FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Smith, MA Anderson, BD AF Smith, MA Anderson, BD TI A window on reality? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID PEDIATRIC-ONCOLOGY-GROUP; REFRACTORY SOLID TUMORS; PHASE-II WINDOW; TOPOTECAN; CHILDREN; CYCLOPHOSPHAMIDE; RECURRENT C1 Natl Canc Inst, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Smith, MA (reprint author), Natl Canc Inst, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NR 11 TC 6 Z9 6 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD APR 15 PY 2004 VL 22 IS 8 BP 1360 EP 1362 DI 10.1200/JCO.2004.01.946 PG 3 WC Oncology SC Oncology GA 813MW UT WOS:000220912200003 PM 15007089 ER PT J AU Chan, ATC Tao, Q Robertson, KD Flinn, IW Mann, RB Klencke, B Kwan, WH Leung, TWT Johnson, PJ Ambinder, RF AF Chan, ATC Tao, Q Robertson, KD Flinn, IW Mann, RB Klencke, B Kwan, WH Leung, TWT Johnson, PJ Ambinder, RF TI Azacitidine induces demethylation of the Epstein-Barr virus genome in tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID DNA METHYLATION; CANCER-CELLS; HISTONE DEACETYLASE; BURKITTS-LYMPHOMA; LATENCY PROMOTER; HODGKINS-DISEASE; CPG METHYLATION; T-CELLS; GENE; 5-AZA-2'-DEOXYCYTIDINE AB Purpose To determine whether therapy with a DNA methyltransferase inhibitor is effective in achieving demethylation and gene re-expression in tumor DNA in patients. Methods Biopsy specimens were obtained from patients with Epstein-Barr virus-associated tumors, enrolled on a clinical trial of 5-azacitidine, within 72 hours of the conclusion of the last infusion of the first cycle of therapy, and compared to pretreatment specimens. Methylation-specific polymerase chain reaction, bisulfite genomic sequencing, and immunohistochemistry were used to assess demethylation and gene re-expression. Results Substantial degrees of demethylation were detected in all latent and lytic Epstein-Barr virus promoters examined. Immunohistochemistry suggested activation of a previously silent viral antigen expression in one instance. Conclusion Pharmacologic reversal of dense CpG methylation in tumor tissue can be achieved in patients. C1 Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD 21231 USA. Chinese Univ Hong Kong, Prince Wales Hosp, Dept Clin Oncol, Shatin, Hong Kong, Peoples R China. Canc Epigenet Tumor Virol Lab, Singapore, Singapore. NCI, Epigenet Gene Regulat & Canc Sect, NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. RP Ambinder, RF (reprint author), Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Bunting Blaustein Bldg Rm 389,1650 Orleans St, Baltimore, MD 21231 USA. EM ambinri@jhmi.edu RI Ambinder, Richard/G-1607-2011 FU NCI NIH HHS [P01 CA 15396, U01 CA 70062] NR 38 TC 69 Z9 73 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD APR 15 PY 2004 VL 22 IS 8 BP 1373 EP 1381 DI 10.1200/JCO.2004.01.185 PG 9 WC Oncology SC Oncology GA 813MW UT WOS:000220912200006 PM 15007085 ER PT J AU Mehr, R Edelman, H Sehgal, D Mage, R AF Mehr, R Edelman, H Sehgal, D Mage, R TI Analysis of mutational lineage trees from sites of primary and secondary Ig gene diversification in rabbits and chickens SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ANTIBODY-AFFINITY MATURATION; SPLENIC GERMINAL-CENTERS; PRIMARY IMMUNE-RESPONSE; CENTER B-CELLS; SOMATIC HYPERMUTATION; ALLELIC EXCLUSION; IN-SITU; V(D)J RECOMBINATION; CLONAL EXPANSION; WAITING-TIMES AB Lineage trees of mutated rearranged Ig V region sequences in B lymphocyte clones often serve to qualitatively illustrate claims concerning the dynamics of affinity maturation. In this study, we use a novel method for analyzing lineage tree shapes, using terms from graph theory to quantify the differences between primary and secondary diversification in rabbits and chickens. In these species, Ig gene diversification starts with rearrangement of a single (in chicken) or a few (in rabbit) V-H genes. Somatic hypermutation and gene conversion contribute to primary diversification in appendix of young rabbits or in bursa of Fabricius of embryonic and young chickens and to secondary diversification during immune responses in germinal centers (GCs). We find that, at least in rabbits, primary diversification appears to occur at a constant rate in the appendix, and the type of Ag-specific selection seen in splenic GCs is absent. This supports the view that a primary repertoire is being generated within the expanding clonally related B cells in appendix of young rabbits and emphasizes the important role that gut-associated lymphoid tissues may play in early development of mammalian immune repertoires. Additionally, the data indicate a higher rate of hypermutation in rabbit and chicken GCs, such that the balance between hypermutation and selection tends more toward mutation and less toward selection in rabbit and chicken compared with murine GCs. C1 Bar Ilan Univ, Fac Life Sci, IL-52900 Ramat Gan, Israel. Natl Inst Immunol, Mol Immunol Grp, New Delhi, India. NIAID, Immunogenet Mol Lab, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Mehr, R (reprint author), Bar Ilan Univ, Fac Life Sci, Bldg 212, IL-52900 Ramat Gan, Israel. EM mehrra@mail.biu.ac.il NR 54 TC 24 Z9 26 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD APR 15 PY 2004 VL 172 IS 8 BP 4790 EP 4796 PG 7 WC Immunology SC Immunology GA 811JN UT WOS:000220768300018 PM 15067055 ER PT J AU Kieffer, TL Finucane, MM Nettles, RE Quinn, TC Broman, KW Ray, SC Persaud, D Siliciano, RF AF Kieffer, TL Finucane, MM Nettles, RE Quinn, TC Broman, KW Ray, SC Persaud, D Siliciano, RF TI Genotypic analysis of HIV-1 drug resistance at the limit of detection: Virus production without evolution in treated adults with undetectable HIV loads SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; POTENT ANTIVIRAL THERAPY; COMBINATION THERAPY; LATENT RESERVOIR; VIRAL LOAD; IN-VIVO; REVERSE-TRANSCRIPTASE; TYPE-1 INFECTION; HIV-1-INFECTED PATIENTS; LIFELONG PERSISTENCE AB Human immunodeficiency virus (HIV) production continues in patients receiving highly active antiretroviral therapy (HAART) with undetectable (<50 copies/mL) virus loads. Our initial cross-sectional study showed that this viremia is composed of viruses that lack new resistance mutations to the HAART regimen. Here we describe a longitudinal, clonal genotypic analysis of plasma virus loads in treated adults who had undetectable virus loads. We document a continuous production of virus in 8 HIV-1-infected adults who maintained suppression of viremia for up to 15 months. Using analytical approaches for distinguishing selected resistance mutations from nonselected mutations and polymerase chain reaction errors, we detected no evolution of resistance in the reverse-transcriptase and protease genes. Sporadic resistance mutations were detected in some viral clones that were not selected for subsequently. Thus, in some patients, HAART suppresses replication to a level that does not allow the evolution of drug resistance over a time frame of years. C1 Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Siliciano, RF (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, 1049 Ross Bldg,720 Rutland Ave, Baltimore, MD 21205 USA. EM rsiliciano@jhmi.edu RI Ray, Stuart/B-7527-2008 OI Ray, Stuart/0000-0002-1051-7260 FU NIAID NIH HHS [AI51178, AI43222]; PHS HHS [F32A1056696, T32A107291] NR 50 TC 137 Z9 138 U1 0 U2 4 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 APR 15 PY 2004 VL 189 IS 8 BP 1452 EP 1465 DI 10.1086/382488 PG 14 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 810WW UT WOS:000220735400016 PM 15073683 ER PT J AU Vestereng, VH Bishop, LR Hernandez, B Kutty, G Larsen, HH Kovacs, JA AF Vestereng, VH Bishop, LR Hernandez, B Kutty, G Larsen, HH Kovacs, JA TI Quantitative real-time polymerase chain-reaction assay allows characterization of Pneumocystis infection in immunocompetent mice SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT Annual Meeting of the Infectious-Diseases-Society-of-America CY OCT 24-27, 2002 CL Chicago, IL SP Infectious Dis Soc Amer ID F-SP MURIS; CARINII INFECTION; IMMUNE-RESPONSE; PCR ASSAY; PNEUMONIA; MODEL AB Pneumocystis causes pneumonia in immunodeficient hosts but also likely causes infection in healthy hosts. To characterize infection in healthy mice, we developed and validated a real-time polymerase chain reaction assay for quantitation of Pneumocystis carinii f. sp. muris. In healthy mice exposed to Pneumocystis-infected animals, organisms were first detected at 2 - 3 weeks, peaked at 5 - 6 weeks, and were cleared by 7 - 9 weeks. The peak organism load in healthy animals was 2 - 3 logs lower than that in immunodeficient animals. This approach should facilitate studies of anti-Pneumocystis immune mechanisms in healthy hosts and provide insights into the development of Pneumocystis pneumonia in immunodeficient hosts. C1 NIH, Dept Crit Care Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Kovacs, JA (reprint author), Bldg 10,Rm 7D43,MSC 1662, Bethesda, MD 20892 USA. EM jkovacs@nih.gov NR 15 TC 26 Z9 28 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD APR 15 PY 2004 VL 189 IS 8 BP 1540 EP 1544 DI 10.1086/382486 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 810WW UT WOS:000220735400026 PM 15073693 ER PT J AU Mothilal, KK Inbaraj, JJ Chignell, CF Gandhidasan, R Murugesan, R AF Mothilal, KK Inbaraj, JJ Chignell, CF Gandhidasan, R Murugesan, R TI Photosensitisation with naphthoquinones and binaphthoquinones: EPR spin trapping and optical studies-formation of semiquinone radical and reactive oxygen species on photoillumination SO JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY A-CHEMISTRY LA English DT Article DE ROS; spin trapping; DMM anthraquinone; superoxide generation ID PHOTODYNAMIC THERAPEUTIC AGENTS; NATURALLY-OCCURRING QUINONES; ANTICANCER AGENTS; SINGLET OXYGEN; PERYLENEQUINONOID PIGMENTS; SUPEROXIDE ANION; ACTIVE OXYGEN; ILLUMINATION; GENERATION; ELECTRON AB Photodynamic action of two naphthoquinones, 7-methyljuglone (MJ) and plumbagin (PG) and two binaphthoquinones, isodiospyrin (IDP) and diospyrin (DP) extracted from the stem of Diospyros paniculata and roots and root barks of Diospyros montana, are studied by using optical and EPR spin trapping techniques. Efficiency of singlet oxygen generation (by RNO bleaching and EPR spectroscopy) and rate of superoxide generation (by SOD inhibitable ferricytochrome c reduction and EPR spin trapping assays) are determined. In anaerobic medium semiquinone anion of IDP was produced both in dark and in light. On photoillumination of aerobic solution, superoxide radical was generated by all the four quinones via electron transfer to O-2. In aqueous solution, the superoxide radical anion formed, rapidly changes to -OH radical via Fenton's reaction. These findings reveal that the photosensitisation of naphthoquinones and binaphthoquinones may proceed via Type I and Type II mechanisms. (C) 2004 Published by Elsevier B.V. C1 Madurai Kamaraj Univ, Sch Chem, Madurai 625021, Tamil Nadu, India. Saraswathi Narayanan Coll, Dept Chem, Madurai 625022, Tamil Nadu, India. