch Publ Hlth, Dept Hlth Behav & Hlth Educ, Ann Arbor, MI 48109 USA. Univ Massachusetts, Ctr Outcomes Res, Worcester, MA 01605 USA. NIA, Geriatr & Clin Gerontol Program, NIH, Bethesda, MD 20892 USA. RP Gold, EB (reprint author), Univ Calif Davis, Sch Med, Dept Epidemiol & Prevent Med, 1 Shields Ave,TB 168, Davis, CA 95616 USA. EM ebgold@ucdavis.edu RI Block, Gladys/E-3304-2010 NR 115 TC 154 Z9 157 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 15 PY 2004 VL 159 IS 12 BP 1189 EP 1199 DI 10.1093/aje/kwh168 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 830MJ UT WOS:000222126000009 PM 15191936 ER PT J AU Ferrucci, L Bandinelli, S Cavazzini, C Lauretani, F Corsi, A Bartali, B Cherubini, A Launer, L Guralnik, JM AF Ferrucci, L Bandinelli, S Cavazzini, C Lauretani, F Corsi, A Bartali, B Cherubini, A Launer, L Guralnik, JM TI Neurological examination findings to predict limitations in mobility and falls in older persons without a history of neurological disease SO AMERICAN JOURNAL OF MEDICINE LA English DT Article ID WHITE-MATTER ABNORMALITIES; CARDIOVASCULAR-HEALTH; DISABILITY; PEOPLE; BRAIN; SARCOPENIA; INFARCTS; STROKE; LIFE AB PURPOSE: To estimate the prevalence of neurological signs and their association with limitations in mobility and falls in a sample of older persons without known neurological disease. METHODS: A neurologist examined 818 participants from the InCHIANTI study who were aged greater than or equal to65 years and who did not have cognitive impairment, treatment with neuroleptics, and a history of neurological disease. Mobility was assessed as walking speed and self-reported ability to walk at least I km without difficulty. Participants were asked to report falls that had occurred in the previous 12 months. RESULTS: Less than 20% (160/818) of participants had no neurological signs. Neurological signs were more prevalent in older participants and those with impaired mobility. When all neurological signs were included in sex-and age-adjusted multivariate models, 10 were mutually independent correlates of poor mobility. After adjusting for age and sex, the number of neurological signs was associated with progressively slower walking speed (P <0.001), a higher probability of reported inability to walk I km (P <0.001), and a history of falls (P <0.05). CONCLUSION: Neurological signs are independent correlates of limitations in mobility and falls in older persons who have no clear history of neurological disease. (C) 2004 by Excerpta Medica Inc. C1 NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. NIA, Lab Epidemiol Demog & Biometry, NIH, Baltimore, MD 21224 USA. Italian Natl Inst Res & Care Aging, Lab Clin Epidemiol, Florence, Italy. Univ Perugia, Inst Gerontol & Geriatr, I-06100 Perugia, Italy. RP Ferrucci, L (reprint author), NIA, Longitudinal Studies Sect, Clin Res Branch, Harbor Hosp, 3001 S Hanover St, Baltimore, MD 21225 USA. EM ferruccilu@grc.nia.nih.gov RI Lauretani, Fulvio/K-5115-2016; OI Lauretani, Fulvio/0000-0002-5287-9972; Cherubini, Antonio/0000-0003-0261-9897 FU PHS HHS [821336, 916413] NR 33 TC 38 Z9 39 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD JUN 15 PY 2004 VL 116 IS 12 BP 807 EP 815 DI 10.1016/j.amjmed.2004.01.010 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 826LF UT WOS:000221829900002 PM 15178496 ER PT J AU Hoppin, AA Umbach, DM London, SJ Alavanja, MCR Sandier, DP AF Hoppin, AA Umbach, DM London, SJ Alavanja, MCR Sandier, DP TI Diesel exhaust, solvents, and other occupational exposures as risk factors for wheeze among farmers SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE agriculture; diesel exhaust; occupational cohort; respiratory symptoms; solvents ID AGRICULTURAL HEALTH; PESTICIDE APPLICATORS; RESPIRATORY SYMPTOMS; GUINEA-PIGS; CHRONIC-BRONCHITIS; PULMONARY-FUNCTION; ORGANIC-SOLVENTS; LUNG-FUNCTION; ASTHMA; WORKERS AB Farmers engage in activities that result in exposure to diesel exhaust, solvents, welding fumes, and other respiratory irritants. Using the Agricultural Health Study, a cohort of pesticide applicators in Iowa and North Carolina, we evaluated the odds of wheeze associated with nonpesticide occupational exposures. We used logistic regression models controlling for age, state, smoking, and history of asthma or atopy to evaluate odds of wheeze in the past year among the 20,898 farmers who provided complete information on all covariates. Driving diesel tractors was associated with elevated odds of wheeze (odds ratio = 1.31; 95% confidence interval = 1.13, 1.52); the odds ratio for driving gasoline tractors was 1.11 (95% confidence interval = 1.02, 1.21). A duration-response relationship was observed for driving diesel tractors but not for driving gasoline tractors. Activities involving solvent exposure, including painting and use of solvents for cleaning, were associated with an increased odds of wheeze in a duration-dependent fashion. The highest odds of wheeze for farm activities were for daily painting (odds ratio = 1.82; 95% confidence interval = 0.89, 3.73), an indication of daily solvent exposure. These results add to the growing body of evidence of adverse respiratory effects of diesel exposure on the lung and suggest exposure to solvents may contribute as well. C1 NIEHS, Epidemiol Branch, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. NCI, Occupat Epidemiol Branch, Dept Hlth & Human Serv, NIH, Rockville, MD USA. RP Hoppin, AA (reprint author), NIEHS, Epidemiol Branch, Dept Hlth & Human Serv, NIH, POB 12233,MD A3-05, Res Triangle Pk, NC 27709 USA. EM hoppin1@niehs.nih.gov OI Sandler, Dale/0000-0002-6776-0018; London, Stephanie/0000-0003-4911-5290 NR 57 TC 14 Z9 14 U1 1 U2 5 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 15 PY 2004 VL 169 IS 12 BP 1308 EP 1313 DI 10.1164/rccm.200309-1228OC PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 827ZX UT WOS:000221943300007 ER PT J AU Waselenko, JK MacVittie, TJ Blakely, WF Pesik, N Wiley, AL Dickerson, WE Tsu, H Confer, DL Coleman, CN Seed, T Lowry, P Armitage, JO Dainiak, N AF Waselenko, JK MacVittie, TJ Blakely, WF Pesik, N Wiley, AL Dickerson, WE Tsu, H Confer, DL Coleman, CN Seed, T Lowry, P Armitage, JO Dainiak, N TI Medical management of the acute radiation syndrome: Recommendations of the Strategic National Stockpile Radiation Working Group SO ANNALS OF INTERNAL MEDICINE LA English DT Review ID COLONY-STIMULATING FACTOR; BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; TOTAL-BODY IRRADIATION; IMPROVES NEUTROPHIL RECOVERY; PERIPHERAL-BLOOD LYMPHOCYTES; EARLY DOSE ASSESSMENT; IONIZING-RADIATION; FUNGAL-INFECTIONS; FLUCONAZOLE PROPHYLAXIS AB Physicians, hospitals, and other health care facilities will assume the responsibility for aiding individuals injured by a terrorist act involving radioactive material. Scenarios have been developed for such acts that include a range of exposures resulting in few to many casualties. This consensus document was developed by the Strategic National Stockpile Radiation Working Group to provide a framework for physicians in internal medicine and the medical subspecialties to evaluate and manage large-scale radiation injuries. Individual radiation close is assessed by determining the time to onset and severity of nausea and vomiting, decline in absolute lymphocyte count over several hours or days after exposure, and appearance of chromosome aberrations (including dicentrics and ring forms) in peripheral blood lymphocytes. Documentation of clinical signs and symptoms (affecting the hematopoietic, gastrointestinal, cerebrovascular, and cutaneous systems) over time is essential for triage of victims, selection of therapy, and assignment of prognosis. Recommendations based on radiation dose and physiologic response are made for treatment of the hematopoietic syndrome. Therapy includes treatment with hematopoietic cytokines; blood transfusion; and, in selected cases, stem-cell transplantation. Additional medical management based on the evolution of clinical signs and symptoms includes the use of antimicrobial agents (quinolones, antiviral therapy, and antifungal agents), antiemetic agents, and analgesic agents. Because of the strong psychological impact of a possible radiation exposure, psychosocial support will be required for those exposed, regardless of the dose, as well as for family and friends. Treatment of pregnant women must account for risk to the fetus. For terrorist or accidental events involving exposure to radioicidines, prophylaxis against malignant disease of the thyroid is also recommended, particularly for children and adolescents. C1 Bridgeport Hosp, Dept Med, Bridgeport, CT USA. Walter Reed Army Med Ctr, Washington, DC USA. Catholic Univ Amer, Washington, DC USA. Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD USA. Armed Forces Radiobiol Res Inst, Bethesda, MD USA. NIH, Bethesda, MD USA. Off Emergency Preparedness & Response, Ctr Dis Control & Prevent, Strateg Natl Stockpile Program, Atlanta, GA USA. Oak Ridge Associated Univ, Oak Ridge, TN USA. Natl Marrow Donor Program, Minneapolis, MN USA. Univ Nebraska, Omaha, NE 68182 USA. Yale New Haven Hlth Syst, New Haven, CT USA. Yale Univ, Sch Med, New Haven, CT 06520 USA. RP Dainiak, N (reprint author), Bridgeport Hosp, Dept Med, 267 Grant St, Bridgeport, CT USA. EM pndain@bpthosp.org NR 120 TC 316 Z9 334 U1 2 U2 19 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 15 PY 2004 VL 140 IS 12 BP 1037 EP 1051 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA 829NK UT WOS:000222055500008 PM 15197022 ER PT J AU Stadtman, E AF Stadtman, E TI Victor Ginsburg on the Editorial Committee of the Archives of Biochemistry and Biophysics SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Editorial Material C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Stadtman, E (reprint author), NHLBI, NIH, Bldg 10, 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 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JUN 15 PY 2004 VL 426 IS 2 BP 106 EP 106 DI 10.1016/j.abb.2003.04.001 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 826IZ UT WOS:000221824100003 ER PT J AU Pendrak, ML Yan, SS Roberts, DD AF Pendrak, ML Yan, SS Roberts, DD TI Sensing the host environment: recognition of hemoglobin by the pathogenic yeast Candida albicans SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Review DE cell adhesion; candidemia; heme oxygenase; extracellular matrix; receptors; environmental sensing; gene regulation; fibronectin; hemoglobin; opportunistic pathogens ID HEME OXYGENASE; SACCHAROMYCES-CEREVISIAE; EPITHELIAL-CELLS; ACUTE HEMOLYSIS; STAPHYLOCOCCUS-AUREUS; SCAVENGER RECEPTOR; OXIDATIVE STRESS; BINDING DOMAIN; UNITED-STATES; FIBRONECTIN AB Adhesion to host cells and tissues is important for several steps in the pathogenesis of disseminated Candida albicans infections. Although such adhesion is evident in vivo and for C. albicans grown in vitro in complex medium, some adhesive activities are absent when cultures are grown in defined media. However, addition of hemoglobin to defined media restores binding and adhesion to several host proteins. This activity of hemoglobin is independent of iron acquisition and is mediated by a cell surface hemoglobin receptor. In addition to regulating expression of adhesion receptors, hemoglobin rapidly induces expression of several genes. One of these, a heme oxygenase, allows the pathogen to utilize exogenous heme or hemoglobin to acquire iron and to produce the cytoprotective molecules a-biliverdin and carbon monoxide. The specific recognition of and responses to hemoglobin demonstrate a unique adaptation of C. albicans to be both a commensal and an opportunistic pathogen in humans. (C) 2004 Elsevier Inc. All rights reserved. C1 Natl Canc Inst, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Roberts, DD (reprint author), Natl Canc Inst, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM syan@cvm.fda.gov; droberts@helix.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 NR 58 TC 32 Z9 41 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JUN 15 PY 2004 VL 426 IS 2 BP 148 EP 156 DI 10.1016/j.abb.2004.02.006 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 826IZ UT WOS:000221824100008 PM 15158665 ER PT J AU Cabib, E AF Cabib, E TI The septation apparatus, a chitin-requiring machine in budding yeast SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Review ID SACCHAROMYCES-CEREVISIAE; CELL-WALL; MYOSIN-II; CYTOKINESIS; RING; SEPTUM; SYNTHASE; LOCALIZATION; ACTOMYOSIN; SEPARATION C1 NIDDKD, Lab Biochem & Genet, Dept Hlth & Human Resources, NIH, Bethesda, MD 20892 USA. Univ Salamanca, CSIC, Inst Microbiol Bioquim, Dept Microbiol & Genet, Salamanca 37007, Spain. RP Cabib, E (reprint author), NIDDKD, Lab Biochem & Genet, Dept Hlth & Human Resources, NIH, Bethesda, MD 20892 USA. EM enricoc@bdg10.niddk.nih.gov NR 35 TC 39 Z9 40 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JUN 15 PY 2004 VL 426 IS 2 BP 201 EP 207 DI 10.1016/j.abb.2004.02.030 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 826IZ UT WOS:000221824100013 PM 15158670 ER PT J AU Ward, MM AF Ward, MM TI Rheumatology care, patient expectations, and the limits of time SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Editorial Material ID UNMET EXPECTATIONS; SATISFACTION; PHYSICIAN; COMMUNICATION C1 NIAMSD, NIH, IRP, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), NIAMSD, NIH, IRP, Bldg 10,Room 9S205,10 Ctr Dr,MSC 1828, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov NR 14 TC 8 Z9 8 U1 2 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD JUN 15 PY 2004 VL 51 IS 3 BP 307 EP 308 DI 10.1002/art.20417 PG 2 WC Rheumatology SC Rheumatology GA 827SF UT WOS:000221920200002 PM 15188310 ER PT J AU Rennebohm, RM Jones, K Huber, AM Ballinger, SH Bowyer, SL Feldman, BM Hicks, J Katona, IM Lindsley, CB Miller, FW Passo, MH Perez, MD Reed, AM Wallace, CA White, PH Zemel, LS Lachenbruch, PA Hayes, JR Rider, LG AF Rennebohm, RM Jones, K Huber, AM Ballinger, SH Bowyer, SL Feldman, BM Hicks, J Katona, IM Lindsley, CB Miller, FW Passo, MH Perez, MD Reed, AM Wallace, CA White, PH Zemel, LS Lachenbruch, PA Hayes, JR Rider, LG CA Juvenile Dermatomyositis Dis Acti TI Normal scores for nine maneuvers of the childhood myositis assessment scale SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article DE juvenile idiopathic inflammatory myopathies; juvenile dermatomyositis; muscle strength assessment; physical function ID JUVENILE DERMATOMYOSITIS; DISEASE AB Objective. To document and evaluate the scores that normal, healthy children achieve when performing 9 maneuvers of the Childhood Myositis Assessment Scale (CMAS). Methods. A total of 303 healthy children, 4-9 years of age, were scored as they performed 9 CMAS maneuvers. The data were then evaluated to determine whether normal scores for some maneuvers are age and sex dependent. Results. All children were able to achieve maximum possible scores for the supine to prone, supine to sit, floor sit, floor rise, and chair rise maneuvers. All but 2 4-year-olds achieved a maximum possible score for the arm raise/duration maneuver. Performance of the head lift and sit-up maneuvers varied significantly, depending primarily on age. Children in all age groups had less difficulty performing the leg lift than the head lift or sit-up. Conclusion. The normative data generated by this study are of value for interpreting the serial CMAS scores of children with idiopathic inflammatory myopathies. C1 Ohio State Univ, Columbus, OH 43210 USA. Childrens Hosp, Columbus, OH 43205 USA. Dalhousie Univ, Halifax, NS, Canada. Isaak Walton Killam Hlth Ctr, Halifax, NS, Canada. James Whitcomb Riley Hosp Children, Indianapolis, IN 46202 USA. Indiana Univ, Indianapolis, IN 46204 USA. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. Univ Toronto, Toronto, ON, Canada. NIEHS, NIH, Bethesda, MD 20892 USA. Univ Hlth Sci, Bethesda, MD USA. Univ Kansas, Kansas City, KS 66103 USA. Childrens Hosp, Cincinnati, OH 45229 USA. Univ Cincinnati, Cincinnati, OH USA. RP Rennebohm, RM (reprint author), Ohio State Univ, Columbus, OH 43210 USA. EM Rennebohmr@pediatrics.ohio-state.edu RI Feldman, Brian/A-8586-2011; OI Rider, Lisa/0000-0002-6912-2458; Miller, Frederick/0000-0003-2831-9593 NR 7 TC 22 Z9 23 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD JUN 15 PY 2004 VL 51 IS 3 BP 365 EP 370 DI 10.1002/art.20397 PG 6 WC Rheumatology SC Rheumatology GA 827SF UT WOS:000221920200012 PM 15188320 ER PT J AU Pillemer, SR Leakan, RA Sankar, V Manny, J Baum, BJ Smith, J Chaudhry, U Fox, PC Radfar, L Ligier, S Brennan, MT AF Pillemer, SR Leakan, RA Sankar, V Manny, J Baum, BJ Smith, J Chaudhry, U Fox, PC Radfar, L Ligier, S Brennan, MT TI Prominent adverse effects of thalidomide in primary Sjogren's syndrome SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Letter ID RHEUMATOID-ARTHRITIS; CLASSIFICATION; CRITERIA; THERAPY C1 NIH, Bethesda, MD 20892 USA. SUNY Buffalo, Buffalo, NY 14260 USA. Hop Maison Neuve Rosemont, Montreal, PQ H1T 2M4, Canada. Carolinas Med Ctr, Charlotte, NC 28203 USA. RP Pillemer, SR (reprint author), NIH, Bethesda, MD 20892 USA. NR 11 TC 15 Z9 16 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD JUN 15 PY 2004 VL 51 IS 3 BP 505 EP 506 DI 10.1002/art.20416 PG 2 WC Rheumatology SC Rheumatology GA 827SF UT WOS:000221920200033 PM 15188341 ER PT J AU Shin, MG Kajigaya, S Tarnowka, M McCoy, JP Levin, BC Young, NS AF Shin, MG Kajigaya, S Tarnowka, M McCoy, JP Levin, BC Young, NS TI Mitochondrial DNA sequence heterogeneity in circulating normal human CD34 cells and granulocytes SO BLOOD LA English DT Article ID MYELODYSPLASTIC SYNDROMES; MUTATIONS; MTDNA; VARIANT; DISEASE; MECHANISMS; MARROW; REGION; REPAIR; AGE AB We have reported marked mitochondrial DNA (mtDNA) sequence heterogeneity among individual CD34 clones from adult bone marrow (BM) and the age-dependent accumulation of mtDNA mutations in this mitotically active tissue. Here, we show direct evidence of clonal expansion of cells containing mtDNA mutations and that the mtDNA sequence may be easily determined by using peripheral blood (PB) as a CD34 cell source. Analysis of 594 circulating CD34 clones showed that 150 (25%) had mtDNA sequences different from the same donor's corresponding aggregate sequence. Examination of single granulocytes indicated that 103 (29%) from the same 6 individuals showed mtDNA heterogeneity, with sequences distinct from the corresponding aggregate tissue sequence and from the sequences of other single granulocytes. Circulating and BM CD34 cells showed virtually identical patterns of mtDNA heterogeneity, and the same changes were seen in progeny granulocytes as in their progenitors, indicating that blood sampling could be used in studies to determine whether mtDNA reflects an individual's cumulative or recent exposure to mutagens; as a marker of individual hematopoietic progenitors, stem cells, and their expansion; and for the detection of minimal residual disease in hematologic malignancies of CD34 cell origin. (C) 2004 by The American Society of Hematology. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. Natl Inst Stand & Technol, Div Biotechnol, Chem Sci & Technol Lab, Gaithersburg, MD USA. RP Young, NS (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Rm 7C103,9000 Rockville Pike, Bethesda, MD 20892 USA. EM youngn@nhibi.nih.gov NR 31 TC 25 Z9 26 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 2004 VL 103 IS 12 BP 4466 EP 4477 DI 10.1182/blood-2003-11-3949 PG 12 WC Hematology SC Hematology GA 828VL UT WOS:000222001700024 PM 15016645 ER PT J AU Lu, J Basu, A Melenhorst, JJ Young, NS Brown, KE AF Lu, J Basu, A Melenhorst, JJ Young, NS Brown, KE TI Analysis of T-cell repertoire in hepatitis-associated aplastic anemia SO BLOOD LA English DT Article ID PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; BONE-MARROW-TRANSPLANTATION; LIVER-DERIVED LYMPHOCYTES; ANTIGEN-DRIVEN SELECTION; AUTOIMMUNE HEPATITIS; MULTIPLE-SCLEROSIS; VIRAL-HEPATITIS; NON-A; NON-B; RHEUMATOID-ARTHRITIS AB Hepatitis-associated aplastic anemia (HAA) is a syndrome of bone marrow failure following an acute attack of seronegative hepatitis. Clinical features and liver histology suggest a central role for an immune-mediated mechanism. To characterize the immune response, we investigated the T-cell repertoire (T-cell receptor [TCR] Vbeta chain subfamily) of intrahepatic lymphocytes in HAA patients by TCR spectratyping. In 6 of 7 HAA liver samples, a broad skewing pattern in the 21 V-beta subfamilies tested was observed. In total, 62% +/- 18% of HAA spectratypes; showed a skewed pattern, similar to 68% +/- 18% skewed spectratype patterns in 3 of 4 patients with confirmed viral hepatitis. Additionally, the T-cell repertoire had similarly low levels of complexity. In the peripheral blood lymphocytes (PBLs) of a separate group of HAA patients prior to treatment, 60% +/- 15% skewed spectratypes were detected, compared with only 18% +/- 8% skewed spectratypes in healthy controls. After successful immunosuppressive treatment, an apparent reversion to a normal T-cell repertoire with a corresponding significant increase in T-cell repertoire complexity was observed in the HAA samples. In conclusion, our data suggest an antigen-driven T-cell expansion in HAA and achievement of a normal T-cell repertoire during recovery from HAA. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Brown, KE (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Rm 7C218,9000 Rockville Pike, Bethesda, MD 20892 USA. EM brownk@nhibi.nih.gov NR 43 TC 48 Z9 59 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 2004 VL 103 IS 12 BP 4588 EP 4593 DI 10.1182/blood-2003-11-3959 PG 6 WC Hematology SC Hematology GA 828VL UT WOS:000222001700040 PM 14988156 ER PT J AU Mamura, M Lee, W Sullivan, TJ Felici, A Sowers, AL Allison, JP Letterio, JJ AF Mamura, M Lee, W Sullivan, TJ Felici, A Sowers, AL Allison, JP Letterio, JJ TI CD28 disruption exacerbates inflammation in Tgf-beta 1(-/-) mice: in vivo suppression by CD4(+)CD25(+) regulatory T cells independent of autocrine TGF-beta 1 SO BLOOD LA English DT Article ID GROWTH-FACTOR-BETA; IMMUNOLOGICAL SELF-TOLERANCE; TGF-BETA; CTLA-4-DEFICIENT MICE; CUTTING EDGE; ANTIGEN 4; HOMEOSTASIS; LYMPHOPROLIFERATION; ACTIVATION; MOUSE AB Tgf-beta1(-/-) mice develop a progressive, lethal, inflammatory syndrome, but mechanisms leading to the spontaneous activation of Tgf-beta1(-/-) T cells remain unclear. Here we show the disruption of CD28 gene expression accelerates disease in Tgf-beta1(-/-) mice, and we link this increase in severity to a reduction in the number of CD4(+)CD25(+) regulatory T cells. CD4(+)CD25(+) T cells develop normally in Tgf-beta1(-/-) mice and display characteristic expression of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), glucocorticoid-induced tumor necrosis factor receptor (GITR), 0107 integrin, and Foxp3. Adoptive transfer of Tgf-beta1(-/-) splenocytes; to Tgf-beta1(+/+)/Rag2(-/-) mice induced an autoimmune inflammatory disease with features similar to those of the Tgf-beta1(-/-) phenotype, and disease transfer was accelerated by the depletion of Tgf-alpha1(-/-) CD4(+)CD25(+) T cells from donor splenocytes. Cotransfer of Tgf-beta1(-/-) CD4(+)CD25(+) T cells clearly attenuated disease in Rag2(-/-) recipients of CD25(+)-depleted Tgrf-beta1(-/-) spleen and lymph node cells, but suppression was incomplete when compared with Tgf-beta1(+/+) CD4(+)CD25(+) T cells. These data demonstrate that CD4+CD25+ regulatory T cells develop in complete absence of endogenous transforming growth factor-beta1 (TGF-beta1) expression and that autocrine TGF-beta1 expression is not essential for these cells to suppress inflammation in vivo. (C) 2004 by The American Society of Hematology. C1 NIH, Lab Cell Regulat & Carcinogenesis, Bethesda, MD USA. NIH, Mol Biol Lab, Canc Res Ctr, Bethesda, MD USA. NICHHD, Lab Mammalian Genes & Dev, Bethesda, MD 20892 USA. Univ Calif Berkeley, Howard Hughes Med Inst, Canc Res Lab, Berkeley, CA 94720 USA. RP Letterio, JJ (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, Bldg 41,Rm B1103,41 Lib Dr MSC 5055, Bethesda, MD 20892 USA. EM letterij@mail.nih.gov OI Mamura, Mizuko/0000-0003-4531-0144 NR 33 TC 54 Z9 62 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 2004 VL 103 IS 12 BP 4594 EP 4601 DI 10.1182/blood-2003-08-2897 PG 8 WC Hematology SC Hematology GA 828VL UT WOS:000222001700041 PM 15016653 ER PT J AU Piekarz, RL Robey, RW Zhan, ZR Kayastha, G Sayah, A Abdeldaim, AH Torrico, S Bates, SE AF Piekarz, RL Robey, RW Zhan, ZR Kayastha, G Sayah, A Abdeldaim, AH Torrico, S Bates, SE TI T-cell lymphoma as a model for the use of histone deacetylase inhibitors in cancer therapy: impact of depsipeptide on molecular markers, therapeutic targets, and mechanisms of resistance SO BLOOD LA English DT Article ID MULTIDRUG-RESISTANCE; DENILEUKIN DIFTITOX; UP-REGULATION; TRANSCRIPTIONAL REGULATION; INTERLEUKIN-2 RECEPTORS; CYTOPLASMIC DOMAINS; GROWTH-INHIBITION; GENE-EXPRESSION; DOWN-REGULATION; LEUKEMIA-CELLS AB Depsipeptide (FK228) is a novel histone deacetylase inhibitor currently in clinical trials and the first to demonstrate clinical activity in patients. Responses have been observed in patients with T-cell lymphomas, despite prior treatment with multiple chemotherapeutic agents. To better understand the effects of histone deacetylase inhibitors on T-cell lymphoma, the human T-cell lymphoma cell line HUT78 was tested for sensitivity and molecular response to depsipeptide. Treatment with depsipeptide, as well as other histone deacetylase inhibitors, caused induction of histone acetylation, induction of p21 expression, and substantial apoptosis without significant cell cycle arrest. Treatment with the caspase inhibitor z-VAD-fmk significantly inhibited depsipeptide-induced apoptosis, enabling detection of cell cycle arrest. Treatment with depsipeptide increased expression of the interleukin-2 (IL-2) receptor, and combination with the IL-2 toxin conjugate denileukin diftitox resulted in more than additive toxicity. Cells selected for resistance to depsipeptide overexpressed the multidrug resistance pump, P-glycoprotein (Pgp). However, cells selected for resistance to depsipeptide in the presence of a Pgp inhibitor had a Pgp-independent mechanism of resistance. These studies confirm the activity of depsipeptide in a T-cell lymphoma model and suggest a general sensitivity of T-cell lymphoma to histone deacetylase inhibitors, an emerging new class of anticancer agents. (C) 2004 by The American Society of Hematology. C1 NCI, Canc Therapeut Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Piekarz, RL (reprint author), 10 Ctr Dr,MSC 1903,Bldg 10,Rm 12C103, Bethesda, MD 20892 USA. EM rpiekarz@nih.gov NR 61 TC 124 Z9 125 U1 2 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 2004 VL 103 IS 12 BP 4636 EP 4643 DI 10.1182/blood-2003-09-3068 PG 8 WC Hematology SC Hematology GA 828VL UT WOS:000222001700049 PM 14996704 ER PT J AU Dallol, A Agathanggelou, A Fenton, SL Ahmed-Choudhury, J Hesson, L Vos, MD Clark, GJ Downward, J Maher, ER Latif, F AF Dallol, A Agathanggelou, A Fenton, SL Ahmed-Choudhury, J Hesson, L Vos, MD Clark, GJ Downward, J Maher, ER Latif, F TI RASSFIA interacts with microtubule-associated proteins and modulates microtubule dynamics SO CANCER RESEARCH LA English DT Article ID TUMOR-SUPPRESSOR GENE; HUMAN-CHROMOSOME 3P21.3; EPIGENETIC INACTIVATION; LUNG-CANCER; IDENTIFICATION; DOMAIN; MAP1B; CELLS; CYTOSKELETON; STABILITY AB The candidate tumor suppressor gene RASSF1A is inactivated in many types of adult and childhood cancers. However, the mechanisms by which RASSF1A exerts its tumor suppressive functions have yet to be elucidated. To this end, we performed a yeast two-hybrid screen to identify novel RASSF1A-interacting proteins in a human brain cDNA library. Seventy percent of interacting clones bad homology to microtubule-associated proteins, including MAP1B and VCY2IP1/C19ORF5. RASSF1A association with MAP1B and VCY2IP1/C19ORF5 was subsequently confirmed in mammalian cell lines. This suggested that RASSF1A may exert its tumor-suppressive functions through interaction with the microtubules. We demonstrate that RASSF1A associates with the microtubules, causing them to exist as hyperstabilized circular bundles. We found that two naturally occurring tumor-associated missense substitutions in the RASSF1A coding region, C65R and R257Q, perturb the association of RASSF1A with the microtubules. The C65R and R257Q in addition to VCY2IP1/C19ORF5 showed reduced ability to induce microtubule acetylation and were unable to protect the microtubules against the depolymerizing action of nocodazole. In addition, wild-type RASSF1A but not the C65R or the R257Q is able to block DNA synthesis. Our data identify a role for RASSF1A in the regulation of microtubules and cell cycle dynamics that could be part of the mechanism(s) by which RASSF1A exerts its growth inhibition on cancer cells. C1 Univ Birmingham, Sect Med & Mol Genet, Div Reprod & Child Hlth, Sch Med, Birmingham B15 2TT, W Midlands, England. Natl Canc Inst, Dept Cell & Canc Biol, Rockville, MD USA. Canc Res UK, Signal Transduct Lab, London Res Inst, London, England. Univ Birmingham, Sch Med, Canc Res UK, Renal Mol Oncol Res Grp, Birmingham, W Midlands, England. RP Latif, F (reprint author), Univ Birmingham, Sect Med & Mol Genet, Div Reprod & Child Hlth, Sch Med, Birmingham B15 2TT, W Midlands, England. EM flatif@hgmp.mrc.ac.uk RI MAHER, EAMONN/A-9507-2008; Dallol, Ashraf/H-8661-2012 OI MAHER, EAMONN/0000-0002-6226-6918; Dallol, Ashraf/0000-0002-8803-228X NR 27 TC 91 Z9 100 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 2004 VL 64 IS 12 BP 4112 EP 4116 DI 10.1158/0008-5472.CAN-04-0267 PG 5 WC Oncology SC Oncology GA 829VH UT WOS:000222077900010 PM 15205320 ER PT J AU Vos, MD Martinez, A Elam, C Dallol, A Taylor, BJ Latif, F Clark, GJ AF Vos, MD Martinez, A Elam, C Dallol, A Taylor, BJ Latif, F Clark, GJ TI A role for the RASSF1A tumor suppressor in the regulation of tubulin polymerization and genomic stability SO CANCER RESEARCH LA English DT Article ID CELL-CYCLE; RAS ONCOGENE; PROTEIN; GENE; INSTABILITY; CHECKPOINTS; APOPTOSIS; CANCER; DOMAIN; ATM AB The high frequency with which the novel tumor suppressor RASSFIA is inactivated by promoter methylation suggests that it plays a key role in the development of many primary human tumors. Yet the mechanism of RASSFIA action remains unknown. We now show that RASSFIA associates with microtubules and that this association is essential for RASSFIA to mediate its growth inhibitory effects. Overexpression of RASSFIA promotes the formation of stable microtubules, whereas a dominant-negative fragment of RASSFIA destabilizes microtubule networks. The RASSF1 protein is expressed as two main isoforms, 1A and 1C. The smaller 1C isoform also associates with microtubules but is less effective at stabilizing them. Because RASSFIA and RASSF1C localize to the mitotic spindle, we examined their effects upon genomic instability. RASSFIA and RASSF1C block activated Ras-induced genomic instability. However, a point mutant of RASSF1C, identified in human tumors, was severely defective for stabilizing tubulin and was unable to block the genomic destabilizing effects of Ras. Thus, we identify a role for RASSF1A/C in the control of microtubule polymerization and potentially in the maintenance of genomic stability. C1 NCI, Dept Cell & Canc Biol, Rockville, MD 20850 USA. Univ Birmingham, Sect Med & Mol Genet, Birmingham, W Midlands, England. NCI, Ctr Canc Res, Bethesda, MD USA. RP Clark, GJ (reprint author), NCI, Dept Cell & Canc Biol, 9610 Med Ctr Dr, Rockville, MD 20850 USA. EM gclark@mail.nih.gov RI Dallol, Ashraf/H-8661-2012; Martinez, Alfredo/A-3077-2013 OI Dallol, Ashraf/0000-0002-8803-228X; Martinez, Alfredo/0000-0003-4882-4044 NR 30 TC 90 Z9 97 U1 1 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 2004 VL 64 IS 12 BP 4244 EP 4250 DI 10.1158/0008-5472.CAN-04-0339 PG 7 WC Oncology SC Oncology GA 829VH UT WOS:000222077900027 PM 15205337 ER PT J AU Huang, Y Anderle, P Bussey, KJ Barbacioru, C Shankavaram, U Dai, ZY Reinhold, WC Papp, A Weinstein, JN Sadee, W AF Huang, Y Anderle, P Bussey, KJ Barbacioru, C Shankavaram, U Dai, ZY Reinhold, WC Papp, A Weinstein, JN Sadee, W TI Membrane transporters and channels: Role of the transportome in cancer chemosensitivity and chemoresistance SO CANCER RESEARCH LA English DT Article ID HUMAN BRAIN-TUMORS; CELL-LINES; P-GLYCOPROTEIN; MOLECULAR PHARMACOLOGY; SYSTEMATIC VARIATION; RNA INTERFERENCE; ANTICANCER DRUGS; H+-ATPASE; EXPRESSION; RESISTANCE AB Membrane transporters and channels (collectively the transportome) govern cellular influx and efflux of ions, nutrients, and drugs. We used oligonucleotide arrays to analyze gene expression of the transportome in 60 human cancer cell lines used by the National Cancer Institute for drug screening. Correlating gene expression with the potencies of 119 standard anticancer drugs identified known drug-transporter interactions and suggested novel ones. Folate, nucleoside, and amino acid transporters positively correlated with chemosensitivity to their respective drug substrates. We validated the positive correlation between SLC29A1 (nucleoside transporter ENT]) expression and potency of nucleoside analogues, azacytidine and inosine-glycodialdehyde. Application of an inhibitor of SLC29A1, nitrobenzylmercaptopurine ribonucleoside, significantly reduced the potency of these two drugs, indicating that SLC29A1 plays a role in cellular uptake. Three ABC efflux transporters (ABCB1, ABCC3, and ABCB5) showed significant negative correlations with multiple drugs, suggesting a mechanism of drug resistance. ABCB1 expression correlated negatively with potencies of 19 known ABCB1 substrates and with Baker's antifol and geldanamycin. Use of RNA interference reduced ABCB1 mRNA levels and concomitantly increased sensitivity to these two drugs, as expected for ABCB1 substrates. Similarly, specific silencing of ABCB5 by small interfering RNA increased sensitivity to several drugs in melanoma cells, implicating ABCB5 as a novel chemoresistance factor. Ion exchangers, ion channels, and subunits of proton and sodium pumps variably correlated with drug potency. This study identifies numerous potential drug-transporter relationships and supports a prominent role for membrane transport in determining chemosensitivity. Measurement of transporter gene expression may prove useful in predicting anticancer drug response. C1 Ohio State Univ, Coll Med & Publ Hlth, Dept Pharmacol, Program Pharmacogenet, Columbus, OH 43210 USA. Ohio State Univ, Coll Med & Publ Hlth, Dept Biomed Informat, Columbus, OH 43210 USA. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD USA. RP Sadee, W (reprint author), Ohio State Univ, Coll Med & Publ Hlth, Dept Pharmacol, Program Pharmacogenet, 5072 Graves Hall,333 W 10th Ave, Columbus, OH 43210 USA. EM sadee-1@medctr.osu.edu FU NIGMS NIH HHS [GM61390] NR 42 TC 190 Z9 196 U1 1 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 2004 VL 64 IS 12 BP 4294 EP 4301 DI 10.1158/0008-5472.CAN-03-3884 PG 8 WC Oncology SC Oncology GA 829VH UT WOS:000222077900034 PM 15205344 ER PT J AU Chakraborty, M Abrams, SI Coleman, CN Camphausen, K Schlom, J Hodge, JW AF Chakraborty, M Abrams, SI Coleman, CN Camphausen, K Schlom, J Hodge, JW TI External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing SO CANCER RESEARCH LA English DT Article ID RECOMBINANT ANTICANCER VACCINES; CARCINOEMBRYONIC ANTIGEN GENE; RENAL-CANCER CELLS; CYTOTOXIC LYMPHOCYTES; IONIZING-RADIATION; IMMUNE-RESPONSES; IN-VIVO; COSTIMULATORY MOLECULES; DIVERSIFIED PRIME; FAS LIGAND AB Local radiation is an established therapy for human tumors. Radiation also has been shown to alter the phenotype of target tissue, including gene products that may make tumor cells more susceptible to T-cell-mediated immune attack. We demonstrate a biological synergy between local radiation of tumor and active vaccine therapy. The model used consisted of mice transgenic for human carcinoembryonic antigen (CEA) and a murine carcinoma cell line transfected with CEA. The vaccine regimen consisted of a prime and boost strategy using vaccinia and avipox recombinants expressing CEA and three T-cell costimulatory molecules. One dose of 8-Gy radiation to tumor induced up-regulation of the death receptor Fas in situ for up to 11 days. However, neither radiation at this dose nor vaccine therapy was capable of inhibiting growth of 8-day established tumor. When vaccine therapy and local radiation of tumor were used in combination, dramatic and significant cures were achieved. This was mediated by the engagement of the Fas/Fas ligand pathway because Ag-bearing tumor cells expressing dominant-negative Fas were not susceptible to this combination therapy. Following the combination of vaccine and local radiation, tumors demonstrated a massive infiltration of T cells not seen with either modality alone. Mice cured of tumors demonstrated CD4(+) and CD8(+) T-cell responses specific for CEA but also revealed the induction of high levels of T-cell responses to two other antigens (gp70 and p53) overexpressed in tumor, indicating the presence of a consequential antigen cascade. Thus, these studies demonstrate a new paradigm for the use of local tumor irradiation in combination with active specific vaccine therapy to elicit durable antitumor responses of established tumors. C1 NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,Bldg 10,Room 8B09,MSC 1750, Bethesda, MD 20892 USA. EM js141c@nih.gov RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 NR 50 TC 216 Z9 222 U1 2 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 2004 VL 64 IS 12 BP 4328 EP 4337 DI 10.1158/0008-5472.CAN-04-0073 PG 10 WC Oncology SC Oncology GA 829VH UT WOS:000222077900038 PM 15205348 ER PT J AU Sundstrom, J Evans, JC Benjamin, EJ Levy, D Larson, MG Sawyer, DB Siwik, DA Colucci, WS Sutherland, P Wilson, PWF Vasan, RS AF Sundstrom, J Evans, JC Benjamin, EJ Levy, D Larson, MG Sawyer, DB Siwik, DA Colucci, WS Sutherland, P Wilson, PWF Vasan, RS TI Relations of plasma matrix metalloproteinase-9 to clinical cardiovascular risk factors and echocardiographic left ventricular measures - The Framingham Heart Study SO CIRCULATION LA English DT Article DE heart failure; hypertrophy; metalloproteinases; remodeling; echocardiography ID MATRIX-METALLOPROTEINASE INHIBITION; EXPERIMENTAL MYOCARDIAL-INFARCTION; FAILING HUMAN HEART; DILATED CARDIOMYOPATHY; TARGETED DELETION; TISSUE INHIBITORS; MMP INDUCTION; UP-REGULATION; FAILURE; DISEASE AB Background - Plasma levels of matrix metalloproteinase-9 (MMP-9), a key determinant of extracellular matrix degradation, are increased in heart failure and in acute coronary syndromes. We investigated cross-sectional relations of plasma MMP-9 to vascular risk factors and echocardiographic left ventricular (LV) measurements. Methods and Results - We studied 699 Framingham Study participants ( mean age, 57 years; 58% women), free of heart failure and previous myocardial infarction, who underwent routine echocardiography. We examined sex-specific distributions of LV internal dimensions ( LVEDD) and wall thickness (LVWT) and sampled persons with both LVEDD and LVWT below the sex-specific median ( referent, n = 299), with increased LVEDD ( LVEDD greater than or equal to 90th percentile, n = 204) and increased LVWT ( LVWT greater than or equal to 90th percentile, n = 221) in a 3: 2: 2 ratio. Plasma MMP-9 was detectable in 138 persons (20%). In multivariable models, increasing heart rate ( OR per SD, 1.41; 95% CI, 1.17 to 1.71) and antihypertensive treatment ( OR, 1.63; 95% CI, 1.06 to 2.50) were key clinical correlates of detectable plasma MMP-9. In multivariable-adjusted models, detectable plasma MMP-9 was associated with increased LVEDD ( OR, 2.84; 95% CI, 1.13 to 7.11), increased LVWT ( OR, 2.54; 95% CI, 1.00 to 6.46), and higher LV mass ( P = 0.06) in men but not in women ( OR for increased LVEDD, 1.37; 95% CI, 0.54 to 3.46; for increased LVWT, 0.99; 95% CI, 0.39 to 2.52; P = 0.59 for LV mass). Conclusions - In our community-based sample, detectable plasma MMP-9 levels were associated with increased LV diastolic dimensions and increased wall thickness in men. These observations indicate that plasma MMP-9 level may be a marker for cardiac extracellular matrix degradation, a process involved in LV remodeling. C1 Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. NHLBI, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Dept Prevent Med, Boston, MA 02118 USA. Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Myocardial Biol Unit, Boston, MA 02118 USA. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. EM vasan@bu.edu RI Sundstrom, Johan/A-6286-2009; OI Sundstrom, Johan/0000-0003-2247-8454; Siwik, Deborah/0000-0002-7166-327X; Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [1K24HL04334, 1R01HL67288-01, N01-HC-25195] NR 50 TC 121 Z9 128 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 15 PY 2004 VL 109 IS 23 BP 2850 EP 2856 DI 10.1161/01.CIR.0000129318.79570.84 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 829DT UT WOS:000222024900006 PM 15173025 ER PT J AU Hassan, R Bera, T Pastan, I AF Hassan, R Bera, T Pastan, I TI Mesothelin: A new target for immunotherapy SO CLINICAL CANCER RESEARCH LA English DT Review ID MONOCLONAL-ANTIBODY K1; ANTITUMOR-ACTIVITY; PSEUDOMONAS EXOTOXIN; MOLECULAR-CLONING; PANCREATIC-CANCER; OVARIAN CANCERS; GENE-EXPRESSION; SERIAL ANALYSIS; NUDE-MICE; IN-VITRO AB Mesothelin is a differentiation antigen present on normal mesothelial cells and overexpressed in several human tumors, including mesothelioma and ovarian and pancreatic adenocarcinoma. The mesothelin gene encodes a precursor protein that is processed to yield the 40-kDa protein, mesothelin, attached to the cell membrane by a glycosylphosphatidyl inositol linkage and a 31-kDa shed fragment named megakaryocyte-potentiating factor. The biological function of mesothelin is not known. Mesothelin is a promising candidate for tumor-specific therapy, given its limited expression in normal tissues and high expression in several cancers. SS1(dsFv)PE38 is a recombinant anti-mesothelin immunotoxin that is undergoing clinical evaluation in patients with mesothelin-expressing tumors. There is evidence that mesothelin is an immunogenic protein and could be exploited as a therapeutic cancer vaccine. A soluble mesothelin variant has been identified and could be a useful tumor marker for malignant mesotheliomas. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hassan, R (reprint author), NCI, Mol Biol Lab, NIH, 37 Convent Dr,Room 5116, Bethesda, MD 20892 USA. EM hassanr@mail.nih.gov NR 34 TC 251 Z9 260 U1 0 U2 17 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 15 PY 2004 VL 10 IS 12 BP 3937 EP 3942 DI 10.1158/1078-0432.CCR-03-0801 PN 1 PG 6 WC Oncology SC Oncology GA 832ED UT WOS:000222249100002 PM 15217923 ER PT J AU Tricoli, JV Schoenfeldt, M Conley, BA AF Tricoli, JV Schoenfeldt, M Conley, BA TI Detection of prostate cancer and predicting progression: Current and future diagnostic markers SO CLINICAL CANCER RESEARCH LA English DT Review ID GLUTATHIONE-S-TRANSFERASE; STEM-CELL ANTIGEN; SERUM CHROMOGRANIN-A; POLYMERASE-CHAIN-REACTION; CPG ISLAND HYPERMETHYLATION; MEMBRANE ANTIGEN; TELOMERASE ACTIVITY; INTRAEPITHELIAL NEOPLASIA; GSTP1 GENE; RADICAL PROSTATECTOMY AB Carcinoma of the prostate is the second leading cause of male cancer-related death in the United States. Better indicators of prostate cancer presence and progression are needed to avoid unnecessary treatment, predict disease course, and develop more effective therapy. Numerous molecular markers have been described in human serum, urine, seminal fluid, and histological specimens that exhibit varying capacities to detect prostate cancer and predict disease course. However, to date, few of these markers have been adequately validated for clinical use. The purpose of this review is to examine the current status of these markers in prostate cancer and to assess the diagnostic potential for future markers from identified genes and molecules that display loss, mutation, or alteration in expression between tumor and normal prostate tissues. In this review we cite 91 molecular markers that display some level of correlation with prostate cancer presence, disease progression, cancer recurrence, prediction of response to therapy, and/or disease-free survival. We suggest criteria to consider when selecting a marker for further development as a clinical tool and discuss five examples of markers (chromogranin A, glutathione S-transferase pi 1, prostate stem cell antigen, prostate-specific membrane antigen, and telomerase reverse transcriptase) that fulfill some of these criteria. Finally, we discuss how to conduct evaluations of candidate prostate cancer markers and some of the issues involved in the validation process. C1 NCI, Diagnost Res Branch, Canc Diagnosis Program, Rockville, MD 20852 USA. NCI, Canc Res Ctr, Aerodigest Clin Canc Res Sect, Bethesda, MD 20892 USA. EMMES Corp, Rockville, MD USA. RP Tricoli, JV (reprint author), NCI, Diagnost Res Branch, Canc Diagnosis Program, 6130 Execut Blvd,Execut Plaza N,Suite 6044, Rockville, MD 20852 USA. EM tricolij@mail.nci.nih.gov NR 137 TC 105 Z9 111 U1 1 U2 11 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 15 PY 2004 VL 10 IS 12 BP 3943 EP 3953 DI 10.1158/1078-0432.CCR-03-0200 PN 1 PG 11 WC Oncology SC Oncology GA 832ED UT WOS:000222249100003 PM 15217924 ER PT J AU Amornphimoltham, P Sriuranpong, V Patel, V Benavides, F Conti, CJ Sauk, J Sausville, EA Molinolo, AA Gutkind, JS AF Amornphimoltham, P Sriuranpong, V Patel, V Benavides, F Conti, CJ Sauk, J Sausville, EA Molinolo, AA Gutkind, JS TI Persistent activation of the Akt pathway in head and neck squamous cell carcinoma: a potential target for UCN-01 SO CLINICAL CANCER RESEARCH LA English DT Article ID PROTEIN-KINASE-C; CONSTITUTIVE ACTIVATION; SELECTIVE INHIBITOR; ANTITUMOR-ACTIVITY; SIGNALING PATHWAY; CANCER CELLS; KAPPA-B; EXPRESSION; APOPTOSIS; SURVIVAL AB Squamous carcinomas of the head and neck (HNSCC) represent the sixth most common cancer among men worldwide and a major cause of morbidity and mortality due to its relatively poor prognosis. As part of ongoing studies addressing the molecular events underlying tumor progression in HNSCC, we have explored the nature of the proliferative pathways in which dysregulation may promote aberrant cell growth in this tumor type. The serine/threonine protein kinase Akt is a downstream target of phosphatidylinositol 3-kinase and a key regulator of normal and cancerous growth and cell fate decisions. Therefore, in this study, we have examined the status of activation of Akt in different stages of squamous cell carcinoma development in mice and in clinical samples from HNSCC patients. By immunohistochemical analysis, using a recently developed phosphorylation state-specific antibody, we demonstrated that Akt activation correlates closely with the progression of mouse skin squamous cell carcinoma. We also observed that activation of Akt is a frequent event in human HNSCC because active Akt can be detected in these tumors with a pattern of expression and localization correlating with the progression of the lesions. In line with these observations, Akt was constitutively activated in a large fraction of HNSCC-derived cell lines. We also provide evidence that the Akt signaling pathway may represent a biologically relevant target for a novel antineoplastic agent, UCN-01, which recently has been shown to be active in cellular and xenograft models for HNSCC at concentrations safely achievable in clinically relevant situations. C1 Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Carcinogenesis, Houston, TX 77030 USA. Univ Maryland, Sch Dent, Dept Diagnost Sci & Pathol, Baltimore, MD 21201 USA. NCI, Dev Therapeut Program, NIH, Rockville, MD USA. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Bldg 30,Room 212, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Gutkind, J. Silvio/A-1053-2009; Benavides, Fernando/E-7872-2011 NR 37 TC 114 Z9 115 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 15 PY 2004 VL 10 IS 12 BP 4029 EP 4037 DI 10.1158/1078-0432.CCR-03-0249 PN 1 PG 9 WC Oncology SC Oncology GA 832ED UT WOS:000222249100014 PM 15217935 ER PT J AU Palayoor, ST Burgos, MA Shoaibi, A Tofilon, PJ Coleman, CN AF Palayoor, ST Burgos, MA Shoaibi, A Tofilon, PJ Coleman, CN TI Effect of radiation and ibuprofen on normoxic renal carcinoma cells overexpressing hypoxia-inducible factors by loss of von Hippel-Lindau tumor suppressor gene function SO CLINICAL CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; PROSTATE-CANCER CELLS; FACTOR 1-ALPHA; FACTORS HIF-1-ALPHA; NECK-CANCER; UNFAVORABLE PROGNOSIS; MESSENGER-RNA; PROTEIN VHL; HIF-ALPHA; EXPRESSION AB Purpose: Tumor hypoxia is a major limiting factor for radiation therapy. Hypoxia-inducible factors (HIFs) are overexpressed in several human cancers and are considered prognostic markers and potential targets for cancer therapy. The purpose of the present study was to investigate the impact of HIFs on radiosensitivity. Experimental Design: Renal clear cell carcinoma (RCC) cell lines overexpressing HIFs under normoxic conditions because of inactivation of von Hippel-Lindau tumor suppressor gene function (VHL-ve) and their matched pairs in which overexpression of HIFs was abolished by expression of functional VHL (VHL+ve) were irradiated. Radiosensitivity was determined by clonogenic assay. HIF and VHL protein levels were evaluated by Western blot analysis. RCC cells were also treated with ibuprofen, a radiosensitizer and HIF inhibitor in prostate cancer cells. The effect of ibuprofen on radiosensitization and HIF and VHL proteins was compared in RCC matched-pair cell lines. Results: The data showed only small differences in the radiosensitivity between the cells overexpressing HIFs and cells with basal HIF levels. The dose-modifying factors for C2, 786-0, and A498 RCC cells were 1.14, 1.14 and 1.15, respectively. Radiation did not alter HIF or VHL protein levels. Ibuprofen inhibited HIFs in VHL+ve cells expressing basal levels of HIFs. In VHL-ve cells overexpressing HIFs, the inhibition was very modest. Ibuprofen radiosensitized C2 RCC cells to the same extent irrespective of their HIF status. Conclusions: Overexpression of HIFs in RCC cells harboring VHL mutations has only a modest effect on the radiosensitivity. Radiosensitization by ibuprofen appears to be independent of HIF status. C1 NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Mol Radiat Therapeut Branch, Div Canc & Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Palayoor, ST (reprint author), NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Rockville Pike,Bldg 10,Room B3B69, Bethesda, MD 20892 USA. EM Palayoor@mail.nih.gov NR 51 TC 14 Z9 15 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 15 PY 2004 VL 10 IS 12 BP 4158 EP 4164 DI 10.1158/1078-0432.CCR-04-0005 PN 1 PG 7 WC Oncology SC Oncology GA 832ED UT WOS:000222249100032 PM 15217953 ER PT J AU Ng, SSW Macpherson, GR Gutschow, M Eger, K Figg, WD AF Ng, SSW Macpherson, GR Gutschow, M Eger, K Figg, WD TI Antitumor effects of thalidomide analogs in human prostate cancer Xenografts implanted in immunodeficient mice SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-A; FACTOR-B CHAINS; PHASE-II TRIAL; ANTIANGIOGENIC AGENT; MULTIPLE-MYELOMA; BETA-RECEPTOR; ANGIOGENESIS; IDENTIFICATION; EXPRESSION; INHIBITOR AB Purpose: Thalidomide has demonstrated clinical activity in various malignancies including androgen-independent prostate cancer. The development of novel thalidomide analogs with better activity/toxicity profiles is an ongoing research effort. Our laboratory previously reported the in vitro antiangiogenic activity of the N-substituted thalidomide analog CPS11 and the tetrafluorinated analogs CPS45 and CPS49. The current study evaluated the therapeutic potential of these analogs in the treatment of prostate cancer in vivo. Experimental Design: Severely combined immunodeficient mice bearing s.c. human prostate cancer (PC3 or 22Rv1) xenografts were treated with the analogs at their maximum tolerated doses. Tumors were then excised and processed for ELISA and CD31 immunostaining to determine the levels of various angiogenic factors and microvessel density (MVD), respectively. Results: CPS11, CPS45, and CPS49 induced prominent and modest growth inhibition in PC3 and 22Rv1 tumors, respectively. Thalidomide had no effect on tumor growth in either xenograft. Vascular endothelial growth factor and basic fibroblast growth factor levels were not significantly altered by any of the thalidomide analogs or thalidomide in both PC3 and 22Rv1 tumors. CPS45, CPS49, and thalidomide significantly reduced PC3 tumor platelet-derived growth factor (PDGF)-AA levels by 58-82% (P < 0.05). Interestingly, treatment with the analogs and thalidomide resulted in differential down-regulation (greater than or equal to1.5-fold) of genes encoding PDGF and PDGF receptor isoforms as determined by DNA microarray analysis. Intratumoral MVD of 22Rv1 xenografts was significantly decreased by CPS45 and CPS49. CPS49 also reduced MVD in PC3 xenografts. Conclusions: Thalidomide analogs CPS11 and 49 are promising anti-cancer agents. PDGF signaling pathway may be a potential target for these thalidomide analogs. Detailed microarray and functional analyses are under way with the aim of elucidating the molecular mechanism(s) of action of these thalidomide analogs. C1 NCI, Mol Pharmacol Sect, Canc Therapeut Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. Univ Bonn, Inst Pharmaceut, Bonn, Germany. Univ Leipzig, Inst Pharm Pharmaceut Chem, Leipzig, Germany. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, Canc Therapeut Branch, Ctr Canc Res,NIH, Bldg 10,Room 5A01,MSC 1910,9000 Rockville Pike, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Ain, Kenneth/A-5179-2012; Figg Sr, William/M-2411-2016 OI Ain, Kenneth/0000-0002-2668-934X; NR 20 TC 37 Z9 39 U1 2 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 15 PY 2004 VL 10 IS 12 BP 4192 EP 4197 DI 10.1158/1078-0432.CCR-03-0700 PN 1 PG 6 WC Oncology SC Oncology GA 832ED UT WOS:000222249100036 PM 15217957 ER PT J AU McCurdy, LH Larkin, BD Martin, JE Graham, BS AF McCurdy, LH Larkin, BD Martin, JE Graham, BS TI Modified vaccinia ankara: Potential as an alternative smallpox vaccine SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID BROAD SPECIES-SPECIFICITY; VIRUS ANKARA; UNITED-STATES; STRAIN MVA; BIOTERRORISM; CELLS; IMMUNOGENICITY; COMPLICATIONS; PROTECTION; ANTIBODIES AB Despite the declaration of smallpox eradication in 1980, the existence of variola stockpiles and the threat of bioterrorism demand that immunity to smallpox through vaccination be maintained. Although the currently available vaccine was used for the most successful medical intervention ever accomplished, it also is associated with side effects that are difficult to accept in a vaccine for a disease that has not been present for >25 years. Herein, we review alternative approaches to maintaining immunity to smallpox through vaccination with attenuated poxviruses, and we suggest modified vaccinia Ankara (MVA) as a leading candidate for an alternative smallpox vaccine. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Graham, BS (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,MSC 3017,Bldg 40,Rm 2502, Bethesda, MD 20892 USA. EM bgraham@nih.gov NR 47 TC 62 Z9 63 U1 0 U2 4 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 2004 VL 38 IS 12 BP 1749 EP 1753 DI 10.1086/421266 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 829YH UT WOS:000222087500017 PM 15227622 ER PT J AU Pittman, AM Myers, AJ Duckworth, J Bryden, L Hanson, M Abou-Sleiman, P Wood, NW Hardy, J Lees, A de Silva, R AF Pittman, AM Myers, AJ Duckworth, J Bryden, L Hanson, M Abou-Sleiman, P Wood, NW Hardy, J Lees, A de Silva, R TI The structure of the tau haplotype in controls and in progressive supranuclear palsy SO HUMAN MOLECULAR GENETICS LA English DT Article ID LINKAGE-DISEQUILIBRIUM; HUMAN GENOME; FRONTOTEMPORAL DEMENTIA; STRONG ASSOCIATION; GENE; DISEASE; IDENTIFICATION; RECOMBINATION; MUTATION; DEGENERATION AB The group of neurodegenerative diseases collectively known as tauopathies are characterized by hallmark lesions consisting of fibrillar aggregates of the microtubule-associated protein, tau (MAPT). Mutations of the tau gene (MAPT) are the cause of frontotemporal dementia with parkinsonism linked to chromosome 17, giving tau a central role in the pathogenic process. The chromosomal region containing MAPT has been shown to evolve into two major haplotypes, H1 and H2, which are defined by linkage disequilibrium (LD) between several polymorphisms over the entire MAPT gene. Studies to date suggest a complete absence of recombination between these two haplotypes. The more common haplotype H1 is over-represented in patients with progressive supranuclear palsy (PSP) and corticobasal degeneration. Using single nucleotide polymorphisms, we mapped LD in the regions flanking MAPT and have established the maximum extent of the haplotype block on chromosome 17q21.31 as a region covering similar to2 Mb. This gene-rich region extends centromerically beyond the corticotrophin releasing hormone receptor 1 gene (CRHR1) to a region of similar to400 kb, where there is a complete loss of LD. The telomeric end is defined by an similar to150 kb region just beyond the WNT3 gene. We show that the entire, fully extended H1 haplotype is associated with PSP, which implicates several other genes in addition to MAPT, as candidate pathogenic loci. C1 UCL, Reta Lila Weston Inst Neurol Studies, London W1T 4JF, England. Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. NIA, NIH, Neurogenet Lab, Bethesda, MD 20892 USA. RP de Silva, R (reprint author), UCL, Reta Lila Weston Inst Neurol Studies, Windeyer Bldg,46 Cleveland St, London W1T 4JF, England. EM rsilva@ion.ucl.ac.uk RI de Silva, Rohan/C-1734-2008; Myers, Amanda/B-1796-2010; Hardy, John/C-2451-2009; Pittman, Alan/D-6231-2012; Lees, Andrew/A-6605-2009; Wood, Nicholas/C-2505-2009 OI de Silva, Rohan/0000-0002-5052-5775; Myers, Amanda/0000-0002-3100-9396; Wood, Nicholas/0000-0002-9500-3348 FU Parkinson's UK [G-4029] NR 41 TC 81 Z9 82 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUN 15 PY 2004 VL 13 IS 12 BP 1267 EP 1274 DI 10.1093/hmg/ddh138 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 825HZ UT WOS:000221748400008 PM 15115761 ER PT J AU Washburn, NR Weir, M Anderson, P Potter, K AF Washburn, NR Weir, M Anderson, P Potter, K TI Bone formation in polymeric scaffolds evaluated by proton magnetic resonance microscopy and X-ray microtomography SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A LA English DT Article DE magnetic resonance microscopy; X-ray microtomography; tissue engineering; bone; polymer scaffold ID TRABECULAR BONE; IN-VIVO; TISSUE; CARTILAGE; MR; MACROMOLECULES; RELAXATION; DENSITY; CULTURE; MODEL AB Magnetic resonance microscopy (MRM) and Xray microtomography (XMT) were used to investigate de novo bone formation in porous poly(ethyl methacrylate) (PEMA) scaffolds, prepared by a novel co-extrusion process. PEMA scaffolds were seeded with primary chick calvarial osteoblasts and cultured under static conditions for up to 8 weeks. Bone formation within porous PEMA scaffolds was confirmed by the application of histologic stains to intact PEMA disks. Disks were treated with Alizarin red to visualize calcium deposits and with Sirius red to visualize regions of collagen deposition. DNA analysis confirmed that cells reached confluence on the scaffolds after 7 weeks in static culture. The formation of bone in PEMA scaffolds was investigated with water proton MRM. Quantitative MRM maps of the magnetization transfer ratio (MTR) yielded maps of protein deposition, and magnetic resonance (MR) relaxation times (T1 and T2) yielded maps of mineral deposition. The location of newly formed bone and local mineral concentrations were confirmed by XMT. By comparing MRM and XMT data from selected regions-of-interest in one sample, the inverse relationship between the MR relaxation times and mineral concentration was validated, and calibration curves for estimating the mineral content of cell-seeded PEMA scaffolds from quantitative MRM images were developed. (C) 2004 Wiley Periodicals, Inc*. C1 Natl Inst Stand & Technol, Div Polymer, Gaithersburg, MD USA. Queen Mary Univ London, Ctr Oral Growth & Dev, London, England. Armed Forces Inst Pathol Annex, Magnet Resonance Microscopy Facil, Rockville, MD 20850 USA. NICHHD, Sect Tissue Biophys & Biomimet, Bethesda, MD USA. RP Potter, K (reprint author), Armed Forces Inst Pathol Annex, Dept Cellular Pathol & Genet, 1413 Res Blvd, Rockville, MD 20850 USA. EM potterk@afip.osd.mil FU NIDCR NIH HHS [DE 14453] NR 39 TC 30 Z9 30 U1 0 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9304 J9 J BIOMED MATER RES A JI J. Biomed. Mater. Res. Part A PD JUN 15 PY 2004 VL 69A IS 4 BP 738 EP 747 DI 10.1002/jbm.a.30054 PG 10 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 827HR UT WOS:000221890800017 PM 15162416 ER PT J AU Sparreboom, A Cox, MC Acharya, MR Figg, WD AF Sparreboom, A Cox, MC Acharya, MR Figg, WD TI Herbal remedies in the United States: Potential adverse interactions with anticancer agents SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID GINKGO-BILOBA EXTRACT; ALTERNATIVE MEDICINE USE; RANDOMIZED CONTROLLED-TRIAL; DRUG-METABOLIZING-ENZYMES; HUMAN LIVER-MICROSOMES; ST-JOHNS-WORT; BREAST-CANCER; GARLIC OIL; ORGANOSULFUR COMPOUNDS; DIALLYL SULFIDE AB Purpose Interest in the use of herbal products has grown dramatically in the Western world. Recent estimates suggest an overall prevalence for herbal preparation use of 13% to 63% among cancer patients. With the narrow therapeutic range associated with most anticancer drugs, there is an increasing need for understanding possible adverse drug interactions in medical oncology. Methods In this article, a literature overview is provided of known or suspected interactions of the 15 best-selling herbs in the United States with conventional allopathic therapies for cancer. Results Herbs with the potential to significantly modulate the activity of drug-metabolizing enzymes (notably cytochrome P450 isozymes and/or the drug transporter P-glycoprotein include garlic (Allium sativum), ginkgo (Ginkgo biloba), echinacea (Echinacea purpurea), ginseng (Panax ginseng), St John's wort (Hypericum perforatum), and kava (Piper methysticum). All of these products participate in potential pharmacokinetic interactions with anticancer drugs. Conclusion It is suggested that health care professionals and consumers should be aware of the potential for adverse interactions with these herbs, question their patients on their use of them, especially among patients whose disease is not responding to treatments as expected, and urge patients to avoid herbs that could confound their cancer care. C1 NCI, Clin Pharmacol Res Core, Med Oncol Clin Res Unit, Ctr Canc Res, Bethesda, MD 20892 USA. RP Sparreboom, A (reprint author), NCI, Clin Pharmacol Res Core, Med Oncol Clin Res Unit, Ctr Canc Res, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM sparreba@mail.nih.gov RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 NR 100 TC 242 Z9 252 U1 5 U2 30 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 2004 VL 22 IS 12 BP 2489 EP 2503 DI 10.1200/JCO.2004.08.182 PG 15 WC Oncology SC Oncology GA 830VY UT WOS:000222153400030 PM 15197212 ER PT J AU Bafica, A Scanga, CA Schito, M Chaussabel, D Sher, A AF Bafica, A Scanga, CA Schito, M Chaussabel, D Sher, A TI Influence of coinfecting pathogens on HIV expression: Evidence for a role of toll-like receptors SO JOURNAL OF IMMUNOLOGY LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; TUMOR-NECROSIS-FACTOR; LONG TERMINAL REPEAT; NF-KAPPA-B; MYCOBACTERIUM-TUBERCULOSIS; HUMAN MACROPHAGES; TRANSGENIC MICE; IN-VITRO; IMMUNE ACTIVATION; GENE-EXPRESSION AB Immune activation of HIV gene expression as a consequence of the host response to coinfecting pathogens has been implicated as an important factor in AIDS progression. Immune responsiveness to many of the infectious agents associated with HIV has been demonstrated to depend on a family of innate recognition molecules, known as Toll-like receptors (TLR). Therefore, M-pathogen interactions could play an indirect role in regulating HIV-associated disease. In this review, we summarize emerging evidence for the influence of TLR recognition on HIV gene activation and AIDS progression. C1 NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NCI, Chem Immunol Sect, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Oswaldo Cruz Fdn, Ctr Pesquisas Goncalo Moniz, Lab Imunoregul & Microbiol, Salvador, BA, Brazil. RP Bafica, A (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bldg 50,Room 6146,50 S Dr, Bethesda, MD 20892 USA. EM abafica@niaid.nih.gov; asher@niaid.nih.gov OI Chaussabel, Damien/0000-0002-6131-7242 NR 68 TC 66 Z9 68 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 2004 VL 172 IS 12 BP 7229 EP 7234 PG 6 WC Immunology SC Immunology GA 828KV UT WOS:000221973100001 PM 15187096 ER PT J AU Andrade, MVM Hiragun, T Beaven, MA AF Andrade, MVM Hiragun, T Beaven, MA TI Dexamethasone suppresses antigen-induced activation of phosphatidylinositol 3-kinase and downstream responses in mast cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FC-EPSILON-RI; LINE RBL-2H3 CELLS; TYROSINE PHOSPHORYLATION; CYTOKINE PRODUCTION; ADENOSINE-RECEPTOR; ALLERGIC RESPONSE; PHOSPHOLIPASE-C; IGE-RECEPTOR; PI 3-KINASE; KINASE AB Dexamethasone and other glucocorticoids suppress Fc4epsilonRI-mediated release of inflammatory mediators from mast cells. Suppression of cytokine production is attributed to repression of cytokine gene transcription but no mechanism has been described for the suppression of degranulation. We show that therapeutic concentrations of dexamethasone inhibit intermediate signaling events, in particular the activation of phosphatidylinositol (PI)3-kinase and downstream signaling events that lead to degranulation in rat basophilic leukemia 2H3 cells. This inhibitory action is mediated via the glucocorticoid receptor and is not apparent when cells are stimulated via Kit in a mouse bone marrow-derived mast cell line. The primary perturbation appears to be the failure of the regulatory p85 subunit of PI3-kinase to engage with the adaptor protein Grb2-associated binder 2 leading to suppression of phosphorylation of phospholipase Cgamma2, the calcium signal, and degranulation. Suppression of PI3-kinase activation by dexamethasone may also contribute to reduced cytokine production because the PI3-kinase inhibitor LY294002, like dexamethasone, inhibits Ag-induced transcription of cytokine genes as well as degranulation. C1 NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Beaven, MA (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10,Room 8N109,9000 Rockville Pike, Bethesda, MD 20892 USA. EM beaven@helix.nih.gov RI ANDRADE, MARCUS/A-4764-2008 OI ANDRADE, MARCUS/0000-0002-3716-0919 NR 61 TC 55 Z9 56 U1 1 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2004 VL 172 IS 12 BP 7254 EP 7262 PG 9 WC Immunology SC Immunology GA 828KV UT WOS:000221973100005 PM 15187100 ER PT J AU Coutsoudis, A Dabis, F Fawzi, W Gaillard, P Haverkamp, G Harris, DR Jackson, JB Leroy, V Meda, N Msellati, P Newell, ML Nduati, R Read, JS Wiktor, S AF Coutsoudis, A Dabis, F Fawzi, W Gaillard, P Haverkamp, G Harris, DR Jackson, JB Leroy, V Meda, N Msellati, P Newell, ML Nduati, R Read, JS Wiktor, S CA Breastfeeding HIV Int Transmission TI Late postnatal transmission of HIV-1 in breast-fed children: An individual patient data meta-analysis SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID MOTHER-TO-CHILD; HUMAN-IMMUNODEFICIENCY-VIRUS; RANDOMIZED-TRIAL; COTE-DIVOIRE; SOUTH-AFRICA; VERTICAL TRANSMISSION; ORAL ZIDOVUDINE; CLINICAL-TRIAL; DOUBLE-BLIND; FOLLOW-UP AB Background. We analyzed individual patient data to determine the contribution of late postnatal transmission to the overall risk of mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) and the timing and determinants of late postnatal transmission. Methods. Eligible trials were conducted where breast-feeding was common; included greater than or equal to2 HIV-1 tests by 3 months, and, if follow-up continued, greater than or equal to2 tests at 3-12 months; and regularly assessed infant-feeding modality. Data on children born before January 2000 were analyzed. Results. Of 4085 children from 9 trials (breast-fed singletons for whom HIV-1 testing was performed), 993 (24%) were definitively infected (placebo arms, 25.9%; treatment arms, 23.4%; P = .08 ). Of 539 children with known timing of infection, 225 (42%) had late postnatal transmission. Late postnatal transmission occurred throughout breast-feeding. The estimated hazard function for time to late postnatal transmission was roughly constant. The cumulative probability of late postnatal transmission at 18 months was 9.3%. The overall risk of late postnatal transmission was 8.9 transmissions/100 child-years of breast-feeding and was significantly higher with lower maternal CD4(+) cell counts and male sex. Conclusions. Late postnatal transmission contributes substantially to overall mother-to-child transmission of HIV-1. The risk of late postnatal transmission is generally constant throughout breast-feeding, and late postnatal transmission is associated with a lower maternal CD4(+) cell count and male sex. Biological and cultural mechanisms underlying the association between sex and late postnatal transmission should be further investigated. Interventions to decrease transmission of HIV-1 through breast-feeding are urgently needed. C1 NICHHD, Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD 20892 USA. RP Read, JS (reprint author), NICHHD, Adolescent & Maternal AIDS Branch, NIH, Execut Bldg,Rm 4B11F,6100 Execut Blv,MSC 7510, Bethesda, MD 20892 USA. EM jennifer_read@nih.gov RI Van de Perre, Philippe/B-9692-2008; Leroy, Valeriane/F-8129-2013 OI Van de Perre, Philippe/0000-0002-3912-0427; Leroy, Valeriane/0000-0003-3542-8616 NR 42 TC 258 Z9 269 U1 1 U2 7 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 2004 VL 189 IS 12 BP 2154 EP 2166 PG 13 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 824PW UT WOS:000221699500002 ER PT J AU Clemens, J Savarino, S Abu-Elyazeed, R Safwat, M Rao, M Wierzba, T Svennerholm, AM Holmgren, J Frenck, R Park, E Naficy, A AF Clemens, J Savarino, S Abu-Elyazeed, R Safwat, M Rao, M Wierzba, T Svennerholm, AM Holmgren, J Frenck, R Park, E Naficy, A TI Development of pathogenicity-driven definitions of outcomes for a field trial of a killed oral vaccine against enterotoxigenic Escherichia coli in Egypt: Application of an evidence-based method SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 37th Joint Conference on Cholera and Other Bacterial Enteric Infections Panel CY DEC 17-19, 2002 CL OKINAWA, JAPAN SP Minist Hlth, Labor & Welfare ID B-SUBUNIT VACCINE; CELL CHOLERA VACCINE; IMMUNOSORBENT-ASSAY; ENDEMIC AREAS; DIARRHEA; CHILDREN; TOXIN; EPIDEMIOLOGY; MALARIA; DISEASE AB Background. To design an efficacy trial of a killed oral vaccine against enterotoxigenic Escherichia coli ( ETEC) diarrhea in Egyptian children, we derived for ETEC diarrhea an empirical definition that increased the probability that diarrhea associated with excretion of ETEC was caused by the detected ETEC. Methods. We conducted a cohort study of 397 Egyptian children < 24 months old and monitored them until they were 3 years old. Vaccine-preventable (VP) ETEC was defined as ETEC expressing &GE;1 of the toxin- (heat-labile [LT] toxin) and colonization-factor antigens (CFA I, II, and IV) in the vaccine. Results. Although fecal excretion of VP-ETEC was highly associated with diarrhea, excretion of LT-ETEC per se was not related to diarrhea (adjusted odds ratio [ORA], 1.16 [95% confidence interval {CI}, 0.90-1.49]). The fecal excretion of antigenic types of VP-ETEC other than LT-ETEC (non-LT VP-ETEC) was highly associated with diarrheal symptoms (ORA, 3.91 [95% CI, 2.78-5.49]; P < .001), and this association was greater for nonbloody than for bloody diarrhea. Conclusions. Because the vaccine had been anticipated to protect primarily against symptomatic ETEC diarrhea, these results indicate that the primary-outcome definition of ETEC diarrhea for the trial should be restricted to nonbloody diarrheal episodes associated with fecal excretion of non-LT VP-ETEC. C1 Int Vaccine Inst, Seoul 151742, South Korea. NICHHD, Bethesda, MD 20892 USA. USN, Med Res Unit 3, Cairo, Egypt. Univ Gothenburg, Gothenburg, Sweden. RP Clemens, J (reprint author), Int Vaccine Inst, Seoul 151742, South Korea. EM jclemens@ivi.int RI Savarino, Stephen/A-8030-2011 FU NICHD NIH HHS [Y1-HD-0026-01] NR 23 TC 20 Z9 20 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 2004 VL 189 IS 12 BP 2299 EP 2307 DI 10.1086/386288 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 824PW UT WOS:000221699500020 PM 15181579 ER PT J AU Shea, TB Zheng, YL Ortiz, D Pant, HC AF Shea, TB Zheng, YL Ortiz, D Pant, HC TI Cyclin-dependent kinase 5 increases perikaryal neurofilament phosphorylation and inhibits neurofilament axonal transport in response to oxidative stress SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE cyclin-dependent kinase 5; oxidative stress; neurofilament; phosphorylation; neurodegeneration; axonal transport ID AMYOTROPHIC-LATERAL-SCLEROSIS; MOTOR-NEURON DISEASE; CDK5 ACTIVATOR P35; NF-H; NEUROFIBRILLARY TANGLES; PROTEIN-KINASE; CELL NEURONS; MOUSE MODEL; HEAVY GENE; IN-VIVO AB Cyclin-dependent kinase 5 (cdk5) phosphorylates the high molecular weight neurofilament (NF) protein. Overexpression of cdk5 inhibits NF axonal transport and induces perikaryal accumulation of disordered phospho-NF cables. Experimental and clinical motor neuron disease is characterized by oxidative stress, increased cdk5 activity, and accumulation of phospho-NFs within perikarya or proximal axons. Because oxidative stress increases cdk5 activity in experimental motor neuron disease, we examined whether oxidative stress induced cdk5-mediated NF phosphorylation. Treatment of cultured neuronal cells with hydrogen peroxide inhibited axonal transport of green fluorescent protein-tagged NF subunits and induced perikaryal accumulation of NF phosphoepitopes normally confined to axons. These effects were prevented by treatment with the cdk5 inhibitor roscovitine or transfection with a construct expressing the endogenous cdk5 inhibitor peptide. These findings indicate that oxidative stress can compromise NF dynamics via hyperactivation of cdk5 and suggest that antioxidants may alleviate multiple aspects of neuropathology in motor neuron disease. (C) 2004 Wiley-Liss, Inc. C1 Univ Massachusetts, Ctr Cellular Neurobiol & Neurodegenerat Res, Dept Sci Biol, Lowell, MA 01854 USA. Univ Massachusetts, Ctr Cellular Neurobiol & Neurodegenerat Res, Dept Biochem, Lowell, MA 01854 USA. NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Shea, TB (reprint author), Univ Massachusetts, Ctr Cellular Neurobiol & Neurodegenerat Res, Dept Sci Biol, 1 Univ Ave, Lowell, MA 01854 USA. EM Thomas_Shea@uml.edu NR 60 TC 37 Z9 37 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD JUN 15 PY 2004 VL 76 IS 6 BP 795 EP 800 DI 10.1002/jnr.20099 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 826NQ UT WOS:000221836200005 PM 15160391 ER PT J AU Thomas, DD Espey, MG Ridnour, LA Hofseth, LJ Mancardi, D Harris, CC Wink, DA AF Thomas, DD Espey, MG Ridnour, LA Hofseth, LJ Mancardi, D Harris, CC Wink, DA TI Hypoxic inducible factor 1 alpha, extracellular signal-regulated kinase, and p53 are regulated by distinct threshold concentrations of nitric oxide SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer; hypoxia; macrophage; inducible NO synthase ID HUMAN BREAST-CANCER; ACTIVATED PROTEIN-KINASE; MURINE MELANOMA-CELLS; SYNTHASE-II GENE; WILD-TYPE P53; TUMOR-GROWTH; GUANYLATE-CYCLASE; CARCINOMA-CELLS; CYCLIC-GMP; EXPRESSION AB NO produced in tumors can either positively or negatively regulate growth. To examine this dichotomy, effects of NO concentration and duration on the posttranslational regulation of several key proteins were examined in human breast MCF7 cells under aerobic conditions. We found that different concentration thresholds of NO appear to elicit a discrete set of signal transduction pathways. At low steady-state concentrations of NO (<50 nM), extracellular signal-regulated kinase (ERK) phosphorylation was induced via a guanylate cyclase-dependent mechanism. Hypoxic inducible factor 1alpha (HIF-1alpha) accumulation was associated with an intermediate amount of NO (>100 nM), whereas p53 serine 15 phosphorylation occurred at considerably higher levels (>300 nM). ERK phosphorylation was transient during NO exposure. HIF-1alpha stabilization paralleled the presence of NO, whereas p53 serine 15 phosphorylation was detected during, and persisted after, NO exposure. The dose-dependent effects of synthetic NO donors were mimicked by activated macrophages cocultured with MCF7 cells at varying ratios. ERK and HIF-1alpha activation was similar in breast cancer cell lines either mutant (MB231) or null (MB157) in p53. The stabilization of HIF-1alpha by NO was not observed with increased MCF7 cell density, demonstrating the interrelationship between NO and O-2 consumption. The findings show that concentration and duration of NO exposure are critical determinants in the regulation of tumor-related proteins. C1 NCI, Tumor Biol Sect, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. Univ S Carolina, Coll Pharm, Dept Basic Pharmaceut Sci, Columbia, SC USA. NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Thomas, DD (reprint author), NCI, Tumor Biol Sect, Radiat Biol Branch, NIH, Bldg 10,Room B3-B69, Bethesda, MD 20892 USA. EM thomasdo@mail.nih.gov; wink@box-w.nih.gov NR 58 TC 154 Z9 159 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 15 PY 2004 VL 101 IS 24 BP 8894 EP 8899 DI 10.1073/pnas.0400453101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 830EQ UT WOS:000222104900013 PM 15178764 ER PT J AU Goldman, RD Shumaker, DK Erdos, MR Eriksson, M Goldman, AE Gordon, LB Gruenbaum, Y Khuon, S Mendez, M Varga, R Collins, FS AF Goldman, RD Shumaker, DK Erdos, MR Eriksson, M Goldman, AE Gordon, LB Gruenbaum, Y Khuon, S Mendez, M Varga, R Collins, FS TI Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DREIFUSS MUSCULAR-DYSTROPHY; DNA-REPLICATION; LIVING CELLS; ENVELOPE; PROTEIN; ORGANIZATION; MUTATIONS; GENE; SITES AB Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder, commonly caused by a point mutation in the lamin A gene that results in a protein lacking 50 aa near the C terminus, denoted LADelta50. Here we show by light and electron microscopy that HGPS is associated with significant changes in nuclear shape, including lobulation of the nuclear envelope, thickening of the nuclear lamina, loss of peripheral heterochromatin, and clustering of nuclear pores. These structural defects worsen as HGPS cells age in culture, and their severity correlates with an apparent increase in LADelta50. Introduction of LADelta50 into normal cells by transfection or protein injection induces the same changes. We hypothesize that these alterations in nuclear structure are due to a concentration-dependent dominant-negative effect of LADelta50, leading to the disruption of lamin-related functions ranging from the maintenance of nuclear shape to regulation of gene expression and DNA replication. C1 Northwestern Univ, Feinberg Sch Med, Dept Cell & Mol Biol, Chicago, IL 60611 USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Karolinska Inst, Novum, Dept Med Nutr, S-14157 Huddinge, Sweden. Tufts Univ, Sch Med, Dept Anat & Cellular Biol, Boston, MA 02111 USA. Rhode Isl Hosp, Dept Pediat, Providence, RI 02903 USA. Hebrew Univ Jerusalem, Inst Life Sci, Dept Genet, IL-91904 Jerusalem, Israel. RP Northwestern Univ, Feinberg Sch Med, Dept Cell & Mol Biol, 303 E Chicago Ave, Chicago, IL 60611 USA. EM r-goldman@northwestern.edu RI Mendez, Melissa/B-1357-2014 OI Mendez, Melissa/0000-0002-3995-2469 NR 33 TC 499 Z9 514 U1 12 U2 65 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 15 PY 2004 VL 101 IS 24 BP 8963 EP 8968 DI 10.1073/pnas.0402943101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 830EQ UT WOS:000222104900025 PM 15184648 ER PT J AU Smith, S Hwang, JY Banerjee, S Majeed, A Gupta, A Myung, K AF Smith, S Hwang, JY Banerjee, S Majeed, A Gupta, A Myung, K TI Mutator genes for suppression of gross chromosomal rearrangements identified by a genome-wide screening in Saccharomyces cerevisiae SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DNA-DAMAGE; POSTREPLICATION REPAIR; CELL-LINE; INSTABILITY; YEAST; CANCER; STABILITY; PEROXIREDOXIN; MAINTENANCE; EXPRESSION AB Different types of gross chromosomal rearrangements (GCRs), including translocations, interstitial deletions, terminal deletions with de novo telomere additions, and chromosome fusions, are observed in many cancers. Multiple pathways, such as S-phase checkpoints, DNA replication, recombination, chromatin remodeling, and telomere maintenance that suppress GCRs have been identified. To experimentally expand our knowledge of other pathway(s) that suppress GCRs, we developed a generally applicable genome-wide screening method. In this screen, we identified 10 genes (ALO1, CDC50, CSM2, ELG1, ESC1, MMS4, RAD5, RAD18, TSA1, and UFO1) that encode proteins functioning in the suppression of GCRs. Moreover, the breakpoint junctions of GCRs from these GCR mutator mutants were determined with modified breakpoint-mapping methods. We also identified nine genes (AKR1, BFR1, HTZ1, IES6, NPL6, RPL13B, RPL27A, RPL35A, and SHU2) whose mutations generated growth defects with the pif1Delta mutation. In addition, we found that some of these mutations changed the telomere size. C1 NHGRI, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Myung, K (reprint author), NHGRI, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, 49 Convent Dr, Bethesda, MD 20892 USA. EM kmyung@nhgri.nih.gov OI Hwang, Ji-Young/0000-0001-8044-1989 NR 51 TC 99 Z9 105 U1 1 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 15 PY 2004 VL 101 IS 24 BP 9039 EP 9044 DI 10.1073/pnas.0403093101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 830EQ UT WOS:000222104900039 PM 15184655 ER PT J AU Canet-Aviles, RM Wilson, MA Miller, DW Ahmad, R McLendon, C Bandyopadhyay, S Baptista, MJ Ringe, D Petsko, GA Cookson, MR AF Canet-Aviles, RM Wilson, MA Miller, DW Ahmad, R McLendon, C Bandyopadhyay, S Baptista, MJ Ringe, D Petsko, GA Cookson, MR TI The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RESOLUTION CRYSTAL-STRUCTURE; OXIDATIVE STRESS; CELL-DEATH; SACCHAROMYCES-CEREVISIAE; PROTEASOME; PEROXIREDOXINS; SUPERFAMILY; APOPTOSIS; MUTATIONS; PATHWAYS AB Loss-of-function DJ-1 mutations can cause early-onset Parkinson's disease. The function of DJ-1 is unknown, but an acidic isoform accumulates after oxidative stress, leading to the suggestion that DJ-1 is protective under these conditions. We addressed whether this represents a posttranslational modification at cysteine residues by systematically mutating cysteine residues in human DJ-1. WT or C53A DJ-1 was readily oxidized in cultured cells, generating a pi 5.8 isoform, but an artificial C106A mutant was not. We observed a cysteine-sulfinic acid at C106 in crystalline DJ-1 but no modification of C53 or C46. Oxidation of DJ-1 was promoted by the crystallization procedure. In addition, oxidation-induced mitochondrial relocalization of DJ-1 and protection against cell death were abrogated in C106A but not C53A or C46A. We suggest that DJ-1 protects against neuronal death, and that this is signaled by acidification of the key