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Murugesan, R (reprint author), Madurai Kamaraj Univ, Sch Chem, Madurai 625021, Tamil Nadu, India. EM rammurugesan@yahoo.com NR 30 TC 6 Z9 8 U1 1 U2 5 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 1010-6030 J9 J PHOTOCH PHOTOBIO A JI J. Photochem. Photobiol. A-Chem. PD APR 15 PY 2004 VL 163 IS 1-2 BP 141 EP 148 DI 10.1016/j.jphotochem.2003.11.007 PG 8 WC Chemistry, Physical SC Chemistry GA 810UC UT WOS:000220728200019 ER PT J AU Stieber, A Gonatas, JO Moore, JS Bantly, A Yim, HS Yim, MB Gonatas, NK AF Stieber, A Gonatas, JO Moore, JS Bantly, A Yim, HS Yim, MB Gonatas, NK TI Disruption of the structure of the Golgi apparatus and the function of the secretory pathway by mutants G93A and G85R of Cu, Zn superoxide dismutase (SOD1) of familial amyotrophic lateral sclerosis SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE Golgi apparatus; amyotrophic lateral sclerosis ID ALS-LINKED SOD1; HYDROGEN-PEROXIDE; CU,ZN-SUPEROXIDE DISMUTASE; ENDOPLASMIC-RETICULUM; MEDIAL CISTERNAE; MOTOR-NEURONS; MOUSE MODEL; CELL-DEATH; K-M; APOPTOSIS AB The Golgi apparatus of motor neurons (GA) is fragmented in sporadic arryotrophic lateral sclerosis (ALS), in familial ALS with SOD1 mutations, and in mice that express SOD1(G93A) of familial ALS, in which it was detected months before paralysis. In paralyzed transgenic mice expressing SOD1(G93A) or SOD1(G85R), mutant proteins aggregated not only in the cytoplasm of motor neurons, but also in astrocytes and oligodendrocytes. Furthermore, aggregation of the G85R protein damaged astrocytes and was associated with rapidly progressing disease. In order to gain insight into the functional state of the fragmented GA, we examined the effects of SOD1 mutants G93A and G85R in Chinese Hamster Ovary Cells (CHO). In contrast to cells expressing the wt and G93A, the G85R expressers had no SOD1 activity. However, cells expressing both mutants, and to a lesser degree the wt, showed decreased survival, fragmentation of the GA, and dysfunction of the secretory pathway, which was assessed by measuring the amount of cell surface co-expressed CD4, a glycoprotein processed through the GA. The G93A and wt proteins were partially recovered in detergent insoluble fractions; while the recovery of G85R was minimal. Both mutants showed equal reductions of cell survival and function of the secretory pathway, in comparison to the wt and cells expressing mutant alsin, a protein found in rare cases of fALS. These results are consistent with the conclusion that the two SOD1 mutants, by an unknown mechanism, promote the dispersion of the GA and the dysfunction of the secretory pathway. This and other in vitro models of mutant SOD1 toxicity may prove useful in the elucidation of pathogenetic mechanisms. (C) 2004 Elsevier B.V. All rights reserved. C1 Univ Penn, Dept Pathol & Lab Med, Ctr Med, Stellar Chance Labs 609, Philadelphia, PA 19104 USA. NHLBI, Biochem Lab, NIH, Bethesda, MD 20893 USA. RP Gonatas, NK (reprint author), Univ Penn, Dept Pathol & Lab Med, Ctr Med, Stellar Chance Labs 609, 422 Curie Blvd, Philadelphia, PA 19104 USA. EM gonatasn@mail.med.upenn.edu FU NINDS NIH HHS [NS36732] NR 53 TC 34 Z9 34 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD APR 15 PY 2004 VL 219 IS 1-2 BP 45 EP 53 DI 10.1016/j.jns.2003.12.004 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 813QB UT WOS:000220920500008 PM 15050437 ER PT J AU Olive, M Goldfarb, L Moreno, D Laforet, E Dagvadorj, A Sambuughin, N Martinez-Matos, JA Martinez, F Alio, J Farrero, E Vicart, P Ferrer, I AF Olive, M Goldfarb, L Moreno, D Laforet, E Dagvadorj, A Sambuughin, N Martinez-Matos, JA Martinez, F Alio, J Farrero, E Vicart, P Ferrer, I TI Desmin-related myopathy: clinical, electrophysiological, radiological, neuropathological and genetic studies SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE desmin-related myopathy; desmin; mutations; synemin; syncoilin; alpha B-crystallin ID MYOFIBRILLAR MYOPATHY; INTERMEDIATE FILAMENTS; SKELETAL MYOPATHY; MUSCULAR-DYSTROPHY; MISSENSE MUTATION; DISTAL MYOPATHY; MUSCLE; CARDIOMYOPATHY; ACCUMULATION; PROTEINS AB Ten Spanish patients from six unrelated families diagnosed with desmin-related myopathy (DRM) were studied. The pattern of DRM inheritance was autosomal dominant in three families, autosomal recessive in one, and there was no family history in two cases. The disease onset was in early adulthood. Cardiac myopathy was the initial presentation in two patients, respiratory insufficiency in one, and lower limb weakness in all others. Cardiac involvement was observed in four patients. Lens opacities were found in four. CK level was normal or slightly elevated, and electrophysiological examination was consistent with myopathy. Muscle biopsies identified intracytoplasmic desmin-immunoreactive inclusions. In addition to desmin, synemin, actin, gelsolin, ubiquitin, alphaB-crystallin and amyloid betaA4 were also present in the deposits. Ultrastructural examination revealed areas of myofibrillary disruption, abnormal electron-dense structures and accumulations of granulofilamentous material. A missense R406W mutation and a novel single amino acid deletion in the desmin gene were identified in two patients; the other patients did not show mutations in desmin, synemin, syncoilin or alphaB-crystallin genes. Analysis of 10 Spanish DRM cases illustrates a wide clinical, myopathological and genetic spectrum of DRM, reinforcing the need for further exploration of genetic causes for this group of disorders. (C) 2004 Elsevier B.V. All rights reserved. C1 Bellvitge Hosp, Inst Neuropatol, Barcelona 08907, Spain. NINDS, Clin Neurogenet Unit, NIH, Bethesda, MD 20892 USA. Univ Barcelona, Bellvitge Hosp, Dept Neurol, Neuromuscular Unit, Barcelona, Spain. Univ Barcelona, Bellvitge Hosp, Dept Radiol, Barcelona, Spain. Univ Barcelona, Bellvitge Hosp, Dept Cardiol, Barcelona, Spain. Univ Barcelona, Bellvitge Hosp, Dept Resp Med, Barcelona, Spain. Univ Paris 06, Lab Cytosquelette & Dev, Paris, France. RP Olive, M (reprint author), Bellvitge Hosp, Inst Neuropatol, C Feixa Llarga S-N,Hosp Llobregat, Barcelona 08907, Spain. EM 25169mop@comb.es OI Olive, Montse/0000-0001-5727-0165 NR 39 TC 46 Z9 50 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD APR 15 PY 2004 VL 219 IS 1-2 BP 125 EP 137 DI 10.1016/j.jns.2004.01.007 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 813QB UT WOS:000220920500019 PM 15050448 ER PT J AU Ried, T AF Ried, T TI Cytogenetics - In color and digitized SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Ried, T (reprint author), NCI, Bethesda, MD 20892 USA. NR 0 TC 5 Z9 6 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 APR 15 PY 2004 VL 350 IS 16 BP 1597 EP 1600 DI 10.1056/NEJMp038242 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 812DI UT WOS:000220819800002 PM 15084690 ER PT J AU Herzog, CR Bodon, N Pittman, B Maronpot, RR Massey, TE Anderson, MW You, M Devereux, TR AF Herzog, CR Bodon, N Pittman, B Maronpot, RR Massey, TE Anderson, MW You, M Devereux, TR TI Carcinogen-specific targeting of chromosome 12 for loss of heterozygosity in mouse lung adenocarcinomas: implications for chromosome instability and tumor progression SO ONCOGENE LA English DT Article DE loss of heterozygosity; chromosome instability; lung carcinogenesis; chromosome 12 ID TOBACCO-SPECIFIC NITROSAMINES; CELL-LINES; HOMOLOGOUS RECOMBINATION; ADDUCT FORMATION; ALLELIC LOSSES; HIGH-FREQUENCY; DNA-DAMAGE; CANCER; MICE; SELECTION AB Genotoxic carcinogens exert their tumorigenic effects in part by inducing genomic instability. We recently showed that loss of heterozygosity (LOH) on chromosome 12 associates significantly with the induction of chromosome instability (CIN) by the likely human lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and vinyl carbamate (VC) during mouse lung carcinogenesis. Here, we demonstrate the carcinogen specificity of this event and its effect on lung tumor evolution. LOH on chromosome 12 was observed in 45% of NNK-induced, 59% of VC-induced, 58% of aflatoxin B1 (AFB1)-induced, 14% of N-ethyl-N-nitrosourea (ENU)-induced and 12% of spontaneous lung adenocarcinomas. The frequency of LOH in each of the carcinogen-induced groups, except ENU, was significantly higher than in the spontaneous group (P<0.001). Deletion mapping revealed four potential candidate regions of 1-4 centiMorgans suspected to contain targeted tumor suppressor genes, with at least one expected to have a role in CIN. The relationship between LOH on chromosome 12 and additional chromosomal alterations occurring during lung tumor progression was also examined. LOH on chromosomes 1 and 14 were moderately frequent during malignant progression in tumors from all treatment groups, occurring in 21-35 and 18-33% of tumors. However, these alterations showed significant concurrence with LOH on chromosome 12 in VC-, NNK- and AFB1-induced tumors (P<0.05). The results suggest that a carcinogen-selective mechanism of lung cancer induction involves the frequent inactivation of genes on chromosome 12, including a stability gene that evidently promotes the evolutionary selection of additional chromosomal alterations during malignant progression. C1 Inst Canc Prevent, Valhalla, NY 10595 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Queens Univ, Kingston, ON K7L 3N6, Canada. Univ Cincinnati, Cincinnati, OH 45267 USA. Washington Univ, St Louis, MO 63110 USA. RP Herzog, CR (reprint author), Inst Canc Prevent, Valhalla, NY 10595 USA. EM cherzog@ifcp.us FU NCI NIH HHS [CA17613] NR 41 TC 15 Z9 15 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 APR 15 PY 2004 VL 23 IS 17 BP 3033 EP 3039 DI 10.1038/sj.onc.1207431 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 812NC UT WOS:000220845200007 PM 14755239 ER PT J AU Huff, J Melnick, R Tomatis, L LaDou, J Teitelbaum, D AF Huff, J Melnick, R Tomatis, L LaDou, J Teitelbaum, D TI Trichloroethylene and cancers in humans SO TOXICOLOGY LA English DT Letter ID OCCUPATIONAL-EXPOSURE; CARCINOGENICITY; WORKERS; BIOASSAYS; TOXICITY; COHORT; RISK; RATS C1 NIEHS, Res Triangle Pk, NC 27709 USA. Univ Calif San Francisco, Sch Med, Int Ctr Occupat Med, San Francisco, CA 94143 USA. Univ Colorado, Sch Med, Denver, CO 80202 USA. Colorado Sch Mines, Denver, CO 80202 USA. RP Huff, J (reprint author), NIEHS, POB 12233,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM huff1@niehs.nih.gov NR 23 TC 11 Z9 12 U1 0 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD APR 15 PY 2004 VL 197 IS 2 BP 185 EP 187 DI 10.1016/j.tox.2003.12.009 PG 3 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 804UD UT WOS:000220322700010 PM 15003328 ER PT J AU Salnikow, K Li, XM Lippmann, M AF Salnikow, K Li, XM Lippmann, M TI Effect of nickel and iron co-exposure on human lung cells SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE ROFA; nickel; iron; ferritin; hypoxia-inducible genes; IL-8 ID OIL FLY-ASH; HYPOXIA-INDUCIBLE FACTOR; EPITHELIAL-CELLS; TRANSITION-METALS; AIR-POLLUTION; HIF-ALPHA; RAT LUNG; EXPOSURE; OXYGEN; INJURY AB Exposure to ambient air particulate matter (PM) is associated with increased mortality and morbidity in susceptible populations. The epidemiological data also suggest a relationship between PM air pollution and impairment of cardiopulmonary function. The mechanisms that may be responsible for these effects are not fully understood and are likely related to perturbations of cellular and molecular functions. One type of PM, residual oil fly ash (ROFA), is of particular interest. ROFA does not contain much organic material, but does contain relatively high quantities of transition metals, predominantly nickel, vanadium, and iron, as well as black carbon and sulfates. In this study, we investigated the effect of two metals (iron and nickel) on the induction of "hypoxia-like" stress and the production of interleukins (ILs) in minimally transformed human airway epithelial cells (1HAEo(-)). We found that exposure to soluble nickel sulfate results in the induction of hypoxia-inducible genes and IL-8 production by the 1HAEo(-) cells. The simultaneous addition of iron in either ferric or ferrous form and nickel completely inhibited IL-8 production and had no effect on "hypoxia-like" stress caused by nickel, suggesting the existence of two different pathways for the induction "hypoxia-like" stress and IL-8 production. The effect of nickel was not related to the blocking of iron entry into cells since the level of intracellular iron was not affected by co-exposure with nickel. The obtained data indicate that nickel can induce different signaling pathways with or without interference with iron metabolism. Our observations suggest that in some cases the excess of iron in PM can cancel the effects of nickel. (C) 2004 Elsevier Inc. All rights reserved. C1 NYU, Sch Med, Nelson Inst Environm Med, EPA PM Hlth Effects Res Ctr, New York, NY 10016 USA. NYU, Sch Med, Nelson Inst Environm Med, NIEHS Environm Hlth Sci Ctr, New York, NY 10016 USA. RP Salnikow, K (reprint author), NCI, Comparat Carcinogenesis Lab, Room 205 E,Bldg 538,POB B, Frederick, MD 21701 USA. EM salnikow@ncifcrf.gov FU NIEHS NIH HHS [ES00260] NR 40 TC 31 Z9 32 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD APR 15 PY 2004 VL 196 IS 2 BP 258 EP 265 DI 10.1016/j.taap.2004.01.003 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 813LP UT WOS:000220908900008 PM 15081272 ER PT J AU Wendler, D AF Wendler, D TI Improving the decision processes of institutional review boards - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NIH, Dept Clin Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Wendler, D (reprint author), NIH, Dept Clin Bioeth, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. NR 0 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 APR 14 PY 2004 VL 291 IS 14 BP 1698 EP 1699 DI 10.1001/jama.291.14.1698-c PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 811RJ UT WOS:000220788700024 ER PT J AU Anderson, GL Limacher, M Assaf, AR Bassford, T Beresford, SAA Black, H Bonds, D Brunner, R Brzyski, R Caan, B Chlebowski, R Curb, D Gass, M Hays, J Heiss, G Hendrix, S Howard, BV Hsia, J Hubbell, A Jackson, R Johnson, KC Judd, H Kotchen, JM Kuller, L LaCroix, AZ Lane, D Langer, RD Lasser, N Lewis, CE Manson, J Margolis, K Ockene, J O'Sullivan, MJ Phillips, L Prentice, RL Ritenbaugh, C Robbins, J Rossouw, JE Sarto, G Stefanick, ML Van Horn, L Wactawski-Wende, J Wallace, R Wassertheil-Smoller, S AF Anderson, GL Limacher, M Assaf, AR Bassford, T Beresford, SAA Black, H Bonds, D Brunner, R Brzyski, R Caan, B Chlebowski, R Curb, D Gass, M Hays, J Heiss, G Hendrix, S Howard, BV Hsia, J Hubbell, A Jackson, R Johnson, KC Judd, H Kotchen, JM Kuller, L LaCroix, AZ Lane, D Langer, RD Lasser, N Lewis, CE Manson, J Margolis, K Ockene, J O'Sullivan, MJ Phillips, L Prentice, RL Ritenbaugh, C Robbins, J Rossouw, JE Sarto, G Stefanick, ML Van Horn, L Wactawski-Wende, J Wallace, R Wassertheil-Smoller, S CA WHI Steering Comm TI Effects of conjugated, equine estrogen in postmenopausal women with hysterectomy - The women's health initiative randomized controlled trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HORMONE-REPLACEMENT THERAPY; CORONARY-HEART-DISEASE; PLUS PROGESTIN; BREAST-CANCER; ARTERY ATHEROSCLEROSIS; BLOOD-PRESSURE; CLINICAL-TRIAL; RISK; METAANALYSIS; PREVENTION AB Context Despite decades of use and considerable research, the role of estrogen alone in preventing chronic diseases in postmenopausal women remains uncertain. Objective To assess the effects on major disease incidence rates of the most commonly used postmenopausal hormone therapy in the United States. Design, Setting, and Participants A randomized, double-blind, placebo-controlled disease prevention trial (the estrogen-alone component of the Women's Health Initiative [WHI]) conducted in 40 US clinical centers beginning in 1993. Enrolled were 10739 postmenopausal women, aged 50-79 years, with prior hysterectomy, including 23% of minority race/ethnicity. Intervention Women were randomly assigned to receive either 0.625 mg/d of conjugated equine estrogen (CEE) or placebo. Main Outcome Measures The primary outcome was coronary heart disease (CHID) incidence (nonfatal myocardial infarction or CHID death). Invasive breast cancer incidence was the primary safety outcome. A global index of risks and benefits, including these primary outcomes plus stroke, pulmonary embolism (PE), colorectal cancer, hip fracture, and deaths from other causes, was used for summarizing overall effects. Results In February 2004, after reviewing data through November 30, 2003, the National Institutes of Health (NIH) decided to end the intervention phase of the trial early. Estimated hazard ratios (HRs) (95% confidence intervals [CIs]) for CEE vs placebo for the major clinical outcomes available through February 29, 2004 (average follow-up 6.8 years), were: CHID, 0.91 (0.75-1.12) with 376 cases; breast cancer, 0.77 (0.59-1.01) with 218 cases; stroke, 1.39 (1.10-1.77) with 276 cases; PE, 1.34 (0.87-2.06) with 85 cases; colorectal cancer, 1.08 (0.75-1.55) with 119 cases; and hip fracture, 0.61 (0.41-0.91) with 102 cases. Corresponding results for composite outcomes were: total cardiovascular disease, 1.12 (1.01-1.24); total cancer, 0.93 (0.81-1.07); total fractures, 0.70 (0.63-0.79); total mortality, 1.04 (0.88-1.22), and the global index, 1.01 (0.91-1.12). For the outcomes significantly affected by CEE, there was an absolute excess risk of 12 additional strokes per 10000 person-years and an absolute risk reduction of 6 fewer hip fractures per 10000 person-years. The estimated excess risk for all monitored events in the global index was a nonsignificant 2 events per 10000 person-years. Conclusions The use of CEE increases the risk of stroke, decreases the risk of hip fracture, and does not affect CHID incidence in postmenopausal women with prior hysterectomy over an average of 6.8 years. A possible reduction in breast cancer risk requires further investigation. The burden of incident disease events was equivalent in the CEE and placebo groups, indicating no overall benefit. Thus, CEE should not be recommended for chronic disease prevention in postmenopausal women. C1 Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, WHI Clin Coordinating Ctr, Seattle, WA 98109 USA. Univ Florida, Hlth Sci Ctr, Div Cardiovasc Med, Gainesville, FL 32610 USA. Brown Univ, Providence, RI 02912 USA. Univ Arizona, Tucson, AZ USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. Univ Nevada, Reno, NV 89557 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Kaiser Permanente, Div Res, Oakland, CA USA. Harbor UCLA Res & Educ Inst, Torrance, CA USA. Univ Hawaii, Honolulu, HI 96822 USA. Univ Cincinnati, Cincinnati, OH USA. Baylor Coll Med, Houston, TX 77030 USA. Univ N Carolina, Chapel Hill, NC USA. Wayne State Univ, Sch Med, Hutzel Hosp, Detroit, MI USA. Howard Univ, MedStar Res Inst, Washington, DC 20059 USA. George Washington Univ, Med Ctr, Washington, DC 20037 USA. Univ Calif Irvine, Orange, CA 92668 USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Tennessee, Memphis, TN USA. Univ Calif Los Angeles, Los Angeles, CA USA. Med Coll Wisconsin, Milwaukee, WI 53226 USA. Univ Pittsburgh, Pittsburgh, PA USA. SUNY Stony Brook, Stony Brook, NY 11794 USA. Univ Calif San Diego, La Jolla, CA 92093 USA. Univ Med & Dent New Jersey, Newark, NJ 07103 USA. Univ Alabama, Birmingham, AL USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA USA. Univ Minnesota, Minneapolis, MN USA. Univ Massachusetts, Fallon Clin, Worcester, MA 01605 USA. Univ Miami, Miami, FL 33152 USA. Emory Univ, Atlanta, GA 30322 USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. Univ Calif Davis, Sacramento, CA 95817 USA. NHLBI, Bethesda, MD 20892 USA. Univ Wisconsin, Madison, WI USA. Stanford Univ, Stanford Prevent Res Ctr, Stanford, CA 94305 USA. Northwestern Univ, Chicago, IL 60611 USA. Univ Buffalo, Buffalo, NY USA. Univ Iowa, Iowa City, IA USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. RP Anderson, GL (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, WHI Clin Coordinating Ctr, 1100 Fairview Ave N,M3-A410,POB 19024, Seattle, WA 98109 USA. EM garnet@whi.org NR 43 TC 2563 Z9 2652 U1 16 U2 113 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 APR 14 PY 2004 VL 291 IS 14 BP 1701 EP 1712 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 811RJ UT WOS:000220788700027 PM 15082697 ER PT J AU Li, MX Jia, M Yang, LX Jiang, H Lanuza, MA Gonzalez, CM Nelson, PG AF Li, MX Jia, M Yang, LX Jiang, H Lanuza, MA Gonzalez, CM Nelson, PG TI The role of the theta isoform of protein kinase C (PKC) in activity-dependent synapse elimination: Evidence from the PKC theta knock-out mouse in vivo and in vitro SO JOURNAL OF NEUROSCIENCE LA English DT Article DE PKC theta; knock-out; synapse elimination; neuromuscular junction; in vivo; in vitro ID NEUROMUSCULAR-JUNCTION; SKELETAL-MUSCLE; POLYNEURONAL INNERVATION; PHOSPHORYLATION; RAT; ACTIVATION; RECEPTORS; FACILITATION; HIPPOCAMPUS; MODULATION AB PKC plays a critical role in competitive activity-dependent synapse modification at the neuromuscular synapse in vitro and in vivo. This action involves a reduction of the strength of inactive inputs to muscle cells that are activated by other inputs. A decrease of postsynaptic responsiveness and a loss of postsynaptic acetyl choline receptors account for the heterosynaptic loss in vitro. The loss is not seen in preparations in which PKC has been blocked pharmacologically. Here, we show that the loss does not occur in in vitro preparations made from animals genetically modified to lack the theta isoform of PKC. Synapse elimination in the newborn period in vivo is delayed but is eventually expressed in knock-out animals. PKC-dependent synapse reduction is suppressed in heterologous cultures combining normal nerve and PKC theta-deficient muscle, as might be expected from the postsynaptic locus of the changes that underlie the activity-dependent plasticity. Preparations in which PKC theta-deficient neurons innervated normal muscle also exhibited a marked deficit in PKC-deficient synapse reduction. The presynaptic action of PKC theta implied by this observation is blocked by TTX, and we propose that activity-related synapse strengthening is decreased by presynaptic PKC theta. Thus, PKC theta in both presynaptic and postsynaptic elements plays a critical role in activity-dependent synapse modulation and loss. We provide a model for activity-dependent synapse loss incorporating these findings. C1 NICHHD, Neurobiol Sect, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. Henry Ford Hlth Syst, William T Gossett Neurol Labs, Detroit, MI 48202 USA. Univ Rovira & Virgili, Fac Med, Unit Histol & Neurobiol, E-43201 Reus, Spain. RP Li, MX (reprint author), NICHHD, Neurobiol Sect, Dev Neurobiol Lab, NIH, Bldg 49,Room 5A38, Bethesda, MD 20892 USA. EM liminxu@mail.nih.gov NR 36 TC 20 Z9 21 U1 1 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD APR 14 PY 2004 VL 24 IS 15 BP 3762 EP 3769 DI 10.1523/JNEUROSCI.3930-03.2004 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 812ND UT WOS:000220845300006 PM 15084656 ER PT J AU Oyler, NA Tycko, R AF Oyler, NA Tycko, R TI Absolute structural constraints on amyloid fibrils from solid-state NMR spectroscopy of partially oriented samples SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; PARALLEL BETA-SHEET; SILK FIBROIN FIBERS; SUPRAMOLECULAR STRUCTURE; ROTATING SOLIDS; PEPTIDE; ORGANIZATION; ANTIPARALLEL; FRAGMENT; MODEL C1 NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDKD, Phys Chem Lab, NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. EM robertt@niddk.nih.gov NR 25 TC 27 Z9 28 U1 1 U2 5 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 APR 14 PY 2004 VL 126 IS 14 BP 4478 EP 4479 DI 10.1021/ja031719k PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 811DJ UT WOS:000220752300009 PM 15070340 ER PT J AU Rockwood, LD Felix, K Janz, S AF Rockwood, LD Felix, K Janz, S TI Elevated presence of retrotransposons at sites of DNA double strand break repair in mouse models of metabolic oxidative stress and MYC-induced lymphoma SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE genomic instability; double strand break repair; oxidative stress; in vivo mutant frequency; LINE-1 retrotransposons ID IN-VIVO; C-MYC; CHROMOSOMAL TRANSLOCATIONS; LINE-1 RETROTRANSPOSITION; GENETIC INSTABILITY; BURKITT-LYMPHOMA; MUTATIONS; DAMAGE; MICE; REARRANGEMENTS AB The chromosomally integrated shuttle vector pUR288 contains a lacZ reporter gene to study mutagenesis in vivo. We used pUR288 to compare patterns of genomic instability in two mouse models, lymphoma resulting from deregulated c-MYC expression (lambda-MYC), and endogenous oxidative stress caused by partial glucose 6-phosphate dehydrogenase (G6PD) deficiency. We found previously that spontaneous mutations in both models were predominantly genomic rearrangements of lacZ with mouse sequences, while most mutations in controls were point mutations. Here, we characterized the fine structure of 68 lacZ/mouse rearrangements from lambda-MYC lymphomas and G6PD deficient mice by sequencing breakpoint junctions and determining the origin of recombining mouse sequences. Fifty-eight of 68 (85%) recombination partners were identified. The structure of rearrangements from both lambda-MYC and G6PD deficient mice were remarkably alike. Intra-chromosomal