cysteine residue, C106. C1 NIA, Neurogenet Lab, Bethesda, MD 20892 USA. Brandeis Univ, Dept Biochem, Waltham, MA USA. Brandeis Univ, Rosenstiel Basic Med Sci Res Ctr, Waltham, MA 02454 USA. RP Cookson, MR (reprint author), NIA, Neurogenet Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM cookson@mail.nih.gov NR 33 TC 568 Z9 582 U1 7 U2 48 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 15 PY 2004 VL 101 IS 24 BP 9103 EP 9108 DI 10.1073/pnas.0402959101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 830EQ UT WOS:000222104900050 PM 15181200 ER PT J AU McQueen, PG McKenzie, FE AF McQueen, PG McKenzie, FE TI Age-structured red blood cell susceptibility and the dynamics of malaria infections SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PLASMODIUM-FALCIPARUM INFECTIONS; STAGE DYNAMICS; ERYTHROCYTES; MODEL; ANEMIA AB Malaria parasites and immune responses in an infected human interact on a dynamic landscape, in which a population of replicating parasites depletes a population of replenishing red blood cells (RBCs). These underlying dynamics receive relatively little attention, but they offer unique insights into the processes that control most malaria infections. Here, we focus on the observation that three of the four malaria-parasite species that infect humans are restricted to particular age classes of RBC. We explicitly incorporate this observation in models of infection dynamics to distinguish common from species-specific pressures on host immune responses, and we find that age structuring has profound effects on the course of infection. For all four species conditions exist under which the parasites may persist at low densities, or may clear, even in the absence of an immune response. Catastrophic anemia can occur even with the two species that attack only the youngest RBCs, although only a small fraction of cells are parasitized at any point. Furthermore, with these two, compensatory erythropoetic responses in the host accelerate parasite population growth. A "basic reproduction rate" characterizes these differences in outcomes. C1 NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP McQueen, PG (reprint author), NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. EM mcqueenp@helix.nih.gov FU Intramural NIH HHS [Z99 TW999999] NR 30 TC 52 Z9 52 U1 0 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 15 PY 2004 VL 101 IS 24 BP 9161 EP 9166 DI 10.1073/pnas.0308256101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 830EQ UT WOS:000222104900060 PM 15178766 ER PT J AU Woodson, K Gillespie, J Hanson, J Emmert-Buck, M Phillips, JM Linehan, WM Tangrea, JA AF Woodson, K Gillespie, J Hanson, J Emmert-Buck, M Phillips, JM Linehan, WM Tangrea, JA TI Heterogeneous gene methylation patterns among pre-invasive and cancerous lesions of the prostate: A histopathologic study of whole mount prostate specimens SO PROSTATE LA English DT Article DE methylation; prostate cancer; histopathologic progression ID B RECEPTOR GENE; CPG-ISLAND; INTRAEPITHELIAL NEOPLASIA; SUPPRESSOR GENE; BLADDER-CANCER; HYPERMETHYLATION; CELLS; CD44; PROGRESSION; METASTASIS AB BACKGROUND. Gene methylation may contribute to prostate carcinogenesis through the silencing of gene transcription. We report on the methylation status of several genes shown to be silenced at different stages of progression using whole mount prostate specimens and laser capture microdissection. This is the first study to evaluate gene methylation patterns across multiple pre-cancerous and invasive cancer foci from the same prostate gland. METHODS. Real-time PCR was used to evaluate methylation of five genes (GSTP1, RASSF1A, RARbeta2, CD44, and EDNRB) across normal epithelium, high-grade prostatic intraepithelial neoplasia (HGPIN), and multiple tumor foci from each of 11 prostate cancer patients. RESULTS. Gene methylation was not found in normal epithelium. To our knowledge, this is the first report of RASSF1A and RARbeta2 methylation in HGPIN lesions (30% prevalence for each gene). In addition, RASSF1A, RARbeta2, and GSTP1 methylation was highly prevalent in tumor foci (>75% for all three genes). Methylation of CD44 and EDNRB was observed in 41 and 38% of tumors but was not present in HGPIN. CONCLUSIONS. These data suggest that genes may be methylated at different points in the histopathologic progression of prostate cancer and these differences can be found in various histologic foci from the same gland. (C) 2004 Wiley-Liss, Inc. C1 Canc Prevent Studies Branch, CCR, NCI, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Pathol Lab, Bethesda, MD USA. NCI, Ctr Canc Res, Urol Oncol Branch, Bethesda, MD USA. RP Woodson, K (reprint author), Canc Prevent Studies Branch, CCR, NCI, 6116 Execut Blvd,Suite 705, Bethesda, MD 20892 USA. EM kw114v@nih.gov NR 21 TC 47 Z9 50 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-4137 J9 PROSTATE JI Prostate PD JUN 15 PY 2004 VL 60 IS 1 BP 25 EP 31 DI 10.1002/pros.20013 PG 7 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 824UE UT WOS:000221711600003 PM 15129426 ER PT J AU Woodard, GE Zhao, J Rosado, JA Brown, J AF Woodard, GE Zhao, J Rosado, JA Brown, J TI Patterning of renal cGMP production by the natriuretic peptide receptor type A and blood pressure in spontaneously hypertensive rats SO REGULATORY PEPTIDES LA English DT Article DE ANP; blood pressure; cGMP; SHR ID Y-CHROMOSOME; RENIN GENE; SYSTEM AB Although important advances have been made over past decades in studying the mechanisms of hypertension, the nature of cellular signaling patterns involved and their relationship remain unclear. High cGMP production rates in isolated renal glomeruli have been presented as a characteristic of spontaneously hypertensive rat (SHR) even before the development of hypertension, which suggests that this event might be a cause of the increase in blood pressure. Using cross-breeding between SHR and WKY parental strains to obtain F1 and F2 hybrids, we have investigated the patterning of high blood pressure and cGMP production rates. We have found that, in the F2 population, the mean blood pressure and both basal and ANP(1-28)-stimulated cGMP production are similar to the parental SHR. In addition, we have found a positive correlation between blood pressure and high cGMP production rates in the F2 population. The higher cGMP production was not a consequence of hypertension, since in DOCA-salt hypertensive rats cGMP production was similar to that observed in normotensive WKY rats. These observations suggest that high cGMP production is a characteristic linked to hypertension. Finally, reciprocal crosses between the SHR and WKY parental strains showed that in the F1 population blood pressure but not cGMP production are associated with the Y chromosome. (C) 2004 Elsevier B.V. All rights reserved. C1 Univ Cambridge, Physiol Lab, Cambridge CB2 3EG, England. RP Woodard, GE (reprint author), NIDDKD, NIH, Bldg 10,Rm 8C-208,10 Ctr Dr,MSC 1752, Bethesda, MD 20892 USA. EM GeoffreyW@intra.niddk.nih.gov RI Woodard, Geoffrey/A-8608-2009; rosado, juan/H-3488-2015 OI rosado, juan/0000-0002-9749-2325 NR 27 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-0115 J9 REGUL PEPTIDES JI Regul. Pept. PD JUN 15 PY 2004 VL 119 IS 1-2 BP 45 EP 51 DI 10.1016/j.regpep.2003.12.002 PG 7 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 816DN UT WOS:000221090700007 PM 15093696 ER PT J AU Hasler, G Buysse, DJ Klaghofer, R Gamma, A Ajdacic, V Eich, D Rossler, W Angst, J AF Hasler, G Buysse, DJ Klaghofer, R Gamma, A Ajdacic, V Eich, D Rossler, W Angst, J TI The association between short sleep duration and obesity in young adults: A 13-year prospective study SO SLEEP LA English DT Article DE sleep duration; obesity; cohort study ID PSYCHIATRIC-SYMPTOMS; UNITED-STATES; BODY-WEIGHT; MORTALITY; OVERWEIGHT; INSOMNIA; WOMEN; ADOLESCENCE; POPULATION; PATTERNS AB Study Objectives: Obesity has become a major health problem with increasing prevalence. Given the limited availability of effective treatment of weight problems, the identification of potentially modifiable risk factors may lead to preventive approaches to obesity. The objective of this study was to test the hypothesis that short sleep duration is associated with obesity and weight gain during young adulthood. Design: Prospective single-age cohort study of young adults. Information was derived from 4 interviews when participants were ages 27, 29, 34, and 40 years. Setting: Community setting. Participants: 496 young adults. Measurements and Results: Trained health professionals administered a semistructured interview for psychiatric and medical conditions and health habits. This study showed an association between short sleep duration and obesity (at age 27 years, odds ratio: 7.4, 95% confidence interval: 1.3-43.1) and a negative association between sleep duration and body mass index in young adults. These associations persisted after controlling for a variety of potentially confounding variables, including family history of weight problems, levels of physical activity, and demographic variables. Associations between sleep duration and obesity diminished after age 34 years. There was a trend (P = .08) for average change rate of weight gain to be negatively associated with average change rate of sleep duration. Conclusions: Because sleep duration is a potentially modifiable risk factor, these findings might have important clinical implications for the prevention and treatment of obesity. C1 NIMH, NIH, Mood & Anxiety Disorders Program, Intramural Res Program, Bethesda, MD 20892 USA. Psychiat Univ Hosp, Zurich, Switzerland. Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. Univ Zurich Hosp, Dept Psychosocial Med, Zurich, Switzerland. RP Hasler, G (reprint author), NIMH, NIH, Mood & Anxiety Disorders Program, Intramural Res Program, 15K N Dr,Room 300C,MSC 2670, Bethesda, MD 20892 USA. EM g.hasler@bluewin.ch RI Loureiro, Nuno/I-6400-2012; Hasler, Gregor/E-4845-2012; OI Loureiro, Nuno/0000-0002-1166-3219; Hasler, Gregor/0000-0002-8311-0138; Ajdacic-Gross, Vladeta/0000-0002-7032-9237 NR 35 TC 345 Z9 356 U1 2 U2 30 PU AMER ACADEMY SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CENTER STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PD JUN 15 PY 2004 VL 27 IS 4 BP 661 EP 666 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 844OW UT WOS:000223169300011 PM 15283000 ER PT J AU Yu, BB Tiwari, RC Cronin, KA Feuer, EJ AF Yu, BB Tiwari, RC Cronin, KA Feuer, EJ TI Cure fraction estimation from the mixture cure models for grouped survival data SO STATISTICS IN MEDICINE LA English DT Article ID TIME AB Mixture cure models are usually used to model failure time data with long-term survivors. These models have been applied to grouped survival data. The models provide simultaneous estimates of the proportion of the patients Cured from disease and the distribution of the survival times for uncured patients (latency distribution). However, a crucial issue with mixture cure models is the identifiability of the cure fraction and parameters of kernel distribution. Cure fraction estimates can be quite sensitive to the choice of latency distributions and length of follow-up time. In this paper, sensitivity of parameter estimates under semi-parametric model and several most commonly used parametric models, namely lognormal, loglogistic, Weibull and generalized Gamma distributions, is explored. The cure fraction estimates from the model with generalized Gamma distribution is found to be quite robust. A simulation study was carried out to examine the effect of follow-up time and latency distribution specification on cure fraction estimation. The cure models with generalized Gamma latency distribution are applied to the population-based survival data for several cancer sites from the Surveillance, Epidemiology and End Results (SEER) Program. Several cautions on the general use of cure model are advised. Copyright (C) 2004 John Wiley Sons, Ltd. C1 Informat Management Serv Inc, Silver Spring, MD 20910 USA. NCI, Stat Applicat & Res Branch, Bethesda, MD 20892 USA. RP Yu, BB (reprint author), Informat Management Serv Inc, 12501 Prosper Dr,Suite 200, Silver Spring, MD 20910 USA. EM vub@inisweb.com NR 19 TC 41 Z9 42 U1 1 U2 4 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 15 PY 2004 VL 23 IS 11 BP 1733 EP 1747 DI 10.1002/sim.1774 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 824CM UT WOS:000221661600005 PM 15160405 ER PT J AU Freidlin, B Korn, EL AF Freidlin, B Korn, EL TI A testing procedure for survival data with few responders SO STATISTICS IN MEDICINE LA English DT Letter ID CANCER; HER2 C1 NCI, Biometr Res Branch, Bethesda, MD 20892 USA. RP Freidlin, B (reprint author), NCI, Biometr Res Branch, 6130 Execut Blvd,EPN 8122, Bethesda, MD 20892 USA. NR 7 TC 2 Z9 2 U1 0 U2 0 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 15 PY 2004 VL 23 IS 11 BP 1818 EP 1823 DI 10.1002/sim.1660 PG 6 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 824CM UT WOS:000221661600011 PM 15160411 ER PT J AU Chiueh, CC Andoh, T Chock, PB AF Chiueh, CC Andoh, T Chock, PB TI Roles of thioredoxin (TRX) in nitric oxide - Dependent preconditioning tolerance against MPTP neurotoxin SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Meeting Abstract CT 10th International Congress of Toxicology CY JUL 11-15, 2004 CL Tampere, FINLAND C1 Taipei Med Univ, Inst Brain & Aging, Taipei, Taiwan. Toyama Med & Pharmaceut Univ, Dept Appl Pharmacol, Toyama, Japan. NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUN 15 PY 2004 VL 197 IS 3 MA 7 BP 139 EP 139 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 833OZ UT WOS:000222348900006 ER PT J AU Rauhala, P Andoh, T Chiueh, CC AF Rauhala, P Andoh, T Chiueh, CC TI Protection of dopaminergic nigral neurons by GSNO against iron-induced oxidant stress SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Meeting Abstract CT 10th International Congress of Toxicology CY JUL 11-15, 2004 CL Tampere, FINLAND C1 Univ Helsinki, Inst Biomed, FIN-00014 Helsinki, Finland. Toyama Med & Pharmaceut Univ, Dept Appl Pharmacol, Toyama, Japan. NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUN 15 PY 2004 VL 197 IS 3 MA 8 BP 139 EP 139 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 833OZ UT WOS:000222348900007 ER PT J AU Pernaute, RS Brownell, AL Isacson, O AF Pernaute, RS Brownell, AL Isacson, O TI Insights into Parkinson's disease models and neurotoxicity using non-invasive imaging SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Meeting Abstract CT 10th International Congress of Toxicology CY JUL 11-15, 2004 CL Tampere, FINLAND C1 Harvard Univ, Sch Med, McLean Hosp,Neuroregenerat Labs, Udall Parkinsons Dis Res Ctr Excellence, Belmont, MA 02478 USA. Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUN 15 PY 2004 VL 197 IS 3 MA 56 BP 151 EP 151 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 833OZ UT WOS:000222348900050 ER PT J AU Sills, RC Morgan, DL Maronpot, RR Johnson, GA AF Sills, RC Morgan, DL Maronpot, RR Johnson, GA TI Contribution of magnetic resonance microscopy in the biologic and mechanistic assessment of carbonyl sulfide neurotoxicity in F344 rats SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Meeting Abstract CT 10th International Congress of Toxicology CY JUL 11-15, 2004 CL Tampere, FINLAND C1 NIEHS, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Ctr In Vivo Microscopy, Durham, NC USA. NR 0 TC 0 Z9 0 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUN 15 PY 2004 VL 197 IS 3 MA 59 BP 151 EP 152 PG 2 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 833OZ UT WOS:000222348900052 ER PT J AU Hussain, SP Hofseth, LJ Wogan, G Wang, XW Harris, CC AF Hussain, SP Hofseth, LJ Wogan, G Wang, XW Harris, CC TI Molecular toxicology and molecular epidemiology: Radical causes of human cancer SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Meeting Abstract CT 10th International Congress of Toxicology CY JUL 11-15, 2004 CL Tampere, FINLAND C1 NCI, Human Carcinogenesis Lab, CCR, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUN 15 PY 2004 VL 197 IS 3 MA 64 BP 153 EP 153 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 833OZ UT WOS:000222348900057 ER PT J AU Hussain, SP He, PJ Mechanic, L Hagiwara, N Harris, CC AF Hussain, SP He, PJ Mechanic, L Hagiwara, N Harris, CC TI Endogenous DNA damage and mutational profiles induced by oxyradical overload diseases in humans SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Meeting Abstract CT 10th International Congress of Toxicology CY JUL 11-15, 2004 CL Tampere, FINLAND C1 NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUN 15 PY 2004 VL 197 IS 3 MA 68 BP 154 EP 154 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 833OZ UT WOS:000222348900061 ER PT J AU Wexler, P AF Wexler, P TI Toxicology Web resources from the US National Library of Medicine and elsewhere SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Meeting Abstract CT 10th International Congress of Toxicology CY JUL 11-15, 2004 CL Tampere, FINLAND C1 Natl Lib Med, Bethesda, MD USA. NR 0 TC 0 Z9 0 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUN 15 PY 2004 VL 197 IS 3 MA 78 BP 157 EP 157 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 833OZ UT WOS:000222348900071 ER PT J AU Merrick, BA Madenspacher, JE Bruno, ME Borchers, CH Dial, JM Dubin, JR Wetmore, BA Jayadev, S Blanchard, KT Stoll, RE Barrett, JC Tomer, KB AF Merrick, BA Madenspacher, JE Bruno, ME Borchers, CH Dial, JM Dubin, JR Wetmore, BA Jayadev, S Blanchard, KT Stoll, RE Barrett, JC Tomer, KB TI Gene and protein expression profiling of rat liver and subcellular fractions after subacute exposure to phenobarbital SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Meeting Abstract CT 10th International Congress of Toxicology CY JUL 11-15, 2004 CL Tampere, FINLAND C1 NIEHS, Natl Ctr Toxicogenom, Res Triangle Pk, NC 27709 USA. Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA. NR 0 TC 0 Z9 0 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUN 15 PY 2004 VL 197 IS 3 MA 87 BP 159 EP 160 PG 2 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 833OZ UT WOS:000222348900080 ER PT J AU Kleeberger, SR AF Kleeberger, SR TI Gene-particulate matter health interactions SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Meeting Abstract CT 10th International Congress of Toxicology CY JUL 11-15, 2004 CL Tampere, FINLAND C1 NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUN 15 PY 2004 VL 197 IS 3 MA 93 BP 161 EP 161 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 833OZ UT WOS:000222348900086 ER PT J AU Bell, DA Tomso, DJ Pittman, GS Campbell, M Inga, A Menendez, D Resnick, MA AF Bell, DA Tomso, DJ Pittman, GS Campbell, M Inga, A Menendez, D Resnick, MA TI Discovery and functional analysis of polymorphisms in gene regulatory elements: Genetic variation in novel p53 responsive genes SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Meeting Abstract CT 10th International Congress of Toxicology CY JUL 11-15, 2004 CL Tampere, FINLAND C1 NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUN 15 PY 2004 VL 197 IS 3 MA 103 BP 164 EP 164 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 833OZ UT WOS:000222348900094 ER PT J AU McManus, ME Negishi, M Hempel, N AF McManus, ME Negishi, M Hempel, N TI The human sulfotransferase SULT1A1 gene is regulated in a synergistic manner by GA binding protein and Sp1 SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Meeting Abstract CT 10th International Congress of Toxicology CY JUL 11-15, 2004 CL Tampere, FINLAND C1 Univ Queensland, Sch Biomed Sci, Brisbane, Qld, Australia. NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. RI Hempel, Nadine/F-1700-2014 OI Hempel, Nadine/0000-0002-5574-8783 NR 0 TC 0 Z9 0 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUN 15 PY 2004 VL 197 IS 3 MA 265 BP 193 EP 193 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 833OZ UT WOS:000222348900198 ER PT J AU Polychronopoulos, P Knockaert, M Blondel, M Bach, S Leost, M Elbi, C Hager, G Nagy, SR Han, DH Denison, M Ffrench, M Ryan, XP Magiatis, P Greengard, P Skaltsounis, L Meijer, L AF Polychronopoulos, P Knockaert, M Blondel, M Bach, S Leost, M Elbi, C Hager, G Nagy, SR Han, DH Denison, M Ffrench, M Ryan, XP Magiatis, P Greengard, P Skaltsounis, L Meijer, L TI Independent actions on cyclin-dependent kinases and aryl hydrocarbon receptor mediate the anti-proliferative effects of indirubins SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Meeting Abstract CT 10th International Congress of Toxicology CY JUL 11-15, 2004 CL Tampere, FINLAND C1 CNRS, Cell Cycle Grp, F-29682 Roscoff, Bretagne, France. CNRS, Biol Stn, UPS 2682, F-29682 Roscoff, Bretagne, France. NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. Univ Calif Davis, Dept Environm Toxicol, Davis, CA 95616 USA. Univ Lyon 1, Lab Cytol Analyt & Cytogenet Mol, F-69373 Lyon 08, France. Univ Athens, Dept Pharm, Div Pharmacognosy & Nat Prod Chem, GR-15771 Athens, Greece. Rockefeller Univ, Mol & Cellular Neurosci Lab, New York, NY 10021 USA. RI Magiatis, Prokopios/A-2008-2008 NR 0 TC 0 Z9 0 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUN 15 PY 2004 VL 197 IS 3 MA 349 BP 216 EP 216 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 833OZ UT WOS:000222348900282 ER PT J AU Crowell, JA Levine, BS McCormick, DL AF Crowell, JA Levine, BS McCormick, DL TI Resveratrol: Drug development for cancer prevention SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Meeting Abstract CT 10th International Congress of Toxicology CY JUL 11-15, 2004 CL Tampere, FINLAND C1 NCI, NIH, DHHS, Bethesda, MD 20892 USA. Univ Illinois, Chicago, IL USA. IIT, Res Inst, Chicago, IL 60616 USA. NR 0 TC 1 Z9 1 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUN 15 PY 2004 VL 197 IS 3 MA 356 BP 218 EP 218 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 833OZ UT WOS:000222348900289 ER PT J AU Goshorn, J AF Goshorn, J TI Information resources for the twenty first century: Web-based databases and other resources developed by the Toxicology and Environmental Health Information Program of the USA National Library of Medicine SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Meeting Abstract CT 10th International Congress of Toxicology CY JUL 11-15, 2004 CL Tampere, FINLAND C1 NIH, Natl Lib Med, HHS, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUN 15 PY 2004 VL 197 IS 3 MA 385 BP 225 EP 225 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 833OZ UT WOS:000222348900318 ER PT J AU Nakajima, T Hata, Y Ito, Y Omura, M Sone, H Toyama, C Gonzalez, FJ Aoyama, T AF Nakajima, T Hata, Y Ito, Y Omura, M Sone, H Toyama, C Gonzalez, FJ Aoyama, T TI Di(2-etrylhexyl)phthalate may reduce mouse fertility via peroxisome proliferator-activated receptor alpha (PPAR alpha) SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Meeting Abstract CT 10th International Congress of Toxicology CY JUL 11-15, 2004 CL Tampere, FINLAND C1 Nagoya Univ, Grad Sch Med, Nagoya, Aichi, Japan. Shinshu Univ, Sch Med, Matsumoto, Nagano 390, Japan. Kyushu Univ, Grad Sch Med Sci, Fukuoka 812, Japan. Natl Inst Environm Studies, Tsukuba, Ibaraki, Japan. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUN 15 PY 2004 VL 197 IS 3 MA 407 BP 231 EP 231 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 833OZ UT WOS:000222348900340 ER PT J AU Karahalil, B Hogue, BA De Souza-Pinto, NC Bohr, VA AF Karahalil, B Hogue, BA De Souza-Pinto, NC Bohr, VA TI Base excision repair capacity in mitochnondria and nuclei: Tissue specific variations SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Meeting Abstract CT 10th International Congress of Toxicology CY JUL 11-15, 2004 CL Tampere, FINLAND C1 Gazi Univ, Fac Pharm, Dept Toxicol, TR-06330 Ankara, Turkey. NIA, NIH, Lab Mol Gerontol, Bethesda, MD 20892 USA. RI Souza-Pinto, Nadja/C-3462-2013 OI Souza-Pinto, Nadja/0000-0003-4206-964X NR 0 TC 0 Z9 0 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUN 15 PY 2004 VL 197 IS 3 MA 510 BP 260 EP 260 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 833OZ UT WOS:000222348900443 ER PT J AU Toyoshiba, H Yamanaka, T Parham, FM Martinez, JM Sone, H Walker, NJ Portier, CJ AF Toyoshiba, H Yamanaka, T Parham, FM Martinez, JM Sone, H Walker, NJ Portier, CJ TI Gene interaction network suggests dioxin induces a significant linkage between Ah-receptor and retinoic acid receptor beta SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Meeting Abstract CT 10th International Congress of Toxicology CY JUL 11-15, 2004 CL Tampere, FINLAND C1 NIEHS, Res Triangle Pk, NC 27709 USA. RI Portier, Christopher/A-3160-2010 OI Portier, Christopher/0000-0002-0954-0279 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUN 15 PY 2004 VL 197 IS 3 MA 515 BP 261 EP 261 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 833OZ UT WOS:000222348900448 ER PT J AU Moscicki, EK Caine, ED AF Moscicki, EK Caine, ED TI Opportunities of life - Preventing suicide in elderly patients SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material ID AGE C1 NIMH, Bethesda, MD 20892 USA. RP Moscicki, EK (reprint author), NIMH, 6001 Execut Blvd,Room 7167, Bethesda, MD 20892 USA. NR 18 TC 5 Z9 5 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUN 14 PY 2004 VL 164 IS 11 BP 1171 EP 1172 DI 10.1001/archinte.164.11.1171 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 830ZN UT WOS:000222162800001 PM 15197040 ER PT J AU Calhoun, EA Collins, MM Pontari, MA O'Leary, MP Leiby, BE Landis, JR Kusek, JW Litwin, MS AF Calhoun, EA Collins, MM Pontari, MA O'Leary, MP Leiby, BE Landis, JR Kusek, JW Litwin, MS CA Members of the Chronic Prostatitis TI The economic impact of chronic prostatitis SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT 96th Annual Meeting of the American-Urological-Association CY JUN 02-07, 2001 CL ANAHEIM, CA SP Amer Urol Assoc ID CHRONIC ABACTERIAL PROSTATITIS; RHEUMATOID-ARTHRITIS; SYMPTOM INDEX; COSTS; PREVALENCE; PAIN; DIAGNOSIS; ACCURACY; MEN AB Background: Little information exists on the economic impact of chronic prostatitis. The objective of this study was to determine the direct and indirect costs associated with chronic prostatitis. Methods: Outcomes were assessed using a questionnaire designed to capture health care resource utilization. Resource estimates were converted into unit costs with direct medical cost estimates based on hospital cost accounting data and indirect costs based on modified labor force, employment, and earnings data from the US Census Bureau. Results: The total direct costs for the 3 months prior to entry into the cohort, excluding hospitalization, were $126915 for the 167 study participants for an average of $954 per person among the 133 consumers. Of the men, 26% reported work loss valued at an average of $551. The average total costs (direct and indirect) for the 3 months was $1099 per person for those 137 men who had re-source consumption with an expected annual total cost per person of $4397. For those study participants with any incurred costs, tests for association revealed that the National Institutes of Health Chronic Prostatitis Symptom Index (P < .001) and each of the 3 subcategories of pain (P = .003), urinary function (P = .03), and quality-of-life (P = .002) were significantly associated with resource use, although the quality-of-life subscale score from the National Institutes of Health Chronic Prostatitis Symptom Index was the only predictor of resource consumption. Conclusions: Chronic prostatitis is associated with substantial costs and lower quality-of-life scores, which predicted resource consumption. The economic impact of chronic prostatitis warrants increased medical attention and resources to identify and test effective treatment strategies. C1 Northwestern Univ, Feinberg Sch Med, Dept Urol, Chicago, IL 60611 USA. Massachusetts Gen Hosp, Med Serv, Gen Med Unit, Boston, MA 02114 USA. Univ Calif Los Angeles, Dept Urol, Los Angeles, CA USA. Univ Calif Los Angeles, Dept Hlth Serv, Los Angeles, CA USA. NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD USA. Univ Penn, Med Ctr, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. Brigham & Womens Hosp, Div Urol Surg, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. Temple Univ, Sch Med, Dept Urol, Philadelphia, PA 19122 USA. RP Calhoun, EA (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Urol, 339 E Chicago Ave,Room 802, Chicago, IL 60611 USA. EM e-calhoun@northwestern.edu RI Landis, J. Richard/A-9330-2010 FU NIDDK NIH HHS [U01 DK53752, T32 DK060455, U01 DK53730, U01 DK53732, U01 DK53734, U01 DK53736] NR 23 TC 57 Z9 67 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUN 14 PY 2004 VL 164 IS 11 BP 1231 EP 1236 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 830ZN UT WOS:000222162800011 PM 15197050 ER PT J AU DeMarchis, L Cropp, C Sheng, ZM Bargo, S Callahan, R AF DeMarchis, L Cropp, C Sheng, ZM Bargo, S Callahan, R TI Candidate target genes for loss of heterozygosity on human chromosome 17q21 SO BRITISH JOURNAL OF CANCER LA English DT Article DE chromosome 17q21; loss of heterozygosity; plakoglobin ID AMINO-ACID SEQUENCE; BREAST-CANCER; MOLECULAR-CLONING; HUMAN PLAKOGLOBIN; GAMMA-CATENIN; E-CADHERIN; BETA-CATENIN; PROTEIN; EXPRESSION; CARCINOMAS AB Loss of heterozygosity (LOH) on chromosome 17q21 has been detected in 30% of primary human breast tumours. The smallest common region deleted occurred in an interval between the D17S746 and D17S846 polymorphic sequences tagged sites that are located on two recombinant P1-bacteriophage clones of chromosome 17q21: 122F4 and 50H1, respectively. To identify the target gene for LOH, we defined a map of this chromosomal region. We found the following genes: JUP, FK506BP10, SC65, Gastrin ( GAS) and HAP1. Of the genes that have been identified in this study, only JUP is located between D17S746 and D17S846. This was of interest since earlier studies have shown that JUP expression is altered in breast, lung and thyroid tumours as well as cell lines having LOH in chromosome 17q21. However, no mutations were detected in JUP using single-strand conformation polymorphism analysis of primary breast tumour DNAs having LOH at 17q21. We could find no evidence that the transcription promoter for JUP is methylated in tumour DNAs having LOH at 17q21. We suspect that the target gene for LOH in primary human breast tumours on chromosome 17q21 is either JUP and results in a haploinsufficiency for expression or may be an unidentified gene located in the interval between D17S846 and JUP. C1 NCI, Mammary Biol & Tumorigenesis Lab, Bethesda, MD 20892 USA. RP Callahan, R (reprint author), NCI, Mammary Biol & Tumorigenesis Lab, Bldg 10,Room 5B50, Bethesda, MD 20892 USA. EM rc54d@nih.gov NR 30 TC 12 Z9 13 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUN 14 PY 2004 VL 90 IS 12 BP 2384 EP 2389 DI 10.1038/sj.bjc.6601848 PG 6 WC Oncology SC Oncology GA 834RB UT WOS:000222427100020 PM 15187990 ER PT J AU Rapley, EA Hockley, S Warren, W Johnson, L Huddart, R Crockford, G Forman, D Leahy, MG Oliver, DT Tucker, K Friedlander, M Phillips, KA Hogg, D Jewett, MAS Lohynska, R Daugaard, G Richard, S Heidenreich, A Geczi, L Bodrogi, I Olah, E Ormiston, WJ Daly, PA Looijenga, LHJ Guilford, P Aass, N Fossa, SD Heimdal, K Tjulandin, SA Liubchenko, L Stoll, H Weber, W Einhorn, L Weber, BL McMaster, M Greene, MH Bishop, DT Easton, D Stratton, M AF Rapley, EA Hockley, S Warren, W Johnson, L Huddart, R Crockford, G Forman, D Leahy, MG Oliver, DT Tucker, K Friedlander, M Phillips, KA Hogg, D Jewett, MAS Lohynska, R Daugaard, G Richard, S Heidenreich, A Geczi, L Bodrogi, I Olah, E Ormiston, WJ Daly, PA Looijenga, LHJ Guilford, P Aass, N Fossa, SD Heimdal, K Tjulandin, SA Liubchenko, L Stoll, H Weber, W Einhorn, L Weber, BL McMaster, M Greene, MH Bishop, DT Easton, D Stratton, M TI Somatic mutations of KIT in familial testicular germ cell tumours SO BRITISH JOURNAL OF CANCER LA English DT Article DE KIT; testicular germ cell tumours ID EXPRESSION; TISSUE; SINGLE; CANCER; GENE AB Somatic mutations of the KIT gene have been reported in mast cell diseases and gastrointestinal stromal tumours. Recently, they have also been found in mediastinal and testicular germ cell tumours (TGCTs), particularly in cases with bilateral disease. We screened the KIT coding sequence ( except exon 1) for germline mutations in 240 pedigrees with two or more cases of TGCT. No germline mutations were found. Exons 10, 11 and 17 of KIT were examined for somatic mutations in 123 TGCT from 93 multiple-case testicular cancer families. Five somatic mutations were identified; four were missense amino-acid substitutions in exon 17 and one was a 12 bp in-frame deletion in exon 11. Two of seven TGCT from cases with bilateral disease carried KIT mutations compared with three out of 116 unilateral cases ( P = 0.026). The results indicate that somatic KIT mutations are implicated in the development of a minority of familial as well as sporadic TGCT. They also lend support to the hypothesis that KIT mutations primarily take place during embryogenesis such that primordial germ cells with KIT mutations are distributed to both testes. C1 Inst Canc Res, Sect Canc Genet, Sutton SM2 5NG, Surrey, England. St James Univ Hosp, Genet Epidemiol Div, Canc Res UK, Ctr Clin, Leeds LS9 7TF, W Yorkshire, England. Strangeways Res Lab, Canc Res UK, Genet Epidemiol Unit, Cambridge CB1 8RN, England. Univ New S Wales, Dept Med Oncol, Div Med, Sydney, NSW, Australia. Prince Wales Hosp, Sydney, NSW, Australia. Peter MacCallum Canc Ctr, Dept Haematol & Med Oncol, Melbourne, Vic 3002, Australia. Princess Margaret Hosp, Toronto, ON M5G 2M9, Canada. Univ Toronto, Toronto, ON M5G 2M9, Canada. Univ Hosp, Dept Radiotherapy & Oncol, Prague 15006, Czech Republic. Rigshosp, Dept Oncol 5073, DK-2100 Copenhagen, Denmark. Fac Med Paris Sud, EPHE, UPRESS 1602, F-94276 Le Kremlin Bicetre, France. CHU, Serv Urol, F-94276 Le Kremlin Bicetre, France. Univ Marburg, Dept Urol Oncol, Marburg, Germany. Natl Inst Oncol, Dept Chemotherapy C, H-1122 Budapest, Hungary. Natl Inst Oncol, Dept Mol Genet, H-1122 Budapest, Hungary. St James Hosp, Dept Med Oncol, Dublin 8, Ireland. Erasmus Univ, Med Ctr Rotterdam, Dr Daniel Den Hoed Canc Ctr, Josephine Nefkens Inst,Pathol Lab Expt Pathooncol, NL-3000 DR Rotterdam, Netherlands. Univ Otago, Canc Genet Lab, Dunedin, New Zealand. Norwegian Radium Hosp, Dept Oncol, N-0027 Oslo, Norway. Univ Oslo, Rikshosp, Dept Med Genet, N-0027 Oslo, Norway. NN Blokhin Russian Canc Res Ctr, Lab Clin Genet, Inst Clin Oncol, Moscow 115478, Russia. UICC Familial Canc & Prevent Project, Clin Canc Res Unit, CH-4051 Basel, Switzerland. Indiana Univ, Indianapolis, IN 46204 USA. Univ Penn, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. RP Rapley, EA (reprint author), Inst Canc Res, Sect Canc Genet, Brookes Lawley Bldg,15 Cotswold Rd, Sutton SM2 5NG, Surrey, England. EM Liz.raphy@icr.ac.uk RI hockley, sarah/A-4059-2011; friedlander, michael/G-3490-2013; Leahy, Michael/K-8697-2015; OI friedlander, michael/0000-0002-6488-0604; Leahy, Michael/0000-0002-9936-0537; Daugaard, Gedske/0000-0002-9618-9180; Phillips, Kelly-Anne/0000-0002-0475-1771; Bishop, Tim/0000-0002-8752-8785 NR 13 TC 65 Z9 68 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUN 14 PY 2004 VL 90 IS 12 BP 2397 EP 2401 DI 10.1038/sj.bjc.6601880 PG 5 WC Oncology SC Oncology GA 834RB UT WOS:000222427100022 PM 15150569 ER PT J AU Jia, YP Wood, F Menu, P Faivre, B Caron, A Alayash, AI AF Jia, YP Wood, F Menu, P Faivre, B Caron, A Alayash, AI TI Oxygen binding and oxidation reactions of human hemoglobin conjugated to carboxylate dextran SO BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS LA English DT Article DE hemoglobin; oxygen affinity; redox reaction; blood substitute ID CHEMICALLY-MODIFIED HEMOGLOBINS; POTENTIAL BLOOD SUBSTITUTE; HEME DEGRADATION-PRODUCTS; CELL-FREE HEMOGLOBIN; NITRIC-OXIDE; HYDROGEN-PEROXIDE; CROSS-LINKING; BOVINE HEMOGLOBINS; REDOX PROPERTIES; GUINEA-PIGS AB Human hemoglobin (Hb) conjugated to benzene tetracarboxylate substituted dextran produces a polymeric Hb (Dex-BTC-Hb) with similar oxygen affinity to that of red blood cells (P-50=28-29 mm Hg). Under physiological conditions, the oxygen affinity (P-50) of Dex-BTC-Hb is 26 mm Hg, while that of native purified human HbA(0) is 14 mm Hg, but it exhibits a slight reduction in cooperativity (n(50)), Bohr effect, and lacks sensitivity to inositol hexaphosphate (IHP), when compared to HbA(0). Oxygen-binding kinetics, measured by rapid mixing stopped-flow method showed comparable oxygen dissociation and association rates for both HbA(0) and Dex-BTC-Hb. The rate constant for NO-mediated oxidation of the oxy form of Dex-BTC-Hb, which is governed by NO entry to the heme pocket, was reduced to half of the value obtained for HbA(0). Moreover, Dex-BTC-Hb is only slightly more sensitive to oxidative reactions than HbA(0), as shown by about 2-fold increase in autoxidation, and slightly higher H2O2 reaction and heme degradation rates. Dextran-BTC-based modification of Hb produced an oxygen-carrying compound with increased oxygen release rates, decreased oxygen affinity and reduced nitric oxide scavenging, desirable properties for a viable blood substitute. However, the reduction in the allosteric function of this protein and the lack of apparent quaternary T --> R transition may hinder its physiological role as an oxygen transporter. (C) 2004 Elsevier B.V. All rights reserved. C1 US FDA, Ctr Biol Evaluat & Res, Lab Biochem & Vasc Biol, Bethesda, MD 20892 USA. Univ Henri Poincare Nancy, Sch Pharm, Dept Hematol & Physiol, F-54001 Nancy, France. RP Alayash, AI (reprint author), US FDA, Ctr Biol Evaluat & Res, Lab Biochem & Vasc Biol, 8800 Rockville Pike,NIH Bldg,29,Room 112, Bethesda, MD 20892 USA. EM Alayash@cber.fda.gov RI FAIVRE , Beatrice/B-7535-2012 NR 44 TC 31 Z9 32 U1 1 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 11 PY 2004 VL 1672 IS 3 BP 164 EP 173 DI 10.1016/j.bbagen.2004.03.009 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 828TW UT WOS:000221997200006 PM 15182936 ER PT J AU Grant, BF Dawson, DA Stinson, FS Chou, SP Dufour, MC Pickering, RP AF Grant, BF Dawson, DA Stinson, FS Chou, SP Dufour, MC Pickering, RP TI The 12-month prevalence and trends in DSM-IV alcohol abuse and dependence: United States, 1991-1992 and 2001-2002 SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE DSM-IV alcohol abuse and dependence; epidemiology; secular trends ID INTERVIEW SCHEDULE AUDADIS; GENERAL-POPULATION SAMPLE; USE DISORDER CRITERIA; III-R; HEAVY DRINKERS; ICD-10 ALCOHOL; DRUG MODULES; EPIDEMIOLOGIC SURVEY; FAMILY-HISTORY; SUBSTANCE USE AB Background: Alcohol abuse and dependence can be disabling disorders, but accurate information is lacking on the prevalence of current DSM-IV alcohol abuse and dependence and how this has changed over the past decade. The purpose of this study was to present nationally representative data on the prevalence of 12-month DSM-IV alcohol abuse and dependence in 2001-2002 and, for the first time, to examine trends in alcohol abuse and dependence between 1991-1992 and 2001-2002. Methods: Prevalences and trends of alcohol abuse and dependence in the United States were derived from face-to-face interviews in the National Institute on Alcohol Abuse and Alcoholism's (NIAAA) 2001-2002 National Epidemologic Survey on Alcohol and Related Conditions (NESARC: n = 43, 093) and NIAAA's 1991-1992 National Longitudinal Alcohol Epidemiologic Survey (NLAES: n = 42, 862). Results: Prevalences of DSM-IV alcohol abuse and dependence in 2001-2002 were 4.65 and 3.81%. Abuse and dependence were more common among males and among younger respondents. The prevalence of abuse was greater among Whites than among Blacks, Asians, and Hispanics. The prevalence of dependence was higher in Whites, Native Americans, and Hispanics than Asians. Between 1991-1992 and 2001-2002, abuse increased while dependence declined. Increases in alcohol abuse were observed among males, females, and young Black and Hispanic minorities, while the rates of dependence rose among males, young Black females and Asian males. Conclusions: This study underscores the need to continue monitoring prevalence and trends and to design culturally sensitive prevention and intervention programs. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. NIAAA, Off Director, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Grant, BF (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, Dept Hlth & Human Serv,NIH, Room 3077,MS 9304,5635 Fishers Lane, Bethesda, MD 20892 USA. EM bgrant@willco.niaaa.nih.gov NR 64 TC 866 Z9 875 U1 2 U2 34 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 11 PY 2004 VL 74 IS 3 BP 223 EP 234 DI 10.1016/j.drugalcdep.2004.02.004 PG 12 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 830MW UT WOS:000222127500001 PM 15194200 ER PT J AU Magdinier, F Yusufzai, TM Felsenfeld, G AF Magdinier, F Yusufzai, TM Felsenfeld, G TI Both CTCF-dependent and -independent insulators are found between the mouse T cell receptor alpha and Dad1 genes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LOCUS-CONTROL REGION; ENHANCER-BLOCKING ACTIVITY; MATRIX-ATTACHMENT REGIONS; BETA-GLOBIN DOMAIN; ALPHA/DELTA LOCUS; BINDING-PROTEIN; TRANSGENE EXPRESSION; NUCLEAR-MATRIX; TCR-ALPHA; CHROMATIN AB The T cell rearrangement of the T cell receptor (TCR) genes TCRalpha and delta is specifically regulated by a complex interplay between enhancer elements and chromatin structure. The alpha enhancer is active in T cells and drives TCRalpha recombination in collaboration with a locus control region-like element located downstream of the Calpha gene on mouse chromosome 14. Twelve kb further downstream lies another gene, Dad1, with a program of expression different from that of TCRalpha. The similar to6-kb locus control region element lying between them contains multiple regulatory sites with a variety of roles in regulating the two genes. Previous evidence has indicated that among these there are widely distributed regions with enhancer blocking (insulating) activity. We have shown in this report that one of these sites, not previously examined, strongly binds the insulator protein CCTC-binding factor (CTCF) in vitro and in vivo and can function in an enhancer blocking assay. However, other regions within the 6-kb element that also can block enhancers clearly do not harbor CTCF sites and thus must reflect the presence of a previously undetected and distinct vertebrate insulator activity. C1 NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Felsenfeld, G (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM gary.felsenfeld@nih.gov RI Magdinier, Frederique/I-4735-2016 OI Magdinier, Frederique/0000-0002-0159-9559 NR 51 TC 36 Z9 38 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 11 PY 2004 VL 279 IS 24 BP 25381 EP 25389 DI 10.1074/jbc.M403121200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 826KL UT WOS:000221827900061 PM 15082712 ER PT J AU Birchenall-Roberts, MC Fu, T Bang, OS Dambach, M Resau, JH Sadowski, CL Bertolette, DC Lee, HJ Kim, SJ Ruscetti, FW AF Birchenall-Roberts, MC Fu, T Bang, OS Dambach, M Resau, JH Sadowski, CL Bertolette, DC Lee, HJ Kim, SJ Ruscetti, FW TI Tuberous sclerosis complex 2 gene product interacts with human SMAD proteins - A molecular link of two tumor suppressor pathways SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GROWTH-FACTOR-BETA; P70 S6 KINASE; TGF-BETA; DEVELOPMENTAL EXPRESSION; SIGNAL-TRANSDUCTION; DOWN-REGULATION; TSC2 GENE; CELLS; INHIBITOR; DIFFERENTIATION AB Tuberin (TSC2) is a tumor suppressor gene. At the cellular level, tuberin is required as a critical regulator of cell growth, neuronal differentiation (Soucek, T., Holzl, G., Bernaschek, G., and Hengstschlager, M. (1998) Oncogene 16, 2197-2204), and tumor suppression (Crino, P. B., and Henske, E. P. (1999) Neurology 53, 1384-1390). Here we report a critical role for tuberin in late stage myeloid cell differentiation. Tuberin strongly augments transforming growth factor (TGF)-beta1 signal transduction pathways, including SMAD activation. We also demonstrate that the amino-terminal region of tuberin interacts specifically with the MH2 domain of SMAD2 and SMAD3 proteins to regulate TGF-beta1-responsive genes such as p21(CIP). Inhibition of tuberin expression by Tsc2 antisense greatly reduces the ability of TGF-beta to transcriptionally regulate p21(CIP), p27(KIP), and cyclin A leading to an abrogation of the antiproliferative effects of TGF-beta1. Also, inhibition of tuberin expression during stimulation of monocytic differentiation with vitamin D-3 and TGF-beta1 significantly impaired myeloid cell growth inhibition and differentiation. Together, the data demonstrate the presence of a novel activation process following TGF-beta1 stimulation that requires tuberin-dependent activity. C1 NCI, SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA. Van Andel Inst, Grand Rapids, MI 49506 USA. NCI Frederick, Expt Immunol Lab, Frederick, MD 21702 USA. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Birchenall-Roberts, MC (reprint author), NCI, SAIC Frederick, Basic Res Program, POB B,Bldg 567-259, Frederick, MD 21702 USA. EM birchena@mail.ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 41 TC 20 Z9 22 U1 1 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 11 PY 2004 VL 279 IS 24 BP 25605 EP 25613 DI 10.1074/jbc.M402790200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 826KL UT WOS:000221827900088 PM 15066998 ER PT J AU Jones, CE Green, EM Stephens, JA Mueser, TC Nossal, NG AF Jones, CE Green, EM Stephens, JA Mueser, TC Nossal, NG TI Mutations of bacteriophage T4 59 helicase loader defective in binding fork DNA and in interactions with T4 32 single-stranded DNA-binding protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID POLAR BRANCH MIGRATION; 4-WAY JUNCTION DNA; ASSEMBLY PROTEIN; GENE-59 PROTEIN; ARCHITECTURAL PROTEINS; REPLICATION PROTEINS; LOADING PROTEIN; RECOMBINATION; PURIFICATION; COMPLEX AB Bacteriophage T4 gene 59 protein greatly stimulates the loading of the T4 gene 41 helicase in vitro and is required for recombination and recombination-dependent DNA replication in vivo. 59 protein binds preferentially to forked DNA and interacts directly with the T4 41 helicase and gene 32 single-stranded DNA-binding protein. The helicase loader is an almost completely alpha-helical, two-domain protein, whose N-terminal domain has strong structural similarity to the DNA-binding domains of high mobility group proteins. We have previously speculated that this high mobility group-like region may bind the duplex ahead of the fork, with the C-terminal domain providing separate binding sites for the fork arms and at least part of the docking area for the helicase and 32 protein. Here, we characterize several mutants of 59 protein in an initial effort to test this model. We find that the I87A mutation, at the position where the fork arms would separate in the model, is defective in binding fork DNA. As a consequence, it is defective in stimulating both unwinding by the helicase and replication by the T4 system. 59 protein with a deletion of the two C-terminal residues, Lys(216) and Tyr(217), binds fork DNA normally. In contrast to the wild type, the deletion protein fails to promote binding of 32 protein on short fork DNA. However, it binds 32 protein in the absence of DNA. The deletion is also somewhat defective in stimulating unwinding of fork DNA by the helicase and replication by the T4 system. We suggest that the absence of the two terminal residues may alter the configuration of the lagging strand fork arm on the surface of the C-terminal domain, so that it is a poorer docking site for the helicase and 32 protein. C1 NIDDK, NIH, Dept Mol & Cell Biol, Bethesda, MD 20892 USA. Univ Toledo, Dept Chem, Toledo, OH 43606 USA. RP Nossal, NG (reprint author), NIDDK, NIH, Dept Mol & Cell Biol, Bldg 8,Rm 2A19, Bethesda, MD 20892 USA. EM ngn@helix.nih.gov NR 38 TC 11 Z9 11 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 11 PY 2004 VL 279 IS 24 BP 25721 EP 25728 DI 10.1074/jbc.M402128200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 826KL UT WOS:000221827900102 PM 15084598 ER PT J AU Edavettal, SC Lee, KA Negishi, M Linhardt, RJ Liu, J Pedersen, LC AF Edavettal, SC Lee, KA Negishi, M Linhardt, RJ Liu, J Pedersen, LC TI Crystal structure and mutational analysis of heparan sulfate 3-O-sulfotransferase isoform 1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID D-GLUCOSAMINYL 3-O-SULFOTRANSFERASE; N-DEACETYLASE/N-SULFOTRANSFERASE; HERPES-SIMPLEX-VIRUS; ANTITHROMBIN-III; ESTROGEN SULFOTRANSFERASE; HUMAN CDNAS; BINDING; BIOSYNTHESIS; EXPRESSION; CRYSTALLOGRAPHY AB Heparan sulfate interacts with antithrombin, a protease inhibitor, to regulate blood coagulation. Heparan sulfate 3-O-sulfotransferase isoform 1 performs the crucial last step modification in the biosynthesis of anticoagulant heparan sulfate. This enzyme transfers the sulfuryl group (SO3) from 3'-phosphoadenosine 5'-phosphosulfate to the 3-OH position of a glucosamine residue to form the 3-O-sulfo glucosamine, a structural motif critical for binding of heparan sulfate to antithrombin. In this study, we report the crystal structure of 3-O-sulfotransferase isoform 1 at 2.5-Angstrom resolution in a binary complex with 3'-phosphoadenosine 5'-phosphate. This structure reveals residues critical for 3'-phosphoadenosine 5'-phosphosulfate binding and suggests residues required for the binding of heparan sulfate. In addition, site-directed mutagenesis analyses suggest that residues Arg-67, Lys-68, Arg-72, Glu-90, His-92, Asp-95, Lys-123, and Arg-276 are essential for enzymatic activity. Among these essential amino acid residues, we find that residues Arg-67, Arg-72, His-92, and Asp-95 are conserved in heparan sulfate 3-O-sulfotransferases but not in heparan N-deacetylase/N-sulfotransferase, suggesting a role for these residues in conferring substrate specificity. Results from this study provide information essential for understanding the biosynthesis of anticoagulant heparan sulfate and the general mechanism of action of heparan sulfate sulfotransferases. C1 Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. Rensselaer Polytech Inst, Dept Chem & Biol Chem, Troy, NY 12180 USA. RP Liu, J (reprint author), Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Rm 309,Beard Hall, Chapel Hill, NC 27599 USA. EM jian_liu@unc.edu FU NIAID NIH HHS [AI50050] NR 39 TC 45 Z9 46 U1 2 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 11 PY 2004 VL 279 IS 24 BP 25789 EP 25797 DI 10.1074/jbc.M401089200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 826KL UT WOS:000221827900109 PM 15060080 ER PT J AU Toyoshima, Y Karas, M Yakar, S Dupont, J Helman, L LeRoith, D AF Toyoshima, Y Karas, M Yakar, S Dupont, J Helman, L LeRoith, D TI TDAG51 mediates the effects of insulin-like growth factor I (IGF-I) on cell survival SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MULTIPLE SIGNALING PATHWAYS; INDUCED APOPTOSIS; PHOSPHATIDYLINOSITOL 3-KINASE; BAD PHOSPHORYLATION; HEMATOPOIETIC-CELLS; INHIBITS APOPTOSIS; NIH-3T3 CELLS; GENE-PRODUCT; RECEPTOR; ACTIVATION AB Insulin-like growth factor-I (IGF-I) receptors and insulin receptors belong to the same subfamily of receptor tyrosine kinases and share a similar set of intracellular signaling pathways, despite their distinct biological actions. In the present study, we evaluated T cell death-associated gene 51 (TDAG51), which we previously identified by cDNA microarray analysis as a gene specifically induced by IGF-I. We characterized the signaling pathways by which IGF-I induces TDAG51 gene expression and the functional role of TDAG51 in IGF-I signaling in NIH-3T3 (NWTb3) cells, which overexpress the human IGF-I receptor. Treatment with IGF-I increased TDAG51 mRNA and protein levels in NWTb3 cells. This effect of IGF-I was specifically mediated by the IGF-IR, because IGF-I did not induce TDAG51 expression in NIH-3T3 cells overexpressing a dominant-negative IGF-I receptor. Through the use of specific inhibitors of various protein kinases, we found that IGF-I induced TDAG51 expression via the p38 MAPK pathway. The ERK, JNK, and phosphatidylinositol 3-kinase pathways were not involved in IGF-I-induced regulation of TDAG51. To assess the role of TDAG51 in IGF-I signaling, we used small interfering RNA ( siRNA) expression vectors directed at two different target sites to reduce the level of TDAG51 protein. In cells expressing these siRNA vectors, TDAG51 protein levels were decreased by 75 - 80%. Furthermore, TDAG51 siRNA expression abolished the ability of IGF-I to rescue cells from serum starvation-induced apoptosis. These findings suggest that TDAG51 plays an important role in the anti-apoptotic effects of IGF-I. C1 NIDDK, Sect Mol & Cellular Physiol, Diabet Branch, NIH, Bethesda, MD 20892 USA. NCI, Mol Oncol Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP LeRoith, D (reprint author), NIDDK, Sect Mol & Cellular Physiol, Diabet Branch, NIH, Rm 8D12,Bldg 10,MSC 1758, Bethesda, MD 20892 USA. EM derek@helix.nih.gov NR 47 TC 47 Z9 48 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 11 PY 2004 VL 279 IS 24 BP 25898 EP 25904 DI 10.1074/jbc.M400661200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 826KL UT WOS:000221827900122 PM 15037619 ER PT J AU Chrencik, JE Staker, BL Burgin, AB Pourquier, P Pommier, Y Stewart, L Redinbo, MR AF Chrencik, JE Staker, BL Burgin, AB Pourquier, P Pommier, Y Stewart, L Redinbo, MR TI Mechanisms of camptothecin resistance by human topoisomerase I mutations SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE topoisomerase; cancer; resistance; protein-DNA complex; X-ray crystallography ID CANCER CELL-LINE; DNA TOPOISOMERASES; CATALYTIC MECHANISM; CRYSTAL-STRUCTURES; SINGLE MUTATION; POINT MUTATION; ACTIVE-SITE; PROTEIN; IDENTIFICATION; COMPLEX AB Human topoisomerase I relaxes superhelical tension associated with DNA replication, transcription and recombination by reversibly nicking one strand of duplex DNA and forming a covalent 3'-phosphotyrosine linkage. This enzyme is the sole target of the camptothecin family of anticancer compounds, which acts by stabilizing the covalent protein-DNA complex and enhancing apoptosis through blocking the advancement of replication forks. Mutations that impart resistance to camptothecin have been identified in several regions of human topoisomerase I. We present the crystal structures of two camptothecin-resistant forms of human topoisomerase I (Phe361Ser at 2.6 Angstrom resolution and Asn722Ser at 2.3 Angstrom resolution) in ternary complexes with DNA and topotecan (Hycamtin((R))), a camptothecin analogue currently in widespread clinical use. While the alteration of Asn722 to Ser leads to the elimination of a water-mediated contact between the enzyme and topotecan , we were surprised to find that a well-ordered water molecule replaces the hydrophobic phenylalanine side-chain in the Phe361Ser structure. We further consider camptothecin-resistant mutations at seven additional sites in human topoisomerase I and present structural evidence explaining their possible impact on drug binding. These results advance our understanding of the mechanism of cell poisoning by camptothecin and suggest specific modifications to the drug that may improve efficacy. (C) 2004 Elsevier Ltd. All rights reserved. C1 Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. DeCODE Genet Inc, BioStruct Grp, Bainbridge Isl, WA 98110 USA. NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. Univ N Carolina, Dept Biochem & Biophys, Program Mol Biol & Biotechnol, Chapel Hill, NC 27599 USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. RP Redinbo, MR (reprint author), Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. EM redinbo@unc.edu NR 47 TC 96 Z9 100 U1 2 U2 8 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 11 PY 2004 VL 339 IS 4 BP 773 EP 784 DI 10.1016/j.jmb.2004.03.007 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 827RV UT WOS:000221919100007 PM 15165849 ER PT J AU Bewley, CA Cai, ML Ray, S Ghirando, R Yamaguchi, M Muramoto, K AF Bewley, CA Cai, ML Ray, S Ghirando, R Yamaguchi, M Muramoto, K TI New carbohydrate specificity and HIV-1 fusion blocking activity of the cyanobacteirial protein MVL : NMR, ITC and sedimentation equilibrium studies SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE high-mannose oligosaccharides; gp120; HIV-1 envelope-mediated fusion; carbohydrate binding proteins; NMR chemical shift mapping ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIGH-MANNOSE OLIGOSACCHARIDES; DOMAIN-SWAPPED DIMER; TRIMERIC COILED-COIL; N CONTAINS 2; CYANOVIRIN-N; INACTIVATING PROTEIN; ENVELOPE GLYCOPROTEIN; STRUCTURAL BASIS; BINDING PROTEIN AB Carbohydrate-binding proteins that bind their carbohydrate ligands with high affinity are rare and therefore of interest because they expand our understanding of carbohydrate specificity and the structural requirements that lead to high-affinity interactions. Here, we use NMR and isothermal titration calorimetry techniques to determine carbohydrate specificity and affinities for a novel cyanobacterial protein, MVL, and show that MVL binds oligomannosides such as Man(6)GlcNAc(2) with sub-micromolar affinities. The amino acid sequence of MVL contains two homologous repeats, each comprising 54 amino acid residues. Using multidimensional NMR techniques, we show that MVL contains two novel carbohydrate recognition domains composed of four non-contiguous regions comprising similar to15 amino acid residues each, and that these residues make numerous intermolecular contacts with their carbohydrate ligands. NMR screening of a comprehensive panel of di-, tri-, and high-mannose oligosaccharides establish that high-affinity binding requires at least the presence of a discrete conformation presented by Manbeta(1 --> 4)GlcNAc in the context of larger oligomannosides. As shown by sedimentation equilibrium and gel-filtration experiments, MVL is a monodisperse dimer in solution, and NMR data establish that the three-dimensional structure must be symmetric. MVL inhibits HIV-1 Envelope-mediated cell fusion with an IC50 value of similar to30 nM. Published by Elsevier Ltd. C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Tohoku Univ, Grad Sch Agr Sci, Sendai, Miyagi 9818555, Japan. RP Bewley, CA (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM carole_bewley@nih.gov FU Intramural NIH HHS [Z01 DK032103-06] NR 49 TC 31 Z9 34 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 11 PY 2004 VL 339 IS 4 BP 901 EP 914 DI 10.1016/j.jmb.2004.04.019 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 827RV UT WOS:000221919100016 PM 15165858 ER PT J AU Roberts, ES Charboneau, L Espina, V Liotta, LA Petricoin, EF Dreher, KL AF Roberts, ES Charboneau, L Espina, V Liotta, LA Petricoin, EF Dreher, KL TI Application of laser capture microdissection and protein microarray technologies in the molecular analysis of airway injury following pollution particle exposure SO JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A-CURRENT ISSUES LA English DT Article ID KAPPA-B ACTIVATION; ACUTE LUNG INJURY; OIL FLY-ASH; PARTICULATE MATTER; IN-VITRO; GENE-EXPRESSION; METALS; CELLS; PROGRESSION; TISSUE AB Understanding the mechanisms by which various types of air pollution particles (particulate matter, PM) mediate adverse health effects would provide biological plausibility to epidemiological associations of increased rates of morbidity and mortality. The majority of information regarding the means by which PM generates lung injury has been derived from in vitro studies. However, it is unclear as to what extent these mechanisms can be extrapolated to the in vivo situation. Current methods to assess mechanisms of PM-induced lung injury make it difficult to obtain site-specific, sensitive, and comprehensive determinations of cellular and molecular pathology associated with PM-induced injury. In the present study, the ability of laser capture microdissection (LCM) and protein microarray technologies were assessed to examine the effect of residual oil fly ash (ROFA) exposure on airway intracellular signaling pathways and transcription factor activation. Sprague-Dawley rats were intratracheally instilled with 0.5 mg/rat of ROFA. LCM was used to recover airway cells and protein extracts derived from the microdissected airways were analyzed by protein microarray. ROFA exposure increased p-ERK:ERK and p-IkappaB:IkappaB, suggesting changes in cell growth, transformation, and inflammation within the airway. These results are consistent with previously reported in vitro findings, demonstrating for the first time the credibility of applying LCM and protein microarray technologies to assess acute lung injury induced by environmental air pollutants. C1 US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. N Carolina State Univ, Coll Vet Med, Dept Mol Biomed Sci, Raleigh, NC 27695 USA. Natl Canc Inst, NIH, Bethesda, MD USA. US FDA, CBER, Rockville, MD USA. RP Dreher, KL (reprint author), US EPA, Natl Hlth & Environm Effects Res Lab, MD-B143-01, Res Triangle Pk, NC 27711 USA. EM DREHER.KEVIN@EPA.GOV OI Espina, Virginia/0000-0001-5080-5972 NR 27 TC 11 Z9 12 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1528-7394 J9 J TOXICOL ENV HEAL A JI J. Toxicol. Env. Health Part A PD JUN 11 PY 2004 VL 67 IS 11 BP 851 EP 861 DI 10.1080/15287390490425768 PG 11 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 820OR UT WOS:000221399700002 PM 15205040 ER PT J AU Smits, KM Benhamou, S Garte, S Weijenberg, MP Alamanos, Y Ambrosone, C Autrup, H Autrup, JL Baranova, H Bathum, L Boffetta, P Bouchardy, C Brockmoller, J Butkiewicz, D Cascorbi, I Clapper, ML Coutelle, C Daly, AK Muzi, G Dolzan, V Duzhak, TG Farker, K Golka, K Haugen, A Hein, DW Hildesheim, A Hirvonen, A Hsieh, LL Ingelman-Sundberg, M Kalina, I Kang, D Katoh, T Kihara, M Ono-Kihara, M Kim, H Kiyohara, C Kremers, P Lazarus, P Le Marchand, L Lechner, MC London, S Manni, JJ Maugard, CM Morgan, GJ Morita, S Nazar-Stewart, V Kristensen, VN Oda, Y Parl, FF Peters, WHM Rannug, A Rebbeck, T Pinto, LFR Risch, A Romkes, M Salagovic, J Schoket, B Seidegard, J Shields, PG Sim, E Sinnett, D Strange, RC Stucker, I Sugimura, H To-Figueras, J Vineis, P Yu, MC Zheng, W Pedotti, P Taioli, E AF Smits, KM Benhamou, S Garte, S Weijenberg, MP Alamanos, Y Ambrosone, C Autrup, H Autrup, JL Baranova, H Bathum, L Boffetta, P Bouchardy, C Brockmoller, J Butkiewicz, D Cascorbi, I Clapper, ML Coutelle, C Daly, AK Muzi, G Dolzan, V Duzhak, TG Farker, K Golka, K Haugen, A Hein, DW Hildesheim, A Hirvonen, A Hsieh, LL Ingelman-Sundberg, M Kalina, I Kang, D Katoh, T Kihara, M Ono-Kihara, M Kim, H Kiyohara, C Kremers, P Lazarus, P Le Marchand, L Lechner, MC London, S Manni, JJ Maugard, CM Morgan, GJ Morita, S Nazar-Stewart, V Kristensen, VN Oda, Y Parl, FF Peters, WHM Rannug, A Rebbeck, T Pinto, LFR Risch, A Romkes, M Salagovic, J Schoket, B Seidegard, J Shields, PG Sim, E Sinnett, D Strange, RC Stucker, I Sugimura, H To-Figueras, J Vineis, P Yu, MC Zheng, W Pedotti, P Taioli, E TI Association of metabolic gene polymorphisms with tobacco consumption in healthy controls SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE pooled analysis; molecular epidemiology; smoking ID SMOKING-BEHAVIOR; NICOTINE METABOLISM; SUSCEPTIBILITY; SMOKERS; RISK; CANCER AB Polymorphisms in genes that encode for metabolic enzymes have been associated with variations in enzyme activity between individuals. Such variations could be associated with differences in individual exposure to carcinogens that are metabolized by these genes. In this study, we examine the association between polymorphisms in several metabolic genes and the consumption of tobacco in a large sample of healthy individuals. The database of the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens was used. All the individuals who were controls from the case-control studies included in the data set with information on smoking habits and on genetic polymorphisms were selected (n = 20,938). Sufficient information was available on the following genes that are involved in the metabolism of tobacco smoke constituents: CYPIAI, GSTMI, GSTTI, NAT2 and GSTPI. None of the tested genes was clearly associated with smoking behavior. Information on smoking dose, available for a subset of subjects, showed no effect of metabolic gene polymorphisms on the amount of smoking. No association between polymorphisms in the genes studied and tobacco consumption was observed; therefore, no effect of these genes on smoking behavior should be expected. (C) 2004 Wiley-Liss, Inc. C1 Osped Maggiore, Ist Ric & Cuza Carrattere Sci, Mol & Genet Epidemiol Unit, Milan, Italy. Vanderbilt Univ, Med Ctr, Nashville, TN USA. Natl Taiwan Univ, Coll Publ Hlth, Inst Epidemiol, Taipei 10764, Taiwan. Univ Turin, Coll Publ Hlth, Inst Epidemiol, Turin, Italy. Univ Turin, Turin, Italy. Hosp Clin Barcelona, Barcelona, Spain. Hamamatsu Univ Sch Med, Shizuoka, Japan. Keele Univ, Keele, Staffs, England. Hop St Justine, Montreal, PQ H3T 1C5, Canada. Univ Oxford, Dept Pharmacol, Oxford OX1 3QT, England. Georgetown Univ, Med Ctr, Washington, DC 20007 USA. Lund Univ, Lund, Sweden. Natl Inst Environm Hlth, Budapest, Hungary. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Deutsch Krebsforschungszentrum, D-6900 Heidelberg, Germany. Dept Bioquim, Rio De Janeiro, Brazil. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. Univ Hosp Nijmegen, Nijmegen, Netherlands. Vanderbilt Univ, Nashville, TN USA. Kanazawa Univ, Kanazawa, Ishikawa 920, Japan. Norwegian Radium Hosp, Inst Canc Res, Oslo, Norway. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. Yao Municipal Hosp, Osaka, Japan. Univ Leeds, Gen Infirm, Leeds LS1 3EX, W Yorkshire, England. Ctr Rene Gauducheau, F-44035 Nantes, France. Univ Hosp Maastricht, Maastricht, Netherlands. Natl Inst Environm Hlth Sci Res, Res Triangle Pk, NC USA. Univ Lisbon, P-1699 Lisbon, Portugal. Univ Hawaii, Honolulu, HI 96822 USA. H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. Inst Pathol, Liege, Belgium. Kyushu Univ, Fukuoka 812, Japan. Chungbuk Natl Univ, Chungbuk, South Korea. Kyoto Univ, Sch Publ Hlth, Kyoto, Japan. Miyazaki Med Coll, Miyazaki 88916, Japan. Seoul Natl Univ, Coll Med, Seoul, South Korea. Safarik Univ, Kosice, Slovakia. Karolinska Inst, Stockholm, Sweden. Chang Gung Univ, Tao Yuan, Taiwan. Finnish Inst Occupat Hlth, Helsinki, Finland. NCI, Rockville, MD USA. Univ Louisville, Louisville, KY 40292 USA. Natl Inst Occupat Hlth, Oslo, Norway. Univ Dortmund, Inst Occupat Physiol, Dortmund, Germany. Univ Jena, Inst Clin Pharmcol, D-6900 Jena, Germany. Univ Ljubljana, Ljubljana, Slovenia. Inst Med Lavoro, Perugia, Italy. Newcastle Univ, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. Univ Bordeaux 2, F-33076 Bordeaux, France. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Ernst Moritz Arndt Univ Greifswald, Greifswald, Germany. Ctr Oncol, Gliwice, Poland. Univ Gottingen, Dept Clin Pharmacol, D-3400 Gottingen, Germany. Int Agcy Res Canc, F-69372 Lyon, France. Univ Auvergne, Clermont Ferrand, France. Univ Aarhus, Aarhus, Denmark. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. Univ Ioannina, GR-45110 Ioannina, Greece. Genet Res Inst, Milan, Italy. Geneva Canc Registry, Geneva, Switzerland. INSERM, Villejuif, France. Univ Maastricht, Maastricht, Netherlands. RP Taioli, E (reprint author), Osped Policlin, Unit Mol & Genet Epidemiol, IRCCS, Padiglione Marangoni,Via F Sforza 35, I-20122 Milan, Italy. EM sget@iol.it RI Hein, David/A-9707-2008; Cascorbi, Ingolf/A-4519-2009; Shields, Peter/I-1644-2012; Kang, Dae Hee/E-8631-2012; Peters, W.H.M./L-4572-2015; Benhamou, Simone/K-6554-2015; Muzi, Giacomo /K-8689-2016; Risch, Angela/H-2669-2013; OI Garte, Seymour/0000-0003-3284-5975; London, Stephanie/0000-0003-4911-5290; Muzi, Giacomo /0000-0002-2784-3513; Risch, Angela/0000-0002-8026-5505; Kim, Heon/0000-0003-0329-5249 FU NCI NIH HHS [R01 CA034627, R01 CA034627-18A1] NR 16 TC 19 Z9 20 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JUN 10 PY 2004 VL 110 IS 2 BP 266 EP 270 DI 10.1002/ijc.20114 PG 5 WC Oncology SC Oncology GA 817ML UT WOS:000221181500017 PM 15069692 ER PT J AU Sitaraman, K Esposito, D Klarmann, G Le Grice, SF Hartley, JL Chatterjee, DK AF Sitaraman, K Esposito, D Klarmann, G Le Grice, SF Hartley, JL Chatterjee, DK TI A novel cell-free protein synthesis system SO JOURNAL OF BIOTECHNOLOGY LA English DT Article DE cell-free protein synthesis; 3-phosphoglycerate; PEP; Gam protein; RecBCD; T7 RNA polymerase ID WHEAT-GERM EXTRACT; ESCHERICHIA-COLI; TRANSLATION SYSTEMS; MESSENGER-RNA; BATCH SYSTEM; REGENERATION; INVITRO; DNA AB An efficient cell-free protein synthesis system has been developed using a novel energy-regenerating source. Using the new energy source, 3-phosphoglycerate (3-PGA), protein synthesis continues beyond 2 h. In contrast, the reaction rate slowed down considerably within 30-45 min using a conventional energy source, phosphoenol pyruvate (PEP) under identical reaction conditions. This improvement results in the production of twice the amount of protein obtained with PEP as an energy source. We have also shown that Gam protein of phage lambda, an inhibitor of RecBCD (ExoV), protects linear PCR DNA templates from degradation in vitro. Furthermore, addition of purified Gam protein in extracts of Escherichia coli BL21 improves protein synthesis from PCR templates to a level comparable to plasmid DNA template. Therefore, combination of these improvements should be amenable to rapid expression of proteins in a high-throughput manner for proteomics and structural genomics applications. (C) 2004 Elsevier B.V. All rights reserved. C1 NCI, SAIC, Frederick, MD 21702 USA. HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Chatterjee, DK (reprint author), NCI, SAIC, 1050 Boyles St,Bldg 327, Frederick, MD 21702 USA. EM chatterjee@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 19 TC 40 Z9 42 U1 3 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1656 J9 J BIOTECHNOL JI J. Biotechnol. PD JUN 10 PY 2004 VL 110 IS 3 BP 257 EP 263 DI 10.1016/j.jbiotec.2004.02.014 PG 7 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 828MQ UT WOS:000221977800005 PM 15163516 ER PT J AU Roca, AL Bar-Gal, GK Eizirik, E Helgen, KM Maria, R Springer, MS O'Brien, SJ Murphy, WJ AF Roca, AL Bar-Gal, GK Eizirik, E Helgen, KM Maria, R Springer, MS O'Brien, SJ Murphy, WJ TI Mesozoic origin for West Indian insectivores SO NATURE LA English DT Article ID MOLECULAR EVIDENCE; BIOGEOGRAPHY; EVOLUTION; MAMMALS; VERTEBRATES; PHYLOGENY; ORDER AB The highly endangered solenodons, endemic to Cuba ( Solenodon cubanus) and Hispaniola ( S. paradoxus), comprise the only two surviving species of West Indian insectivores(1,2). Combined gene sequences (13.9 kilobases) from S. paradoxus established that solenodons diverged from other eulipotyphlan insectivores 76 million years ago in the Cretaceous period, which is consistent with vicariance, though also compatible with dispersal. A sequence of 1.6 kilobases of mitochondrial DNA from S. cubanus indicated a deep divergence of 25 million years versus the congeneric S. paradoxus, which is consistent with vicariant origins as tectonic forces separated Cuba and Hispaniola(3,4). Efforts to prevent extinction of the two surviving solenodon species would conserve an entire lineage as old or older than many mammalian orders. C1 SAIC Frederick, Lab Genom Divers, Basic Res Program, Frederick, MD 21702 USA. NCI, Lab Genom Divers, Frederick, MD 21702 USA. Pontificia Univ Catolica Rio Grande do Sul, Ctr Biol Genom & Mol, Porto Alegre, RS, Brazil. Univ Adelaide, Sch Earth & Environm Sci, Adelaide, SA 5005, Australia. ZOODOM, Parque Zool Nacl, Santo Domingo, Dominican Rep. Univ Calif Riverside, Dept Biol, Riverside, CA 92521 USA. RP Roca, AL (reprint author), SAIC Frederick, Lab Genom Divers, Basic Res Program, Frederick, MD 21702 USA. EM roca@ncifcrf.gov; obrien@ncifcrf.gov; murphywi@ncifcrf.gov RI Eizirik, Eduardo/K-8034-2012 OI Eizirik, Eduardo/0000-0002-9658-0999 NR 30 TC 77 Z9 80 U1 1 U2 27 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUN 10 PY 2004 VL 429 IS 6992 BP 649 EP 651 DI 10.1038/nature02597 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 827PJ UT WOS:000221912600037 PM 15190349 ER PT J AU Johnson, J Ostojic, J Lannfelt, L Glaser, A Basun, H Rogaeva, E Kawarai, T Bruni, A Hyslop, PHSG Goate, A Pastor, P Chakraverty, S Norton, J Morris, JC Hardy, J Singleton, A AF Johnson, J Ostojic, J Lannfelt, L Glaser, A Basun, H Rogaeva, E Kawarai, T Bruni, A Hyslop, PHSG Goate, A Pastor, P Chakraverty, S Norton, J Morris, JC Hardy, J Singleton, A TI No evidence for tau duplications in frontal temporal dementia families showing genetic linkage to the tau locus in which tau mutations have not been found SO NEUROSCIENCE LETTERS LA English DT Article DE MAPT; Tau; genetics; FTDP-17; alpha-synuclem ID PROGRESSIVE SUPRANUCLEAR PALSY; PARKINSONS-DISEASE; FRONTOTEMPORAL DEMENTIA; ALZHEIMERS-DISEASE; MICE; DEGENERATION; ASSOCIATION; HAPLOTYPE; PROTEIN AB Given the remarkable similarities between the genetics of tau diseases and the genetics of alpha-synuclein diseases, and given the fact that we have recently found a triplication of the alpha-synuclein locus in a family in which we had shown linkage to the alpha-synuclein locus, we determined to test whether some of the several families with autosomal dominant frontal temporal dementia which show genetic linkage to the tau locus but in which tau mutations have not been found could be caused by similar structural mutations. We did not find any such mutations. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. Ctr Reg Neurogenet, I-88046 Lamezia Terme, CZ, Italy. Univ Toronto, Ctr Res Neurodegenerat Dis, Toronto, ON M5S 3H2, Canada. Univ Uppsala Hosp, Dept Publ Hlth Geriatr, S-75125 Uppsala, Sweden. RP Hardy, J (reprint author), NIA, Neurogenet Lab, NIH, Bldg 10,Room 6C103,MSC1589, Bethesda, MD 20892 USA. EM hardyj@mail.nih.gov RI Singleton, Andrew/C-3010-2009; Morris, John/A-1686-2012; Pastor, Pau/C-9834-2009; Hardy, John/C-2451-2009 OI Pastor, Pau/0000-0002-7493-8777; NR 17 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JUN 10 PY 2004 VL 363 IS 2 BP 99 EP 101 DI 10.1016/j.neulet.2004.03.070 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 827ZN UT WOS:000221942300001 PM 15172093 ER PT J AU Luzuriaga, K McManus, M Mofenson, L Britto, P Graham, B Sullivan, JL AF Luzuriaga, K McManus, M Mofenson, L Britto, P Graham, B Sullivan, JL CA PACTG 356 Investigators TI A trial of three antiretroviral regimens in HIV-1-infected children SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; DISEASE PROGRESSION; INFECTED CHILDREN; IN-VIVO; THERAPY; INFANTS; REPLICATION; DYNAMICS AB BACKGROUND Depletion of CD4 T-cell counts or progression of human immunodeficiency virus (HIV) disease occurs rapidly in children, but few data address the efficacy of aggressive therapy for HIV-infected children. METHODS We evaluated the safety, tolerability, and activity of three regimens of antiretroviral therapy in a multicenter, open-label, phase 1 - 2 trial. Children infected with HIV type 1 (HIV-1) were stratified at entry according to age - three months or younger ( early therapy) or older than three months ( delayed therapy) - and assigned sequentially to one of three regimens. Children continued to receive treatment for up to 200 weeks if the plasma HIV-1 RNA level was less than 1000 copies per milliliter by 16 weeks. RESULTS Plasma HIV-1 RNA levels fell from a median of 5.3 log copies per milliliter ( range, 3.3 to 6.4 log copies per milliliter) at baseline to less than 1000 copies per milliliter at 16 weeks in 32 of 52 infants ( 62 percent). Plasma HIV-1 RNA levels were below 400 copies per milliliter at 48 weeks in 26 infants ( 50 percent) and at 200 weeks in 23 infants ( 44 percent). An intention-to-treat analysis revealed that significantly more children who received stavudine, lamivudine, nevirapine, and nelfinavir had plasma HIV-1 RNA levels of less than 400 copies per milliliter at 48 weeks ( 83 percent) and 200 weeks ( 72 percent) than children who received reverse-transcriptase inhibitors alone ( P=0.001 and P=0.01, respectively). Fewer infants in the delayed-therapy group than in the early-therapy group ( 30 percent vs. 60 percent) had plasma HIV-1 RNA levels of less than 400 copies per milliliter at 200 weeks ( P=0.03). Treatment-associated adverse effects were infrequent. CONCLUSIONS In this phase 1 - 2 trial involving HIV-1 - infected children, an age of three months or younger at the initiation of therapy and treatment with stavudine, lamivudine, nevirapine, and nelfinavir were associated with improved long-term viral suppression. Larger, randomized trials are required to define the optimal time to initiate therapy and the optimal regimen for these infants. C1 Univ Massachusetts, Sch Med, Dept Pediat, Worcester, MA 01605 USA. Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA. NICHHD, NIH, Rockville, MD USA. Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. RP Luzuriaga, K (reprint author), Univ Massachusetts, Sch Med, Dept Pediat, 373 Plantat St,Suite 318,Biotech 2, Worcester, MA 01605 USA. EM katherine.luzuriaga@umassmed.edu OI Mofenson, Lynne/0000-0002-2818-9808 FU NIAID NIH HHS [AI32391, AI32907, AI4845]; NICHD NIH HHS [HD01489] NR 13 TC 93 Z9 96 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 10 PY 2004 VL 350 IS 24 BP 2471 EP 2480 DI 10.1056/NEJMoa032706 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 827GH UT WOS:000221887200006 PM 15190139 ER PT J AU Lonser, RR Kim, J Butman, JA Vortmeyer, AO Choo, DI Oldfield, EH AF Lonser, RR Kim, J Butman, JA Vortmeyer, AO Choo, DI Oldfield, EH TI Tumors of the endolymphatic sac in von Hippel-Lindau disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SUPPRESSOR GENE; HEMANGIOBLASTOMAS; ADENOCARCINOMA C1 Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, Neurootol Branch, NIH, Bethesda, MD USA. NIH, Dept Diagnost Radiol, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Univ Cincinnati, Childrens Hosp, Med Ctr, Dept Otolaryngol, Cincinnati, OH USA. RP Lonser, RR (reprint author), Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bldg 10,Rm 5D37, Bethesda, MD 20892 USA. EM lonserr@ninds.nih.gov RI Butman, John/A-2694-2008; OI Butman, John/0000-0002-1547-9195 NR 17 TC 55 Z9 58 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 10 PY 2004 VL 350 IS 24 BP 2481 EP 2486 DI 10.1056/NEJMoa040666 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 827GH UT WOS:000221887200007 PM 15190140 ER PT J AU Gladwin, MT Sachdev, V Ognibene, FP AF Gladwin, MT Sachdev, V Ognibene, FP TI Pulmonary hypertension as a risk factor for death in patients with sickle cell disease - The authors reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID HEMOGLOBIN C1 NIH, Bethesda, MD 20892 USA. RP Gladwin, MT (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM mgladwin@nih.gov NR 4 TC 0 Z9 0 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 10 PY 2004 VL 350 IS 24 BP 2522 EP 2522 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 827GH UT WOS:000221887200024 ER PT J AU Andersen, JF Gudderra, NP Francischetti, IMB Valenzuela, JG Ribeiro, JMC AF Andersen, JF Gudderra, NP Francischetti, IMB Valenzuela, JG Ribeiro, JMC TI Recognition of anionic phospholipid membranes by an antihemostatic protein from a blood-feeding insect SO BIOCHEMISTRY LA English DT Article ID BUG RHODNIUS-PROLIXUS; OXIDE TRANSPORT PROTEIN; NITRIC-OXIDE; BLOODSUCKING BUG; HIGH-AFFINITY; HEME PROTEIN; BINDING; NITROPHORIN; LIPOCALIN; COMPLEX AB The saliva of blood-feeding insects contains a variety of molecules having antihemostatic activity. Here, we describe nitrophorin 7 (NP7), a salivary protein that binds with high affinity to anionic phospholipid membranes. The protein is apparently targeted to the negatively charged surfaces of activated platelets and other cells, where it can serve as a vasodilator, antihistamine, platelet aggregation inhibitor, and anticoagulant. As with other members of the nitrophorin group, NP7 reversibly binds a molecule of NO and binds histamine with high affinity. The protein differs from other nitrophorins in that it binds to membranes containing phosphatidylserine. Sedimentation and surface plasmon resonance experiments, revealed two classes of phospholipid-binding sites having K-d values of 4.8 and 755 nM. NP7 inhibits prothrombin activation by blocking phospholipid binding sites for the prothrombinase complex on the surfaces of vesicles and activated platelets. As a NO complex, NP7 inhibits collagen and ADP-induced platelet aggregation and induces disaggregation of ADP-stimulated platelets by an NO-mediated mechanism. Molecular modeling of NP7 revealed a putative, positively charged membrane interaction surface comprised mainly of a helix lying outside of the lipocalin beta-barrel structure. C1 NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Andersen, JF (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy, Rockville, MD 20852 USA. EM jandersen@niaid.nih.gov OI Ribeiro, Jose/0000-0002-9107-0818 FU Intramural NIH HHS [Z01 AI000810-11, Z99 AI999999] NR 35 TC 59 Z9 61 U1 0 U2 5 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 8 PY 2004 VL 43 IS 22 BP 6987 EP 6994 DI 10.1021/bi049655t PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 826CV UT WOS:000221807500017 PM 15170336 ER PT J AU Li, QY Cao, CH Chackerian, B Schiller, J Gordon, M Ugen, KE Morgan, D AF Li, QY Cao, CH Chackerian, B Schiller, J Gordon, M Ugen, KE Morgan, D TI Overcoming antigen masking of anti-amyloidbeta antibodies reveals breaking of B cell tolerance by virus-like particles in amyloidbeta immunized amyloid precursor protein transgenic mice SO BMC NEUROSCIENCE LA English DT Article ID ALZHEIMERS-DISEASE; BETA-PEPTIDE; CEREBRAL-HEMORRHAGE; PLAQUES; MODEL; MOUSE; NEUROPATHOLOGY; AUTOANTIBODIES; PATHOGENESIS; PRESENILIN-1 AB Background: In prior work we detected reduced anti-Abeta antibody titers in Abeta-vaccinated transgenic mice expressing the human amyloid precursor protein (APP) compared to nontransgenic littermates. We investigated this observation further by vaccinating APP and nontransgenic mice with either the wild-type human Abeta peptide, an Abeta peptide containing the "Dutch Mutation", E22Q, or a wild-type Abeta peptide conjugated to papillomavirus virus-like particles (VLPs). Results: Anti-Abeta antibody titers were lower in vaccinated APP than nontransgenic mice even when vaccinated with the highly immunogenic Abeta E22Q. One concern was that human Abeta derived from the APP transgene might mask anti-Abeta antibodies in APP mice. To test this possibility, we dissociated antigen-antibody complexes by incubation at low pH. The low pH incubation increased the anti-Abeta antibody titers 20-40 fold in APP mice but had no effect in sera from nontransgenic mice. However, even after dissociation, the anti-Abeta titers were still lower in transgenic mice vaccinated with wild-type Abeta or E22Q Abeta relative to non-transgenic mice. Importantly, the dissociated anti-Abeta titers were equivalent in nontransgenic and APP mice after VLP-based vaccination. Control experiments demonstrated that after acid-dissociation, the increased antibody titer did not cross react with bovine serum albumin nor alpha-synuclein, and addition of Abeta back to the dissociated serum blocked the increase in antibody titers. Conclusions: Circulating human Abeta can interfere with ELISA assay measurements of anti-Abeta titers. The E22Q Abeta peptide vaccine is more immunogenic than the wild-type peptide. Unlike peptide vaccines, VLP-based vaccines against Abeta abrogate the effects of Abeta self-tolerance. C1 Univ S Florida, Dept Pharmacol, Alzheimers Res Lab, Tampa, FL 33612 USA. NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Morgan, D (reprint author), Univ S Florida, Dept Pharmacol, Alzheimers Res Lab, Tampa, FL 33612 USA. EM qli@hsc.usf.edu; ccao@hsc.usf.edu; brycec@nih.gov; schillej@dc37a.nci.nih.gov; mgordon@hsc.usf.edu; kugen@hsc.usf.edu; dmorgan@hsc.usf.edu RI Ugen, Kenneth/H-6544-2011; Morgan, David/J-5989-2012; Gordon, Marcia N./K-2420-2012 OI Gordon, Marcia N./0000-0002-4051-9283 FU NIA NIH HHS [AG 18478, AG20227, R01 AG018478, R01 AG020227] NR 20 TC 30 Z9 31 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2202 J9 BMC NEUROSCI JI BMC Neurosci. PD JUN 8 PY 2004 VL 5 AR 21 DI 10.1186/1471-2202-5-21 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 835UT UT WOS:000222511700001 PM 15186505 ER PT J AU Nash, TE Del Brutto, H Butman, JA Corona, T Delgado-Escueta, A Duron, RM Evans, CAW Gilman, RH Gonzalez, AE Loeb, JA Medina, MT Pietsch-Escueta, S Pretell, EJ Takayanagui, OM Theodore, W Tsang, VCW Garcia, HH AF Nash, TE Del Brutto, H Butman, JA Corona, T Delgado-Escueta, A Duron, RM Evans, CAW Gilman, RH Gonzalez, AE Loeb, JA Medina, MT Pietsch-Escueta, S Pretell, EJ Takayanagui, OM Theodore, W Tsang, VCW Garcia, HH TI Calcific neurocysticercosis and epileptogenesis SO NEUROLOGY LA English DT Review ID RURAL GUATEMALAN COMMUNITIES; PARTIAL STATUS EPILEPTICUS; TAENIA-SOLIUM TAENIASIS; CT LESIONS; PERILESIONAL GLIOSIS; COMPUTED-TOMOGRAPHY; PARTIAL SEIZURES; INDIAN PATIENTS; EPILEPSY; CYSTICERCOSIS AB Neurocysticercosis is responsible for increased rates of seizures and epilepsy in endemic regions. The most common form of the disease, chronic calcific neurocysticercosis, is the end result of the host's inflammatory response to the larval cysticercus of Taenia solium. There is increasing evidence indicating that calcific cysticercosis is not clinically inactive but a cause of seizures or focal symptoms in this population. Perilesional edema is at times also present around implicated calcified foci. A better understanding of the natural history, frequency, epidemiology, and pathophysiology of calcific cysticercosis and associated disease manifestations is needed to define its importance, treatment, and prevention. C1 NIAID, Parasit Dis Lab, Dept Diagnost Radiol, Ctr Clin,NIH, Bethesda, MD 20892 USA. NINDS, NIH, Bethesda, MD 20892 USA. Hosp Clin Kennedy, Dept Neurol Sci, Guayaquil, Ecuador. Inst Nacl Neurol & Neurocirug, Mexico City, DF, Mexico. Univ Calif Los Angeles, Los Angeles, CA USA. Univ London Imperial Coll Sci Technol & Med, Dept Infect Dis & Microbiol, London SW7 2AZ, England. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. Univ Peruana Cayetano Heredia, Dept Microbiol, Lima, Peru. Univ Nacl Mayor San Marcos, Sch Vet Med, Lima 14, Peru. Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. Wayne State Univ, Dept Neurol, Detroit, MI USA. Univ Nacl Autonoma Honduras, Tegucigalpa, Honduras. Epilepsy Fdn Amer, Los Angeles, CA USA. Inst Nacl Ciencias Neurol, Cysticercosis Unit, Lima, Peru. Univ Sao Paulo, Sch Med Riberao Preto, Dept Neurol, BR-14049 Ribeirao Preto, Brazil. Ctr Dis Control, Div Parasit Dis, Natl Ctr Infect Dis, Atlanta, GA 30333 USA. RP Nash, TE (reprint author), NIAID, Parasit Dis Lab, Dept Diagnost Radiol, Ctr Clin,NIH, Bethesda, MD 20892 USA. EM tnash@niaid.nih.gov RI Butman, John/A-2694-2008; Takayanagui, Osvaldo/C-8159-2013; OI Takayanagui, Osvaldo/0000-0002-8190-0275; Duron, Reyna M./0000-0002-9425-2289; Butman, John/0000-0002-1547-9195 FU Wellcome Trust [057434] NR 49 TC 115 Z9 117 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUN 8 PY 2004 VL 62 IS 11 BP 1934 EP 1938 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 827HN UT WOS:000221890400006 PM 15184592 ER PT J AU Plewnia, C Hoppe, J Cohen, LG Gerloff, C AF Plewnia, C Hoppe, J Cohen, LG Gerloff, C TI Improved motor skill acquisition after selective stimulation of central norepinephrine SO NEUROLOGY LA English DT Article ID REUPTAKE INHIBITOR; CORTEX INJURY; RECOVERY; STROKE; AMPHETAMINE; PHYSIOTHERAPY; REBOXETINE AB It has been proposed that the beneficial effects of training on motor function can be enhanced by stimulation of alpha-adrenergic mechanisms. Consistent with this view, a single oral dose of the selective norepinephrine reuptake inhibitor reboxetine was found to enhance motor skill acquisition (rapid elbow flexion) and corticomotor excitability tested with transcranial magnetic stimulation in the absence of effects on basal motor performance. Therefore, alpha-adrenergic mechanisms could possibly be manipulated to magnify training effects in neurorehabilitation. C1 Univ Tuebingen, Hertie Inst Clin Brain Res, Dept Gen Neurol, Cort Physiol Res Grp, Tubingen, Germany. Univ Tuebingen, Dept Psychiat, Neurophysiol Sect, Tubingen, Germany. Natl Inst Neurol Disorders & Stroke, Human Cort Physiol Sect, NIH, Bethesda, MD USA. RP Gerloff, C (reprint author), Univ Tubingen, Sch Med, Dept Neurol, Cort Physiol Res Grp, Hoppe Seyler Str 3, D-72076 Tubingen, Germany. EM christian.gerloff@uni-tuebingen.de RI Plewnia, Christian/D-1652-2015 NR 10 TC 25 Z9 25 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUN 8 PY 2004 VL 62 IS 11 BP 2124 EP 2126 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 827HN UT WOS:000221890400046 PM 15184632 ER PT J AU Li, TW Evdokimov, E Shen, RF Chao, CC Tekle, E Wang, T Stadtman, ER Yang, DCH Chock, PB AF Li, TW Evdokimov, E Shen, RF Chao, CC Tekle, E Wang, T Stadtman, ER Yang, DCH Chock, PB TI Sumoylation of heterogeneous nuclear ribonucleoproteins, zinc finger proteins, and nuclear pore complex proteins: A proteomic analysis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TRANSCRIPTIONAL REGULATION; SUMO ISOPEPTIDASE; BINDING-PROTEIN; E3 LIGASE; UBIQUITIN; LOCALIZATION; RANBP2; DNA; RANGAP1; DOMAINS AB SUMO, a small ubiquitin-related modifier, is known to covalently attach to a number of nuclear regulatory proteins such as p53, IkappaB, promyelocytic leukemia protein and c-Jun. The sumoylation reaction is catalyzed by the SUMO protease, which exposes the C-terminal active glycine residue of the nascent SUMO, the heterodimeric SUMO activating enzyme, the SUMO conjugating enzyme, Ubc9, and SUMO protein ligases, in a manner similar to ubiquitinylation. Identification of SUMO-regulated proteins is hampered by the fact that many sumoylated proteins are present at a level below normal detection limit. This limitation was overcome by either in vivo overexpression of Myc-SUMO or in vitro sumoylation with excess biotin-SUMO and Ubc9. Sumoylated proteins so obtained were affinity purified or isolated by immunoprecipitation. The isolated sumoylated proteins were identified by sequence analysis using mass spectrometric methods. Results reveal that several heterogeneous nuclear ribonucleoproteins (hnRNPs), zinc finger proteins, and nuclear pore complex proteins were sumoylated. The sumoylation of hnRNP All, hnRNP F, and hnRNP K were confirmed in vivo by coimmunoprecipitation. In view of the facts that hnRNPs have been implicated in RNA splicing, transport, stability, and translation, our findings suggest that sumoylation could play an important role in regulating mRNA metabolism. C1 Natl Heart Lung & Blood Inst, Lab Biochem & Proteom Core Facil, Bethesda, MD 20892 USA. Georgetown Univ, Dept Chem, Washington, DC 20057 USA. USN, Med Res Ctr, Rickettsial Dis Dept, Infect Dis Directorate, Silver Spring, MD 20910 USA. RP Yang, DCH (reprint author), Natl Heart Lung & Blood Inst, Lab Biochem & Proteom Core Facil, Bethesda, MD 20892 USA. EM pbc@helix.nih.gov RI Chao, Chien-Chung/A-8017-2011; Yang, David/A-7294-2009 NR 33 TC 117 Z9 124 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 8 PY 2004 VL 101 IS 23 BP 8551 EP 8556 DI 10.1073/pnas.0402889101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 829HC UT WOS:000222037000012 PM 15161980 ER PT J AU Yusufzai, TM Felsenfeld, G AF Yusufzai, TM Felsenfeld, G TI The 5 '-HS4 chicken beta-globin insulator is a CTCF-dependent nuclear matrix-associated element SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ENHANCER-BLOCKING; CHROMATIN INSULATOR; IGF2 GENE; ATTACHMENT; DROSOPHILA; DNA; PROTEIN; SITES; ORGANIZATION; METHYLATION AB The protein CTCF plays an essential role in the action of a widely distributed class of vertebrate enhancer-blocking insulators, of which the first example was found in a DNA sequence element, HS4, at the 5' end of the chicken beta-globin locus. HS4 contains a binding site for CTCF that is necessary and sufficient for insulator action. Purification of CTCF has revealed that it interacts with proteins involved in subnuclear architecture, notably nucleophosmin, a 38-kDa nucleolar phosphoprotein that is concentrated in nuclear matrix preparations. In this report we show that both CTCF and the HS4 insulator element are incorporated in the matrix; HS4 incorporation depends on the presence of an intact CTCF-binding site. However the DNA sequence in the neighborhood of HS4 is not like that of canonical matrix attachment regions, and its incorporation into the matrix fraction is not sensitive to ribonuclease, suggesting that the insulator is a distinct matrix-associated element. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Felsenfeld, G (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM gary.felsenfeld@nih.gov NR 35 TC 107 Z9 115 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 8 PY 2004 VL 101 IS 23 BP 8620 EP 8624 DI 10.1073/pnas.0402938101 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 829HC UT WOS:000222037000024 PM 15169959 ER PT J AU Bielekova, B Richert, N Howard, T Blevins, G Markovic-Plese, S McCartin, J Wurfel, J Ohayon, J Waidmann, TA McFarland, HF Martin, R AF Bielekova, B Richert, N Howard, T Blevins, G Markovic-Plese, S McCartin, J Wurfel, J Ohayon, J Waidmann, TA McFarland, HF Martin, R TI Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon beta SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CONTROLLED TRIAL; CLINICAL-TRIAL; IL-2 RECEPTOR; THERAPY; UVEITIS AB Identifying effective treatment combinations for MS patients failing standard therapy is an important goal. We report the results of a phase II open label baseline-to-treatment trial of a humanized monoclonal antibody against CD25 (daclizumab) in 10 multiple sclerosis patients with incomplete response to IFN-beta therapy and high brain inflammatory and clinical disease activity. Daclizumab was very well tolerated and led to a 78% reduction in new contrast-enhancing lesions and to a significant improvement in several clinical outcome measures. C1 NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Dept Neurol, Chapel Hill, NC 27599 USA. Humboldt Univ, Inst Neuroimmunol, Charite, D-10117 Berlin, Germany. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Martin, R (reprint author), NINDS, Neuroimmunol Branch, NIH, 10 Ctr Dr,MSC 1400, Bethesda, MD 20892 USA. EM martinr@ninds.nih.gov NR 16 TC 217 Z9 225 U1 2 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 8 PY 2004 VL 101 IS 23 BP 8705 EP 8708 DI 10.1073/pnas.0402653101 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 829HC UT WOS:000222037000039 PM 15161974 ER PT J AU Sijwali, PS Kato, K Seydel, KB Gut, J Lehman, J Klemba, M Goldberg, DE Miller, LH Rosenthal, PJ AF Sijwali, PS Kato, K Seydel, KB Gut, J Lehman, J Klemba, M Goldberg, DE Miller, LH Rosenthal, PJ TI Plasmodium falciparum cysteine protease falcipain-1 is not essential in erythrocytic stage malaria parasites SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RECOMBINANT FALCIPAIN-2; HOST ERYTHROCYTE; FOOD VACUOLE; LIFE-CYCLE; PROTEINASE; INHIBITORS; EXPRESSION; INVASION; GENE; HEMOGLOBINASE AB Among potential new targets for antimalarial chemotherapy are Plasmodium falciparum cysteine proteases, known as falcipains. Falcipain-2 and falcipain-3 are food vacuole hemoglobinases that may have additional functions. The function of falcipain-1 remains uncertain. To better characterize the role of falcipain-1 in erythrocytic parasites, we disrupted the falcipain-1 gene and characterized recombinant parasites. Disruption of the falcipain-1 gene was confirmed with Southern blots, and loss of expression of falcipain-1 was confirmed with immunoblots and by loss of labeling with a specific protease inhibitor. Compared with wild-type parasites, falcipain-1 knockout parasites developed normally, with the same morphology, multiplication rate, and invasion efficiency, and without significant differences in sensitivity to cysteine protease inhibitors. In wild-type and knockout parasites, cysteine protease inhibitors blocked hemoglobin hydrolysis in trophozoites, with a subsequent block in rupture of erythrocytes by mature schizonts, but they did not inhibit erythrocyte invasion by merozoites. Our results indicate that although falcipain-1 is expressed by erythrocytic parasites, it is not essential for normal development during this stage or for erythrocyte invasion. C1 Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, San Francisco, CA 94143 USA. NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. Washington Univ, Howard Hughes Med Inst, St Louis, MO 63110 USA. Washington Univ, Dept Med, St Louis, MO 63110 USA. Washington Univ, Dept Mol Microbiol, St Louis, MO 63110 USA. RP Rosenthal, PJ (reprint author), Univ Calif San Francisco, Box 0811, San Francisco, CA 94143 USA. EM rosnthl@itsa.ucsf.edu FU NCRR NIH HHS [P41 RR001081, RR01081]; NIAID NIH HHS [AI35800, AI41718, R01 AI035800, R29 AI035800, R56 AI035800] NR 35 TC 81 Z9 86 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 8 PY 2004 VL 101 IS 23 BP 8721 EP 8726 DI 10.1073/pnas.0402738101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 829HC UT WOS:000222037000042 PM 15166288 ER PT J AU Chang, KO Sosnovtsev, SV Belliot, G Kim, Y Saif, LJ Green, KY AF Chang, KO Sosnovtsev, SV Belliot, G Kim, Y Saif, LJ Green, KY TI Bile acids are essential for porcine enteric calicivirus replication in association with down-regulation of signal transducer and activator of transcription 1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID VIRUS-LIKE PARTICLES; INTESTINAL CONTENTS; NUCLEAR RECEPTOR; TYROSINE PHOSPHORYLATION; SERIAL PROPAGATION; GNOTOBIOTIC PIGS; UNITED-STATES; IFN-GAMMA; PROTEIN; PATHWAY AB A porcine enteric calicivirus (PEC), strain Cowden in the family Caliciviridae (genus Sapovirus), can be propagated in a continuous cell line, LLC-PK cells, but only in the presence of an intestinal content fluid filtrate from gnotobiotic pigs. This cell culture system is presently the only in vitro model among caliciviruses that cause gastrointestinal disease, including members of the genera Sapovirus and Norovirus. We report here the identification of bile acids as active factors in intestinal content fluid essential for PEC growth. Bile acids that allowed PEC growth induced an increase in cAMP concentration in LLC-PK cells that was associated with down-regulation of IFNI-mediated signal transducer and activator of transcription 1 phosphorylation, a key element in innate immunity. In addition, cAMP/protein kinase A pathway inhibitors, suramin, MDL12330A, or H89 suppressed bile acid-mediated PEC replication. We propose a mechanism for enteric calicivirus growth dependent on bile acids, ubiquitous molecules present in the intestine at the site of the virus replication that involves the protein kinase A cell-signaling pathway and a possible down-regulation of innate immunity. C1 NIAID, Infect Dis Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Ohio State Univ, Dept Vet Prevent Med, Food Anim Hlth Res Program, Ohio Agr Res & Dev Ctr, Wooster, OH 44691 USA. RP Chang, KO (reprint author), NIAID, Infect Dis Lab, NIH, Dept Hlth & Human Serv, 9000 Rockville Pike,Bldg 50,Room 6318, Bethesda, MD 20892 USA. EM kchang@niaid.nih.gov; kgreen@niaid.nih.gov FU NIAID NIH HHS [R01 AI49716] NR 38 TC 66 Z9 68 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 8 PY 2004 VL 101 IS 23 BP 8733 EP 8738 DI 10.1073/pnas.0401126101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 829HC UT WOS:000222037000044 PM 15161971 ER PT J AU Irarrazabal, CE Liu, JC Burg, MB Ferraris, JD AF Irarrazabal, CE Liu, JC Burg, MB Ferraris, JD TI ATM, a DNA damage-inducible kinase, contributes to activation by high NaCl of the transcripton factor TonEBP/OREBP SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ENHANCER-BINDING PROTEIN; CANINE KIDNEY-CELLS; IN-VIVO; PHOSPHORYLATION; P53; HYPERTONICITY; EXPRESSION; GENE; TRANSACTIVATION; DIMERIZATION AB High NaCl activates the transcription factor tonicity-responsive enhancer/osmotic response element-binding protein (TonEBP/OREBP), resulting in increased transcription of several protective genes, including the glycine betaine/gamma-aminobutyric acid transporter (BGT1). High NaCl damages DNA, and DNA damage activates ataxia telangiectasia mutated (ATM) kinase through autophosphorylation on Ser-1981. TonEBP/OREBP contains ATM consensus phosphorylation sites at Ser-1197, Ser-1247, and Ser-1367. The present studies test whether ATM is involved in activation of TonEBP/OREBP by high NaCl. We find that raising osmolality from 300 to 500 mosmol/kg by adding NaCl activates ATM, as indicated by phosphorylation at Ser-1981. High urea and radiation also activate ATM, but they do not increase TonEBP/OREBP transcriptional activity like high NaCl does. Wortmannin, which inhibits ATM, reduces NaCl-induced TonEBP/OREBP transcriptional activation and BGT1 mRNA increase. Overexpression of wild-type TonEBP/OREBP increases ORE/TonE reporter activity much more than does overexpression of TonEBP/OREBP S1197A, S1247A, or S1367A. In AT cells (which express nonfunctional ATM), TonEBP/OREBP transcriptional and transactivating activity are further increased by expression of wild-type ATM but not of S1981A ATM. TonEBP/OREBP reciprocally coimmunoprecipitates with ATM kinase, demonstrating physical association. Additionally, antibody to ATM kinase supershifts TonEBP/OREBP bound to its cognate ORE/TonE DNA element. In AT cells, wortmannin further decreases high NaCl-incluced increase in transcriptional activity, consistent with participation of signaling kinase(s) in addition to ATM. In conclusion, signaling via ATM is necessary for full activation of TonEBP/OREBP by high NaCl, but it is not sufficient. C1 NHLBI, Natl Inst Hlth, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Irarrazabal, CE (reprint author), NHLBI, Natl Inst Hlth, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM irarrazc@nhibi.nih.gov NR 29 TC 72 Z9 74 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 8 PY 2004 VL 101 IS 23 BP 8809 EP 8814 DI 10.1073/pnas.0403062101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 829HC UT WOS:000222037000057 PM 15173573 ER PT J AU Kenworthy, AK Nichols, BJ Remmert, CL Hendrix, GM Kumar, M Zimmerberg, J Lippincott-Schwartz, J AF Kenworthy, AK Nichols, BJ Remmert, CL Hendrix, GM Kumar, M Zimmerberg, J Lippincott-Schwartz, J TI Dynamics of putative raft-associated proteins at the cell surface SO JOURNAL OF CELL BIOLOGY LA English DT Article DE lipid rafts; membrane microdomains; lateral diffusion; fluorescence recovery after photobleaching; cholesterol ID GLYCOSYLPHOSPHATIDYLINOSITOL-ANCHORED PROTEIN; FLUORESCENCE CORRELATION SPECTROSCOPY; INFLUENZA-VIRUS HEMAGGLUTININ; PLASMA-MEMBRANE MICRODOMAINS; LIPID RAFTS; LATERAL DIFFUSION; LIVING CELLS; LIVE CELLS; BIOLOGICAL-MEMBRANES; MODEL MEMBRANES AB Lipid rafts are conceptualized as membrane microdomains enriched in cholesterol and glycosphingolipid that serve as platforms for protein segregation and signaling. The properties of these domains in vivo are unclear. Here, we use fluorescence recovery after photobleaching to test if raft association affects a protein's ability to laterally diffuse large distances across the cell surface. The diffusion coefficients (D) of several types of putative raft and nonraft proteins were systematically measured under steady-state conditions and in response to raft perturbations. Raft proteins diffused freely over large distances (>4 mum), exhibiting Ds that varied 10-fold. This finding indicates that raft proteins do not undergo long-range diffusion as part of discrete, stable raft domains. Perturbations reported to affect lipid rafts in model membrane systems or by biochemical fractionation (cholesterol depletion, decreased temperature, and cholesterol loading) had similar effects on the diffusional mobility of raft and nonraft proteins. Thus, raft association is not the dominant factor in determining long-range protein mobility at the cell surface. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20895 USA. Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. Vanderbilt Univ, Sch Med, Dept Cell & Dev Biol, Nashville, TN 37232 USA. MRC, Mol Biol Lab, Cambridge CB2 2QH, England. NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20817 USA. RP Lippincott-Schwartz, J (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bldg 18T,Rm 101,18 Lib Dr, Bethesda, MD 20895 USA. EM jlippin@helix.nih.gov FU NCI NIH HHS [CA68485, P30 CA068485]; NIDDK NIH HHS [P60 DK020593, DK20593, DK58404, P30 DK020593, P30 DK058404] NR 87 TC 293 Z9 300 U1 4 U2 21 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 7 PY 2004 VL 165 IS 5 BP 735 EP 746 DI 10.1083/jcb.200312170 PG 12 WC Cell Biology SC Cell Biology GA 828PW UT WOS:000221986200014 PM 15173190 ER PT J AU Benitez-Temino, B Morcuende, S Mentis, GZ de la Cruz, RR Pastor, AM AF Benitez-Temino, B Morcuende, S Mentis, GZ de la Cruz, RR Pastor, AM TI Expression of Trk receptors in the oculomotor system of the adult cat SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE abducens nucleus; neurotrophins; motoneurons; tyrosin protein kinases ID NERVE GROWTH-FACTOR; RAT SPINAL-CORD; ABDUCENS INTERNUCLEAR NEURONS; SEPTAL CHOLINERGIC NEURONS; MEDIAL RECTUS MOTONEURONS; MAMMALIAN CENTRAL NEURONS; NEUROTROPHIC FACTOR; MESSENGER-RNA; SENSORY NEURONS; MOTOR-NEURONS AB We examined the expression of the three Trk receptors for neurotrophins (TrkA, TrkB, and TrkC) in the extraocular motor nuclei of the adult cat by using antibodies directed against the full-Trk proteins in combination with horseradish peroxidase retrograde tracing. The three receptors were present in all neuronal populations investigated, including abducens motoneurons and internuclear neurons, medial rectus motoneurons of the oculomotor nucleus, and trochlear motoneurons. They were also present in the vestibular and prepositus hypoglossi nuclei. TrkA, TrkB, and TrkC immunopositive cells were found in similar percentages in the oculomotor and in the trochlear nuclei. In the abducens nucleus, however, a significantly higher percentage of cells expressed TrkB than the other two receptors, among both motoneurons (81.8%) and internuclear neurons (88.4%). The percentages obtained for the three Trk receptors in identified neuronal populations pointed to the colocalization of two or three receptors in a large number of cells. We used confocal microscopy to elucidate the subcellular location of Trk receptors. In this case, abducens motoneurons and internuclear neurons were identified with antibodies against choline acetyltransferase and calretinin, respectively. We found a different pattern of staining for each neurotrophin receptor, suggesting the possibility that each receptor and its cognate ligand may use a different route for cellular signaling. Therefore, the expression of Trk receptors in oculomotor, trochlear, and abducens motoneurons, as well as abducens internuclear neurons, suggests that their associated neurotrophins may exert an influence on the normal operation of the oculomotor circuitry. The presence of multiple Trk receptors on individual cells indicates that they likely act in concert with each other to regulate distinct functions. Published 2004 Wiley-Liss, Inc.(dagger). C1 Univ Sevilla, Dept Fisiol & Zool, Fac Biol, E-41012 Seville, Spain. NINDS, Lab Neural Control, NIH, Bethesda, MD 20892 USA. RP Pastor, AM (reprint author), Univ Sevilla, Dept Fisiol & Zool, Fac Biol, Avda Reina Mercedes 6, E-41012 Seville, Spain. EM ampastor@us.es RI Benitez Temino, Beatriz/F-8888-2015; OI Benitez Temino, Beatriz/0000-0002-3852-1093; Rodriguez de la Cruz, Rosa Maria/0000-0001-5301-5108; Morcuende, Sara/0000-0003-1471-7005 NR 93 TC 18 Z9 18 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 7 PY 2004 VL 473 IS 4 BP 538 EP 552 DI 10.1002/cne.20095 PG 15 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 818DH UT WOS:000221225300007 PM 15116389 ER PT J AU Odom, S Gomez, G Kovarova, M Furumoto, Y Ryan, JJ Wright, HV Gonzalez-Espinosa, C Hibbs, ML Harder, KW Rivera, J AF Odom, S Gomez, G Kovarova, M Furumoto, Y Ryan, JJ Wright, HV Gonzalez-Espinosa, C Hibbs, ML Harder, KW Rivera, J TI Negative regulation of immunoglobulin E-dependent allergic responses by Lyn kinase SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE Lyn kinase; IgE; mast cells; allergy; degranulation ID FC-EPSILON-RI; AFFINITY IGE RECEPTOR; GLYCOSPHINGOLIPID-ENRICHED MICRODOMAINS; PROTEIN-TYROSINE KINASE; MAST-CELL DEGRANULATION; CYTOKINE PRODUCTION; DEFICIENT MICE; AUTOIMMUNE-DISEASE; HISTAMINE-RELEASE; MEMBRANE DOMAINS AB A role for Lyn kinase as a positive regulator of immunoglobulin (Ig)E-dependent allergy has long been accepted. Contrary to this belief, Lyn kinase was found to have an important role as a negative regulator of the allergic response. This became apparent from the hyperresponsive degranulation of lyn(-/-) bone marrow-derived mast cells, which is driven by hyperactivation of Fyn kinase that occurs, in part, through the loss of negative regulation by COOH-terminal Src kinase (Csk) and the adaptor, Csk-binding protein. This phenotype is recapitulated in vivo as young lyn(-/-) mice showed an enhanced anaphylactic response. In vivo studies also demonstrated that as lyn(-/-) mice aged, their serum IgE increased as well as occupancy of the high affinity IgE receptor (FcepsilonRI). This was mirrored by increased circulating histamine, increased mast cell numbers, increased cell surface expression of the high affinity IgE receptor (FcepsilonRI), and eosinophilia. The increased IgE production was not a consequence of increased Fyn kinase activity in lyn(-/-) mice because both lyn(-/-) and lyn(-/-) fyn(-/-) mice showed high IgE levels. Thus, lyn(-/-) mice and mast cells thereof show multiple allergy-associated traits, causing reconsideration of the possible efficacy in therapeutic targeting of Lyn in allergic disease. C1 NIAMSD, Mol Inflammat Sect, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. Virginia Commonwealth Univ, Dept Biol, Richmond, VA 23284 USA. CINVESTAV Zona Sur, Dept Pharmacol, Mexico City 14330, DF, Mexico. Ludwig Inst Canc Res, Melbourne Tumour Biol Branch, Melbourne, Vic 3050, Australia. RP NIAMSD, Mol Inflammat Sect, Mol Immunol & Inflammat Branch, NIH, Bldg 10,Room 9N228, Bethesda, MD 20892 USA. EM juan_rivera@nih.gov RI Hibbs, Margaret/D-7013-2011 NR 45 TC 155 Z9 159 U1 1 U2 4 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 7 PY 2004 VL 199 IS 11 BP 1491 EP 1502 DI 10.1084/jem.20040382 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 829KS UT WOS:000222047800005 PM 15173205 ER PT J AU Pradel, G Hayton, K Aravind, L Iyer, LM Abrahamsen, MS Bonawitz, A Mejia, C Templeton, TJ AF Pradel, G Hayton, K Aravind, L Iyer, LM Abrahamsen, MS Bonawitz, A Mejia, C Templeton, TJ TI A multidomain adhesion protein family expressed in Plasmodium falciparum is essential for transmission to the mosquito SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE malaria; gametocyte; gamete; Anopheles; sporozoite ID HUMAN MALARIA; CRYPTOSPORIDIUM-PARVUM; BLOCKING VACCINES; GENOME SEQUENCE; SEXUAL STAGE; FIBRINOGEN; PARASITES; DOMAIN; TRANSFORMATION; IDENTIFICATION AB The recent sequencing of several apicomplexan genomes has provided the opportunity to characterize novel antigens essential for the parasite life cycle that might lead to the development of new diagnostic and therapeutic markets. Here we have screened the Plasmodium falciparum genome sequence for genes encoding extracellular multidomain putative adhesive proteins. Three of these identified genes, named PfCCp1, PfCCp2, and PfCCp3, have multiple adhesive modules including a common Limulus coagulation factor C domain also found in two additional Plasmodium genes. Orthologues were identified in the Cryptosporidium parvum genome sequence, indicating an evolutionary conserved function. Transcript and protein expression analysis shows sexual stage-specific expression of PfCCp1, PfCCp2, and PfCCp3, and cellular localization studies revealed plasma membrane-associated expression in mature gametocytes. During gametogenesis, PfCCps are released and localize surrounding complexes of newly emerged microgametes and macrogametes. PfCCp expression markedly decreased after formation of zygotes. To begin to address PfCCp function, the PfCCp2 and PfCCp3 gene loci were disrupted by homologous recombination, resulting in parasites capable of forming oocyst sporozoites but blocked in the salivary gland transition. Our results describe members of a conserved apicomplexan protein family expressed in sexual stage Plasmodium parasites that may represent candidates for subunits of a transmission-blocking vaccine. C1 Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, New York, NY 10021 USA. NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. Natl Ctr Biotechnol Informat, Natl Lib Med, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Biomed Genom Ctr, St Paul, MN 55108 USA. Univ Minnesota, Dept Vet Pathobiol, St Paul, MN 55108 USA. RP Templeton, TJ (reprint author), Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, 1300 York Ave,Box 62, New York, NY 10021 USA. EM tjt2001@med.cornell.edu NR 40 TC 60 Z9 63 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 7 PY 2004 VL 199 IS 11 BP 1533 EP 1544 DI 10.1084/jem.20031274 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 829KS UT WOS:000222047800009 PM 15184503 ER PT J AU Schaefer, M Rothemund, Y Heinze, HJ Rotte, M AF Schaefer, M Rothemund, Y Heinze, HJ Rotte, M TI Short-term plasticity of the primary somatosensory cortex during tool use SO NEUROREPORT LA English DT Article DE cortical reorganization; magnetoencephalography; plasticity; tool use; somatosensory cortex ID FUNCTIONAL-ORGANIZATION; CORTICAL REPRESENTATION; ARM AMPUTATION; REORGANIZATION; HUMANS; ATTENTION; BRAIN; MAPS AB Plastic changes within the primary somatosensory cortex (SI) related to tool use are reported. Subjects manipulated a small object with a pair of tongs or with their hand. Functional organization of SI during tool use was compared with that during executing the task with the fingers and during rest, respectively. Topography of SI was assessed using neuromagnetic source imaging based on tactile stimulation of the first (DI) and fifth digit (D5). We found that cortical representations of DI and D5 are further apart during tool use than during non-tool use and rest. Our data suggest that somatosensory cortical maps are part of the neural network representing the modified schema of the hand in which the tool was incorporated. C1 NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Dept Psychol, Nashville, TN 37203 USA. Otto Von Guericke Univ, Dept Neurol 2, D-39120 Magdeburg, Germany. RP Schaefer, M (reprint author), NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. EM schaefem@ninds.nih.gov NR 22 TC 19 Z9 20 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JUN 7 PY 2004 VL 15 IS 8 BP 1293 EP 1297 DI 10.1097/01.wnr.0000129573.36301.db PG 5 WC Neurosciences SC Neurosciences & Neurology GA 871NN UT WOS:000225140500015 PM 15167552 ER PT J AU Tohnya, TM Kim, S Fine, HA Dunn, L Figg, WD Sparreboom, A AF Tohnya, TM Kim, S Fine, HA Dunn, L Figg, WD Sparreboom, A TI Determination of SU5416, a novel angiogenesis inhibitor, in human plasma by liquid chromatography SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE SU5416; angiogenesis inhibitor ID ACUTE MYELOID-LEUKEMIA; GROWTH; ACTIVATION; AGENT AB A high-performance liquid chromatographic (HPLC) assay with UV detection has been developed for the quantitative determination of the antiangiogenic agent SU5416 in human plasma. Sample pretreatment involved a single protein-precipitation step with acetonitrile containing the internal standard. chrysin. Separation of the compounds of interest was achieved on a column packed with HP Zorbax C-8 material (5 mum particle size: length: 150 mm: i.d.: 4.6 mm) using a dual solvent system of 0.01 M aqueous ammonium acetate and acetonitrile delivered as a nonlinear gradient at a flow-rate of 1.00 ml/min. Simultaneous UV detection was performed at 440 nm (SU5416) and 268 nm (chrysin). The calibration graph was fit to log-transformed response-concentration data over a range of 10-5000 ng/ml. Values for accuracy and precision, obtained from six quality controls analyzed on different days in replicates of 3 or 6, ranged 92.9-109 and 0.8-6.2%, respectively. The developed method was successfully applied to study the pharmacokinetics of SU5416 in a cancer patient receiving the drug as a I h infusion. (C) 2004 Elsevier B.V. All rights reserved. C1 NCI, Ctr Canc Res, Clin Pharmacol Res Core, Med Oncol Clin Res Unit, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Ctr Canc Res, Clin Pharmacol Res Core, Med Oncol Clin Res Unit, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 FU NCI NIH HHS [CA62399] NR 13 TC 1 Z9 1 U1 0 U2 0 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 5 PY 2004 VL 805 IS 1 BP 135 EP 140 DI 10.1016/j.chromb.2004.02.036 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 819JC UT WOS:000221310200018 PM 15113549 ER PT J AU Yanagida, A Isozaki, M Shibusawa, Y Shindo, H Ito, Y AF Yanagida, A Isozaki, M Shibusawa, Y Shindo, H Ito, Y TI Purification of glucosyltransferase from cell-lysate of Streptococcus mutans by counter-current chromatography using aqueous polymer two-phase system SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE Streptococcus mutans; glucosyltransferase ID WATER-INSOLUBLE GLUCAN; COIL PLANET CENTRIFUGE; ONE-STEP PURIFICATION; STATIONARY PHASE; TEA POLYPHENOLS; PROTEINS; ADHERENCE; BINDING; SUCROSE; CARIOGENICITY AB Counter-current chromatography (CCC) using a cross-axis coil planet centrifuge (X-axis CPC) was applied to the purification of glucosyltransferase (GTF) from a cell-lysate of cariogenic bacteria. The purification was performed using an aqueous polymer two-phase system composed of 4.4% (w/w) polyethylene glycol (PEG) 8000-6% (w/w) dextran T500 containing 10 mM phosphate buffer at pH 9.2 by eluting the upper phase (UP) at 1.0 ml/min. The bacterial GTF in the cell-lysate of Streptococcus mutans was selectively retained in the dextran-rich lower stationary phase. The column contents were diluted and subjected to hydroxyapatite (HA) chromatography to remove the polymers from the GTF. Fractions eluted with 500 mM potassium phosphate buffer were analyzed by GTF enzymatic activity as well as sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The GTF purity in the final product was increased about 87 times as that in the cell-lysate with a good recovery rate of about 79% through this purification process. (C) 2004 Elsevier B.V. All rights reserved. C1 Tokyo Univ Pharm & Life Sci, Sch Pharm, Dept Analyt Chem, Hachioji, Tokyo 1920392, Japan. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Yanagida, A (reprint author), Tokyo Univ Pharm & Life Sci, Sch Pharm, Dept Analyt Chem, 1432-1 Horinouchi, Hachioji, Tokyo 1920392, Japan. EM yanagida@ps.toyaku.ac.jp NR 34 TC 9 Z9 12 U1 1 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 5 PY 2004 VL 805 IS 1 BP 155 EP 160 DI 10.1016/j.jchromb.2004.02.039 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 819JC UT WOS:000221310200021 PM 15113552 ER PT J AU Cox, S Harvey, BK Sanchez, JF Wang, JY Wang, Y AF Cox, S Harvey, BK Sanchez, JF Wang, JY Wang, Y TI Mediation of BMP7 neuroprotection by MAPK and PKCIN rat primary cortical cultures SO BRAIN RESEARCH LA English DT Article DE bone morphogenctic protein 7; neuroprotection; mitogen activated protein kinase; protein kinase C ID ACTIVATED PROTEIN-KINASE; BONE MORPHOGENETIC PROTEIN; GROWTH-FACTOR-BETA; OSTEOGENIC PROTEIN-1; CEREBRAL-ISCHEMIA; MESANGIAL CELLS; DNA-SYNTHESIS; C ACTIVATION; STROKE RATS; IN-VITRO AB We have previously demonstrated that pretreatment with bone morphogenetic protein 7 (BMP7), a trophic factor in the TGF superfamily, reduces ischemia-induced brain infarction induced by middle cerebral artery ligation in rats. Since the mitogen-activated protein kinase (MAPK) pathway is involved in many TGFbeta-mediated responses, we examined the interaction of BMP7 and MAPK in primary cultures obtained from the cerebral cortex of E16-17 rat embryos. Lactate dehydrogenase (LDH) in the media was used as an index of cell death. BMP7 did not alter LDH levels at low concentration (1.25 nM), but exhibited increased cellular toxicity at higher concentration (> 12.5 nM). BMP7 at the low concentration significantly attenuated H2O2-induced increases in LDH activity and decreases in neuronal density. Pharmacological interactions were used to examine if MAPK was involved in this response. BMP7-induced protection was antagonized by the p42,44 MAPK kinase inhibitors PD98059 and U0125. The p38 MAPK antagonist SB203580, and their inactive analog SB202474, also attenuated BMP7-induced protection, suggesting that the interaction with p38 MAPK is nonspecific. Previous studies have indicated that SB202474 has inhibitory effects on other protein kinases. We found that the protein kinase C inhibitor chelerythrine antagonized BMP7-induced protection against H2O2. Western blot analysis indicated that BMP7 increased phosphorylation of p42,44 MAPK and PKC. Taken together, our data suggest that BMP7 is neuroprotective at low concentrations in primary cortical cell culture. The protective effects of BMP7 may involve the activation of p42,44 MAPK and PKC. Published by Elsevier B.V. C1 NIDA, NIH, Baltimore, MD 21224 USA. Natl Def Med Ctr, Dept Physiol, Taipei, Taiwan. RP Wang, Y (reprint author), NIDA, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM ywang@intra.nida.nih.gov NR 34 TC 31 Z9 32 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 4 PY 2004 VL 1010 IS 1-2 BP 55 EP 61 DI 10.1016/j.brainres.2004.02.068 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 823RQ UT WOS:000221631200007 PM 15126117 ER PT J AU Borlongan, CV Lind, JG Dillon-Carter, O Yu, GL Hadman, M Cheng, C Carroll, J Hess, DC AF Borlongan, CV Lind, JG Dillon-Carter, O Yu, GL Hadman, M Cheng, C Carroll, J Hess, DC TI Bone marrow grafts restore cerebral blood flow and blood brain barrier in stroke rats SO BRAIN RESEARCH LA English DT Article DE neural transplantation; cerebral ischemia; stem cell; striatum; immunosuppression; neuroprotection; green fluorescent protein ID TISSUE-PLASMINOGEN-ACTIVATOR; ACUTE ISCHEMIC-STROKE; STROMAL CELLS; FUNCTIONAL RECOVERY; CYCLOSPORINE-A; STEM-CELLS; INTRACEREBRAL TRANSPLANTATION; NEUROTROPHIC FACTOR; PARKINSONS-DISEASE; THERAPEUTIC BENEFIT AB We monitored alterations in cerebral blood flow (CBF) and blood-brain barrier (BBB) permeability following middle cerebral artery occlusion (MCAo) and intrastriatal transplantation of mouse bone marrow stromal cells (BMSCs) or saline infusion in adult Sprague-Dawley rats. Laser Doppler and Evans Blue assay revealed that BMSC grafts close-dependently restored CBF and BBB to near normal levels at a much earlier period (Days 4-5 post-MCAo) in transplanted stroke animals compared to stroke animals that received saline infusion (Days 11-14 post-MCAo). Xenogratted BMSCs survived in the absence of immunosuppression, and elevated levels of transforming growth factor-beta superfamily of neurotrophic factors were detected in transplanted stroke animals. These data suggest that early restoration of CBF and BBB following transplantation of BMSCs could mediate the reported functional outcomes in stroke animals. (C) 2004 Elsevier B.V. All rights reserved. C1 Med Coll Georgia, Dept Neurol, Augusta, GA 30912 USA. Med Coll Georgia, Inst Mol Med Genet, Augusta, GA 30912 USA. Med Coll Georgia, Sch Grad Studies, Augusta, GA 30912 USA. Agusta VAMC, Res & Affiliat Serv Line, Augusta, GA 30912 USA. NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Borlongan, CV (reprint author), Med Coll Georgia, Dept Neurol, 1120 15th St,B1-3080, Augusta, GA 30912 USA. EM cborlongan@mail.mcg.edu OI Borlongan, Cesar/0000-0002-2966-9782 FU NINDS NIH HHS [R21-NS43439-01, R21-NS43487-01] NR 62 TC 101 Z9 113 U1 0 U2 8 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 4 PY 2004 VL 1010 IS 1-2 BP 108 EP 116 DI 10.1016/j.brainres.2004.02.072 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 823RQ UT WOS:000221631200013 PM 15126123 ER PT J AU Kim, JR Lee, SM Cho, SH Kim, JH Kim, BH Kwon, J Choi, CY Kim, YD Lee, SR AF Kim, JR Lee, SM Cho, SH Kim, JH Kim, BH Kwon, J Choi, CY Kim, YD Lee, SR TI Oxidation of thioredoxin reductase in HeLa cells stimulated with tumor necrosis factor-alpha SO FEBS LETTERS LA English DT Article DE thioredoxin reductase; selenocysteine; reactive oxygen species; apoptosis ID HUMAN MITOCHONDRIAL THIOREDOXIN; MANGANOUS SUPEROXIDE-DISMUTASE; CYSTEINE-SULFINIC ACID; MAMMALIAN THIOREDOXIN; REDOX REGULATION; ACTIVE-SITE; GLUTATHIONE-PEROXIDASE; GLUTAREDOXIN SYSTEMS; SELENOCYSTEINE; APOPTOSIS AB Stimulation of cells with tumor necrosis factor-alpha (TNF-alpha) results in the increase in generation of H2O2 in mitochondria that leads to apoptosis. The effect of H2O2 produced by TNF-alpha on the redox status of selenocysteine (SeCys) residue essential for mitochondrial thioredoxin reductase (TrxR2) was investigated in HeLa cells. TNF-alpha caused accumulation of oxidized TrxR2 with a thioselenide bond. The conditional induction of SeCys-deficient TrxR2 resulted in the increased production of H2O2 and apoptosis. These results suggest that the SeCys residue of TrxR2 plays a critical role in cell survival by serving as an electron donor for Trx-II and subsequent peroxiredoxin-III, which is a primary line of defense against H2O2 in mitochondria. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 Ewha Womans Univ, Dept Biol Sci, Div Mol Life Sci, Ctr Cell Signaling Res, Seoul 120750, South Korea. Yeungnam Univ, Coll Med, Taejon 705717, South Korea. Natl Heart Lung & Blood Inst, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. Sungkyunkwan Univ, Dept Biol Sci, Suwon 440746, South Korea. Pusan Natl Univ, Dept Thorac & Cardiovasc Surg, Pusan 602739, South Korea. RP Lee, SR (reprint author), Ewha Womans Univ, Dept Biol Sci, Div Mol Life Sci, Ctr Cell Signaling Res, Seoul 120750, South Korea. EM Leesr@ewha.ac.kr NR 54 TC 25 Z9 27 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 4 PY 2004 VL 567 IS 2-3 BP 189 EP 196 DI 10.1016/j.febslet.2004.04.055 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 827HJ UT WOS:000221890000007 PM 15178321 ER PT J AU Bokesch, HR Charan, RD Meragelman, KM Beutler, JA Gardella, R O'Keefe, BR McKee, TC McMahon, JB AF Bokesch, HR Charan, RD Meragelman, KM Beutler, JA Gardella, R O'Keefe, BR McKee, TC McMahon, JB TI Isolation and characterization of anti-HIV peptides from Dorstenia contrajerva and Treculia obovoidea SO FEBS LETTERS LA English DT Article DE peptide; gp4l; Moraceae; Dorstenia contrajerva; Treculia obovoidea ID VIRUS-INACTIVATING PROTEIN; CYANOVIRIN-N; GP120; GP41; GLYCOPROTEIN; LECTIN; POTENT AB Using a high throughput screen based on the interaction of the HIV-1 gp41 ectodomain with the virucidal protein cyanovirin-N (CV-N), we isolated two new peptides which inhibited the binding of CV-N to gp41 and which subsequently showed anti-HIV activity in a whole cell assay. A 5-kDa (contrajervin) and 10 kDa (treculavirin) peptide were isolated from Dorstenia contrajerva and Treculia obovoidea, respectively. Treculavirin was composed of two subunits, each containing 50 amino acid residues, which are covalently linked by at least one disulfide bond between the subunits. Both peptides were shown to bind to gp41 and gp120 and to inhibit the cytopathic effects of HIV-1(RF) infection in a human T-lymphoblastoid cell line (CEM-SS). (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 NCI, SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. NCI, Ctr Canc Res, Mol Targets Dev Program, Frederick, MD 21702 USA. RP McKee, TC (reprint author), NCI, SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. EM manuscripts@ncifcrf.gov RI Beutler, John/B-1141-2009 OI Beutler, John/0000-0002-4646-1924 FU NCI NIH HHS [N01-CO-12400] NR 16 TC 11 Z9 12 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUN 4 PY 2004 VL 567 IS 2-3 BP 287 EP 290 DI 10.1016/j.febslet.2004.04.085 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 827HJ UT WOS:000221890000024 PM 15178338 ER PT J AU Nebert, DW Dalton, TP Okey, AB Gonzalez, FJ AF Nebert, DW Dalton, TP Okey, AB Gonzalez, FJ TI Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID LUNG-CANCER; HYDROXYLASE-ACTIVITY; AH RECEPTOR; DETERMINES SUSCEPTIBILITY; JAPANESE POPULATION; CYTOCHROMES P450; DEFICIENT MICE; GENE; MOUSE; POLYMORPHISMS AB The mammalian CYP1A1, CYP1A2, and CYP1B1 genes (encoding cytochromes P450 1A1, 1A2, and 1B1, respectively) are regulated by the aromatic hydrocarbon receptor (AHR). The CYP1 enzymes are responsible for both metabolically activating and detoxifying numerous polycyclic aromatic hydrocarbons (PAHs) and aromatic amines present in combustion products. Many substrates for CYP1 enzymes are AHR ligands. Differences in AHR affinity between inbred mouse strains reflect variations in CYP1 inducibility and clearly have been shown to be associated with differences in risk of toxicity or cancer caused by PAHs and arylamines. Variability in the human AHR affinity exists, but differences in human risk of toxicity or cancer related to AHR activation remain unproven. Mouse lines having one or another of the Cyp1 genes disrupted have shown paradoxical effects; in the test tube or in cell culture these enzymes show metabolic activation of PAHs or arylamines, whereas in the intact animal these enzymes are sometimes more important in the role of detoxification than metabolic potentiation. Intact animal data contradict pharmaceutical company policies that routinely test drugs under development; if a candidate drug shows CYP1 inducibility, further testing is generally discontinued for fear of possible toxic or carcinogenic effects. In the future, use of "humanized" mouse lines, containing a human AHR or CYP1 allele in place of the orthologous mouse gene, is one likely approach to show that the AHR and the CYP1 enzymes in human behave similarly to that in mouse. C1 Univ Cincinnati, Med Ctr, Dept Environm Hlth, Cincinnati, OH 45267 USA. Univ Cincinnati, Med Ctr, Ctr Environm Genet, Cincinnati, OH 45267 USA. Univ Toronto, Dept Pharmacol, Toronto, ON M5S 1A8, Canada. USN Hosp, NCI, Lab Metab, NIH, Bethesda, MD 20814 USA. RP Nebert, DW (reprint author), Univ Cincinnati, Med Ctr, Dept Environm Hlth, POB 670056, Cincinnati, OH 45267 USA. EM dan.nebert@uc.edu NR 59 TC 658 Z9 687 U1 12 U2 82 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 4 PY 2004 VL 279 IS 23 BP 23847 EP 23850 DI 10.1074/jbc.R400004200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 824RA UT WOS:000221702500001 PM 15028720 ER PT J AU Lee, SB Varnai, P Balla, A Jalink, K Rhee, SG Balla, T AF Lee, SB Varnai, P Balla, A Jalink, K Rhee, SG Balla, T TI The pleckstrin homology domain of phosphoinositide-specific phospholipase C delta(4) is not a critical determinant of the membrane localization of the enzyme SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID C-DELTA 4; INOSITOL 1,4,5-TRISPHOSPHATE; HIGH-AFFINITY; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; BILAYER-MEMBRANES; PH DOMAINS; BINDING; KINASE; PLC; PROTEIN AB The inositol lipid and phosphate binding properties and the cellular localization of phospholipase Cdelta(4) (PLCdelta(4)) and its isolated pleckstrin homology (PH) domain were analyzed in comparison with the similar features of the PLCdelta(1) protein. The isolated PH domains of both proteins showed plasma membrane localization when expressed in the form of a green fluorescent protein fusion construct in various cells, although a significantly lower proportion of the PLCdelta(4) PH domain was membrane-bound than in the case of PLCdelta(1)PH-GFP. Both PH domains selectively recognized phosphatidylinositol 4,5-bisphosphate (PI(4,5)P-2), but a lower binding of PLCdelta(4)PH to lipid vesicles containing PI(4,5)P-2 was observed. Also, higher concentrations of inositol 1,4,5-trisphosphate (Ins(1,4,5)P-3) were required to displace the PLCdelta(4)PH from the lipid vesicles, and a lower Ins(1,4,5)P-3 affinity of PLCdelta(4)PH was found in direct Ins(1,4,5)P-3 binding assays. In sharp contrast to the localization of its PH domain, the full-length PLCdelta(4) protein localized primarily to intracellular membranes mostly to the endoplasmic reticulum ( ER). This ER localization was in striking contrast to the well documented PH domain-dependent plasma membrane localization of PLCdelta(1). A truncated PLCdelta(4) protein lacking the entire PH domain still showed the same ER localization as the full-length protein, indicating that the PH domain is not a critical determinant of the localization of this protein. Most important, the full-length PLCdelta(4) enzyme still showed binding to PI(4,5)P-2-containing micelles, but Ins(1,4,5)P-3 was significantly less potent in displacing the enzyme from the lipid than with the PLCdelta(1) protein. These data suggest that although structurally related, PLCdelta(1) and PLCdelta(4) are probably differentially regulated in distinct cellular compartments by PI(4,5)P-2 and that the PH domain of PLCdelta(4) does not act as a localization signal. C1 NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. NHLI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. Semmelweis Univ, Dept Physiol, Fac Med, H-1444 Budapest, Hungary. Netherlands Canc Inst, Div Cell Biol, NL-1066 CX Amsterdam, Netherlands. RP Balla, T (reprint author), NICHHD, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Rm 6A35,49 Convent Dr, Bethesda, MD 20892 USA. EM tambal@box-t.nih.gov OI Balla, Andras/0000-0002-6450-2793; Balla, Tamas/0000-0002-9077-3335 NR 42 TC 13 Z9 16 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 4 PY 2004 VL 279 IS 23 BP 24362 EP 24371 DI 10.1074/jbc.M312772200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 824RA UT WOS:000221702500062 PM 15037625 ER PT J AU Rose, JJ Foley, JF Murphy, PM Venkatesan, S AF Rose, JJ Foley, JF Murphy, PM Venkatesan, S TI On the mechanism and significance of ligand-induced internalization of human neutrophil chemokine receptors CXCR1 and CXCR2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN INTERLEUKIN-8 RECEPTOR; CLATHRIN-MEDIATED ENDOCYTOSIS; CELL-SURFACE EXPRESSION; LIPID RAFTS; SIGNAL-TRANSDUCTION; LEADING-EDGE; CHEMOATTRACTANT RECEPTORS; MEMBRANE MICRODOMAINS; BIOLOGICAL-MEMBRANES; ANCHORED PROTEINS AB It is well established that leukocyte chemotactic receptors, a subset of G protein-coupled receptors, undergo endocytosis after stimulation by ligand. However, the significance of this phenomenon to cell motility and other important leukocyte functions induced by chemoattractants has not been clearly defined. Here we show that in primary human neutrophils, the threshold levels of agonist required for endocytosis of the chemotactic receptors CXCR1 and CXCR2 were similar to10-fold or higher than those needed for maximal chemotactic and calcium flux responses. Moreover, when stimulated by agonists at concentrations that are high enough for chemotaxis but too low for receptor endocytosis, neutrophil CXCR1 and CXCR2 could be reactivated in response to repeated application of the same agonist. Both receptors were excluded from Triton X-100-insoluble lipid rafts, and at high agonist concentrations were rapidly endocytosed by a clathrin/rab5/dynamin-dependent pathway. These data support the conclusion that neutrophil migration in response to CXCR1 or CXCR2 agonists is not dependent on endocytosis of CXCR1 or CXCR2. Rather than being integral to the process of cell migration, receptor endocytosis may be a terminal stop signal when cells reach the focus of inflammation where the chemoattractant concentrations are the highest. C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Venkatesan, S (reprint author), NIAID, Mol Microbiol Lab, NIH, Bldg 10,Rm 6A05, Bethesda, MD 20892 USA. EM aradhana@helix.nih.gov NR 92 TC 63 Z9 64 U1 3 U2 11 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 4 PY 2004 VL 279 IS 23 BP 24372 EP 24386 DI 10.1074/jbc.M401364200 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 824RA UT WOS:000221702500063 PM 15028716 ER PT J AU Jia, YZ Qi, C Kashireddi, P Surapureddi, S Zhu, YJ Rao, MS Le Roith, D Chambon, P Gonzalez, FJ Reddy, JK AF Jia, YZ Qi, C Kashireddi, P Surapureddi, S Zhu, YJ Rao, MS Le Roith, D Chambon, P Gonzalez, FJ Reddy, JK TI Transcription coactivator PBP, the peroxisome proliferator-activated receptor (PPAR)-binding protein, is required for PPAR alpha-regulated gene expression in liver SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACYL-COA OXIDASE; NUCLEAR RECEPTORS; BINDING-PROTEIN; EMBRYONIC-DEVELOPMENT; INTERACTING PROTEIN; TRAP220 COMPONENT; LIGAND METABOLISM; BETA-OXIDATION; NORMAL GROWTH; MOUSE-LIVER AB Nuclear receptor coactivator PBP (peroxisome proliferator-activated receptor (PPAR)-binding protein) functions as a coactivator for PPARs and other nuclear receptors. PBP serves as an anchor for TRAP ( thyroid hormone receptor-associated proteins)/mediator multi-subunit cofactor transcription complex. Disruption of the PBP/TRAP220 gene results in embryonic lethality around embryonic day 11.5 by affecting placental, cardiac, hepatic, and bone marrow development. Because PPAR isoforms alpha, gamma, and beta/delta function as important regulators of lipid homeostasis in mammals, it becomes important to assess the requirement of coactivator PBP in the regulation of PPAR functions in vivo. Sustained activation of PPARalpha by structurally diverse classes of chemicals of biological importance, designated peroxisome proliferators, leads to proliferation of peroxisomes in liver, induction of PPARalpha target genes including those involved in fatty acid oxidation, and the eventual development of liver tumors. Here, we show that targeted deletion of PBP in liver parenchymal cells, using the Cre-loxP system, results in the near abrogation of PPARalpha ligand-induced peroxisome proliferation and liver cell proliferation, as well as the induction of PPARalpha-regulated genes in PBP-deficient liver cells. In contrast, scattered PBP+/+ hepatocytes in these livers showed DNA synthesis and were markedly hypertrophic with peroxisome proliferation in response to PPARalpha ligands. Chromatin immunoprecipitation data suggest that in PBP conditional null livers, there appears to be reduced association of cofactors, especially of CBP and TRAP150, to the mouse enoyl-CoA hydratase/L-3-hydroxyacyl-CoA dehydrogenase gene promoter. These observations suggest that PBP is required for the stabilization of multiprotein cofactor complexes. In essence, the absence of PBP in hepatocytes in vivo appears to mimic the absence of PPARalpha, indicating that coactivator PBP is essential for PPARalpha-regulated gene expression in liver parenchymal cells. C1 Northwestern Univ, Dept Pathol, Feinberg Sch Med, Chicago, IL 60611 USA. NIH, Diabet Branch, Bethesda, MD 20892 USA. Univ Strasbourg 1, Coll France, Inst Genet & Biol Mol & Cellulaire, CNRS INSERM, F-67404 Illkirch Graffenstaden, France. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Reddy, JK (reprint author), Northwestern Univ, Dept Pathol, Feinberg Sch Med, 303 E Chicago Ave, Chicago, IL 60611 USA. EM jkreddy@northwestern.edu FU NCI NIH HHS [CA104578]; NIGMS NIH HHS [GM23750] NR 56 TC 76 Z9 81 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 4 PY 2004 VL 279 IS 23 BP 24427 EP 24434 DI 10.1074/jbc.M402391200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 824RA UT WOS:000221702500069 PM 15150259 ER PT J AU Maeda, H Nagata, S Wolfgang, CD Bratthauer, GL Bera, TK Pastan, I AF Maeda, H Nagata, S Wolfgang, CD Bratthauer, GL Bera, TK Pastan, I TI The T cell receptor gamma chain alternate reading frame protein (TARP), a prostate-specific protein localized in mitochondria SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ANDROGEN-REGULATED GENE; CANCER CELLS; EPITHELIAL-CELLS; MOLECULAR-CLONING; CITRATE METABOLISM; EXPRESSION; MEMBRANE; ANTIGEN; BINDING; TUMORS AB We previously showed that mRNA encoding TARP ( T cell receptor gamma chain alternate reading frame protein) is exclusively expressed in the prostate in males and is up-regulated by androgen in LNCaP cells, an androgen-sensitive prostate cancer cell line. We have now developed an anti-TARP monoclonal antibody named TP1, and show that TARP protein is up-regulated by androgen in both LNCaP and MDA-PCa-2b cells. We used TP1 to determine the subcellular localization of TARP by Western blotting following subcellular fractionation and immunocytochemistry. Both methods showed that TARP is localized in the mitochondria of LNCaP cells, MDA-PCa-2b cells, and PC-3 cells transfected with a TARP-expressing plasmid. We also transfected a plasmid encoding TARP fused to green fluorescent protein into LNCaP, MDA-Pca-2b, and PC-3 cells and confirmed its specific mitochondrial localization in living cells. Fractionation of mitochondria shows that TARP is located in the outer mitochondrial membrane. Immunohistochemistry using a human prostate cancer sample showed that TP1 reacted in a dot-like cytoplasmic pattern consistent with the presence of TARP in mitochondria. These data demonstrate that TARP is the first prostate-specific protein localizing in mitochondria and indicate that TARP, an androgen-regulated protein, may act on mitochondria to carry out its biological functions. C1 NCI, Mol Biol Lab, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. Armed Forces Inst Pathol, Dept Gynecol & Breast Pathol, Washington, DC 20306 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, NIH, Ctr Canc Res, 37 Convent Dr,Room 5106, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov NR 46 TC 16 Z9 17 U1 1 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 4 PY 2004 VL 279 IS 23 BP 24561 EP 24568 DI 10.1074/jbc.M402492200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 824RA UT WOS:000221702500085 PM 15150260 ER PT J AU Filizola, M Hassan, SA Artoni, A Coller, BS Weinstein, H AF Filizola, M Hassan, SA Artoni, A Coller, BS Weinstein, H TI Mechanistic insights from a refined three-dimensional model of integrin alpha(IIb)beta(3) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SCREENED COULOMB POTENTIALS; MURINE MONOCLONAL-ANTIBODY; GLANZMANNS-THROMBASTHENIA; INTEGRIN ALPHA-V-BETA-3; EXTRACELLULAR SEGMENT; CRYSTAL-STRUCTURE; SOLVENT MODEL; BINDING; ALPHA-IIB-BETA-3; PROTEINS AB The integrin alpha(IIb)beta(3) plays an important role in platelet function, and abnormalities of this protein result in a serious bleeding disorder, known as Glanzmann thrombasthenia. Although crystallographic data exist for the related integrin alpha(V)beta(3), to date, there are no high resolution structures of integrin alpha(IIb)beta(3) available in the literature. Therefore, it is still unclear how specific elements of the alpha(IIb) subunit contribute to integrin alpha(IIb)beta(3) function. Here we describe a refined model of the alpha(IIb) N-terminal portion of integrin alpha(IIb)beta(3) obtained by using the alpha(V)beta(3) template combined with a new method for predicting the conformations of the unique alpha(IIb) loop regions comprising residues 71-85, 114-125, and 148-164. The refined model was probed based on a structural prediction that differentiates it from standard homology models: specifically, that Lys-118 of alpha(IIb) contacts Glu-171 of beta(3). To test this hypothesis experimentally, the mutant integrin chains alpha(IIb) K118C and beta(3) E171C were cotransfected into HEK 293 cells. We show that the cells expressed the mutants alpha(IIb)beta(3) on their surface as a disulfide-linked dimer, supporting the close proximity between alpha(IIb) Lys-118 and beta(3) Glu-171 predicted from the refined model. This validated model provides a specific structural context for the analysis and interpretation of structure-function relations of integrin alpha(IIb)beta(3). In addition, it suggests mechanistic hypotheses pertaining to both naturally occurring mutations responsible for Glanzmann thrombasthenia and to point mutations that affect ligand binding. C1 Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10021 USA. Rockefeller Univ, Lab Blood & Vasc Biol, New York, NY 10021 USA. NIH, Ctr Mol Modeling, Div Computat Biosci, CIT, Bethesda, MD 20892 USA. RP Filizola, M (reprint author), Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, Box 75,1300 York Ave, New York, NY 10021 USA. EM maf2037@med.cornell.edu OI Filizola, Marta/0000-0002-4382-8276 FU NHLBI NIH HHS [HL19278]; NIDA NIH HHS [T32 DA074135, DA00060] NR 25 TC 6 Z9 6 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 4 PY 2004 VL 279 IS 23 BP 24624 EP 24630 DI 10.1074/jbc.M400243200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 824RA UT WOS:000221702500092 PM 15056669 ER PT J AU Richman, RW Tombler, E Lau, KK Anantharam, A Rodriguez, J O'Bryan, JP Diverse-Pierluissi, MA AF Richman, RW Tombler, E Lau, KK Anantharam, A Rodriguez, J O'Bryan, JP Diverse-Pierluissi, MA TI N-type Ca2+ channels as scaffold proteins in the assembly of signaling molecules for GABA(B) receptor effects SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CALCIUM-CHANNELS; TYROSINE-KINASE; COUPLED RECEPTORS; GENE-EXPRESSION; PHOSPHORYLATION; MODULATION; CROSSTALK; CASCADES; PATHWAYS; SRC AB An emerging concept in signal transduction is the organization of neuronal receptors and channels into microdomains in which signaling proteins are brought together to regulate functional responses. With the multiplicity of potential protein-protein interactions arises the need for the regulation and timing of these interactions. We have identified N-type Ca2+ channel-signaling molecule complexes formed at different times upon activation of gamma-aminobutyric acid, type B, receptors. The first type of interaction involves pre-association of signaling proteins such as Src kinase with the Ca2+ channel, because it is rapidly activated by the receptors and regulates the magnitude of the inhibition of the Ca2+ channel. The second type of interaction involves signaling molecules that are recruited to the channel by receptor activation and control the rate of the channel response. Recruitment of members of the Ras pathway has two effects as follows: 1) modulation of the rate of onset of the gamma-aminobutyric acid-mediated inhibition of Ca2+ current, and 2) activation of MAP kinase. Our results suggest that the Ca2+ channel alpha(1) subunit functions as a dynamic scaffold allowing assembly of intracellular signaling components that alter channel activity and route signals to the MAP kinase pathway. C1 Mt Sinai Sch Med, Dept Pharmacol & Biol Chem, New York, NY 10029 USA. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Diverse-Pierluissi, MA (reprint author), Mt Sinai Sch Med, Dept Pharmacol & Biol Chem, 1 Gustave L Levy Pl, New York, NY 10029 USA. EM maria.diverse@mssm.edu FU NINDS NIH HHS [NS37443] NR 22 TC 11 Z9 14 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 4 PY 2004 VL 279 IS 23 BP 24649 EP 24658 DI 10.1074/jbc.M312182200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 824RA UT WOS:000221702500095 PM 15047708 ER PT J AU Shulman-Peleg, A Nussinov, R Wolfson, HJ AF Shulman-Peleg, A Nussinov, R Wolfson, HJ TI Recognition of functional sites in protein structures SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE binding sites similarity; 3D database searches; protein function prediction; pharmacophore; computer-aided drug design ID 3D COORDINATE TEMPLATES; INTERACTIONS IN-SILICO; ACID-BINDING PROTEIN; MOLECULAR-SURFACE; FATTY-ACID; LIGAND INTERACTIONS; CRYSTAL-STRUCTURES; ASTRAL COMPENDIUM; ACTIVE-SITES; IDENTIFICATION AB Recognition of regions on the surface of one protein, that are similar to a binding site of another is crucial for the prediction of molecular interactions and for functional classifications. We first describe a novel method, SiteEngine, that assumes no sequence or fold similarities and is able to recognize proteins that have similar binding sites and may perform similar functions. We achieve high efficiency and speed by introducing a low-resolution surface representation via chemically important surface points, by hashing triangles of physico-chemical properties and by application of hierarchical scoring schemes for a thorough exploration of global and local similarities. We proceed to rigorously apply this method to functional site recognition in three possible ways: first, we search a given functional site on a large set of complete protein structures. Second, a potential functional site on a protein of interest is compared with known binding sites, to recognize similar features. Third, a complete protein structure is searched for the presence of an a priori unknown functional site, similar to known sites. Our method is robust and efficient enough to allow computationally demanding applications such as the first and the third. From the biological standpoint, the first application may identify secondary binding sites of drugs that may lead to side-effects. The third application finds new potential sites on the protein that may provide targets for drug design. Each of the three applications may aid in assigning a function and in classification of binding patterns. We highlight the advantages and disadvantages of each type of search, provide examples of large-scale searches of the entire Protein Data Base and make functional predictions. (C) 2004 Elsevier Ltd. All rights reserved. C1 Tel Aviv Univ, Sackler Fac Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Sch Comp Sci, IL-69978 Tel Aviv, Israel. SAIC NCI Fredrick Inc, Lab Expt & Computat Biol, Basic Res Program, Ft Detrick, MD 21702 USA. RP Nussinov, R (reprint author), Tel Aviv Univ, Sackler Fac Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. EM ruthn@ncifcrf.gov RI Wolfson, Haim/A-1837-2011 FU NCI NIH HHS [N01-CO-12400] NR 72 TC 180 Z9 185 U1 1 U2 4 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 4 PY 2004 VL 339 IS 3 BP 607 EP 633 DI 10.1016/j.jmb.2004.04.012 PG 27 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 825QN UT WOS:000221773200010 PM 15147845 ER PT J AU Bourbon, HM Aguilera, A Ansari, AZ Asturias, FJ Berk, AJ Bjorklund, S Blackwell, TK Borggrefe, T Carey, M Carlson, M Conaway, JW Conaway, RC Emmons, SW Fondell, JD Freedman, LP Fukasawa, T Gustafsson, CM Han, M He, X Herman, PK Hinnebusch, AG Holmberg, S Holstege, FC Jaehning, JA Kim, YJ Kuras, L Leutz, A Lis, JT Meisterernest, M Naar, AM Nasmyth, K Parvin, JD Ptashne, M Reinberg, D Ronne, H Sadowski, I Sakurai, H Sipiczki, M Sternberg, PW Stillman, DJ Strich, R Struhl, K Svejstrup, JQ Tuck, S Winston, F Roeder, RG Kornberg, RD AF Bourbon, HM Aguilera, A Ansari, AZ Asturias, FJ Berk, AJ Bjorklund, S Blackwell, TK Borggrefe, T Carey, M Carlson, M Conaway, JW Conaway, RC Emmons, SW Fondell, JD Freedman, LP Fukasawa, T Gustafsson, CM Han, M He, X Herman, PK Hinnebusch, AG Holmberg, S Holstege, FC Jaehning, JA Kim, YJ Kuras, L Leutz, A Lis, JT Meisterernest, M Naar, AM Nasmyth, K Parvin, JD Ptashne, M Reinberg, D Ronne, H Sadowski, I Sakurai, H Sipiczki, M Sternberg, PW Stillman, DJ Strich, R Struhl, K Svejstrup, JQ Tuck, S Winston, F Roeder, RG Kornberg, RD TI A unified nomenclature for protein subunits of Mediator complexes linking transcriptional regulators to RNA polymerase II SO MOLECULAR CELL LA English DT Letter ID SACCHAROMYCES-CEREVISIAE; MAMMALIAN MEDIATOR; NUCLEAR RECEPTORS; BINDING PROTEIN; METAZOAN CELLS; REPEAT DOMAIN; IN-VITRO; ACTIVATION; YEAST; HOLOENZYME C1 Univ Toulouse 3, CNRS, UMR5547, Ctr Dev Biol, F-31062 Toulouse, France. Univ Seville, Fac Biol, Dept Genet, E-41012 Seville, Spain. Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. Univ Wisconsin, Genome Ctr, Madison, WI 53706 USA. Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Microbiol Mol Genet & Immunol, Los Angeles, CA 90095 USA. Umea Univ, Dept Med Biochem & Biophys, SE-90187 Umea, Sweden. Joslin Diabet Ctr, Boston, MA 02215 USA. Univ Ulm, Dept Immunol, D-89081 Ulm, Germany. Univ Calif Los Angeles, Sch Med, Dept Biol Chem, Los Angeles, CA 90095 USA. Columbia Univ, Dept Genet & Dev, New York, NY 10032 USA. Stowers Inst Med Res, Kansas City, MO 64110 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY 10461 USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Physiol & Biophys, Piscataway, NJ 08854 USA. Merck & Co Inc, Merck Res Labs, Dept Mol Endocrinol, West Point, PA 19486 USA. Keio Univ, Sch Med, Dept Microbiol, Shinjuku Ku, Tokyo 1608582, Japan. Karolinska Inst, Dept Med Nutr, SE-14186 Huddinge, Sweden. Univ Colorado, Dept Mol Cellular & Dev Biol, Howard Hughes Med Inst, Boulder, CO 80309 USA. Harvard Univ, Childrens Hosp, Sch Med, Boston, MA 02115 USA. Ohio State Univ, Dept Mol Genet, Columbus, OH 43210 USA. NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. Inst Mol Biol, Dept Genet, DK-1353 Copenhagen, Denmark. UMC Utrecht, Div Biomed Genet, Genom Lab, NL-3508 AB Utrecht, Netherlands. Univ Colorado, Hlth Sci Ctr, Dept Biochem & Mol Genet, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Program Mol Biol, Denver, CO 80262 USA. Yonsei Univ, Natl Creat Res Initiat Ctr Genome Regulat, Dept Biochem, Seoul 120749, South Korea. CNRS, Ctr Genet Mol, UPR2167, F-91198 Gif Sur Yvette, France. Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany. Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA. GSF Munich, Gene Express Natl Res Ctr Environm & Hlth, D-81377 Munich, Germany. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. Res Inst Mol Pathol, A-1030 Vienna, Austria. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Biochem, Div Nucle Acids Enzymol,Howar Hughes Med Inst, Piscataway, NJ 08854 USA. Uppsala Univ, Dept Med Biochem & Microbiol, SE-75007 Uppsala, Sweden. Swedish Univ Agr Sci, Dept Plant Biol & Forest Genet, SE-75007 Uppsala, Sweden. Univ British Columbia, Dept Biochem & Mol Biol, Vancouver, BC V6T 1Z3, Canada. Kanazawa Univ, Fac Med, Sch Hlth Sci, Kanazawa, Ishikawa 9200942, Japan. Univ Debrecen, Dept Genet, H-4010 Debrecen, Hungary. CALTECH, HHMI, Pasadena, CA 91125 USA. CALTECH, Div Biol, Pasadena, CA 91125 USA. Univ Utah, Hlth Sci Ctr, Dept Pathol, Salt Lake City, UT 84132 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Imperial Canc Res Fund, Clare Hall Labs, London Res Inst, Canc Res UK, S Mimms EN6 3LD, Herts, England. Umea Univ, UCMP, SE-90187 Umea, Sweden. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Rockefeller Univ, Biochem & Mol Biol Lab, New York, NY 10021 USA. Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA. RP Bourbon, HM (reprint author), Univ Toulouse 3, CNRS, UMR5547, Ctr Dev Biol, 118 Route Narbonne, F-31062 Toulouse, France. EM bourbon@cict.fr; roeder@rockefeller.edu; kornberg@stanford.edu RI Parvin, Jeffrey/C-8955-2009; Holmberg, Steen/N-1128-2014; Leutz, Achim/K-9643-2013; OI Holmberg, Steen/0000-0002-0262-3207; Leutz, Achim/0000-0001-8259-927X; Kuras, Laurent/0000-0003-2932-0940; Ronne, Hans/0000-0002-1645-6091; Conaway, Joan/0000-0002-2786-0663; Stillman, David/0000-0002-5268-2416; Carey, Michael/0000-0003-3899-6280; Svejstrup, Jesper/0000-0003-4964-6147; Aguilera, Andres/0000-0003-4782-1714 FU NIGMS NIH HHS [R01 GM062891] NR 48 TC 153 Z9 212 U1 4 U2 20 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD JUN 4 PY 2004 VL 14 IS 5 BP 553 EP 557 DI 10.1016/j.molcel.2004.05.011 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 827QM UT WOS:000221915500002 PM 15175151 ER PT J AU Gan, L Conway, JF Firek, BA Cheng, NQ Hendrix, RW Steven, AC Johnson, JE Duda, RL AF Gan, L Conway, JF Firek, BA Cheng, NQ Hendrix, RW Steven, AC Johnson, JE Duda, RL TI Control of crosslinking by quaternary structure changes during bacteriophage HK97 maturation SO MOLECULAR CELL LA English DT Article ID VIRUS; PROTEIN; DNA; HEAD; TRANSITIONS; MICROSCOPY; RESOLUTION; MECHANISM; STATES; MODEL AB Radical structural changes drive the maturation of the capsid of HK97, a lambda-like, dsDNA bacteriophage of Escherichia coli. These include expansion from similar to560 to similar to660 Angstrom in diameter, metamorphosis from a round to an angular shape, and formation of covalent crosslinks between adjacent capsomers. Analogous transformations also occur in unrelated viruses and protein complexes. We find that expansion and crosslinking happen concurrently during maturation at low pH. Expansion causes residues on three different subunits to move up to 35 Angstrom to form 420 active sites that each catalyze the formation of a lysine-asparagine crosslink between adjacent subunits, making crosslink formation an indirect reporter of structural change. Intermediate crosslinking patterns support a previously proposed model of expansion, while hydrophobic properties aid in distinguishing discrete intermediates. A structure derived from cryo-EM images reveals the free intermediate conformation of penton arms, supporting our model for coordinated movement of hexons and pentons on the capsid lattice. C1 Univ Pittsburgh, Phittsburgh Bacteriophage Inst, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Biol Sci, Pittsburgh, PA 15260 USA. Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. Inst Biol Struct JP Ebel, F-38027 Grenoble, France. NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. RP Duda, RL (reprint author), Univ Pittsburgh, Phittsburgh Bacteriophage Inst, Pittsburgh, PA 15260 USA. EM duda@pitt.edu RI Gan, Lu/F-8317-2011; Conway, James/A-2296-2010 OI Gan, Lu/0000-0002-8685-4896; Conway, James/0000-0002-6581-4748 FU NIAID NIH HHS [R01 AI 40101]; NIGMS NIH HHS [R01 GM 47795] NR 31 TC 40 Z9 41 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JUN 4 PY 2004 VL 14 IS 5 BP 559 EP 569 DI 10.1016/j.molcel.2004.05.015 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 827QM UT WOS:000221915500003 PM 15175152 ER PT J AU Wang, L Brown, JL Cao, R Zhang, Y Kassis, JA Jones, RS AF Wang, L Brown, JL Cao, R Zhang, Y Kassis, JA Jones, RS TI Hierarchical recruitment of Polycomb group silencing complexes SO MOLECULAR CELL LA English DT Article ID HISTONE METHYLTRANSFERASE ACTIVITY; DROSOPHILA BITHORAX COMPLEX; CHROMATIN-REMODELING FACTOR; H3 LYSINE-27 METHYLATION; DNA-BINDING PROTEIN; HOMEOTIC GENE; TRANSCRIPTIONAL REPRESSION; RESPONSE ELEMENT; GROUP PRODUCTS; ZESTE PROTEIN AB Polycomb group (PcG) proteins maintain the transcriptional silence of target genes through many cycles of cell division. Here, we provide evidence for the sequential binding of PcG proteins at a Polycomb response element (PRE) in proliferating cells in which the sequence-specific DNA binding Pho and Phol proteins directly recruit E(z)-containing complexes, which in turn methylate histone H3 at lysine 27 (H3mK27). This provides a tag that facilitates binding by a Pc-containing complex. In wing imaginal discs, these PcG proteins also are present at discrete locations at or downstream of the promoter of a silenced target gene, Ubx. E(z)-dependent H3mK27 is also present near the Ubx promoter and is needed for PC binding. The location of E(z)- and Pc-containing complexes downstream of the Ubx transcription start site suggests that they may inhibit transcription by interfering with assembly of the preinitiation complex or by blocking transcription initiation or elongation. C1 So Methodist Univ, Dept Biol Sci, Dallas, TX 75275 USA. NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Curriculum Genet & Mol, Chapel Hill, NC 27599 USA. RP Jones, RS (reprint author), So Methodist Univ, Dept Biol Sci, Dallas, TX 75275 USA. EM rjones@maii.smu.edu OI Kassis, Judith/0000-0001-9268-3213 FU NIGMS NIH HHS [GM 068804, GM 46567] NR 57 TC 285 Z9 295 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JUN 4 PY 2004 VL 14 IS 5 BP 637 EP 646 DI 10.1016/j.molcel.2004.05.009 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 827QM UT WOS:000221915500009 PM 15175158 ER PT J AU Berrettini, W Bierut, L Crowley, TJ Cubells, JF Frascella, J Gelernter, J Hewitt, JK Kreek, MJ Lachman, H Leppert, M Li, MD Madden, P Miner, C Pollock, JD Pomerleau, O Rice, JP Rutter, JL Shurtleff, D Swan, GE Tischfield, JA Tsuang, M Uhl, GR Vanyukov, M Volkow, ND Wanke, K AF Berrettini, W Bierut, L Crowley, TJ Cubells, JF Frascella, J Gelernter, J Hewitt, JK Kreek, MJ Lachman, H Leppert, M Li, MD Madden, P Miner, C Pollock, JD Pomerleau, O Rice, JP Rutter, JL Shurtleff, D Swan, GE Tischfield, JA Tsuang, M Uhl, GR Vanyukov, M Volkow, ND Wanke, K TI Setting priorities for genomic research SO SCIENCE LA English DT Letter ID OPIOID RECEPTOR; TOBACCO USE; GENE; POLYMORPHISM; ALCOHOL C1 NIDA, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. Univ Colorado, Sch Med, Div Subst Dependence, Dept Psychiat, Denver, CO 80262 USA. Yale Univ, Sch Med, VACHS, West Haven, CT 06516 USA. Yale Univ, Sch Med, Dept Psychiat, Div Human Genet,VA Med Ctr 116A2, West Haven, CT 06516 USA. Univ Colorado, Inst Behav Genet, Boulder, CO 80309 USA. Rockefeller Univ, Lab Biol Addict Dis, New York, NY 10021 USA. Albert Einstein Coll Med, Dept Psychiat & Med, Bronx, NY 10461 USA. Univ Utah, Eccles Inst Human Genet, Dept Human Genet, Salt Lake City, UT 84108 USA. Univ Texas, Hlth Sci Ctr, Dept Psychiat, Program Genom & Bioinformat Drug Addict, San Antonio, TX 78229 USA. Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. SRI Int, Ctr Hlth Sci, Menlo Pk, CA 94025 USA. Rutgers State Univ, Dept Genet, Nelson Biol labs, Piscataway, NJ 08854 USA. Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21224 USA. Univ Pittsburgh, Pittsburgh, PA 15261 USA. NCI, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. RP Pollock, JD (reprint author), NIDA, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM jpollock@nida.nih.gov; jrutter@nida.nih.gov RI Pollock, Jonathan/B-1554-2009 NR 11 TC 15 Z9 15 U1 1 U2 4 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 4 PY 2004 VL 304 IS 5676 BP 1445 EP 1446 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825YR UT WOS:000221795800017 PM 15178784 ER PT J AU Merikangas, KR Risch, N AF Merikangas, KR Risch, N TI Setting priorities for genomic research - Response SO SCIENCE LA English DT Letter ID SMOKING-BEHAVIOR; ADOLESCENCE; GENES C1 NIMH, Sect Dev Genet Epidemiol, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. Kaiser Permanente, Div Res, Oakland, CA 94612 USA. RP Merikangas, KR (reprint author), NIMH, Sect Dev Genet Epidemiol, NIH, Dept Hlth & Human Serv, 15K N Dr,Mail Stop Code 2670, Bethesda, MD 20892 USA. NR 15 TC 2 Z9 2 U1 1 U2 1 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUN 4 PY 2004 VL 304 IS 5676 BP 1446 EP 1447 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825YR UT WOS:000221795800018 ER PT J AU Paez, JG Janne, PA Lee, JC Tracy, S Greulich, H Gabriel, S Herman, P Kaye, FJ Lindeman, N Boggon, TJ Naoki, K Sasaki, H Fujii, Y Eck, MJ Sellers, WR Johnson, BE Meyerson, M AF Paez, JG Janne, PA Lee, JC Tracy, S Greulich, H Gabriel, S Herman, P Kaye, FJ Lindeman, N Boggon, TJ Naoki, K Sasaki, H Fujii, Y Eck, MJ Sellers, WR Johnson, BE Meyerson, M TI EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy SO SCIENCE LA English DT Article ID GROWTH-FACTOR RECEPTOR; TYROSINE KINASE; BRAF GENE; INHIBITOR; SENSITIVITY; TRIAL; AMPLIFICATION; COMBINATION; PACLITAXEL; EFFICACY AB Receptor tyrosine kinase genes were sequenced in non - small cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15 of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. EGFR mutations were found in additional lung cancer samples from U. S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinib-insensitive tumors or cell lines. These results suggest that EGFR mutations may predict sensitivity to gefitinib. C1 Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biol Chem, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Mol Pharmacol, Boston, MA 02115 USA. MIT & Harvard, Broad Inst, Cambridge, MA 02142 USA. Natl Naval Med Res Inst, Genet Branch, NCI, Bethesda, MD 20889 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Nagoya City Univ, Sch Med, Dept Surg 2, Nagoya, Aichi 4678601, Japan. RP Sellers, WR (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM William_Sellers@dfci.harvard.edu; Bruce_Johnson@dfci.harvard.edu; Matthew_Meyerson@dfci.harvard.edu RI kaye, frederic/E-2437-2011; Meyerson, Matthew/E-7123-2012; Tang, Amy/L-3226-2016 OI Tang, Amy/0000-0002-5772-2878 NR 26 TC 5475 Z9 5795 U1 95 U2 525 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 4 PY 2004 VL 304 IS 5676 BP 1497 EP 1500 DI 10.1126/science.1099314 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825YR UT WOS:000221795800043 PM 15118125 ER PT J AU Yu, L Alva, A Su, H Dutt, P Freundt, E Welsh, S Baehrecke, EH Lenardo, MJ AF Yu, L Alva, A Su, H Dutt, P Freundt, E Welsh, S Baehrecke, EH Lenardo, MJ TI Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8 SO SCIENCE LA English DT Article ID DOMAIN KINASE RIP; INDUCED APOPTOSIS; NECROSIS; PROTEIN; MECHANISMS; BECLIN-1; TUMORIGENESIS; DEGRADATION; APG7P/CVT2P; INHIBITION AB Caspases play a central role in apoptosis, a well-studied pathway of programmed cell death. Other programs of death potentially involving necrosis and autophagy may exist, but their relation to apoptosis and mechanisms of regulation remains unclear. We de. ne a new molecular pathway in which activation of the receptor-interacting protein (a serine-threonine kinase) and Jun amino-terminal kinase induced cell death with the morphology of autophagy. Autophagic death required the genes ATG7 and beclin 1 and was induced by caspase-8 inhibition. Clinical therapies involving caspase inhibitors may arrest apoptosis but also have the unanticipated effect of promoting autophagic cell death. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. Univ Maryland, Inst Biotechnol, Ctr Biosyst Res, College Pk, MD 20742 USA. Univ Oxford, Weatherall Inst Mol Med, Oxford OX39D, England. RP Lenardo, MJ (reprint author), NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. EM lenardo@nih.gov RI Su, Helen/H-9541-2015 OI Su, Helen/0000-0002-5582-9110 FU NIGMS NIH HHS [GM59136] NR 28 TC 845 Z9 889 U1 8 U2 56 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 4 PY 2004 VL 304 IS 5676 BP 1500 EP 1502 DI 10.1126/science.1096645 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825YR UT WOS:000221795800044 PM 15131264 ER PT J AU Hildesheim, J Fornace, AJ AF Hildesheim, J Fornace, AJ TI The dark side of light: the damaging effects of UV rays and the protective efforts of MAP kinase signaling in the epidermis SO DNA REPAIR LA English DT Review DE keratinocyte; UV radiation; MAPK; oncogene; tumor suppressor ID ACTIVATED PROTEIN-KINASE; TUMOR-NECROSIS-FACTOR; SQUAMOUS-CELL CARCINOMAS; NONMELANOMA SKIN-CANCER; CYCLOBUTANE PYRIMIDINE DIMERS; RADIATION-INDUCED APOPTOSIS; CYCLIN-DEPENDENT KINASES; FAS-LIGAND EXPRESSION; GLOBAL GENOMIC REPAIR; B-INDUCED APOPTOSIS C1 NCI, Canc Res Ctr, Gene Response Sect, NIH, Bethesda, MD 20892 USA. RP Hildesheim, J (reprint author), NCI, Canc Res Ctr, Gene Response Sect, NIH, Bldg 37,Room 6144,37 Convent Dr, Bethesda, MD 20892 USA. EM jh30h@nih.gov RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X NR 189 TC 19 Z9 19 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD JUN 3 PY 2004 VL 3 IS 6 BP 567 EP 580 DI 10.1016/j.dnarep.2004.02.012 PG 14 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 824NV UT WOS:000221694200001 PM 15135725 ER PT J AU Cistulli, C Lavrik, OI Prasad, R Hou, E Wilson, SH AF Cistulli, C Lavrik, OI Prasad, R Hou, E Wilson, SH TI AP endonuclease and poly(ADP-ribose) polymerase-1 interact with the same base excision repair intermediate SO DNA REPAIR LA English DT Article DE base excision repair; AP endonuclease; poly(ADP-ribose) polymerase-1; FEN1 ID HUMAN APURINIC/APYRIMIDINIC ENDONUCLEASE; HUMAN APURINIC ENDONUCLEASE; CELL NUCLEAR ANTIGEN; DNA-REPAIR; EXONUCLEASE ACTIVITY; ALTERED EXPRESSION; MAMMALIAN-CELLS; BOVINE TESTIS; BETA; DAMAGE AB Base excision repair (BER) is a defense system that protects cells from deleterious effects secondary to modified or missing DNA bases. BER is known to involve apurinic/apyrimidinic endonuclease (APE) and DNA polymerase B (B-pol) among other enzymes, and recent studies have suggested that poly(ADP-ribose) polymerase- 1 (PARP-1) also plays a role by virtue of its binding to BER intermediates. The main role of APE is cleavage of the DNA backbone at abasic sites, and the enzyme also can catalyze 3'- to 5'-exonuclease activity at the cleaved abasic site. Photocross-linking studies with mouse embryonic fibroblast (MEF) cell extracts described here indicated that APE and PARP- 1 interact with the same APE-cleaved abasic site BER intermediate. The model BER intermediate used includes a synthetic abasic site sugar, i.e. tetrahydrofuran (THF), in place of the natural deoxyribose. APE cross-linked efficiently with this intermediate, but not with a molecule lacking the 5'-THF phosphate group, and the same property was demonstrated for PARP- 1. The addition of purified APE to the MEF extract reduced the amount of PARP- I cross-linked to the BER intermediate, suggesting that APE can compete with PARP- 1. APE and PARP- 1 were antagonists of each other in in vitro BER related reactions on this model BER intermediate. These results suggest that PARP- I and APE can interact with the same BER intermediate and that competition between these two proteins may influence their respective BER related functions. (C) 2004 Elsevier B.V. All rights reserved. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. Russian Acad Sci, Siberian Div, Novosibirsk Bioorgan Chem Inst, Novosibirsk 630090, Russia. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, 11 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov RI Lavrik, Olga /G-4641-2013 NR 48 TC 56 Z9 60 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD JUN 3 PY 2004 VL 3 IS 6 BP 581 EP 591 DI 10.1016/j.dnarep.2003.09.012 PG 11 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 824NV UT WOS:000221694200002 PM 15135726 ER PT J AU Liu, CY Pouliot, JJ Nash, HA AF Liu, CY Pouliot, JJ Nash, HA TI The role of TDP1 from budding yeast in the repair of DNA damage SO DNA REPAIR LA English DT Article DE topoisomerase 1; phosphoglycolate; tyrosyl-DNA phosphodiesterase; camptothecin; bleomycin; spontaneous mutagenesis ID I COVALENT COMPLEXES; BASE EXCISION-REPAIR; TOPOISOMERASE-I; SACCHAROMYCES-CEREVISIAE; PHOSPHODIESTERASE TDP1; CRYSTAL-STRUCTURE; GENE; PATHWAYS; LESIONS; PROTEIN AB The TDP1 gene encodes a protein that can hydrolyze certain types of 3-terminal phosphodiesters, but the relevance of these catalytic activities to gene function has not been previously tested. In this work we engineered a point mutation in TDP1 and present evidence that, as per design, it severely diminishes tyrosyl-DNA phosphodiesterase enzyme activity without affecting protein folding. The phenotypes of yeast strains that express this mutant show that the contribution of TDP1 to the repair of two kinds of damaged termini-induced, respectively, by camptothecin (CPT) and by bleomycin-strongly depends on enzyme activity. In routine assays of cell survival and growth the contribution of this activity is often overshadowed by other repair pathways. However, the value of TDP1 in the economy of the cell is highlighted by our discovery of several phenotypes that are evident even without deliberate inactivation of parallel pathways. These non-redundant mutant phenotypes include increased spontaneous mutation rate, transient accumulation of cells in a mid-anaphase checkpoint after exposure to camptothecin and. in cells that overexpress topoisomerase 1 (Top1), decreased survival of camptothecin -induced damage. The relationship between the role of TDP1 in Saccharomyces and its role in metazoans is discussed. (C) 2004 Elsevier B.V. All rights reserved. C1 NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. RP NIMH, Mol Biol Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM howardnash@mail.nih.gov NR 38 TC 32 Z9 32 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD JUN 3 PY 2004 VL 3 IS 6 BP 593 EP 601 DI 10.1016/j.dnarep.2004.03.030 PG 9 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 824NV UT WOS:000221694200003 PM 15135727 ER PT J AU Duan, DH Lewin, NE Sigano, DM Blumberg, PM Marquez, VE AF Duan, DH Lewin, NE Sigano, DM Blumberg, PM Marquez, VE TI Conformationally constrained analogues of diacylglycerol. 21. A solid-phase method of synthesis of diacylglycerol lactones as a prelude to a combinatorial approach for the synthesis of protein kinase C isozyme-specific ligands SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PHORBOL ESTER RECEPTORS; BINDING-AFFINITY; ASSAY; DAG AB A solid-phase method for the synthesis of diacylglycerol lactones as protein kinase C ligands was developed, and a small array of nine compounds were selected with the idea of testing this methodology and forecasting the reliability of the biological data as a preamble for the construction of large chemical libraries to be synthesized under the same conditions. The process started with the loading of 5-(hydroxymethyl)-5-[(4-methoxyphenoxy)methyl]-3,4,5-trihydrofuran-2-one (1) to a 3,4-dihydro-2H-pyran resin packed inside IRORI MacroKan reactors. The elements of diversity were introduced at the alpha-alkylidene (R-1) and acyl (R-2) positions using a set of three different aldehydes and three different acid chlorides, respectively. An LDA-mediated aldol condensation with (RCHO)-C-1 in the presence of ZnCl2 followed by a DBU-catalyzed elimination of the triflate of the resulting aldol gave the alpha-alkylidene intermediates as mixtures of geometric isomers. Removal of the aryl-protecting group followed by acylation with (RCOCl)-C-2 introduced the second element of diversity. Acid-assisted cleavage of the compounds from the resin afforded the final targets. The biological results obtained using the crude samples directly obtained from the resin compared well with those from pure materials, as the K-i values between the two sets varied only by a factor between 1.5 and 3.7. C1 NCI, Med Chem Lab, Canc Res Ctr, NIH, Frederick, MD 21702 USA. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Marquez, VE (reprint author), NCI, Med Chem Lab, Canc Res Ctr, NIH, Frederick, MD 21702 USA. EM marquezv@dc37a.nci.nih.gov RI Sigano, Dina/M-6144-2014 OI Sigano, Dina/0000-0001-7489-9555 NR 18 TC 13 Z9 13 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 3 PY 2004 VL 47 IS 12 BP 3248 EP 3254 DI 10.1021/jm030610k PG 7 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 825FH UT WOS:000221740900030 PM 15163204 ER PT J AU Bazykin, GA Kondrashov, FA Ogurtsov, AY Sunyaev, S Kondrashov, AS AF Bazykin, GA Kondrashov, FA Ogurtsov, AY Sunyaev, S Kondrashov, AS TI Positive selection at sites of multiple amino acid replacements since rat-mouse divergence SO NATURE LA English DT Article ID PROTEIN EVOLUTION; MAXIMUM-LIKELIHOOD; GENOME; NUCLEOTIDE; DROSOPHILA; SEQUENCE; HUMANS; GENES; MODEL AB New alleles become fixed owing to random drift of nearly neutral mutations or to positive selection of substantially advantageous mutations(1-3). After decades of debate, the fraction of fixations driven by selection remains uncertain(4-9). Within 9,390 genes, we analysed 28,196 codons at which rat and mouse differ from each other at two nucleotide sites and 1,982 codons with three differences. At codons where rat-mouse divergence involved two non-synonymous substitutions, both of them occurred in the same lineage, either rat or mouse, in 64% of cases; however, independent substitutions would occur in the same lineage with a probability of only 50%. All three non-synonymous substitutions occurred in the same lineage for 46% of codons, instead of the 25% expected. Furthermore, comparison of 12 pairs of prokaryotic genomes also shows clumping of multiple nonsynonymous substitutions in the same lineage. This pattern cannot be explained by correlated mutation or episodes of relaxed negative selection, but instead indicates that positive selection acts at many sites of rapid, successive amino acid replacement. C1 Princeton Univ, Dept Ecol & Evolut Biol, Princeton, NJ 08544 USA. Univ Calif Davis, Sect Evolut & Ecol, Davis, CA 95616 USA. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Div Genet, Boston, MA 02115 USA. RP Bazykin, GA (reprint author), Princeton Univ, Dept Ecol & Evolut Biol, Princeton, NJ 08544 USA. EM gbazykin@princeton.edu RI Bazykin, Georgii/E-4601-2012; Kondrashov, Fyodor Alexeevich/H-6331-2015 OI Bazykin, Georgii/0000-0003-2334-2751; Kondrashov, Fyodor Alexeevich/0000-0001-8243-4694 NR 25 TC 47 Z9 48 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 3 PY 2004 VL 429 IS 6991 BP 558 EP 562 DI 10.1038/nature02601 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825OL UT WOS:000221767700039 PM 15175752 ER PT J AU Morfini, G Szebenyi, G Brown, H Pant, HC Pigino, G DeBoer, S Beffert, U Brady, ST AF Morfini, G Szebenyi, G Brown, H Pant, HC Pigino, G DeBoer, S Beffert, U Brady, ST TI A novel CDK5-dependent pathway for regulating GSK3 activity and kinesin-driven motility in neurons SO EMBO JOURNAL LA English DT Article DE axonal transport; CDK5; GSK-3; kinesin; protein phosphatase PP1 ID CYCLIN-DEPENDENT KINASE-5; GLYCOGEN-SYNTHASE KINASE-3; FAST AXONAL-TRANSPORT; ANCHORING PROTEIN AKAP220; LIGHT-CHAINS; CDC2-LIKE KINASE; TRANSGENIC MICE; ALZHEIMERS-DISEASE; MAMMALIAN-CELLS; SQUID AXOPLASM AB Neuronal transmission of information requires polarized distribution of membrane proteins within axonal compartments. Membrane proteins are synthesized and packaged in membrane-bounded organelles (MBOs) in neuronal cell bodies and later transported to axons by microtubule-dependent motor proteins. Molecular mechanisms underlying targeted delivery of MBOs to discrete axonal subdomains (i.e. nodes of Ranvier or presynaptic terminals) are poorly understood, but regulatory pathways for microtubule motors may be an essential step. In this work, pharmacological, biochemical and in vivo experiments define a novel regulatory pathway for kinesin-driven motility in axons. This pathway involves enzymatic activities of cyclin-dependent kinase 5 (CDK5), protein phosphatase 1 (PP1) and glycogen synthase kinase-3 (GSK3). Inhibition of CDK5 activity in axons leads to activation of GSK3 by PP1, phosphorylation of kinesin light chains by GSK3 and detachment of kinesin from transported cargoes. We propose that regulating the activity and localization of components in this pathway allows nerve cells to target organelle delivery to specific subcellular compartments. Implications of these findings for pathogenesis of neurodegenerative diseases such as Alzheimer's disease are discussed. C1 Univ Illinois, Dept Anat & Cell Biol, Chicago, IL 60612 USA. Marine Biol Lab, Woods Hole, MA 02543 USA. UT SW, Dept Cell Biol, Dallas, TX USA. UT SW, Ctr Basic Neurosci, Dallas, TX USA. NINDS, Neurochem Lab, Bethesda, MD 20892 USA. UT SW, Dept Mol Genet, Dallas, TX USA. RP Univ Illinois, Dept Anat & Cell Biol, M-C 512,808 S Wood St, Chicago, IL 60612 USA. EM stbrady@uic.edu FU NINDS NIH HHS [R01 NS043408, NS23320, NS23868, NS41170, NS43408, R01 NS023320, R01 NS023868, R01 NS041170, R56 NS023868] NR 78 TC 169 Z9 178 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD JUN 2 PY 2004 VL 23 IS 11 BP 2235 EP 2245 DI 10.1038/sj.emboj.7600237 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 833JK UT WOS:000222333400006 PM 15152189 ER PT J AU Yach, D Hawkes, C Gould, CL Hofman, KJ AF Yach, D Hawkes, C Gould, CL Hofman, KJ TI The global burden of chronic diseases - Overcoming impediments to prevention and control SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HEALTH; CHALLENGES; SOUTH; SMOKING; DEATHS AB Chronic diseases are the largest cause of death in the world. In 2002, the leading chronic diseases-cardiovascular disease, cancer, chronic respiratory disease, and diabetes-caused 29 million deaths worldwide. Despite growing evidence of epidemiological and economic impact, the global response to the problem remains inadequate. Stakeholders include governments, the World Health Organization and other United Nations bodies, academic and research groups, nongovernmental organizations, and the private sector. Lack of financial support retards capacity development for prevention, treatment, and research in most developing countries. Reasons for this include that up-to-date evidence related to the nature of the burden of chronic diseases is not in the hands of decision makers and strong beliefs persist that chronic diseases afflict only the affluent and the elderly, that they arise solely from freely acquired risks, and that their control is ineffective and too expensive and should wait until infectious diseases are addressed. The influence of global economic factors on chronic disease risks impedes progress, as does the orientation of health systems toward acute care. We identify 3 policy levers to address these impediments: elevating chronic diseases on the health agenda of key policymakers, providing them with better evidence about risk factor control, and persuading them of the need for health systems change. A more concerted, strategic, and multisectoral policy approach, underpinned by solid research, is essential to help reverse the negative trends in the global incidence of chronic disease. C1 WHO, CH-1211 Geneva 27, Switzerland. US Natl Inst Hlth, Fogarty Int Ctr, Washington, DC USA. RP Yach, D (reprint author), WHO, 20 Ave Appia, CH-1211 Geneva 27, Switzerland. EM yachd@who.int RI Stockwell, Tim/B-6662-2012 NR 68 TC 563 Z9 593 U1 1 U2 44 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 2 PY 2004 VL 291 IS 21 BP 2616 EP 2622 DI 10.1001/jama.291.21.2616 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 825EM UT WOS:000221738800025 PM 15173153 ER PT J AU Beggs, JM Plenz, D AF Beggs, JM Plenz, D TI Neuronal avalanches are diverse and precise activity patterns that are stable for many hours in cortical slice cultures SO JOURNAL OF NEUROSCIENCE LA English DT Article DE activity pattern; avalanche; information storage; memory; cortical network; organotypic culture; spontaneous activity; multi-electrode array ID CORTEX-STRIATUM COCULTURES; NEURAL-NETWORKS; EPILEPTIFORM DISCHARGES; SYNCHRONIZED ACTIVITY; NEOCORTICAL SLICE; VISUAL-CORTEX; PROPAGATION; DYNAMICS; GENERATION; MEMORY AB A major goal of neuroscience is to elucidate mechanisms of cortical information processing and storage. Previous work from our laboratory (Beggs and Plenz, 2003) revealed that propagation of local field potentials (LFPs) in cortical circuits could be described by the same equations that govern avalanches. Whereas modeling studies suggested that these "neuronal avalanches" were optimal for information transmission, it was not clear what role they could play in information storage. Work from numerous other laboratories has shown that cortical structures can generate reproducible spatiotemporal patterns of activity that could be used as a substrate for memory. Here, we show that although neuronal avalanches lasted only a few milliseconds, their spatiotemporal patterns were also stable and significantly repeatable even many hours later. To investigate these issues, we cultured coronal slices of rat cortex for 4 weeks on 60-channel microelectrode arrays and recorded spontaneous extracellular LFPs continuously for 10 hr. Using correlation-based clustering and a global contrast function, we found that each cortical culture spontaneously produced 4736 +/- 2769 (mean +/- SD) neuronal avalanches per hour that clustered into 30 +/- 14 statistically significant families of spatiotemporal patterns. In 10 hr of recording, over 98% of the mutual information shared by these avalanche patterns were retained. Additionally, jittering analysis revealed that the correlations between avalanches were temporally precise to within +/-4 msec. The long-term stability, diversity, and temporal precision of these avalanches indicate that they fulfill many of the requirements expected of a substrate for memory and suggest that they play a central role in both information transmission and storage within cortical networks. C1 NIMH, Unit Neural Network Physiol, Lab Syst Neurosci, Bethesda, MD 20892 USA. RP Plenz, D (reprint author), NIMH, Unit Neural Network Physiol, Lab Syst Neurosci, Bldg 36,Room 2D-26,9000 Rockville Pike, Bethesda, MD 20892 USA. EM plenzd@intra.nimh.nih.gov NR 60 TC 278 Z9 282 U1 3 U2 18 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 2 PY 2004 VL 24 IS 22 BP 5216 EP 5229 DI 10.1523/JNEUROSCI.0540-04.2004 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 827EY UT WOS:000221883100016 PM 15175392 ER PT J AU Arant, CB Wessel, TR Olson, MB Merz, CNB Sopko, G Rogers, WJ Sharaf, BL Reis, SE Smith, KM Johnson, BD Handberg, E Mankad, S Pepine, CJ AF Arant, CB Wessel, TR Olson, MB Merz, CNB Sopko, G Rogers, WJ Sharaf, BL Reis, SE Smith, KM Johnson, BD Handberg, E Mankad, S Pepine, CJ TI Hemoglobin level is an independent predictor for adverse cardiovascular outcomes in women undergoing evaluation for chest pain - Results from the national heart, lung, and blood institute women's ischemia syndrome evaluation study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID SYNDROME EVALUATION WISE; STAGE RENAL-DISEASE; ANEMIA; FAILURE; ATHEROSCLEROSIS; ERYTHROPOIETIN; MORTALITY AB OBJECTIVES This study was designed to investigate the relationship between hemoglobin level (Hgb) and adverse cardiovascular outcomes in women with suspected ischemia. BACKGROUND Low Hgb levels correlate with increased cardiovascular morbidity and mortality in patients presenting with acute myocardial infarction (MI) or congestive heart failure (CHF). However, the prognostic significance of Hgb in women with suspected ischemia is unclear. METHODS As part of the National Heart, Lung, and Blood Institute (NHLBI)-sponsored Women's Ischemia Syndrome Evaluation (WISE), we prospectively studied 936 women referred for coronary angiography to evaluate suspected ischemia. We compared Hgb levels with cardiovascular risk factors, core lab interpreted angiograms, inflammatory markers, and adverse cardiovascular outcomes. RESULTS Of women enrolled, 864 (mean age 58.4 +/- 11.6 years) had complete Hgb, angiogram, and follow-up (mean 3.3 +/- 1.7 years) data. The mean Hgb was 12.9 g/dl (range 7.7 to 16.4 g/dl) and 184 women (21%) were anemic (Hgb <12 g/dl). Anemic women had higher creatinine and were more likely to be nonwhite and have a history of diabetes, hypertension, and CHF (p < 0.05). However, we found no difference in EF or severity of coronary artery disease. Anemic women had a higher risk of death from any cause (10.3% vs. 5.4%; p = 0.02) and total adverse outcomes (26% vs. 16%, p < 0.01). In a multivariable model, decreasing Hgb was associated with significantly higher risk of adverse outcomes (hazard ratio = 1.20, p = 0.002). Also, anemic women had shorter survival time free of adverse outcome (p < 0.001). CONCLUSIONS Our findings extend previous reports, linking lower hemoglobin levels with higher risk for adverse cardiovascular outcomes, to women evaluated for suspected ischemia in the absence of acute MI or CHF. (C) 2004 by the American College of Cardiology Foundation. C1 Univ Florida, Coll Med, Div Cardiovasc Med, Gainesville, FL 32610 USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. Univ Pittsburgh, Med Ctr, Cardiovasc Inst, Pittsburgh, PA USA. Rhode Isl Hosp, Div Med, Dept Cardiol, Providence, RI USA. Univ Alabama, Div Cardiol, Birmingham, AL USA. Cedars Sinai Med Ctr, Div Cardiol, Dept Med, Cedars Sinai Res Inst, Los Angeles, CA 90048 USA. NHLBI, Div Heart & Vasc Dis, Natl Inst Hlth, Bethesda, MD USA. RP Pepine, CJ (reprint author), Univ Florida, Coll Med, Div Cardiovasc Med, POB 100277, Gainesville, FL 32610 USA. EM chrsarant@aol.com RI Reis, Steven/J-3957-2014 FU NHLBI NIH HHS [N01-HV-68162, N01-HV-68164, U01-HL64829-01, U01-HL65924-01, U01-HL64914-01, N01-HV-68163, N01-HV-68161] NR 20 TC 61 Z9 69 U1 0 U2 1 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 2 PY 2004 VL 43 IS 11 BP 2009 EP 2014 DI 10.1016/j.jacc.2004.01.038 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 824VR UT WOS:000221715800013 PM 15172405 ER PT J AU Elkin, M Orgel, A Kleinman, HK AF Elkin, M Orgel, A Kleinman, HK TI An angiogenic switch in breast cancer involves estrogen and soluble vascular endothelial growth factor receptor 1 SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID GENE-EXPRESSION; TUMOR-GROWTH; FACTOR VEGF; CELLS; FLT-1; TRANSCRIPTION; ANTIESTROGENS; COREGULATORS; KINASE; EGR-1 AB Estrogen is involved in breast tumorigenesis, but the precise mechanisms for its oncogenic and angiogenic actions are poorly understood. Angiogenesis is regulated, in part, by these critical components: vascular endothelial growth factor (VEGF) and its two receptors (VEGFR-1 and VEGFR-2). VEGFR-2 is a positive angiogenic signal transducer, whereas VEGFR-1, especially its soluble form (soluble VEGFR-1), is a negative regulator of VEGF availability. We found that breast epithelial cells express soluble VEGFR-1 and hypothesized that because estrogen can regulate expression of members of the VEGF family, it might stimulate angiogenesis in breast cancer by decreasing expression of soluble VEGFR-1. Soluble VEGFR-1 expression decreased in estrogen receptor (ER)-positive but not in ER-negative breast cancer cell lines treated with estrogen. Pretreatment of the cells with the ER antagonist ICI 182,780 blocked the effect. The estrogen-mediated decrease in soluble VEGFR-1 expression was accompanied by a statistically significant increase in angiogenesis in vivo. Our data suggest that inhibition of soluble VEGFR-1 expression represents a novel mechanism-an estrogen-driven angiogenic switch-possibly responsible for breast carcinoma progression. C1 Natl Inst Dent & Craniofacial Res, Cell Biol Sect, NIH, Bethesda, MD 20892 USA. RP Kleinman, HK (reprint author), Natl Inst Dent & Craniofacial Res, Cell Biol Sect, NIH, Bldg 30,Rm 433,30 Convent Dr MSC, Bethesda, MD 20892 USA. EM hkleinman@dir.nidcr.nih.gov NR 28 TC 40 Z9 40 U1 1 U2 1 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 2 PY 2004 VL 96 IS 11 BP 875 EP 878 DI 10.1093/jnci/djh140 PG 4 WC Oncology SC Oncology GA 824VO UT WOS:000221715500017 PM 15173272 ER PT J AU Solomon, J Mavinkurve, S Cox, D Summers, RM AF Solomon, J Mavinkurve, S Cox, D Summers, RM TI Computer-assisted detection of subcutaneous melanomas: Feasibility assessment SO ACADEMIC RADIOLOGY LA English DT Article DE image processing; melanomas; computer-assisted detection ID PROGNOSTIC-FACTORS; METASTASES AB Rationale and Objectives. Subcutaneous melanomas may be missed on computed tomography because of their peripheral location or perceived unimportance, yet they can have clinical significance. The use of a novel computer-assisted detection scheme to locate subcutaneous melanoma lesions in body CT images was investigated. Materials and Methods. The detection software segments subcutaneous fat from the rest of the body and searches for soft tissue density lesions that match a size and shape constraint. Sensitivity and specificity of the proposed method was analyzed by comparing automated lesion detection results in eight patients with 118 subcutaneous melanomas with ground truth data derived from manual tracings of a trained observer. Results. The sensitivity of subcutaneous melanoma detection was 86%. The false-positive rate was 3.1 per slice. Analysis of the false-positives showed that the most common cause was incorrect classification of muscle as a nodule. Conclusion. This study showed the feasibility of a fully automatic subcutaneous melanoma lesion detection system having good sensitivity. The false-positive rate was high, but avenues for further reduction were identified. C1 Sensor Syst Inc, Sterling, VA USA. Ctr Clin, Dept Diagnost Radiol, NIH, Bethesda, MD USA. NCI, Surg Oncol Branch, NIH, Bethesda, MD USA. RP Solomon, J (reprint author), 9000 Rockville Pike,Bldg 10,Rm B25231, Bethesda, MD 20892 USA. NR 9 TC 4 Z9 4 U1 0 U2 0 PU ASSOC UNIV RADIOLOGISTS PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523-2251 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD JUN PY 2004 VL 11 IS 6 BP 678 EP 685 DI 10.1016/j.acra.2004.01.005 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 823YX UT WOS:000221651500009 PM 15172370 ER PT J AU Pandit, SD Li, KCP AF Pandit, SD Li, KCP TI A primer on molecular biology for imagers: IV. Concepts and basic methods in molecular biology SO ACADEMIC RADIOLOGY LA English DT Article C1 Ctr Clin, Mol Imaging Lab, Dept Diagnost Radiol, NIH, Bethesda, MD 20892 USA. RP Pandit, SD (reprint author), Ctr Clin, Mol Imaging Lab, Dept Diagnost Radiol, NIH, 10-1N306,9000 Rockville Pike, Bethesda, MD 20892 USA. EM spandit@mail.cc.nih.gov NR 7 TC 5 Z9 5 U1 0 U2 1 PU ASSOC UNIV RADIOLOGISTS PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523-2251 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD JUN PY 2004 VL 11 IS 6 BP 686 EP 697 DI 10.1016/j.acra.2004.03.046 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 823YX UT WOS:000221651500010 PM 15172371 ER PT J AU Banumathi, S Zwart, PH Ramagopal, UA Dauter, M Dauter, Z AF Banumathi, S Zwart, PH Ramagopal, UA Dauter, M Dauter, Z TI Structural effects of radiation damage and its potential for phasing SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID X-RAY-DIFFRACTION; PROTEIN CRYSTALS; MACROMOLECULAR CRYSTALLOGRAPHY; SYNCHROTRON-RADIATION; REFINEMENT; RESOLUTION; CRYOCRYSTALLOGRAPHY AB A detailed analysis of radiation-damage-induced structural and intensity changes is presented on the model protein thaumatin. Changes in reflection intensities induced by irradiation display a parabolic character. The most pronounced structural changes observed were disulfide-bond breakage and associated main-chain and side-chain movements as well as decarboxylation of aspartate and glutamate residues. The structural changes induced on the sulfur atoms were successfully used to obtain high-quality phase estimates via an RIP procedure. Results obtained with ACORN suggest that the contribution originating from the partial structure may play an important role in phasing even at less than atomic resolution. C1 Brookhaven Natl Lab, Natl Canc Inst, MCL, Synchrotron Radiat Res Sect, Upton, NY 11973 USA. Brookhaven Natl Lab, SAIC frederick Inc, Basic Res Program, Upton, NY 11973 USA. RP Dauter, Z (reprint author), Brookhaven Natl Lab, Natl Canc Inst, MCL, Synchrotron Radiat Res Sect, Upton, NY 11973 USA. EM dauter@bnl.gov FU NCI NIH HHS [N01-CO-12400] NR 40 TC 50 Z9 50 U1 0 U2 5 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD JUN PY 2004 VL 60 BP 1085 EP 1093 DI 10.1107/S0907444904007917 PN 6 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 822WZ UT WOS:000221572600012 PM 15159568 ER PT J AU Prahl, A Pazgier, M Hejazi, M Lockau, W Lubkowski, J AF Prahl, A Pazgier, M Hejazi, M Lockau, W Lubkowski, J TI Structure of the isoaspartyl peptidase with L-asparaginase activity from Escherichia coli SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID N-TERMINAL NUCLEOPHILE; LUPINUS-ARBOREUS; DEVELOPING SEEDS; PROTEINS AB The crystal structure of the Escherichia coli enzyme (EcAIII) with isoaspartyl dipeptidase and L-asparaginase activity has been solved and refined to a resolution of 1.65 Angstrom, with crystallographic R-factor and R-free values of 0.178 and 0.209, respectively. EcAIII belongs to the family of N-terminal hydrolases. The amino-acid sequence of EcAIII is homologous to those of putative asparaginases from plants. The structure of EcAIII is similar to the structures of glycosylasparaginases. The mature and catalytically active form of EcAIII is a heterotetramer consisting of two alpha-subunits and two beta-subunits. Both of the equivalent active sites present in the EcAIII tetramer is assisted by a metal-binding site. The metal cations, modelled here as Na+, have not previously been observed in glycosylasparaginases. This reported structure helps to explain the inability of EcAIII and other plant-type asparaginases to hydrolyze N-4-(beta-N-acetylglucosaminyl)-L-asparagine, the substrate of glycosylasparaginases. C1 NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. Humboldt Univ, Inst Biol, D-10115 Berlin, Germany. RP Lubkowski, J (reprint author), NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM jacek@ncifcrf.gov RI Pazgier, Marzena/B-7295-2012; Prahl, Adam/H-7654-2014 NR 24 TC 13 Z9 14 U1 1 U2 4 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD JUN PY 2004 VL 60 BP 1173 EP 1176 DI 10.1107/S0907444904003403 PN 6 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 822WZ UT WOS:000221572600036 PM 15159592 ER PT J AU Weitzman, S Wang, C Rosamond, WD Chambless, LE Cooper, LS Shahar, E Goff, DC AF Weitzman, S Wang, C Rosamond, WD Chambless, LE Cooper, LS Shahar, E Goff, DC TI Is diabetes an independent risk factor for mortality after myocardial infarction? The ARIC (Atherosclerosis Risk in Communities) Surveillance Study SO ACTA DIABETOLOGICA LA English DT Article DE diabetes mortality; myocardial infarction; case-fatality; racial differences; gender differences ID CORONARY-HEART-DISEASE; ETHNIC-DIFFERENCES; NATIONAL-HEALTH; US ADULTS; MELLITUS; SURVIVAL; IMPACT; PREVALENCE; SMOKING AB We investigated the age-, gender- and race-specific 1-year case fatality rates of diabetic and non-diabetic individuals with a myocardial infarction. Data were obtained from the Atherosclerosis Risk in Communities (ARIC) Surveillance Study, which monitors both hospitalized myocardial infarction and coronary heart disease (CHD) deaths in residents aged 35-74 years in four communities in the USA. The study population comprised 3242 hospitalized myocardial infarctions (HMIs) in diabetic subjects and 9826 HMIs in non-diabetic individuals between 1987 and 1997. Age-adjusted and gender- and race-specific odds ratios (OR) for 1-year case fatality comparing diabetic to non-diabetic patients were 2.0 (95% CI, 1.6-2.4) for white men and 1.4 (95% CI, 1.1-1.8) for white women. Further adjustment for severity of HMI, history of previous MI, stroke and hypertension, and therapy variables showed significantly higher case fatality in white diabetic men than in non-diabetic white men (OR=1.5; 95% CI, 1.2-1.9), but no significant association in the other race-gender groups. The age-adjusted odds of out of hospital death was significantly higher among white diabetic men (OR=1.7; 95% CI, 1.2-2.3), white women (OR=2.3; 95% CI, 1.4-3.8), and African-American women (OR=2.9; 95% CI, 1.5-5.9) as compared to their non-diabetic counterparts. In conclusion, diabetes is an independent factor for mortality within one year following a myocardial infarction among white men, and following out-of hospital coronary death in white men and women and in African-American women. It is possible that these differences could be explained, at least in part, by a less than optimal medical management of the high cardiovascular risk profile of these patients after hospital discharge. C1 Ben Gurion Univ Negev, Fac Hlth Sci, Dept Epidemiol, IL-84105 Beer Sheva, Israel. Univ N Carolina, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. Wake Forest Sch Med, Dept Publ Hlth Sci, Winston Salem, NC USA. RP Weitzman, S (reprint author), Ben Gurion Univ Negev, Fac Hlth Sci, Dept Epidemiol, POB 653, IL-84105 Beer Sheva, Israel. EM weitzman@bgumail.bgu.ac.il FU NHLBI NIH HHS [N01-HC-55016, N01-HC-55018, N01-HC-55020, N01-HC-55021, N01-HC-55019, N01-HC-55022, N01-HC-55015, N01-HC-55017] NR 25 TC 10 Z9 12 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0940-5429 J9 ACTA DIABETOL JI Acta Diabetol. PD JUN PY 2004 VL 41 IS 2 BP 77 EP 83 DI 10.1007/s00592-004-0148-9 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 833QP UT WOS:000222353600008 PM 15224209 ER PT J AU Shao, RG Cao, CX Pommier, Y AF Shao, RG Cao, CX Pommier, Y TI Abrogation of Chk1-mediated S/G2 checkpoint by UCN-01 enhances ara-C-induced cytotoxicity in human colon cancer cells SO ACTA PHARMACOLOGICA SINICA LA English DT Article DE 7-hydroxystaurosporine; chk1 protein kinase; DNA repair; cell cycle ID PROTEIN-KINASE-C; S-PHASE CHECKPOINT; DNA-DAMAGE; 7-HYDROXYSTAUROSPORINE UCN-01; SELECTIVE INHIBITOR; ANTITUMOR-ACTIVITY; CHK1; P53; PATHWAY; CDC25C AB AIM: To investigate whether 7-hydroxystaurosporine (UCN-01) affects cell cycle progression in arabinosylcytosine (ara-C) treated human colon carcinoma HT-29 cells. METHODS: Cytotoxicity, DNA synthesis, cell cycle distribution, protein level, and kinase activity were determined by clonogenic assay, flow cytometry, DNA synthesis assay, immunoblotting, and kinase assays, respectively. RESULTS: UCN-01 abrogated an S/G2-phase checkpoint in HT-29 cells treated with ara-C. When UCN-01 was added after treatment with ara-C, the rate of recovery of DNA synthesis was enhanced and colony-forming ability diminished. Thus, premature recovery of DNA synthesis was associated with increased cytotoxicity. Measurements of cyclin A and B protein levels, Cdk2 and Cdc2 kinase activities, Cdc25C phosphorylation, and Chk1 kinase activity were consistent with UCN-01-induced abrogation of the S/G2-phase checkpoint in ara-C treated cells. CONCLUSION: The abrogation of the S/G2 checkpoint may be due to inhibition of Chk1 kinase by UCN-01. The enhanced cytotoxicity produced when UCN-01 was combined with ara-C suggested a rationale for the use of this drug combination for tumors that might be susceptible to cell cycle checkpoint abrogation. C1 Chinese Acad Med Sci, Peking Union Med Coll, Inst Med Biotechnol, Beijing 100050, Peoples R China. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Shao, RG (reprint author), Chinese Acad Med Sci, Peking Union Med Coll, Inst Med Biotechnol, Beijing 100050, Peoples R China. EM shaor@public3.bta.net.cn NR 24 TC 26 Z9 33 U1 0 U2 0 PU SHANGHAI INST MATERIA MEDICA PI SHANGHAI PA 555 ZU CHONG ZHI RD, ZHANG JIANG HI-TECH PARK, SHANGHAI, PUDONG 201203, PEOPLES R CHINA SN 1671-4083 J9 ACTA PHARMACOL SIN JI Acta Pharmacol. Sin. PD JUN PY 2004 VL 25 IS 6 BP 756 EP 762 PG 7 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 826MT UT WOS:000221833900009 PM 15169628 ER PT J AU Willinger, M AF Willinger, M TI Commentary on 'Increased sibling mortality in children with fetal alcohol syndrome' by L. Burd et al. SO ADDICTION BIOLOGY LA English DT Editorial Material ID INFANT-DEATH-SYNDROME; RISK-FACTORS C1 NICHHD, Pregancy & Perinatol Branch, Ctr Res Mothers & Children, NIH, Bethesda, MD 20892 USA. RP Willinger, M (reprint author), NICHHD, Pregancy & Perinatol Branch, Ctr Res Mothers & Children, NIH, 6100 Execut Blvd,Bldg 6100,Room 4B03, Bethesda, MD 20892 USA. EM willingm@mail.nih.gov NR 6 TC 1 Z9 1 U1 0 U2 0 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 2004 VL 9 IS 2 BP 187 EP 188 DI 10.1080/13556210410001717097 PG 2 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 831VP UT WOS:000222224800014 ER PT J AU Aung, AT Pickworth, WB Moolchan, ET AF Aung, AT Pickworth, WB Moolchan, ET TI History of marijuana use and tobacco smoking topography in tobacco-dependent adolescents SO ADDICTIVE BEHAVIORS LA English DT Article DE adolescent; smoking topography; tobacco; marijuana; African American ID CIGARETTE-SMOKING; CESSATION; ALCOHOL AB 7Adolescent tobacco smokers have higher rates of marijuana (MJ) use than nonsmokers. Because MJ smoking typically involves deeper inhalation and longer breathholding than tobacco smoking, we hypothesized greater puff volume, longer puff duration and puff interval, and higher puff velocity during tobacco smoking among (1) MJ-using teens; (2) teens whose onset of MJ smoking occurred before tobacco (MBT). One hundred and three tobacco-dependent adolescents presented for smoking cessation treatment (66.0% female, 71.0% European American, mean age 15.3 +/- 1.25 years) smoked one cigarette of their own brand in the laboratory prior to study entry. Topography and associated physiological measures among current recreational ( < 5 days in a 14-day period) MJ users (n = 25), current heavy ( greater than or equal to 5 days in a 14-day period) MJ users (n = 22) and current non-MJ-smoking teens (n = 56) were compared. There were no differences in tobacco smoking topography or physiological measures by recent MJ-smoking history or by order of substance initiation. Significantly more African American than European American adolescent smokers reported MJ use before tobacco. Our findings in adolescent smokers are consistent with results from adult studies in which history of MJ smoking was not associated with changes in tobacco smoking topography. (C) 2004 Elsevier Ltd. All rights reserved. C1 NIDA, Clin Pharmacol & Treatment Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Moolchan, ET (reprint author), NIDA, Clin Pharmacol & Treatment Res Branch, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM emoolcha@intra.nida.nih.gov NR 19 TC 22 Z9 22 U1 1 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 2004 VL 29 IS 4 BP 699 EP 706 DI 10.1016/j.addbeh.2004.02.012 PG 8 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 824IL UT WOS:000221679900005 PM 15135551 ER PT J AU Jones, DN Schroeder, JR Moolchan, ET AF Jones, DN Schroeder, JR Moolchan, ET TI Time spent with friends who smoke and quit attempts among teen smokers SO ADDICTIVE BEHAVIORS LA English DT Article DE adolescence; tobacco; smoking cessation; peer relations; social identity ID CIGARETTE-SMOKING; ADOLESCENTS; PREDICTORS; CESSATION; SELF AB Social interactions, as well as pharmacological effects, can reinforce smoking behavior. in adolescents and pose challenges to smoking cessation. We hypothesized that time spent with friends who smoke would be inversely related to both the number and duration of previous quit attempts for teens receiving smoking cessation treatment. Demographic- and smoking-related data were collected from 98 adolescent smokers enrolled in an accruing smoking cessation study (68% female, 70% Caucasian, mean age 15.3 years). Among smokers who had at least one quit attempt, time spent with friends who smoke was inversely associated with the number of prior quit attempts (chi(2)=9.55, P=.0085) but not with their duration, suggesting a potential relationship between an adolescent's affiliation with smoking peers, smoking identity, and fewer quit attempts. (C) 2004 Elsevier Ltd. All rights reserved. C1 NIDA, Teen Tobacco Addict Treatment Res Clin, IRP, NIH, Baltimore, MD 21224 USA. RP Moolchan, ET (reprint author), NIDA, Teen Tobacco Addict Treatment Res Clin, IRP, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM emoolcha@intra.nida.nih.gov RI Reis, Aline/G-9573-2012 NR 16 TC 10 Z9 12 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 2004 VL 29 IS 4 BP 723 EP 729 DI 10.1016/j.addbeh.2004.02.026 PG 7 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 824IL UT WOS:000221679900008 PM 15135554 ER PT J AU Warner, HR AF Warner, HR TI Head-to-head debate between Richard Miller and Paul Hasty/Jan Vijg. Aging Cell Vol. 3, Issue 2 (2004) SO AGING CELL LA English DT Editorial Material ID GENOME MAINTENANCE; MECHANISMS; REPAIR; MICE C1 NIA, Biol Aging Program, Bethesda, MD 20895 USA. RP Warner, HR (reprint author), NIA, Biol Aging Program, Bldg 31, Bethesda, MD 20895 USA. EM warnerh@gw.nia.nih.gov NR 13 TC 2 Z9 2 U1 0 U2 0 PU BLACKWELL PUBL LTD PI OXFORD PA 108 COWLEY RD, OXFORD OX4 1JF, OXON, ENGLAND SN 1474-9718 J9 AGING CELL JI Aging Cell PD JUN PY 2004 VL 3 IS 3 BP 141 EP 142 DI 10.1111/j.1474-9728.2004.00092.x PG 2 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 827CX UT WOS:000221877300007 PM 15153182 ER PT J AU Ferrucci, L Ble, A Bandinelli, S Lauretani, F Suthers, K Guralnik, JM AF Ferrucci, L Ble, A Bandinelli, S Lauretani, F Suthers, K Guralnik, JM TI A flame burning within SO AGING CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Editorial Material DE aging; cytokines; homeostasis; immunosenescence; inflammation; morbidity ID BODY-COMPOSITION; OLDER PERSONS; INFLAMMATION; DISEASES; INTERLEUKIN-6; RECEPTORS; FAILURE; HUMANS AB Inflammation is a human being's primary defense against threats to homeostasis that are encountered every day. Especially in old age, when regulatory mechanisms responsible for inflammatory responses may be ineffective or damaged, the result can be adverse pathological conditions, and an increased risk of morbidity and mortality. The inflammation response is a plastic network composed of redundant signaling among several different mediators. These mediators have a reciprocal relationship with other biological sub-systems, including hormone regulation, the autonomic nervous system, and oxidative/anti-oxidant balance. Studying this complex architecture requires parallel and multiple research strategies from epidemiological to biochemical level, from observational studies to innovative intervention approaches. Given that the inflammatory response is a critical age-related process, understanding its regulatory action is essential in avoiding hazardous consequences in old age. (C) 2004, Editrice Kurtis. C1 Harbor Hosp, ASTRA Unit, NIA, Clin Res Branch,Longitudinal Studies Sect, Baltimore, MD USA. NIA, Intramural Res Program, Baltimore, MD USA. INRCA Geriatr Dept, Lab Clin Epidemiol, Florence, Italy. RP Ferrucci, L (reprint author), Harbor Hosp, ASTRA Unit, NIA, Clin Res Branch,Longitudinal Studies Sect, 2001 S Hanover St, Baltimore, MD USA. EM ferruccilu@grc.nia.nih.gov RI Lauretani, Fulvio/K-5115-2016 OI Lauretani, Fulvio/0000-0002-5287-9972 NR 21 TC 35 Z9 35 U1 0 U2 1 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 2004 VL 16 IS 3 BP 240 EP 243 PG 4 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 852AE UT WOS:000223726800010 PM 15462468 ER PT J AU Wyatt, LS Earl, PL Liu, JY Smith, JM Montefiori, DC Robinson, HL Moss, B AF Wyatt, LS Earl, PL Liu, JY Smith, JM Montefiori, DC Robinson, HL Moss, B TI Multiprotein HIV type 1 clade B DNA and MVA vaccines: Construction, expression, and immunogenicity in rodents of the MVA component SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL INDUCTION; ENVELOPE GLYCOPROTEIN; GAG-POL; RHESUS-MONKEYS; HOST-RANGE; NEUTRALIZING ANTIBODIES; PROTECTIVE IMMUNITY; MUCOSAL CHALLENGE; CLINICAL-TRIAL AB Recombinant modified vaccinia virus Ankara (MVA) expressing SIV or SHIV Gag-Pol and Env, alone or in conjunction with a related DNA vaccine, effectively controls immunodeficiency virus infections in nonhuman primates. Here we describe the construction, characterization, and immunogenicity of MVA/HIV 48, a candidate HIV-1 clade B Gag-Pol-Env vaccine. A novel transfer vector was designed to allow the incorporation of HIV genes regulated by vaccinia virus promoters together with a reporter gene into a single site in the MVA genome and to automatically delete the reporter after the initial isolation of the recombinant MVA. MVA/HIV 48 contains chimeric HIV-1 HXB-2/BH10 gag-pol sequences, a deletion of integrase, inactivating point mutations in reverse transcriptase, and HIV-1 ADA env sequences with a truncation of most of the cytoplasmic domain to enhance expression on the plasma membrane. Cells infected with MVA/HIV 48 expressed HIV proteins, which were processed to the expected size. The Env was inserted into the plasma membrane and was functional in a CCR5 coreceptor-dependent cell fusion assay. Moreover, virus-like particles were released into the medium and budding particles containing Env were visualized by immunoelectron microscopy. Rodents that were immunized with MVA/HIV 48 produced antibodies, which neutralized a heterologous HIV-MN strain, and Gag-specific CD8 T cells. In the accompanying paper, we show that MVA/HIV 48 provided efficient boosting of an HIV DNA vaccine. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. Emory Univ, Vaccine Res Ctr, Atlanta, GA 30322 USA. Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, MSC 0445, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU NCRR NIH HHS [P51 RR00165]; NIAID NIH HHS [P01 AI 43045, P01 AI 49364]; NIDA NIH HHS [P30 DA 12121] NR 56 TC 26 Z9 27 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JUN PY 2004 VL 20 IS 6 BP 645 EP 653 DI 10.1089/0889222041217428 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 833OJ UT WOS:000222347000011 PM 15242542 ER PT J AU Smith, JM Amara, RR McClure, HM Patel, M Sharma, S Yi, H Chennareddi, L Herndon, JG Butera, ST Heneine, W Ellenberger, DL Parekh, B Earl, PL Wyatt, LS Moss, B Robinson, HL AF Smith, JM Amara, RR McClure, HM Patel, M Sharma, S Yi, H Chennareddi, L Herndon, JG Butera, ST Heneine, W Ellenberger, DL Parekh, B Earl, PL Wyatt, LS Moss, B Robinson, HL TI Multiprotein HIV type 1 clade B DNA/MVA vaccine: Construction, safety, and immunogenicity in macaques SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ANKARA BOOST REGIMEN; REVERSE-TRANSCRIPTASE; AIDS VACCINE; GAG-POL; ENVELOPE GLYCOPROTEIN; DISEASE PROGRESSION; MUTATIONAL ANALYSIS; MUCOSAL CHALLENGE; RHESUS MACAQUES AB Recently, a simian/human immunodeficiency virus (SHIV) vaccine consisting of priming with a Gag-Pol-Env-expressing DNA and boosting with a Gag-Pol-Env-expressing recombinant modified vaccinia Ankara (rMVA) has successfully controlled a virulent SHIV challenge in a macaque model. In this, and the accompanying paper, we report on the construction and testing of a Gag-Pol-Env DNA/MVA vaccine for HIV-1/AIDS. The DNA vaccine, pGA2/JS2, expresses aggregates of Gag proteins and includes safety mutations that render it integration, reverse transcription, and packaging defective. The rMVA vaccine, MVA/HIV 48, is integration and reverse transcription defective and has a truncated Env to enhance expression on the plasma membrane. In a study in rhesus macaques, priming with pGA2/JS2 and boosting with MVA/HIV 48 raised high frequencies of T cells for Gag and Env and lower frequencies of T cells for PR, RT, and Tat. Stimulations with five peptide pools for Gag and seven peptide pools for Env revealed epitopes for cellular immune responses throughout Gag and Env. On average, CD4 T cells from the vaccinated animals recognized 7.1 peptide pools and CD8 T cells, 3.2 peptide pools. Both the height and the breadth of the elicited cellular response provide hope that this multiprotein DNA/MVA vaccine will successfully control clade B isolates of HIV-1, as well as contribute to the control of other clades and recombinant forms of HIV-1/AIDS. C1 Emory Univ, Yerkes Natl Primate Ctr, Atlanta, GA 30329 USA. Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30329 USA. Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30329 USA. Emory Univ, Sch Med Electron Microscopy Core, Atlanta, GA 30329 USA. Ctr Dis Control & Prevent, HIV & Retrovirol Branch, Div AIDS STD & TB Dis, Natl Ctr HIV STD & TB Prevent, Atlanta, GA 30333 USA. Ctr Dis Control & Prevent, HIV Immunol & Diaignost Branch, Div AIDS STD & TB Dis, Natl Ctr HIV STD & TB Prevent, Atlanta, GA 30333 USA. NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Robinson, HL (reprint author), Emory Univ, Yerkes Natl Primate Ctr, 954 Gatewood Rd, Atlanta, GA 30329 USA. EM hrobins@rmy.emory.edu FU NCRR NIH HHS [P51 RR00165]; NIAID NIH HHS [P01 AI49364]; NIDA NIH HHS [P30 DA 12121] NR 45 TC 43 Z9 44 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JUN PY 2004 VL 20 IS 6 BP 654 EP 665 DI 10.1089/0889222041217419 PG 12 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 833OJ UT WOS:000222347000012 PM 15242543 ER PT J AU Gunzerath, L Faden, V Zakhari, S Warren, K AF Gunzerath, L Faden, V Zakhari, S Warren, K TI National Institute on Alcohol Abuse and Alcoholism report on moderate drinking SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Editorial Material DE moderate drinking; dietary guidelines ID CORONARY-HEART-DISEASE; BREAST-CANCER RISK; CHRONIC HEPATITIS-C; ALL-CAUSE MORTALITY; LIVER FIBROSIS PROGRESSION; TYPE-2 DIABETES-MELLITUS; POPULATION-BASED COHORT; AGE-RELATED MACULOPATHY; US MALE PHYSICIANS; BEAVER DAM EYE AB In support of the 2005 update of the U.S. Department of Agriculture/U.S. Department of Health and Human Services Dietary Guidelines, the National Institute on Alcohol Abuse and Alcoholism was asked to assess the strength of the evidence related to health risks and potential benefits of moderate alcohol consumption, with particular focus on the areas of cardiovascular disease, breast cancer, obesity, birth defects, breastfeeding, and aging. The findings were reviewed by external researchers with extensive research backgrounds on the consequences and benefits of alcohol consumption. This report now serves as the National Institutes of Health's formal position paper on the health risks and potential benefits of moderate alcohol use. C1 NIAAA, Strateg Res Planning Branch, Off Sci Affairs, NIH, Bethesda, MD 20892 USA. NIAAA, Div Metab & Hlth Effects, NIH, Bethesda, MD 20892 USA. NIAAA, Div Epidemiol & Prevent Res, NIH, Bethesda, MD 20892 USA. RP Gunzerath, L (reprint author), NIAAA, Strateg Res Planning Branch, Off Sci Affairs, NIH, 5635 Fishers Lane,Room 2013, Bethesda, MD 20892 USA. EM Lg72x@nih.gov NR 223 TC 134 Z9 140 U1 3 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2004 VL 28 IS 6 BP 829 EP 847 DI 10.1097/01.ALC.0000128382.79375.B6 PG 19 WC Substance Abuse SC Substance Abuse GA 830KY UT WOS:000222122100001 PM 15201626 ER PT J AU Flannery, BA Morgenstern, J McKay, J Wechsberg, WM Litten, RZ AF Flannery, BA Morgenstern, J McKay, J Wechsberg, WM Litten, RZ TI Co-occurring alcohol and cocaine dependence: Recent findings from clinical and field studies SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE alcohol; cocaine; dual dependence; clinical studies; field studies. ID DRUG-USE; DRINKING AB This article represents the proceedings of a symposium held at the 2003 annual meeting of the Research Society on Alcoholism in Ft. Lauderdale, FL. The organizer and chair was Barbara A. Flannery, and the discussant was Raye Z. Litten. The presentations were (1) Examining treatment trajectories of alcohol and cocaine dependent patients, by Jon Morgenstern; (2) Outcomes of alcoholics with and without cocaine dependence in a continuing care study, by James R. McKay; (3) Characteristics of non-treatment seeking cocaine and alcohol dependent African Americans, by Barbara A. Flannery; and (4) Cocaine and alcohol use among sex workers in South Africa, by Wendee M. Wechsberg. C1 RTI Int, Baltimore, MD 21224 USA. Mt Sinai Sch Med, New York, NY 10029 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. RTI Int, Res Triangle Pk, NC USA. NIAAA, Bethesda, MD USA. RP Flannery, BA (reprint author), RTI Int, 6801 Eastern Ave,Ste 203, Baltimore, MD 21224 USA. EM bflannery@rti.org NR 7 TC 17 Z9 17 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2004 VL 28 IS 6 BP 976 EP 981 DI 10.1097/01.ALC.0000128232.30331.65 PG 6 WC Substance Abuse SC Substance Abuse GA 830KY UT WOS:000222122100016 PM 15218883 ER PT J AU Morise, AP Olson, MB Merz, CNB Mankad, S Rogers, WJ Pepine, CJ Reis, SE Sharaf, BL Sopko, G Smith, K Pohost, GM Shaw, L AF Morise, AP Olson, MB Merz, CNB Mankad, S Rogers, WJ Pepine, CJ Reis, SE Sharaf, BL Sopko, G Smith, K Pohost, GM Shaw, L TI Validation of the accuracy of pretest and exercise test scores in women with a low prevalence of coronary disease: The NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE) study SO AMERICAN HEART JOURNAL LA English DT Article ID ASSOCIATION TASK-FORCE; ARTERY-DISEASE; PRACTICE GUIDELINES; AMERICAN-COLLEGE; MEN; ELECTROCARDIOGRAPHY AB Background Recently revised American College of Cardiology/American Heart Association guidelines have suggested that exercise test scores be used in decisions concerning patients with suspected coronary artery disease (CAD). Pretest and exercise test scores derived for use in women without known CAD have not been tested in women with a low prevalence of CAD. Methods Within the Women's Ischemia Syndrome Evaluation (WISE) study, we evaluated 563 women undergoing coronary angiography for suspected myocardial ischemia. The prevalence of angiographic CAD was 26%. Overall, 189 women underwent treadmill exercise testing. Prognostic end points included death, myocardial infarction, stroke, and revascularization. Results Each score stratified women into 3 probability groups (P < .001) according to the prevalence of coronary disease: Pretest: low 20/164 (12%), intermediate 53/245 (22%), high 75/154 (49%); Exercise test: low 11/83 (13%), intermediate 22/74 (30%), high 17/32 (53%). However, the Duke score did not stratify as well: low 7/46 (15%), intermediate 36/126 (29%), high 6/17 (35%); P = .44. When pretest and exercise scores were considered together, the best stratification with the exercise test score was in the intermediate pretest group (P < .03). The Duke score did not stratify this group at all (P = .98). Pretest and exercise test scores also stratified women according to prognostic end points: pretest-low 7/164 (4.3%), intermediate 28/245 (11.4%), high 27/154 (17.5%), P < .01; exercise test-low 4/83 (4.8%) and intermediate-high 17/106 (16%), P = .014. Conclusion Both pretest and exercise test scores performed better than the Duke score in stratifying women with a low prevalence of angiographic CAD. The exercise test score appears useful in women with an intermediate pretest score, consistent with American College of Cardiology/American Heart Association guidelines. C1 W Virginia Univ, Cardiol Sect, Dept Med, Morgantown, WV 26506 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. Cedars Sinai Med Ctr, Div Cardiol, Dept Med, Los Angeles, CA 90048 USA. Allegheny Gen Hosp, Div Cardiol, Dept Med, Pittsburgh, PA 15212 USA. Univ Alabama, Dept Med, Div Cardiol, Birmingham, AL 35294 USA. Univ Florida, Div Cardiovasc Med, Dept Med, Gainesville, FL USA. Univ Pittsburgh, Med Ctr, Div Cardiol, Dept Med, Pittsburgh, PA USA. Rhode Isl Hosp, Div Cardiol, Providence, RI USA. NHLBI, Div Heart & Vasc Dis, Baltimore, MD USA. Univ So Calif, Div Cardiovasc Med, Los Angeles, CA USA. Atlanta Cardiovasc Res Inst, Atlanta, GA USA. RP Morise, AP (reprint author), W Virginia Univ, Cardiol Sect, Dept Med, Rm 2203,HSC South, Morgantown, WV 26506 USA. EM amorise@pol.net RI Reis, Steven/J-3957-2014 FU NHLBI NIH HHS [N01-HV-68161, N01-HV-68162, U01-HL64924-01, N01-HV-68163, N01-HV-68164, U01-HL64914-01] NR 20 TC 13 Z9 16 U1 0 U2 0 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 2004 VL 147 IS 6 BP 1085 EP 1092 DI 10.1016/j.ahj.2003.12.034 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 832JE UT WOS:000222263000028 PM 15199360 ER PT J AU Levine, C Faclen, R Grady, C Hammerschmidt, D Eckenwiler, L Sugarman, J AF Levine, C Faclen, R Grady, C Hammerschmidt, D Eckenwiler, L Sugarman, J CA Consortium Examine Clinical Res Et TI The limitations of "vulnerability" as a protection for human research participants SO AMERICAN JOURNAL OF BIOETHICS LA English DT Article DE vulnerability; research ethics; decisional capacity; research involving children; research involving prisoners; international research ID CLINICAL-RESEARCH; ETHICS AB Vulnerability is one of the least examined concepts in research ethics. Vulnerability was linked in the Belmont Report to questions of justice in the selection of subjects. Regulations and policy documents regarding the ethical conduct of research have focused on vulnerability in terms of limitations of the capacity to provide informed consent. Other interpretations of vulnerability have emphasized unequal power relationships between politically and economically disadvantaged groups and investigators or sponsors. So many groups are now considered to be vulnerable in the context of research, particularly international research, that the concept has lost force. In addition, classifying groups as vulnerable not only stereotypes them, but also may not reliably protect many individuals from harm. Certain individuals require ongoing protections of the kind already established in law and regulation, but attention must also be focused on characteristics of the research protocol and environment that present ethical challenges. C1 United Hosp Fund, Clarksburg, WV 26301 USA. Johns Hopkins Univ, Baltimore, MD 21218 USA. Natl Inst Hlth, Bethesda, MD USA. Univ Minnesota, Minneapolis, MN 55455 USA. Old Dominion Univ, Norfolk, VA 23529 USA. RP Levine, C (reprint author), United Hosp Fund, Clarksburg, WV 26301 USA. NR 26 TC 116 Z9 120 U1 2 U2 16 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 1526-5161 J9 AM J BIOETHICS JI Am. J. Bioeth. PD SUM PY 2004 VL 4 IS 3 BP 44 EP 49 DI 10.1080/15265160490497083 PG 6 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 861SU UT WOS:000224439700017 PM 16192138 ER PT J AU Levine, C Faden, R Grady, C Hammerschmidt, D Eckenwiler, L Sugarman, J AF Levine, C Faden, R Grady, C Hammerschmidt, D Eckenwiler, L Sugarman, J TI A response to commentators on "the limitations of 'vulnerability' as a protection for human research participants" SO AMERICAN JOURNAL OF BIOETHICS LA English DT Letter C1 United Hosp Fund, New York, NY USA. Johns Hopkins Univ, Baltimore, MD USA. NIH, Baltimore, MD USA. Univ Minnesota, Minneapolis, MN USA. Old Dominion Univ, Norfolk, VA USA. RP Levine, C (reprint author), United Hosp Fund, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 1526-5161 J9 AM J BIOETHICS JI Am. J. Bioeth. PD SUM PY 2004 VL 4 IS 3 BP W32 EP W32 DI 10.1080/15265160490508954 PG 1 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 861SU UT WOS:000224439700056 ER PT J AU Kaplan, B Martin, BM Livneh, A Pras, M Gallo, GR AF Kaplan, B Martin, BM Livneh, A Pras, M Gallo, GR TI Biochemical subtyping of amyloid in formalin-fixed tissue samples confirms and supplements immunohistologic data SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE amyloidoses; immunoglobulin light chain; microextraction; immunochemistry; amino acid sequence ID IMMUNOGLOBULIN LIGHT-CHAIN; PARAFFIN-EMBEDDED TISSUES; CONSTANT-REGION; CHEMICAL-CHARACTERIZATION; ABDOMINAL FAT; PROTEINS; DEPOSITION; AL; IDENTIFICATION; TRANSTHYRETIN AB The systemic amyloidoses are a heterogeneous group of congophilic fibrillar protein deposition diseases that should be subtyped chemically by immunohistologic methods. Biochemical methods sometimes are required to confirm or identify the amyloid type in unfixed or in formalin-fixed tissue samples. We report the results of formic acid extraction and immunochemical and biochemical characterization of deposits in formalin-fixed tissue samples from 10 cases of amyloidosis and 3 from nonamyloid monoclonal immunoglobulin light chain deposition disease. The results in 11 of 13 cases demonstrated concordance with the previous immunohistochemical and/or biochemical data obtained in unfixed tissue samples from the same specimens, and in 2 of 13, the protein deposits that previously could not be classified by standard immunohistochemical methods were identified by amino acid sequence. An additional new finding of constant-region rather than variable-region fragments as the major constituent protein in 1 case of lambda light chain amyloidosis demonstrated the value of the method and its importance for future applications. C1 NYU, Sch Med, Med Ctr, Dept Pathol, New York, NY 10016 USA. Chaim Sheba Med Ctr, Heller Inst Med Res, Dept Med, IL-52621 Tel Hashomer, Israel. Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. NIMH, Bethesda, MD 20892 USA. RP Gallo, GR (reprint author), NYU, Sch Med, Med Ctr, Dept Pathol, 560 1St Ave, New York, NY 10016 USA. NR 31 TC 40 Z9 41 U1 0 U2 0 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD JUN PY 2004 VL 121 IS 6 BP 794 EP 800 DI 10.1309/Y6CYXF4ELL1GKQBU PG 7 WC Pathology SC Pathology GA 823YV UT WOS:000221651300003 PM 15198349 ER PT J AU Bonner, MR Xiong, W Bennett, WP Lan, Q Wright, ME Lubin, JH Field, RW Alavanja, MCR AF Bonner, MR Xiong, W Bennett, WP Lan, Q Wright, ME Lubin, JH Field, RW Alavanja, MCR TI Radon, glutathione-S-transferase M1 and lung cancer in US women. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 15-18, 2004 CL Salt Lake City, UT 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 2004 VL 159 IS 11 SU S BP S61 EP S61 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 826GH UT WOS:000221816800244 ER PT J AU Chen, A Gladen, BC Klebanoff, MA Rogan, WJ Longnecker, MP AF Chen, A Gladen, BC Klebanoff, MA Rogan, WJ Longnecker, MP TI Maternal smoking during pregnancy as a risk factor for overweight in offspring by age 8 years. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 15-18, 2004 CL Salt Lake City, UT SP Soc Epidemiol Res C1 NIEHS, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RI Rogan, Walter/I-6034-2012 OI Rogan, Walter/0000-0002-9302-0160 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 2004 VL 159 IS 11 SU S BP S34 EP S34 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 826GH UT WOS:000221816800134 ER PT J AU Dunson, DB AF Dunson, DB TI Bayesian isotonic regression in epidemiology. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 15-18, 2004 CL Salt Lake City, UT SP Soc Epidemiol Res C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 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 2004 VL 159 IS 11 SU S BP S71 EP S71 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 826GH UT WOS:000221816800283 ER PT J AU Engel, LS Hill, DA Hoppin, JA Lubin, JH Lynch, CF Pierce, J Samanic, C Sandler, DP Blair, A Alavanja, MC AF Engel, LS Hill, DA Hoppin, JA Lubin, JH Lynch, CF Pierce, J Samanic, C Sandler, DP Blair, A Alavanja, MC TI Pesticide use and breast cancer risk among farmers' wives in the agricultural health study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 15-18, 2004 CL Salt Lake City, UT SP Soc Epidemiol Res C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2004 VL 159 IS 11 SU S BP S35 EP S35 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 826GH UT WOS:000221816800141 ER PT J AU Herrell, R Febo, V Canino, G Merikangas, KR AF Herrell, R Febo, V Canino, G Merikangas, KR TI Risk behaviors for sexually transmitted infections in high-risk children of migrant and island Puerto Ricans. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 15-18, 2004 CL Salt Lake City, UT SP Soc Epidemiol Res C1 NIMH, Sect Dev Genet Epidemiol, 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 2004 VL 159 IS 11 SU S BP S4 EP S4 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 826GH UT WOS:000221816800017 ER PT J AU Jackson, LV Correa-Villasenor, A Stewart, A Lees, PSJ Breysse, PN Dominici, F Matanoski, G AF Jackson, LV Correa-Villasenor, A Stewart, A Lees, PSJ Breysse, PN Dominici, F Matanoski, G TI Differential effect of maternal proxy report of paternal work histories by exposure assessment method. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 15-18, 2004 CL Salt Lake City, UT SP Soc Epidemiol Res C1 NICHHD, 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 2004 VL 159 IS 11 SU S BP S77 EP S77 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 826GH UT WOS:000221816800307 ER PT J AU Jackson, LW Lees, PSJ Stewart, PA Correa-Villasenor, A Breysse, PN Dominici, F Matanoski, G AF Jackson, LW Lees, PSJ Stewart, PA Correa-Villasenor, A Breysse, PN Dominici, F Matanoski, G TI Retrospective assessment of occupational lead exposure in a community-based case-control study. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 15-18, 2004 CL Salt Lake City, UT SP Soc Epidemiol Res C1 NICHHD, 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 2004 VL 159 IS 11 SU S BP S77 EP S77 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 826GH UT WOS:000221816800305 ER PT J AU Leitzmann, F Gao, YT Rashid, A Wang, BS Deng, J Shen, MS Fraumeni, JF Hsing, AW AF Leitzmann, F Gao, YT Rashid, A Wang, BS Deng, J Shen, MS Fraumeni, JF Hsing, AW TI Physical activity in relation to risk of biliary tract cancer: A population-based study in Chinam. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 15-18, 2004 CL Salt Lake City, UT SP Soc Epidemiol Res C1 NCI, 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 2004 VL 159 IS 11 SU S BP S11 EP S11 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 826GH UT WOS:000221816800044 ER PT J AU Lim, U Stolzenberg-Solomon, R Katki, H Pietinen, P Taylor, P Virtamo, J Albanes, D AF Lim, U Stolzenberg-Solomon, R Katki, H Pietinen, P Taylor, P Virtamo, J Albanes, D TI Total and high-density lipoprotein cholesterol in relation to lymphoid cancers in male smokers: A prospective study. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 15-18, 2004 CL Salt Lake City, UT SP Soc Epidemiol Res C1 NCI, NIH, Rockville, MD 20852 USA. RI Katki, Hormuzd/B-4003-2015; Albanes, Demetrius/B-9749-2015 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 2004 VL 159 IS 11 SU S BP S12 EP S12 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 826GH UT WOS:000221816800049 ER PT J AU Paneth, N Bellinger, D Breslau, N Hoover, R Kramer, M Potischman, N Stein, A AF Paneth, N Bellinger, D Breslau, N Hoover, R Kramer, M Potischman, N Stein, A TI Life course epidemiology: Revisiting prenatal influences SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 15-18, 2004 CL Salt Lake City, UT SP Soc Epidemiol Res C1 Michigan State Univ, E Lansing, MI 48824 USA. Harvard Univ, Cambridge, MA 02138 USA. McGill Univ, Montreal, PQ H3A 2T5, Canada. NCI, Bethesda, MD 20892 USA. Emory Univ, Atlanta, GA 30322 USA. RI Breslau , Naomi/I-3196-2012 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 2004 VL 159 IS 11 SU S BP S30 EP S30 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 826GH UT WOS:000221816800121 ER PT J AU Perkins, NJ Schisterman, EF AF Perkins, NJ Schisterman, EF TI The Youden index and the corresponding optimal cut-point corrected for measurement error SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 15-18, 2004 CL Salt Lake City, UT SP Soc Epidemiol Res C1 NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 21201 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 2004 VL 159 IS 11 SU S BP S48 EP S48 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 826GH UT WOS:000221816800190 ER PT J AU Roberts, K Stolzenberg-Solomon, RZ Pietinen, P Taylor, P Virtamo, J Albanes, D AF Roberts, K Stolzenberg-Solomon, RZ Pietinen, P Taylor, P Virtamo, J Albanes, D TI A prospective study of anthropometric and clinical measurements associated with insulin resistance and colorectal cancer in male smokers. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 15-18, 2004 CL Salt Lake City, UT SP Soc Epidemiol Res C1 NCI, Natl Epidemiol Branch, Rockville, MD 20852 USA. RI Albanes, Demetrius/B-9749-2015 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 2004 VL 159 IS 11 SU S BP S13 EP S13 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 826GH UT WOS:000221816800053 ER PT J AU Samanic, C Chow, WH Gridley, G Fraumeni, JF Jarvholm, B AF Samanic, C Chow, WH Gridley, G Fraumeni, JF Jarvholm, B TI Body mass index and cancer risk in a cohort of Swedish construction workers. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 15-18, 2004 CL Salt Lake City, UT SP Soc Epidemiol Res C1 NCI, 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 2004 VL 159 IS 11 SU S BP S11 EP S11 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 826GH UT WOS:000221816800042 ER PT J AU Stolzenberg-Solomon, RZ Leitzman, M Chang, SS Johnson, K Johnson, C Buys, S Hoover, R Zeigler, R AF Stolzenberg-Solomon, RZ Leitzman, M Chang, SS Johnson, K Johnson, C Buys, S Hoover, R Zeigler, R TI Dietary folate intake, alcohol use and postmenopausal breast cancer risk in the Prostate, Lung, Colorectal, Ovarian (PLCO) Cancer Screening Trial SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 15-18, 2004 CL Salt Lake City, UT SP Soc Epidemiol Res C1 NCI, NEB, DCEG, NIH,DHHS, Rockville, MD 20854 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 2004 VL 159 IS 11 SU S BP S69 EP S69 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 826GH UT WOS:000221816800276 ER PT J AU Whitcomb, BW Schisterman, EF Hu, J AF Whitcomb, BW Schisterman, EF Hu, J TI Limit of detection bias and the correction of variance estimates SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract CT 37th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 15-18, 2004 CL Salt Lake City, UT SP Soc Epidemiol Res C1 NICHD, DESPR, 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 2004 VL 159 IS 11 SU S BP S51 EP S51 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 826GH UT WOS:000221816800202 ER PT J AU van der Walt, JM Noureddine, MA Kittappa, R Hauser, MA Scott, WK McKay, R Zhang, FY Stajich, JM Fujiwara, K Scott, BL Pericak-Vance, MA Vance, JM Martin, ER AF van der Walt, JM Noureddine, MA Kittappa, R Hauser, MA Scott, WK McKay, R Zhang, FY Stajich, JM Fujiwara, K Scott, BL Pericak-Vance, MA Vance, JM Martin, ER TI Fibroblast growth factor 20 polymorphisms and haplotypes strongly influence risk of Parkinson disease SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID MIDBRAIN DOPAMINERGIC-NEURONS; PEDIGREE DISEQUILIBRIUM TEST; FIBROBLAST-GROWTH-FACTOR; NEUROTROPHIC FACTOR; GENERAL PEDIGREES; LINKAGE; ASSOCIATION; FGF-20 AB The pathogenic process responsible for the loss of dopaminergic neurons within the substantia nigra of patients with Parkinson disease (PD) is poorly understood. Current research supports the involvement of fibroblast growth factor (FGF20) in the survival of dopaminergic cells. FGF20 is a neurotrophic factor that is preferentially expressed within the substantia nigra of rat brain. The human homologue has been mapped to 8p21.3-8p22, which is within an area of PD linkage revealed through our published genomic screen. To test whether FGF20 influences risk of PD, we genotyped five single-nucleotide polymorphisms (SNPs) lying within the FGF20 gene, in a large family study. We analyzed our sample (644 families) through use of the pedigree disequilibrium test (PDT), the genotype PDT, the multilocus-genotype PDT, and the family-based association test to assess association between risk of PD and alleles, genotypes, multilocus genotypes, and haplotypes. We discovered a highly significant association of PD with one intronic SNP, rs1989754 (P=.0006), and two SNPs, rs1721100 (P=.02) and ss20399075 (P=.0008), located in the 3' regulatory region in our overall sample. Furthermore, we detected a haplotype (A-G-C-C-T) that is positively associated with risk of PD (P=.0003), whereas a second haplotype (A-G-G-G-C) was found to be negatively associated with risk of PD (P=.0009). Our results strongly support FGF20 as a risk factor for PD. C1 Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Duke Univ, Med Ctr, Ctr Human Genet, Durham, NC 27710 USA. NINDS, NIH, Bethesda, MD 20892 USA. RP Martin, ER (reprint author), Duke Univ, Med Ctr, Dept Med, 595 LaSalle St,Box 3468, Durham, NC 27710 USA. EM eden.martin@duke.edu RI Scott, William/A-7593-2009 FU NIA NIH HHS [R01 AG020135]; NINDS NIH HHS [2 P50 NS39764-03, P01 NS026630, P01 NS26630, P50 NS039764] NR 23 TC 92 Z9 95 U1 1 U2 8 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 2004 VL 74 IS 6 BP 1121 EP 1127 DI 10.1086/421052 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 823ZB UT WOS:000221651900005 PM 15122513 ER PT J AU Chen, YZ Bennett, CL Huynh, HM Blair, IP Puls, I Irobi, J Dierick, I Abel, A Kennerson, ML Rabin, BA Nicholson, GA Auer-Grumbach, M Wagner, K De Jonghe, P Griffin, JW Fischbeck, KH Timmerman, V Cornblath, DR Chance, PF AF Chen, YZ Bennett, CL Huynh, HM Blair, IP Puls, I Irobi, J Dierick, I Abel, A Kennerson, ML Rabin, BA Nicholson, GA Auer-Grumbach, M Wagner, K De Jonghe, P Griffin, JW Fischbeck, KH Timmerman, V Cornblath, DR Chance, PF TI DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4) SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID CHROMOSOME 9Q34; MOTOR-NEURON; RNA HELICASE; PROTEIN; COMPLEX; ATAXIA; DISORDERS; SURVIVAL; ATROPHY; DECAY AB Juvenile amyotrophic lateral sclerosis (ALS4) is a rare autosomal dominant form of juvenile amyotrophic lateral sclerosis (ALS) characterized by distal muscle weakness and atrophy, normal sensation, and pyramidal signs. Individuals affected with ALS4 usually have an onset of symptoms at age <25 years, a slow rate of progression, and a normal life span. The ALS4 locus maps to a 1.7-Mb interval on chromosome 9q34 flanked by D9S64 and D9S1198. To identify the molecular basis of ALS4, we tested 19 genes within the ALS4 interval and detected missense mutations (T3I, L389S, and R2136H) in the Senataxin gene (SETX). The SETX gene encodes a novel 302.8-kD protein. Although its function remains unknown, SETX contains a DNA/RNA helicase domain with strong homology to human RENT1 and IGHMBP2, two genes encoding proteins known to have roles in RNA processing. These observations of ALS4 suggest that mutations in SETX may cause neuronal degeneration through dysfunction of the helicase activity or other steps in RNA processing. C1 Univ Washington, Dept Pediat, Div Genet & Dev Med, Seattle, WA 98195 USA. Univ Washington, Dept Neurol, Seattle, WA 98195 USA. NINDS, Neurogenet Branch, Bethesda, MD 20892 USA. Univ Antwerp VIB, Dept Mol Genet, B-2020 Antwerp, Belgium. Univ Antwerp Hosp, Dept Neurol, Antwerp, Belgium. Univ Sydney, ANZAC Res Inst, Neurobiol Lab, Sydney, NSW 2006, Australia. Concord Hosp, Sydney, NSW, Australia. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. Karl Franzens Univ Graz, Inst Med Biol & Human Genet, Graz, Austria. RP Chance, PF (reprint author), Univ Washington, Dept Pediat, Div Genet & Dev Med, Box 356320,Room RR247, Seattle, WA 98195 USA. EM pchance@u.washington.edu RI Kennerson, Marina/B-5058-2014 FU NINDS NIH HHS [R01 NS042810, NS42810] NR 26 TC 409 Z9 427 U1 0 U2 21 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 2004 VL 74 IS 6 BP 1128 EP 1135 DI 10.1086/421054 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 823ZB UT WOS:000221651900006 PM 15106121 ER PT J AU Bleyer, AJ Hart, TC AF Bleyer, AJ Hart, TC TI Medullary cystic kidney disease type 2 SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Letter ID JUVENILE HYPERURICEMIC NEPHROPATHY; UMOD GENE; UROMODULIN; MUTATIONS; CLUSTER; MCKD C1 Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC 27103 USA. NIDCR, Div Intramural Res, CRC, NIH, Bethesda, MD USA. RP Bleyer, AJ (reprint author), Wake Forest Univ, Bowman Gray Sch Med, 300 S Hawthorne Rd, Winston Salem, NC 27103 USA. NR 9 TC 3 Z9 3 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUN PY 2004 VL 43 IS 6 BP 1142 EP 1142 DI 10.1053/j.ajkd.2004.03.039 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 835QE UT WOS:000222499800025 PM 15168406 ER PT J AU Bachli, EB Brack, T Eppler, E Stallmach, T Trueb, RM Huizing, M Gahl, WA AF Bachli, EB Brack, T Eppler, E Stallmach, T Trueb, RM Huizing, M Gahl, WA TI Hermansky-Pudlak syndrome type 4 in a patient from Sri Lanka with pulmonary fibrosis SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE albinism; platelets; pulmonary fibrosis; mutation analysis ID LYSOSOME-RELATED ORGANELLES; PALE EAR EP; VESICLE FORMATION; BETA-3A SUBUNIT; OCULOCUTANEOUS ALBINISM; AP-3 ADAPTER; GENE; MUTATIONS; HPS1; BIOGENESIS AB Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and a platelet storage pool deficiency. Some patients also develop fatal pulmonary fibrosis and some have granulomatous colitis. Si.,c human genes HPS1, ADB3A, HPS3, HPS4, HPS5, and HPS6 have been identified as cause of the six known subtypes of HPS. While there exist nearly 500 Puerto Rican and non-Puerto Rican HPS-1 patients, very few HPS-4 patients have been reported, and most of these have not been described in detail. We now delineate the clinical characteristics of an HPS-4 patient homozygous for a novel HPS-4 mutation, P685delC. The patient, the first individual with HPS reported from Sri Lanka, had severe pulmonary fibrosis, typical of HPS-1 disease, without granulomatous colitis. We conclude that pulmonary fibrosis occurs as part of HPS-4 and that HPS should be considered in all ethnic groups. (C) 2004 Wiley-Liss, Inc. C1 Univ Zurich Hosp, Dept Med, CH-8091 Zurich, Switzerland. Univ Zurich Hosp, Dept Pneumol, CH-8091 Zurich, Switzerland. NHGRI, Sect Human Biochem Genet, Human Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland. Univ Zurich Hosp, Dept Pathol, CH-8091 Zurich, Switzerland. Univ Zurich, Inst Anat, Dept Cell Biol, Zurich, Switzerland. RP Bachli, EB (reprint author), Univ Zurich Hosp, Dept Med, Raemistr 100, CH-8091 Zurich, Switzerland. EM esther.baechli@usz.ch NR 46 TC 15 Z9 17 U1 1 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUN 1 PY 2004 VL 127A IS 2 BP 201 EP 207 DI 10.1002/njmg.a.20683 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 821MR UT WOS:000221465500017 PM 15108212 ER PT J AU Romero, R Chaiworapongsa, T Kuivaniemi, H Tromp, G AF Romero, R Chaiworapongsa, T Kuivaniemi, H Tromp, G TI Bacterial vaginosis, the inflammatory response and the risk of preterm birth: A role for genetic epidemiology in the prevention of preterm birth SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Review ID TUMOR-NECROSIS-FACTOR; AMNIOTIC-FLUID INFECTION; PLACEBO-CONTROLLED TRIAL; FACTOR-ALPHA PRODUCTION; ABNORMAL VAGINAL FLORA; NON-SPECIFIC VAGINITIS; PREMATURE RUPTURE; INTRAAMNIOTIC INFECTION; ENVIRONMENT INTERACTION; PREGNANT-WOMEN C1 NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI 48201 USA. Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48202 USA. RP Romero, R (reprint author), NICHD, Perinatol Res Branch, NIH, DHHS, 4707 St Antoine Blvd, Detroit, MI 48201 USA. RI Tromp, Gerard/B-2677-2017; OI Tromp, Gerard/0000-0002-7761-0806; Kuivaniemi, Helena/0000-0001-5753-8766 NR 149 TC 115 Z9 122 U1 1 U2 8 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 2004 VL 190 IS 6 BP 1509 EP 1519 DI 10.1016/ajog.2004.01.002 PG 11 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 834MB UT WOS:000222414100003 PM 15284723 ER PT J AU Chaiworapongsa, T Romero, R Espinoza, J Bujoid, E Kim, YM Gocalves, LF Gomez, R Edwin, S AF Chaiworapongsa, T Romero, R Espinoza, J Bujoid, E Kim, YM Gocalves, LF Gomez, R Edwin, S TI Evidence supporting a rote for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia - Young Investigator Award SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 70th Annual Meeting of the Central-Association-of-Obstetricians-and-Gynecologists CY OCT 01-04, 2003 CL La Jolla, CA SP Cent Assoc Obstetricians & Gynecologists DE preeclampsia; soluble vascular endothelial growth factor receptor 1; early-onset preeclampsia; vascular endothelial growth factor ID HUMAN PLACENTA; RECEPTOR; PATHOGENESIS; WOMEN; CELLS; PROTEINURIA; ACTIVATION; PREGNANCY; FLK-1/KDR; SURVIVAL AB Objective: Soluble vascular endothelial growth factor receptor I (sVEGFR-1), which antagonizes VEGF functions, has been implicated in the pathophysiology of preeclampsia. The purpose of this study was to determine whether preeclampsia is associated with a change in the plasma concentration of sVEGFR-1, and, if so, whether such a change is correlated with the severity of the disease. Methods: A cross-sectional study was conducted to determine the concentrations of sVEGFR-1 in plasma obtained from normal pregnant women (n = 61) and patients with preeclampsia (n = 6 1). Plasma concentrations of sVEGFR-1 were determined by enzyme-linked immunoassay. Results: Preeclampsia had a higher median plasma concentration of sVEGFR-1 than normal pregnancy (P < .001). The median plasma concentration of sVEGFR-1 was higher in early-onset (less than or equal to 34 weeks) than late-onset ( > 34 weeks) preeclampsia (P = .005), and higher in severe than in mild preeclampsia (P = .002). In normal pregnancy, there was a correlation between plasma concentration of sVEGFR-1 and gestational age (r = 0.5; P < .001). In contrast, there was a negative correlation between plasma concentration of sVEGFR-1 and gestational age at the onset of preeclampsia (r = -0.5; P < .001). Conclusion: Preeclampsia is associated with an increased plasma sVEGFR-1 concentration. The elevation of sVEGFR-1 concentration is correlated with the severity of the disease. These observations suggest the participation of VEGF and its soluble receptor in the pathophysiology of preeclampsia. (C) 2004 Elsevier Inc. All rights reserved. C1 NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. Wayne State Univ, Hutzel Hosp, Dept Obstet & Gynecol, Detroit, MI 48202 USA. Hosp Dr Sotero del Rio, Dept Obstet & Gynecol, Puente Alto, Chile. RP Romero, R (reprint author), Wayne State Univ, NICHD, Perinatol Res Branch, NIH,DHHS,Hutzel Hosp,Dept OB GYN, 4707 St Antoine Blvd, Detroit, MI 48201 USA. EM warfiela@mail.nih.gov NR 25 TC 200 Z9 205 U1 0 U2 4 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JUN PY 2004 VL 190 IS 6 BP 1541 EP 1547 DI 10.1016/j.ajog.2004.03.043 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 834MB UT WOS:000222414100009 PM 15284729 ER PT J AU He, LS Wu, XL Meylan, F Olson, DP Simone, J Hewgill, D Siegel, R Lipsky, PE AF He, LS Wu, XL Meylan, F Olson, DP Simone, J Hewgill, D Siegel, R Lipsky, PE TI Monitoring caspase activity in living cells using fluorescent proteins and flow cytometry SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID RESONANCE ENERGY-TRANSFER; ALPHA-INDUCED APOPTOSIS; LUNG-CANCER CELLS; CRYSTAL-STRUCTURE; FACTOR RECEPTOR; TRANSFER FRET; SINGLE-LASER; ACTIVATION; DEATH; PROTEASES AB A molecular probe was developed to monitor caspase activity in living cells by flow cytometry. It consists of CFP and YFP with a peptide linker containing two caspase-cleavage sites (LEVD). Its expression resulted in intense fluorescence resonance energy transfer (FRET), whereas cleavage of this linker by caspases eliminated FRET because of physical separation of the CFP and YFP moieties. Using flow cytometry, cells expressing this probe exhibited two patterns, strong FRET and diminished or absent FRET. The appearance of diminished FRET was inhibited by a pan-caspase inhibitor z-VAD or D->A mutations in the LEVD sequence and was markedly increased by apoptosis-inducing agents, etoposide and camptothecin, or overexpression of a caspase 8-red fluorescent protein fusion protein. Importantly, this probe's ability to monitor caspase activity was comparable with results obtained with fluorogenic substrates or fluorochrome-labeled inhibitors of caspases. Specific caspase inhibitors indicated the probe was highly sensitive to cleavage by caspase 6 and 8, less sensitive to caspase 4, and resistant to other caspases. Activation of caspase 8 by Fas engagement markedly increased the probe's cleavage, whereas treatment of caspase 8-deficient cells with anti-Fas did not increase cleavage. However, staurosporine induced cleavage of the probe in caspase 8-deficient cells by a mechanism that was inhibited by overexpression of bcl-x. Taken together, the data indicate that this caspase-sensitive probe can be used to monitor the basal and apoptosis-related activities of caspases. including an initiator caspase, caspase 8, and effector caspases, such as caspase 6. C1 NIAMSD, Flow Cytometry Sect, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. NIAMSD, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP He, LS (reprint author), NIAMSD, Flow Cytometry Sect, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. EM Lihe@mail.nih.gov RI Siegel, Richard/C-7592-2009 OI Siegel, Richard/0000-0001-5953-9893 NR 48 TC 23 Z9 26 U1 1 U2 6 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JUN PY 2004 VL 164 IS 6 BP 1901 EP 1913 DI 10.1016/S0002-9440(10)63751-0 PG 13 WC Pathology SC Pathology GA 823HK UT WOS:000221601000005 PM 15161627 ER EF