deletions and inversions were common, occurring in 41% (24/58) of rearrangements, while 59% (34/58) were random translocations between lacZ and other chromosomes. Signatures of double strand break repair by nonhomologous endjoining were observed at breakpoint junctions; 37% (25/68) contained 1-4 bp microhomologies, while the remaining breakpoints had no sequence homology. Long interspersed nuclear element-1 (LINE-1 or L1) retrotransposons, which constitute similar to10% of the mouse genome. were present at 25% (17/68) of breakpoints, suggesting their participation in rearrangements. The similarity in the structure of rearrangements is consistent with the hypothesis that genetic rearrangements in lambda-MYC lymphomas and G6PD deficient mice result from the same mechanism, mutagenic repair of DNA double strand breaks arising from oxidative damage. (C) 2004, Elsevier B.V. All rights reserved. C1 NCI, Genet Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Janz, S (reprint author), NCI, Genet Lab, Canc Res Ctr, NIH, Bldg 37,Room 3140A, Bethesda, MD 20892 USA. EM sj4s@nih.gov NR 31 TC 16 Z9 16 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD APR 14 PY 2004 VL 548 IS 1-2 BP 117 EP 125 DI 10.1016/j.mrfmmm.2004.01.005 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 814BA UT WOS:000220949000013 PM 15063142 ER PT J AU Houtman, JCD Higashimoto, Y Dimasi, N Cho, SW Yamaguchi, H Bowden, B Regan, C Malchiodi, EL Mariuzza, R Schuck, P Appella, E Samelson, LE AF Houtman, JCD Higashimoto, Y Dimasi, N Cho, SW Yamaguchi, H Bowden, B Regan, C Malchiodi, EL Mariuzza, R Schuck, P Appella, E Samelson, LE TI Binding specificity of multiprotein signaling complexes is determined by both cooperative interactions and affinity preference SO BIOCHEMISTRY LA English DT Article ID CELL ANTIGEN RECEPTOR; PHOSPHOLIPASE C-GAMMA-1 PLC-GAMMA-1; TYROSYL-PHOSPHOPEPTIDE BINDING; SH3 DOMAIN; ANALYTICAL ULTRACENTRIFUGATION; SEDIMENTATION ANALYSIS; ALTERNATIVE MODES; STRUCTURAL BASIS; ACTIVATION; PROTEINS AB The generation of multiprotein complexes at receptors and adapter proteins is crucial for the activation of intracellular signaling pathways. In this study, we used multiple biochemical and biophysical methods to examine the binding properties of several SH2 and SH3 domain-containing signaling proteins as they interact with the adapter protein linker for activation of T-cells (LAT) to form multiprotein complexes. We observed that the binding specificity of these proteins for various LAT tyrosines appears to be constrained both by the affinity of binding and by cooperative protein-protein interactions. These studies provide quantitative information on how different binding parameters can determine in vivo binding site specificity observed for multiprotein signaling complexes. C1 NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, Bethesda, MD 20892 USA. ORS, Prot Biophys Resource, Div Bioengn & Phys Sci, OD,NIH, Bethesda, MD 20892 USA. Univ Maryland, Maryland Biotechnol Inst, Ctr Adv Res Biotechnol, WM Keck Lab Struct Biol, Rockville, MD 20850 USA. RP Samelson, LE (reprint author), NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. EM samelson@helix.nih.gov NR 38 TC 69 Z9 70 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD APR 13 PY 2004 VL 43 IS 14 BP 4170 EP 4178 DI 10.1021/bi0357311 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 810AK UT WOS:000220677000014 PM 15065860 ER PT J AU Kovacs, M Toth, J Nyitray, L Sellers, JR AF Kovacs, M Toth, J Nyitray, L Sellers, JR TI Two-headed binding of the unphosphorylated nonmuscle heavy meromyosin-ADP complex to actin SO BIOCHEMISTRY LA English DT Article ID SMOOTH-MUSCLE MYOSIN; PHOSPHORYLATION-DEPENDENT REGULATION; REGULATORY LIGHT-CHAIN; IMAGE-RECONSTRUCTION; 2 HEADS; DOMAIN; CONTRACTION; TROPOMYOSIN; MECHANISMS; ASYMMETRY AB The enzymatic and motor function of smooth muscle and nonmuscle myosin II is activated by phosphorylation of the regulatory light chains located in the head portion of myosin. Dimerization of the heads, which is brought about by the coiled-coil tail region, is essential for regulation since single-headed fragments are active regardless of the state of phosphorylation. Utilizing the fluorescence signal on binding of myosin to pyrene-labeled actin filaments, we investigated the interplay of actin and nucleotide binding to thiophosphorylated and unphosphorylated recombinant nonmuscle IIA heavy meromyosin constructs. We show that both heads of either thiophosphorylated or unphosphorylated heavy meromyosin bind very strongly to actin (K(d) < 10 nM) in the presence or absence of ADP. The heads have high and indistinguishable affinities for ADP (K(d) around 1 muM) when bound to actin. These findings are in line with the previously observed unusually loose coupling between nucleotide and actin binding to nonmuscle myosin IIA subfragment-1 (Kovacs et al. (2003) J. Biol. Chem. 278, 38132.). Furthermore, they imply that the structure of the two heads in the ternary actomyosin-ADP complex is symmetrical and that the asymmetrical structure observed in the presence of ATP and the absence of actin in previous investigations (Wendt et al. (2001) Proc. Natl. Acad. Sci. U.S.A. 98, 4361) is likely to represent an ATPase intermediate that precedes the actomyosin-ADP state. C1 NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. Eotvos Lorand Univ, Dept Biochem, H-1117 Budapest, Hungary. RP Sellers, JR (reprint author), NHLBI, Mol Cardiol Lab, NIH, Bldg 10,Room 8N202, Bethesda, MD 20892 USA. EM sellersj@nhlbi.nih.gov RI Kovacs, Mihaly/A-6841-2011 NR 34 TC 11 Z9 12 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD APR 13 PY 2004 VL 43 IS 14 BP 4219 EP 4226 DI 10.1021/bi0360071 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 810AK UT WOS:000220677000020 PM 15065866 ER PT J AU Chatti, K Farrar, WL Duhe, RJ AF Chatti, K Farrar, WL Duhe, RJ TI Tyrosine phosphorylation of the Janus kinase 2 activation loop is essential for a high-activity catalytic state but dispensable for a basal catalytic state SO BIOCHEMISTRY LA English DT Article ID MEMBRANE-PROXIMAL REGION; GROWTH-FACTOR RECEPTOR; CONSTITUTIVE ACTIVATION; REQUIRES PHOSPHORYLATION; ADENOSINE-TRIPHOSPHATE; PSEUDOKINASE DOMAIN; CRYSTAL-STRUCTURE; ABL ONCOGENE; JAK2; PROTEIN AB The phosphorylation of an "activation loop" within protein kinases is commonly associated with establishing catalytic competence, and phosphorylation of the Tyr(1007) residue in the activation loop of Janus kinase 2 (JAK2) has been shown to be essential for intracellular propagation of cytokine-initiated signaling. We provide evidence for the presence of a basal activity state of JAK2, which was observed in the absence of activation loop phosphorylation. Phosphorylation of the JAK2 activation loop was essential for conversion to the high-activity state, characterized by high-efficiency ATP utilization during autophosphorylation. Mutagenesis of activation loop tyrosine residues Tyr(1007/1008) to phenylalanine residues impaired, but did not abolish, the enzyme's ability to autophosphorylate. The activation loop mutant JAK2 could also transphosphorylate an inactive JAK2 fragment coexpressed in Sf21 cells, providing evidence of exogenous substrate phosphorylation. The mutant enzyme remained in a basal activity state characterized by low-efficiency ATP utilization during autophosphorylation. Mutagenesis of a critical Lys(882) residue to a glutamate residue abolished all evidence of kinase activity, confirming that the observed activity of Tyr-to-Phe mutants was not due to another kinase. Our data are consistent with the proposal that JAK2 is an inefficient but active enzyme in the absence of activation loop phosphorylation and is capable of conversion to a high-activity state by autophosphorylation under physiological ATP concentrations. This theoretically precludes the need for an upstream activating kinase. The activation process of JAK2 may be envisioned as a multistate process involving at least two kinetically distinct states of activity. C1 Univ Mississippi, Med Ctr, Dept Pharmacol & Toxicol, Jackson, MS 39216 USA. NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Cytokine Mol Mech Sect, Frederick, MD 21702 USA. RP Duhe, RJ (reprint author), Univ Mississippi, Med Ctr, Dept Pharmacol & Toxicol, Jackson, MS 39216 USA. EM RDUHE@pharmacology.umsmed.edu FU ODCDC CDC HHS [R06/CCR419466] NR 50 TC 29 Z9 29 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 APR 13 PY 2004 VL 43 IS 14 BP 4272 EP 4283 DI 10.1021/bi036109b PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 810AK UT WOS:000220677000025 PM 15065871 ER PT J AU Tozser, J Shulenin, S Louis, JM Copeland, TD Oroszlan, S AF Tozser, J Shulenin, S Louis, JM Copeland, TD Oroszlan, S TI In vitro processing of HIV-1 nucleocapsid protein by the viral proteinase: Effects of amino acid substitutions at the scissile bond in the proximal zinc finger sequence SO BIOCHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; INFECTIOUS-ANEMIA VIRUS; CYS-HIS BOX; STRAND TRANSFER; CLEAVAGE SITES; REVERSE TRANSCRIPTION; SUBSTRATE-SPECIFICITY; CAPSID PROTEIN; TYPE-1; REPLICATION AB The human immunodeficiency virus type 1 (HIV-1) nucleocapsid protein flanked by Gag sequences (r-preNC) was expressed in Escherichia coli and purified. HIV-1 proteinase cleaved r-preNC to the "mature" NCp7 form, which is comprised of 55 residues. Further incubation resulted in cleavages of NCp7 itself between Phe16 and Asn17 of the proximal zinc finger domain and between Cys49 and Thr50 in the C-terminal part. Kinetic parameters determined for the cleavage of oligopeptides corresponding to the cleavage sites in r-preNC correlated well with the sequential processing of r-preNC. Mutations of Asn17 were introduced to alter the susceptibility of NC protein to HIV-1 proteinase. While mutating Asn17 to Ala resulted in a protein which was processed in a manner similar to that of the wild type, mutating it to Phe or Leu resulted in proteins which were processed at a substantially higher rate at this site than the wild type. Mutation of Asnl7 to Lys or Gly resulted in proteins which were very poorly cleaved at this site. Oligopeptides containing the same amino acid substitutions at the cleavage site of the proximal zinc finger domain were also tested as substrates of the proteinase, and the kinetic parameters agreed well with the semiquantitative results obtained with the protein substrates. C1 NCI, Frederick Canc Res & Dev Ctr, HIV Drug Resistance Program, Frederick, MD 21702 USA. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Oroszlan, S (reprint author), NCI, Frederick Canc Res & Dev Ctr, HIV Drug Resistance Program, POB B,Bldg 536,Room 6, Frederick, MD 21702 USA. EM oroszlans@ncifcrf.gov RI Tozser, Jozsef/A-7840-2008; OI Tozser, Jozsef/0000-0003-0274-0056; Tozser, Jozsef/0000-0001-5076-8729 NR 58 TC 4 Z9 6 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD APR 13 PY 2004 VL 43 IS 14 BP 4304 EP 4312 DI 10.1021/bi035625z PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 810AK UT WOS:000220677000028 PM 15065874 ER PT J AU Zhang, ZQ Wietgrefe, SW Li, QS Shore, MD Duan, LJ Reilly, C Lifson, JD Haase, AT AF Zhang, ZQ Wietgrefe, SW Li, QS Shore, MD Duan, LJ Reilly, C Lifson, JD Haase, AT TI Roles of substrate availability and infection of restina and activated CD4(+) T cells in transmission and acute simian immunodeficiency virus infection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LYMPHOCYTES IN-VITRO; HIV-1 INFECTION; LYMPHOID-TISSUES; HETEROSEXUAL TRANSMISSION; ANTIRETROVIRAL THERAPY; RHESUS MACAQUES; TYPE-1; SIV; REPLICATION; INDIVIDUALS AB in studies of sexual mucosal transmission and early stages of simian immunodeficiency virus (SIV) and HIV infections, productive infection predominates in CD4(+) T cell populations, in both ostensibly resting and activated cells. The surprising ability of SIV and HIV to replicate in resting cells in vivo, in contrast to propagation of infection in vitro, suggested a model in which during the early stages of infection these viruses exploit the greater availability of resting cells to maintain unbroken chains of transmission from an infected resting cell to another resting cell nearby. Because immune activation in response to infection provides more activated CD4(+) Tcells, these viruses take advantage of the greater efficiency of virus production and spread in activated cells for propagation and dissemination of infection. In this article, we report the results of experimental tests of this model, including visualization at the light microscopic level and direct analysis of virus production by cells in tissues. Analysis of tissues of rhesus macaques inoculated intravaginally or i.v. with SIV supports the proposed roles of target cell availability, susceptibility, and virus production by infected resting and activated CD4(+) T cells in mucosal transmission and early infection, and points to a potential role for topical anti-inflammatory agents in moderating the initial propagation of infection. C1 Univ Minnesota, Sch Med, Dept Microbiol, Minneapolis, MN 55455 USA. Univ Minnesota, Div Sch Publ Hlth, Dept Biostat, Minneapolis, MN 55455 USA. NCI, Sci Applicat Int Corp Frederick Inc, AIDS Vaccine Program, Frederick, MD 21702 USA. RP Haase, AT (reprint author), Univ Minnesota, Sch Med, Dept Microbiol, MMC 196,420 Delaware St SE, Minneapolis, MN 55455 USA. EM ashley@mail.ahc.umn.edu FU NCI NIH HHS [N01-CO-12400, N01CO12400]; NIAID NIH HHS [R01 AI048484, AI028246, AI048484, R37 AI028246] NR 44 TC 148 Z9 151 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 13 PY 2004 VL 101 IS 15 BP 5640 EP 5645 DI 10.1073/pnas.0308425101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 812TJ UT WOS:000220861500062 PM 15064398 ER PT J AU Xu, HZ Svarovskaia, ES Barr, R Zhang, YJ Khan, MA Strebel, K Pathak, VK AF Xu, HZ Svarovskaia, ES Barr, R Zhang, YJ Khan, MA Strebel, K Pathak, VK TI A single amino acid substitution in human APOBEC3G antiretroviral enzyme confers resistance to HIV-1 virion infectivity factor-induced depletion SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; VIF PROTEIN; ANTIVIRAL ACTIVITY; T-LYMPHOCYTES; SOR GENE; DNA; HYPERMUTATION; DEGRADATION; UBIQUITINATION; REPLICATION AB HIV-1 and other retroviruses occasionally undergo hypermutation, characterized by a high rate of G-to-A substitution. Recently, the human apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G (APOBEC3G), first identified as CEM15, was shown to be packaged into retroviral virions and to deaminate deoxycytidine to deoxyuridine in newly synthesized viral minus-strand DNA, thereby inducing G-to-A hypermutation. This innate mechanism of resistance to retroviral infection is counteracted by the HIV-1 viral infectivity factor (Vif), which protects the virus by preventing the incorporation of APOBEC3G into virions by rapidly inducing its ubiquitination and proteasomal degradation. To gain insights into the mechanism by which Vif protects HIV-1 from APOBEC3G, we substituted several amino acids in human APOBEC3G with equivalent residues in simian APOBEC3Gs that are resistant to HIV-1 Vif and determined the effects of the mutations on HIV-1 replication in the presence and absence of Vif. We found that a single amino acid substitution mutant of human APOBEC3G (D128K) can interact with HIV-1 Vif but is not depleted from cells; thus, it inhibits HIV-1 replication in an HIV-1 Vif-resistant manner. Interestingly, rhesus macaque simian immunodeficiency virus 239 or HIV-2 Vif coexpression depleted the intracellular steady state levels of the D128K mutant and abrogated its antiviral activity, indicating that it can be a substrate for the proteasomal pathway. The HIV-1 Vif-resistant mutant APOBEC3G could provide a gene therapy approach to combat HIV-1 infection. C1 NCI, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21702 USA. NIAID, Viral Biochem Sect, NIH, Bethesda, MD 20892 USA. RP Pathak, VK (reprint author), NCI, HIV Drug Resistance Program, Ctr Canc Res, Bldg 535,Room 334, Frederick, MD 21702 USA. EM vpathak@ncifcrf.gov NR 32 TC 171 Z9 176 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 APR 13 PY 2004 VL 101 IS 15 BP 5652 EP 5657 DI 10.1073/pnas.0400830101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 812TJ UT WOS:000220861500064 PM 15054139 ER PT J AU Pietrini, P Furey, ML Ricciardi, E Gobbini, MI Wu, WHC Cohen, L Guazzelli, M Haxby, JV AF Pietrini, P Furey, ML Ricciardi, E Gobbini, MI Wu, WHC Cohen, L Guazzelli, M Haxby, JV TI Beyond sensory images: Object-based representation in the human ventral pathway SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE haptic perception; fMRI; supramodal cortex ID CROSS-MODAL PLASTICITY; VISUAL-CORTEX; BLIND HUMANS; ACTIVATION PATTERNS; NEURAL SYSTEMS; FACES; PERCEPTION; PERIOD; AREAS AB We investigated whether the topographically organized, category-related patterns of neural response in the ventral visual pathway are a representation of sensory images or a more abstract representation of object form that is not dependent on sensory modality. We used functional MRI to measure patterns of response evoked during visual and tactile recognition of faces and manmade objects in sighted subjects and during tactile recognition in blind subjects. Results showed that visual and tactile recognition evoked category-related patterns of response in a ventral extrastriate visual area in the inferior temporal gyrus that were correlated across modality for manmade objects. Blind subjects also demonstrated category-related patterns of response in this "visual" area, and in more ventral cortical regions in the fusiform gyrus, indicating that these patterns are not due to visual imagery and, furthermore, that visual experience is not necessary for category-related representations to develop in these cortices. These results demonstrate that the representation of objects in the ventral visual pathway is not simply a representation of visual images but, rather, is a representation of more abstract features of object form. C1 Univ Pisa, Sch Med, Dept Expt Pathol, Lab Clin Biochem, I-56126 Pisa, Italy. NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Princeton Univ, Dept Psychol, Princeton, NJ 08544 USA. NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. Univ Pisa, Sch Med, Psychol Branch, Dept Psychiat Neurobiol Pharmacol & Biotechnol, I-56126 Pisa, Italy. RP Pietrini, P (reprint author), Univ Pisa, Sch Med, Dept Expt Pathol, Lab Clin Biochem, I-56126 Pisa, Italy. EM pietro.pietrini@med.unipi.it RI Furey, Maura/H-5273-2013; Ricciardi, Emiliano/E-6929-2011 OI Ricciardi, Emiliano/0000-0002-7178-9534 NR 24 TC 235 Z9 240 U1 2 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 APR 13 PY 2004 VL 101 IS 15 BP 5658 EP 5663 DI 10.1073/pnas.0400707101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 812TJ UT WOS:000220861500065 PM 15064396 ER PT J AU Thaler, C Gray, AC Lipscombe, D AF Thaler, C Gray, AC Lipscombe, D TI Cumulative inactivation of N-type Ca(V)2.2 calcium channels modified by alternative splicing SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID II-III LOOP; CA2+ CHANNEL; ELECTROPHYSIOLOGICAL CHARACTERIZATION; ALPHA(1B) SUBUNIT; NERVE-TERMINALS; BETA-SUBUNIT; SYNTAXIN; ISOFORMS; NEURONS; BRAIN AB The Ca(V)2 family of voltage-gated calcium channels, present in presynaptic nerve terminals, regulates exocytosis and synaptic transmission. Cumulative inactivation of these channels occurs during trains of action potentials, and this may control short-term dynamics at the synapse. Inactivation during brief, repetitive stimulation is primarily attributed to closed-state inactivation, and several factors modulate the susceptibility of voltage-gated calcium channels to this form of inactivation. We show that alternative splicing of an exon in a cytoplasmic region of the Ca(V)2.2 channel modulates its sensitivity to inactivation during trains of action potential waveforms. The presence of this exon, exon 18a, protects the Ca(V)2.2 channel from entry into closed-state inactivation specifically during short (10 ms to 3 s) and small depolarizations of the membrane potential (-60 mV to -50 mV). The reduced sensitivity to closed-state inactivation within this dynamic range likely underlies the differential responsiveness of Ca(V)2.2 splice isoforms to trains of action potential waveforms. Regulated alternative splicing of Ca(V)2.2 represents a possible mechanism for modulating short-term dynamics of synaptic efficacy in different regions of the nervous system. C1 Brown Univ, Dept Neurosci, Providence, RI 02912 USA. NIAAA, Lab Mol Physiol, Sect Cellular Biophoton, NIH, Rockville, MD 20852 USA. RP Lipscombe, D (reprint author), Brown Univ, Dept Neurosci, Providence, RI 02912 USA. EM diane-lipscombe@brown.edu FU NIMH NIH HHS [T32 MH19118, T32 MH019118]; NINDS NIH HHS [F32 NS043082, NS29967, NS43082, R01 NS029967] NR 35 TC 30 Z9 31 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 13 PY 2004 VL 101 IS 15 BP 5675 EP 5679 DI 10.1073/pnas.0303402101 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 812TJ UT WOS:000220861500068 PM 15060274 ER PT J AU Smothers, BA Yahr, HT Ruhl, CE AF Smothers, BA Yahr, HT Ruhl, CE TI Detection of alcohol use disorders in general hospital admissions in the United States SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID INTERVIEW SCHEDULE AUDADIS; CHANGE DRINKING BEHAVIOR; POPULATION SAMPLE; DRUG MODULES; PREVALENCE; RELIABILITY; DIAGNOSIS; IDENTIFICATION; CONSUMPTION; MOTIVATION AB Background: Previous studies in which research-based assessment for alcohol problems at admission was compared with physician diagnoses indicated that many alcohol diagnoses in hospitalized patients were missed. We estimated the extent to which hospital records documented detection of alcohol abuse or dependence and other alcohol-related problems in a national sample of hospital admissions having a research-based diagnosis of alcohol use disorder ("interview-positive admissions"). We also estimated rates of inpatient alcohol intervention and referral for treatment. Methods: A complex, multistage, probability sample was designed to represent nonmaternity, acute-care admissions to nonfederal, short-stay, general hospitals in the contiguous United States. The study included 2040 admissions, 1613 male and 427 female. Research-based diagnoses of current (ie, past 12 months) Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition alcohol use disorder were derived from a structured, computer-assisted, personal interview containing the Alcohol Use Disorders and Associated Disabilities Interview Schedule. Information on detection, inpatient intervention, and treatment referral were obtained via retrospective analysis of closed hospital records covering the index visit. Results: Record-documented diagnoses of alcohol-related problems were found in 40% to 42% of interview-positive admissions. Inpatient intervention rate was estimated at 21% for interview-positive admissions, and treatment referral rate, 24%. For detected interview-positive admissions, estimated rates of intervention and referral were 50% and 53%, respectively. Conclusions: Estimated rates of detection, inpatient intervention, and treatment referral of alcohol use disorders in hospital admissions were low. Current-drinking hospital admissions should be screened for alcohol problems as part of the admission routine, with further professional evaluation, intervention, and treatment referral as indicated. C1 NIAAA, Div Epidemiol & Prevent Res, NIH, Bethesda, MD 20892 USA. Social & Sci Syst, Silver Spring, MD USA. RP Smothers, BA (reprint author), NIAAA, Div Epidemiol & Prevent Res, NIH, 5635 Fishers Ln,Room 2073, Bethesda, MD 20892 USA. EM bs86h@nih.gov FU AHRQ HHS [HS100970018]; NIAAA NIH HHS [N01AA82014, N01AA90007] NR 40 TC 57 Z9 58 U1 1 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 APR 12 PY 2004 VL 164 IS 7 BP 749 EP 756 DI 10.1001/archinte.164.7.749 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 812GR UT WOS:000220828500006 PM 15078644 ER PT J AU Arighi, CN Hartnell, LM Aguilar, RC Haft, CR Bonifacino, JS AF Arighi, CN Hartnell, LM Aguilar, RC Haft, CR Bonifacino, JS TI Role of the mammalian retromer in sorting of the cation-independent mannose 6-phosphate receptor SO JOURNAL OF CELL BIOLOGY LA English DT Article DE lysosomal enzymes; multivesicular bodies; sorting nexins; yeast vacuole; clathrin adaptors ID TRANS-GOLGI NETWORK; FACTOR-II RECEPTOR; GGA PROTEINS INTERACT; CYTOPLASMIC DOMAIN; ENDOCYTIC PATHWAY; MULTIVESICULAR ENDOSOMES; QUANTITATIVE-ANALYSIS; MEMBRANE-PROTEINS; LYSOSOMAL-ENZYMES; PLASMA-MEMBRANE AB The cation-independent mannose 6-phosphate receptor (CI-MPR) mediates sorting of lysosomal hydrolase precursors from the TGN to endosomes. After releasing the hydrolase precursors into the endosomal lumen, the unoccupied receptor returns to the TGN for further rounds of sorting. Here, we show that the mammalian retromer complex participates in this retrieval pathway. The hVps35 subunit of retromer interacts with the cytosolic domain of the CI-MPR. This interaction probably occurs in an endosomal compartment, where most of the retromer is localized. In particular, retromer is associated with tubular-vesicular profiles that emanate from early endosomes or from intermediates in the maturation from early to late endosomes. Depletion of retromer by RNA interference increases the lysosomal turnover of the CI-MPR, decreases cellular levels of lysosomal hydrolases, and causes swelling of lysosomes. These observations indicate that retromer prevents the delivery of the CI-MPR to lysosomes, probably by sequestration into endosome-derived tubules from where the receptor returns to the TGN. C1 Natl Inst Child Hlth & Human Dev, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Diabet & Digest & Kidney Dis, Div Diabet Endocrinol & Metab, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), Natl Inst Child Hlth & Human Dev, Cell Biol & Metab Branch, NIH, Bldg 18T,Room 101, Bethesda, MD 20892 USA. EM juan@helix.nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 NR 77 TC 323 Z9 331 U1 6 U2 20 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD APR 12 PY 2004 VL 165 IS 1 BP 123 EP 133 DI 10.1083/jcb.200312055 PG 11 WC Cell Biology SC Cell Biology GA 813AP UT WOS:000220880300012 PM 15078903 ER PT J AU Pommier, Y Sordet, O Antony, S Hayward, RL Kohn, KW AF Pommier, Y Sordet, O Antony, S Hayward, RL Kohn, KW TI Apoptosis defects and chemotherapy resistance: molecular interaction maps and networks SO ONCOGENE LA English DT Review DE cancer chemotherapy; apoptosis; multidrug resistance; camptothecins ID NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; PROSTATE-CANCER CELLS; ETOPOSIDE-INDUCED APOPTOSIS; SURVIVAL-SIGNALING PATHWAY; BCL-2 FAMILY-MEMBERS; PHOSPHATIDYLINOSITOL 3,4,5-TRISPHOSPHATE 5-PHOSPHATASE; PERMEABILITY TRANSITION PORE; PROTEASOME INHIBITOR PS-341; PROTEIN-KINASE B/AKT AB Intrinsic (innate) and acquired (adaptive) resistance to chemotherapy critically limits the outcome of cancer treatments. For many years, it was assumed that the interaction of a drug with its molecular target would yield a lethal lesion, and that determinants of intrinsic drug resistance should therefore be sought either at the target level (quantitative changes or/and mutations) or upstream of this interaction, in drug metabolism or drug transport mechanisms. It is now apparent that independent of the factors above, cellular responses to a molecular lesion can determine the outcome of therapy. This review will focus on programmed cell death (apoptosis) and on survival pathways (Bcl-2, Apaf-1, AKT, NF-kappaB) involved in multidrug resistance. We will present our molecular interaction mapping conventions to summarize the AKT and IkappaB/NF-kappaB networks. They complement the p53, Chk2 and c-Abl maps published recently. We will also introduce the 'permissive apoptosis-resistance' model for the selection of multidrug-resistant cells. C1 NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH,DHHS, Bethesda, MD 20892 USA. Western Gen Hosp, Canc Res United Kingdom, Edinburgh EH4 2XU, Midlothian, Scotland. RP Pommier, Y (reprint author), Inst Pasteur, Lab Genom Stabil, Pavillon Fernbach,Room 26,25 Rue Dr Roux, F-75724 Paris, France. EM pommiery@pasteur.fr RI Sordet, Olivier/M-3271-2014 NR 202 TC 363 Z9 381 U1 4 U2 24 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD APR 12 PY 2004 VL 23 IS 16 BP 2934 EP 2949 DI 10.1038/sj.onc.1207515 PG 16 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 811VO UT WOS:000220799600019 PM 15077155 ER PT J AU Slebos, RJC Little, RE Umbach, DM Antipkin, Y Zadaorozhnaja, TD Mendel, NA Sommer, CA Conway, K Parrish, E Gulino, S Taylor, JA AF Slebos, RJC Little, RE Umbach, DM Antipkin, Y Zadaorozhnaja, TD Mendel, NA Sommer, CA Conway, K Parrish, E Gulino, S Taylor, JA TI Mini-and microsatellite mutations in children from Chernobyl accident cleanup workers SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE minisatellite; microsatellite; germline mutation; Chernobyl accident ID LUNG-CANCER; GERMLINE; INSTABILITY; CELLS; HYPERMUTABILITY; LIQUIDATORS; LAVAGE; TRACT AB Knowledge about possible genotoxic effects of low-dose radiation on the human germline is limited and relies primarily on extrapolations from high-dose exposures. To test whether ionizing radiation can cause paternal genetic mutations that are transmitted to offspring, we enrolled families of 88 Chernobyl cleanup workers exposed to ionizing radiation. We analyzed DNA isolated from lymphocytes for mutations via DNA blotting with the multi-locus minisatellite probes 33.6 and 33.15 and via PCR in a panel of six tetranucleotide repeats. Children conceived before and children conceived after their father's exposure showed no statistically significant differences in mutation frequencies. We saw an increase in germline microsatellite mutations after radiation exposure that was not statistically significant. We found no dependence of mutation rate on increasing exposure. A novel finding was that the tetranucleotide marker D7S 1482 demonstrated germline hypermutability. In conclusion, our results do not support an increased level of germline minisatellite mutations but suggest a modest increase in germline mutations in tetranucleotide repeats. Small sample size, however, limited statistical power. (C) 2003 Elsevier B.V. All rights reserved. C1 Burroughs Wellcome Co, Res Triangle Pk, NC 27709 USA. Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Res Triangle Pk, NC USA. Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC USA. Ukranian Inst Pediat Obstet & Gynecol, Kiev, Ukraine. Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. RP Taylor, JA (reprint author), Burroughs Wellcome Co, Res Triangle Pk, NC 27709 USA. EM taylor@niehs.nih.gov OI taylor, jack/0000-0001-5303-6398 NR 23 TC 32 Z9 37 U1 3 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD APR 11 PY 2004 VL 559 IS 1-2 BP 143 EP 151 DI 10.1016/j.mrgentox.2004.01.003 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 815AC UT WOS:000221014200015 PM 15066582 ER PT J AU Pastrana, DV Buck, CB Pang, YYS Thompson, CD Castle, PE FitzGerald, PC Kjaer, SK Lowy, DR Schiller, JT AF Pastrana, DV Buck, CB Pang, YYS Thompson, CD Castle, PE FitzGerald, PC Kjaer, SK Lowy, DR Schiller, JT TI Reactivity of human sera in a sensitive, high-throughput pseudovirus-based papillomavirus neutralization assay for HPV16 and HPV18 SO VIROLOGY LA English DT Article DE papillomavirus; neutralization; vector; vaccine; scrology; antibodies; HPV; virion; pseudovirus; virus-like particles ID VIRUS-LIKE PARTICLES; CERVICAL INTRAEPITHELIAL NEOPLASIA; COTTONTAIL RABBIT PAPILLOMAVIRUS; ANTIBODY-MEDIATED NEUTRALIZATION; MINOR CAPSID PROTEIN; IN-VITRO; BOVINE PAPILLOMAVIRUS; MONOCLONAL-ANTIBODIES; LINEAR EPITOPES; L1/L2 CAPSIDS AB Sensitive high-throughput neutralization assays, based upon pseudoviruses carrying a secreted alkaline phosphatase (SEAP) reporter gene, were developed and validated for human papillornavirus (HPV)16, HPV18, and bovine papillomavirus 1 (BPV1). SEAP pseudoviruses were produced by transient transfection of codon-modified papillornavirus structural genes into an SV40 T antigen expressing line derived from 293 cells, yielding sufficient pseudovirus from one flask for thousands of titrations. In a 96-well plate format, in this initial characterization, the assay was reproducible and appears to be as sensitive as, but more specific than, a standard papillornavirus-like particle (VLP)-based enzyme-linked immunosorbent assay (ELISA). The neutralization assay detected type-specific HPV16 or HPV18 neutralizing antibodies (titers of 160-10240) in sera of the majority of a group of women infected with the corresponding HPV type, but not in virgin women. Sera from HPV16 VLP vaccinees had high anti-HPV16 neutralizing titers (mean: 45000; range: 5120-163840), but no anti-HPV18 neutralizing activity. The SEAP pseudovirus-based neutralization assay should be a practical method for quantifying potentially protective antibody responses in HPV natural history and prophylactic vaccine studies. Published by Elsevier Inc. C1 Natl Canc Inst, Cellular Oncol Lab, Bethesda, MD 20842 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Genome Anal Unit, Bethesda, MD 20892 USA. Danish Canc Soc, Inst Canc Epidemiol, Dept Virus Hormones & Canc, Copenhagen, Denmark. RP Schiller, JT (reprint author), Natl Canc Inst, Cellular Oncol Lab, Bldg 37 Room 4106, Bethesda, MD 20842 USA. EM schillej@dc37a.nci.nih.gov OI Kjaer, Susanne/0000-0002-8347-1398; Buck, Christopher/0000-0003-3165-8094 NR 59 TC 221 Z9 237 U1 1 U2 10 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 APR 10 PY 2004 VL 321 IS 2 BP 205 EP 216 DI 10.1016/j.virol.2003.12.027 PG 12 WC Virology SC Virology GA 811FN UT WOS:000220757900005 PM 15051381 ER PT J AU Biacchesi, S Skiadopoulos, MH Tran, KC Murphy, BR Collins, PL Buchholz, UJ AF Biacchesi, S Skiadopoulos, MH Tran, KC Murphy, BR Collins, PL Buchholz, UJ TI Recovery of human metapneumovirus from cDNA: optimization of growth in vitro and expression of additional genes SO VIROLOGY LA English DT Article DE metapneumovirus; paramyxovirus; recombinant virus; respiratory disease; vaccines; expression vector ID RESPIRATORY SYNCYTIAL VIRUS; ANTIGENOMIC PROMOTERS; TRACT INFECTIONS; RNA REPLICATION; YOUNG-CHILDREN; TRANSCRIPTION; SEQUENCE; BRONCHIOLITIS; REQUIRES; DISEASE AB Human metapneumovirus (HMPV) is a recently recognized causative agent of respiratory tract disease in individuals of all ages and especially young infants. HMPV remains poorly characterized and has been reported to replicate inefficiently in vitro. Complete consensus sequences were recently determined for two isolates representing the two proposed HMPV genetic subgroups (Biacchesi et al., Virology 315 (1) (2003) 1). We have developed a reverse genetic system to produce one of these isolates, CAN97-83, entirely from cDNA. We also recovered aversion, rHMPV-GFP, in which the enhanced green fluorescent protein (GFP)was expressed from a transcription cassette inserted as the first gene, leaving the 41-nt leader region and first 16 nt of the N gene undisturbed. The ability to monitor GFP expression in living cells greatly facilitated the initial recovery of this slow-growing virus. In addition, the ability to express a foreign gene from an engineered transcription cassette confirmed the identification of the HMPV transcription signals and identified the F gene-end signal as being highly efficient for transcription termination. The ability to recover virus containing a foreign insert in this position indicated that the viral promoter is contained within the Y-terminal 57 nt of the genome. Recombinant HMPV replicated in vitro as efficiently as biologically derived HMPV, whereas the kinetics and final yield of rHMPV-GFP were reduced several-fold. Conditions for trypsin treatment were investigated, providing for improved virus yields. Another version of HMPV, rHMPV+G1F23, was recovered that contained a second copy of the G gene and two extra copies of F in promoter-proximal positions in the order G1-F2-F3. Thus, this recombinant genome would encode 11 mRNAs rather than eight and would be 17.3 kb long, 30% longer than that of the natural virus. Nonetheless, the rHMPV+G1F23 virus replicated in vitro with an efficiency that was only modestly reduced compared to rHMPV and was essentially the same as rHMPV-GFP. Northern blot analysis showed that the increased number and promoter-proximal location of the added copies of the F and G genes resulted in a more than 6- and 14-fold increase in the expression of F and G mRNA, respectively, and sequence analysis confirmed the intactness of the added genes in recovered virus. Thus, it should be feasible to construct an HMPV vaccine virus containing extra copies of the G and F putative protective antigen genes to increase antigen expression or to provide representation of additional antigenic lineages or subgroups of HMPV. Published by Elsevier Inc. C1 NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Buchholz, UJ (reprint author), NIAID, Infect Dis Lab, Bldg 50,Room 6507,50 S Dr MSC 8007, Bethesda, MD 20892 USA. EM ubuchholz@niaid.nih.gov RI Biacchesi, Stephane/A-6924-2010 NR 30 TC 78 Z9 82 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 APR 10 PY 2004 VL 321 IS 2 BP 247 EP 259 DI 10.1016/j.virol.2003.12.020 PG 13 WC Virology SC Virology GA 811FN UT WOS:000220757900009 PM 15051385 ER PT J AU Puri, A Rawat, SS Lin, HMJ Finnegan, CA Mikovits, J Ruscetti, FW Blumenthal, R AF Puri, A Rawat, SS Lin, HMJ Finnegan, CA Mikovits, J Ruscetti, FW Blumenthal, R TI An inhibitor of glycosphingolipid metabolism blocks HIV-1 infection of primary T-cells SO AIDS LA English DT Article DE HIV-1 infection; glycosphingolipids; 1-phenyl-2-hexadecanoylamino-3-morpholino-1; -propanol (PPMP); Gb3; GM3; CD4 lymphocytes; membrane fusion ID IMMUNODEFICIENCY-VIRUS ENTRY; GLUCOSYLCERAMIDE SYNTHASE; ERYTHROCYTE GLYCOSPHINGOLIPIDS; FUSION; GP120; CHOLESTEROL; LEVEL; CXCR4; CD4; GM3 AB Objective: HIV-1 uses CD4 and chemokine receptors to enter cells. However, other target membrane components may also be involved. This study examines the role of glycosphingolipids (GSL) in HIV-1 entry into primary lymphocytes and its modulation by an inhibitor of GSL biosynthesis. Methods: CD4 lymphocytes purified from normal or the p-group subtype individuals that were defective in Gb3 synthesis were treated with a GSL biosynthesis inhibitor, I phenyl-2-hexadecanoylamino-3-morpholino-1-propanol (PPMP). The PPMP-treated cells were tested for HIV-1 replication by measuring p24 antigen production for 7-14 days post-infection and for susceptibility to HIV-1 Env-mediated fusion monitored by a fluorescent dye transfer assay. The effects of PPMP treatment on HIV-1 binding to CD4 lymphocytes were also examined by measuring HIV-1 p24. Results: CD4 lymphocytes from p donors that are devoid of Gb3, but have elevated levels of GM3 were highly susceptible to HIV-1 fusion/entry. Pre-treatment of primary human CD4 lymphocytes from normal or p-sub-group type with PPMP, significantly reduced HIV-1 replication with no change in CD4 and CXCR4 levels. Inhibition of HIV-1 infection was due to the block in HIV-1 Env-mediated plasma membrane fusion. Binding of HIV-1 to CD4 lymphocytes was not affected by PPMP treatment. Conclusion: Manipulation of glycosphingolipid metabolic pathways may alter susceptibility of CD4 lymphocytes to HIV-1 entry. (C) 2004 Lippincott Williams Wilkins. C1 NCI Frederick, SAIC Frederick Inc, Ctr Canc Res, Lab Expt & Computat Biol, Frederick, MD 21702 USA. NCI Frederick, SAIC Frederick Inc, Lab Antiviral Drug Mech, Frederick, MD 21702 USA. NCI Frederick, SAIC Frederick Inc, Ctr Canc Res, Basic Res Lab, Frederick, MD 21702 USA. RP Blumenthal, R (reprint author), NCI Frederick, SAIC Frederick Inc, Ctr Canc Res, Lab Expt & Computat Biol, Frederick, MD 21702 USA. EM blumen@helix.nih.gov NR 25 TC 31 Z9 32 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD APR 9 PY 2004 VL 18 IS 6 BP 849 EP 858 DI 10.1097/01.aids.0000111432.91384.fa PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 818DJ UT WOS:000221225500002 PM 15060432 ER PT J AU Matsuzaki, M Hasegawa, T Takeda, A Kikuchi, A Furukawa, K Kato, Y Itoyama, Y AF Matsuzaki, M Hasegawa, T Takeda, A Kikuchi, A Furukawa, K Kato, Y Itoyama, Y TI Histochemical features of stress-induced aggregates in alpha-synuclein overexpressing cells SO BRAIN RESEARCH LA English DT Article DE alpha-synuclein; overexpressing cell; histochemical feature ID FAMILIAL PARKINSONS-DISEASE; LEWY BODIES; OXIDATIVE DAMAGE; IN-VITRO; MUTATION; DEMENTIA; GENE; NEURODEGENERATION; IRON; RNA AB a-Synuclein is a major component of intracytoplasmic inclusions including Lewy bodies (LB), Lewy neurites (LN) and glial cytoplasmic inclusions, and plays a key role in neurodegenerative processes in Parkinson's disease (PD) and other synucleinopathies. Although the molecular mechanisms of the disease process still remain to be elucidated, recent studies have suggested that an interaction between reactive oxygen species (ROS) and alpha-synuclein may be closely associated with the initiation and/or the progression of synucleinopathies. In this study, we established human dopaminergic SH-SY5Y cell lines overexpressing wild-type or Mutant a-synuclein and exposed them to various ROS generators. After the exposure to ROS, alpha-synuclein aggregates were formed in the cytoplasm of these cells, and these were immunopositive for ubiquitin, nitrotyrosine and dityrosine, and positive for thioflavin S staining. Thus, the obtained cytoplasmic aggregates shared many features with inclusion bodies in synucleinopathies. The gamma-tubulin and molecular chaperones coexisted as well, suggesting that the aggregate formation is associated with the intracellular transport along microtubules and may reflect protective responses against neuronal insults. This cellular model not only will be informative for our Understanding of the pathophysiological process in synucleinopathies, but also can be applied to the screening of neuroprotective Molecules with therapeutic potential. (C) 2004 Elsevier B.V. All rights reserved. C1 Tohoku Univ, Sch Med, Dept Neurol, Sendai, Miyagi 9808574, Japan. NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. Himeji Inst Technol, Sch Humanities Environm Policy, Himeji, Hyogo 67122, Japan. RP Takeda, A (reprint author), Tohoku Univ, Sch Med, Dept Neurol, 1-1 Seiryo-Machi, Sendai, Miyagi 9808574, Japan. EM atakeda@em.neurol.med.tohoku.ac.jp NR 29 TC 30 Z9 30 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD APR 9 PY 2004 VL 1004 IS 1-2 BP 83 EP 90 DI 10.1016/j.brainres.2004.01.017 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 812EH UT WOS:000220822300009 PM 15033422 ER PT J AU Bosetti, F Baracca, A Lenaz, G Solaini, G AF Bosetti, F Baracca, A Lenaz, G Solaini, G TI Increased state 4 mitochondrial respiration and swelling in early post-ischemic reperfusion of rat heart SO FEBS LETTERS LA English DT Article DE mitochondrion; ischemia and reperfusion; respiration; uncoupling; heart ID SUBSARCOLEMMAL MITOCHONDRIA; OXIDATIVE-PHOSPHORYLATION; PERMEABILITY TRANSITION; UNCOUPLING PROTEINS; CYTOCHROME-OXIDASE; ATP SYNTHASE; ISCHEMIA; OXYGEN; CARDIOPROTECTION; CARDIOLIPIN AB Isolated rat hearts were exposed to 30 min ischemia or to 30 min ischemia followed by 2, 5 or 40 min reperfusion and mitochondria were isolated at these different time points. ADP-stimulated, succinate-dependent respiration rate (state 3) was not significantly changed at the different time points examined. In contrast, state 4 (non-ADP-stimulated) respiration rate was significantly increased after 30 min ischemia, and it increased further during the first post-ischemic reperfusion period. Mitochondrial swelling, as evaluated under conditions of the major controlled ion channels (i.e. permeability transition pore and ATP-dependent mitochondrial K+ channel) closed, significantly increased in parallel. It is suggested that the inner mitochondrial membrane permeability is increased under exposure of the heart to ischemia and early reperfusion, and that the phenomenon is reversible upon subsequent long periods of reperfusion. (C) 2004 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 Scuola Super Univ Perfezionamento S Anna, I-56127 Pisa, Italy. NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. Univ Bologna, Dipartimento Biochim G Moruzzi, Bologna, Italy. RP Solaini, G (reprint author), Scuola Super Univ Perfezionamento S Anna, Piazza Martiri 33, I-56127 Pisa, Italy. EM gsolaini@sssup.it RI Lenaz, Giorgio/B-5751-2013; OI SOLAINI, GIANCARLO/0000-0001-7825-0446 FU Telethon [GP0280Y01] NR 29 TC 22 Z9 22 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 APR 9 PY 2004 VL 563 IS 1-3 BP 161 EP 164 DI 10.1016/S0014-5793(04)00294-7 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 811LK UT WOS:000220773200031 PM 15063742 ER PT J AU Xavier, S Piek, E Fujii, M Javelaud, D Mauviel, A Flanders, KC Samuni, AM Felici, A Reiss, M Yarkoni, S Sowers, A Mitchell, JB Roberts, AB Russo, A AF Xavier, S Piek, E Fujii, M Javelaud, D Mauviel, A Flanders, KC Samuni, AM Felici, A Reiss, M Yarkoni, S Sowers, A Mitchell, JB Roberts, AB Russo, A TI Amelioration of radiation-induced fibrosis - Inhibition of transforming growth factor-beta signaling by halofuginone SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INDUCED PULMONARY FIBROSIS; TGF-BETA; IONIZING-RADIATION; GENE-REGULATION; IN-VIVO; CELLS; SMAD3; FIBROBLASTS; ACTIVATION; SKIN AB Radiation-induced fibrosis is an untoward effect of high dose therapeutic and inadvertent exposure to ionizing radiation. Transforming growth factor-beta (TGF-beta) has been proposed to be critical in tissue repair mechanisms resulting from radiation injury. Previously, we showed that interruption of TGF-beta signaling by deletion of Smad3 results in resistance to radiation-induced injury. In the current study, a small molecular weight molecule, halofuginone ( 100 nM), is demonstrated by reporter assays to inhibit the TGF-beta signaling pathway, by Northern blotting to elevate inhibitory Smad7 expression within 15 min, and by Western blotting to inhibit formation of phospho-Smad2 and phospho-Smad3 and to decrease cytosolic and membrane TGF-beta type II receptor (TbetaRII). Attenuation of TbetaRII levels was noted as early as 1 h and down-regulation persisted for 24 h. Halofuginone blocked TGF-beta-induced delocalization of tight junction ZO-1, a marker of epidermal mesenchymal transition, in NMuMg mammary epithelial cells and suggest halofuginone may have in vivo anti-fibrogenesis characteristics. After documenting the in vitro cellular effects, halofuginone (intraperitoneum injection of 1, 2.5, or 5 mug/mouse/day) efficacy was assessed using ionizing radiation-induced ( single dose, 35 or 45 Gy) hind leg contraction in C3H/Hen mice. Halofuginone treatment alone exerted no toxicity but significantly lessened radiation-induced fibrosis. The effectiveness of radiation treatment ( 2 gray/day for 5 days) of squamous cell carcinoma (SCC) tumors grown in C3H/Hen was not affected by halofuginone. The results detail the molecular effects of halofuginone on the TGF-beta signal pathway and show that halofuginone may lessen radiation-induced fibrosis in humans. C1 NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. Hop St Louis, INSERM, U532, F-75010 Paris, France. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Mol Genet & Microbiol, New Brunswick, NJ 08903 USA. Collgard Biopharmaceut Ltd, IL-49170 Petah Tiqwa, Israel. RP Russo, A (reprint author), Bldg 10,Rm B3-B69, Bethesda, MD 20892 USA. EM russo@helix.nih.gov RI Reiss, Michael/A-8314-2009; MAUVIEL, Alain/F-6251-2013 NR 57 TC 121 Z9 131 U1 1 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 APR 9 PY 2004 VL 279 IS 15 BP 15167 EP 15176 DI 10.1074/jbc.M309798200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 808UT UT WOS:000220594700083 PM 14732719 ER PT J AU Harndahl, L Wierup, N Enerback, S Mulder, H Manganiello, VC Sundler, F Degerman, E Ahren, B Holst, LS AF Harndahl, L Wierup, N Enerback, S Mulder, H Manganiello, VC Sundler, F Degerman, E Ahren, B Holst, LS TI beta-cell-targeted overexpression of phosphodiesterase 3B in mice causes impaired insulin secretion, glucose intolerance, and deranged islet morphology SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES; GLUCAGON-LIKE PEPTIDE-1; PROTEIN-KINASE; PANCREATIC-ISLETS; CARDIAC MYOCYTES; DEFICIENT MICE; RAT ISLETS; CAMP; ARCHITECTURE; EXPRESSION AB The second messenger cAMP mediates potentiation of glucose-stimulated insulin release. Use of inhibitors of cAMP-hydrolyzing phosphodiesterase (PDE) 3 and overexpression of PDE3B in vitro have demonstrated a regulatory role for this enzyme in insulin secretion. In this work, the physiological significance of PDE3B-mediated degradation of cAMP for the regulation of insulin secretion in vivo and glucose homeostasis was investigated in transgenic mice overexpressing PDE3B in pancreatic beta-cells. A 2-fold overexpression of PDE3B protein and activity blunted the insulin response to intravenous glucose, resulting in reduced glucose disposal. The effects were "dose"-dependent because mice overexpressing PDE3B 7-fold failed to increase insulin in response to glucose and hence exhibited pronounced glucose intolerance. Also, the insulin secretory response to intravenous glucagon-like peptide 1 was reduced in vivo. Similarly, islets stimulated in vitro exhibited reduced insulin secretory capacity in response to glucose and glucagon-like peptide 1. Perifusion experiments revealed that the reduction specifically affected the first phase of glucose-stimulated insulin secretion. Furthermore, morphological examinations demonstrated deranged islet cytoarchitecture. In conclusion, these results are consistent with an essential role for PDE3B in cAMP-mediated regulation of insulin release and glucose homeostasis. C1 Biomed Ctr, Dept Cell & Mol Biol, SE-22184 Lund, Sweden. Biomed Ctr, Dept Physiol Sci, SE-22184 Lund, Sweden. Gothenburg Univ, Dept Med Biochem, SE-40530 Gothenburg, Sweden. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Holst, LS (reprint author), Biomed Ctr, Dept Cell & Mol Biol, C11, SE-22184 Lund, Sweden. EM Lena.Stenson-Holst@medkem.lu.se RI Mulder, Hindrik/E-1045-2012 NR 45 TC 39 Z9 41 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 9 PY 2004 VL 279 IS 15 BP 15214 EP 15222 DI 10.1074/jbc.M308952200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 808UT UT WOS:000220594700088 PM 14736883 ER PT J AU Botos, J Xian, WJ Smith, DF Smith, CL AF Botos, J Xian, WJ Smith, DF Smith, CL TI Progesterone receptor deficient in chromatin binding has an altered cellular state SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STEROID-HORMONE RECEPTORS; TUMOR VIRUS PROMOTER; HEAT-SHOCK-PROTEIN; C-TERMINAL DOMAIN; GLUCOCORTICOID-RECEPTOR; SUBNUCLEAR TRAFFICKING; MONOCLONAL-ANTIBODIES; MOLECULAR CHAPERONES; IMMUNOPHILIN FKBP51; ESTROGEN-RECEPTOR AB Our previous work has shown that the progesterone receptor (PR) can exist in two distinct functional states in mammary adenocarcinoma cells. The differences in function included the ability to activate a promoter in organized chromatin, sensitivity to ligand, and ligand-independent activation. To determine whether these functional differences were because of altered cellular processing, we carried out biochemical analyses of the functionally distinct PRs. Although the majority of PR is localized to the nucleus, biochemical partitioning resulted in a loosely bound (cytosolic) fraction, and a tightly bound (nuclear) fraction. In the absence of progestins, the functionally distinct PRs differed significantly in partitioning between the two fractions. To characterize these fractions further, we analyzed interactions of unliganded PR with chaperones by coimmunoprecipitation. We determined that PR in the cytosolic fraction associated with hsp90 and p23. In contrast, PR in the nuclear fraction consisted of complexes containing hsp90, p23, and FKBP51 as well as PR that was dimerized and highly phosphorylated. Hormone treatment significantly reduced the formation of all PR-chaperone complexes. The hsp90 inhibitor, geldanamycin, similarly blocked transcriptional activity of both functionally distinct receptors. However, the two forms of the PR differed in their ability to associate with the mouse mammary tumor virus promoter in organized chromatin. These findings provide new information about the composition and distribution of mature progesterone receptor complexes in mammary adenocarcinoma cells, and suggest that differences in receptor subcellular distribution have a significant impact on their function. These findings also reveal that transiently expressed steroid receptors may not always be processed like their endogenous counterparts. C1 NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. Mayo Clin, Dept Biochem & Mol Biol, Scottsdale, AZ 85259 USA. RP Smith, CL (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, 41 Lib Dr, Bethesda, MD 20892 USA. EM smithcat@exchange.nih.gov NR 51 TC 8 Z9 10 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 APR 9 PY 2004 VL 279 IS 15 BP 15231 EP 15239 DI 10.1074/jbc.M309718200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 808UT UT WOS:000220594700090 PM 14744870 ER PT J AU Sik, A Passer, BJ Koonin, EV Pellegrini, L AF Sik, A Passer, BJ Koonin, EV Pellegrini, L TI Self-regulated cleavage of the mitochondrial intramembrane-cleaving protease PARL yields P beta, a nuclear-targeted peptide SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DYNAMIN-RELATED PROTEIN; RHOMBOID PROTEASE; PATHWAY; ESTABLISHMENT; APOPTOSIS; MECHANISM; COMPLEX; NEURONS; FAMILY; PCP1 AB Regulated intramembrane proteolysis (RIP) is an emerging paradigm in signal transduction. RIP is mediated by intramembrane-cleaving proteases (I-CliPs), which liberate biologically active nuclear or secreted domains from their membrane-tethered precursor proteins. The yeast Pcp1p/Rbd1p protein is a Rhomboid-like I-CliP that regulates mitochondrial membrane remodeling and fusion through cleavage of Mgm1p, a regulator of these essential activities. Although this ancient function is conserved in PARL ((P) under bar resenilins-(a) under bar ssociated (R) double under bar homboid-(l) under bar ike protein), the mammalian ortholog of Pcp1p/Rbd1p, the two proteins show a strong divergence at their N termini. However, the N terminus of PARL is significantly conserved among vertebrates, particularly among mammals, suggesting that this domain evolved a distinct but still unknown function. Here, we show that the cytosolic N-terminal domain of PARL is cleaved at positions 52-53(alpha-site) and 77-78 (beta-site). Whereas alpha-cleavage is constitutive and removes the mitochondrial targeting sequence, beta-cleavage appears to be developmentally controlled and dependent on PARL I-CliP activity supplied in trans. The beta-cleavage of PARL liberates Pbeta, a nuclear targeted peptide whose sequence is conserved only in mammals. Thus, in addition to its evolutionarily conserved function in regulating mitochondrial dynamics, PARL might mediate a mammalian-specific, developmentally regulated mitochondria-to-nuclei signaling through regulated proteolysis of its N terminus and release of the Pbeta peptide. C1 Univ Laval, Ctr Rech Robert Giffard, Quebec City, PQ G1J 2G3, Canada. Univ Laval, Dept Psychiat, Quebec City, PQ G1J 2G3, Canada. Mol Engines Labs, F-75011 Paris, France. Natl Lib Med, NCBI, NIH, Bethesda, MD 20894 USA. RP Pellegrini, L (reprint author), CRULRG, Mol Neurobiol Lab, 2601 Chemin Canardiere, Quebec City, PQ G1J 2G3, Canada. EM Luca.Pellegrini@crulrg.ulaval.ca NR 33 TC 43 Z9 44 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 APR 9 PY 2004 VL 279 IS 15 BP 15323 EP 15329 DI 10.1074/jbc.M313756200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 808UT UT WOS:000220594700101 PM 14732705 ER PT J AU Allende, ML Dreier, JL Mandala, S Proia, RL AF Allende, ML Dreier, JL Mandala, S Proia, RL TI Expression of the sphingosine 1-phosphate receptor, S1P(1), on T-cells controls thymic emigration SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTOR; THYMOCYTE EMIGRATION; VASCULAR MATURATION; ENDOTHELIAL-CELLS; SPHINGOSINE-1-PHOSPHATE; FTY720; LYSOPHOSPHOLIPIDS; EDG-1; IMMUNOSUPPRESSANT; PHOSPHORYLATION AB S1P1 is a widely distributed G protein-coupled receptor whose ligand, sphingosine 1-phosphate, is present in high concentrations in the blood. The sphingosine 1-phosphate receptor-signaling pathway is believed to have potent effects on cell trafficking in the immune system. To determine the precise role of the S1P1 receptor on T-cells, we established a T-cell-specific S1P1 knock-out mouse. The mutant mice showed a block in the egress of mature T-cells into the periphery. The expression of the S1P1 receptor was up-regulated in mature thymocytes, and its deletion altered the chemotactic responses of thymocytes to sphingosine 1-phosphate. The results indicated that the expression of the S1P1 receptor on T-cells controls their exit from the thymus and entry into the blood and, thus, has a central role in regulating the numbers of peripheral T-cells. C1 NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. Merck Res Labs, Dept Immunol & Rheumatol, Rahway, NJ 07065 USA. RP Proia, RL (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, Bldg 10,Rm 9N-314,10 Ctr Dr, Bethesda, MD 20892 USA. EM proia@nih.gov RI Proia, Richard/A-7908-2012 NR 37 TC 276 Z9 290 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 APR 9 PY 2004 VL 279 IS 15 BP 15396 EP 15401 DI 10.1074/jbc.M314291200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 808UT UT WOS:000220594700109 PM 14732704 ER PT J AU Ando, H Watabe, H Valencia, JC Yasumoto, K Furumura, M Funasaka, Y Oka, M Ichihashi, M Hearing, VJ AF Ando, H Watabe, H Valencia, JC Yasumoto, K Furumura, M Funasaka, Y Oka, M Ichihashi, M Hearing, VJ TI Fatty acids regulate pigmentation via proteasomal degradation of tyrosinase - A new aspect of ubiquitin-proteasome function SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; LINOLEIC-ACID; MULTICATALYTIC PROTEINASE; MELANOMA-CELLS; MAMMALIAN TYROSINASE; ENDOTHELIAL-CELLS; CIS-FATTY; KAPPA-B; ACTIVATION; PATHWAY AB Fatty acids are common components of biological membranes that are known to play important roles in intracellular signaling. We report here a novel mechanism by which fatty acids regulate the degradation of tyrosinase, a critical enzyme associated with melanin biosynthesis in melanocytes and melanoma cells. Linoleic acid ( unsaturated fatty acid, C18: 2) accelerated the spontaneous degradation of tyrosinase, whereas palmitic acid ( saturated fatty acid, C16:0) retarded the proteolysis. The linoleic acid-induced acceleration of tyrosinase degradation could be abrogated by inhibitors of proteasomes, the multicatalytic proteinase complexes that selectively degrade intracellular ubiquitinated proteins. Linoleic acid increased the ubiquitination of many cellular proteins, whereas palmitic acid decreased such ubiquitination, as compared with untreated controls, when a proteasome inhibitor was used to stabilize ubiquitinated proteins. Immunoprecipitation analysis also revealed that treatment with fatty acids modulated the ubiquitination of tyrosinase, i.e. linoleic acid increased the amount of ubiquitinated tyrosinase whereas, in contrast, palmitic acid decreased it. Furthermore, confocal immunomicroscopy showed that the colocalization of ubiquitin and tyrosinase was facilitated by linoleic acid and diminished by palmitic acid. Taken together, these data support the view that fatty acids regulate the ubiquitination of tyrosinase and are responsible for modulating the proteasomal degradation of tyrosinase. In broader terms, the function of the ubiquitin-proteasome pathway might be regulated physiologically, at least in part, by fatty acids within cellular membranes. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Kobe Univ, Sch Med, Dept Dermatol, Kobe, Hyogo 6500017, Japan. RP Hearing, VJ (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37,Rm 1B25, Bethesda, MD 20892 USA. EM hearingv@nih.gov NR 50 TC 78 Z9 80 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 APR 9 PY 2004 VL 279 IS 15 BP 15427 EP 15433 DI 10.1074/jbc.M313701200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 808UT UT WOS:000220594700113 PM 14739285 ER PT J AU Singer, AL Bunnell, SC Obstfeld, AE Jordan, MS Wu, JN Myung, PS Samelson, LE Koretzky, GA AF Singer, AL Bunnell, SC Obstfeld, AE Jordan, MS Wu, JN Myung, PS Samelson, LE Koretzky, GA TI Roles of the proline-rich domain in SLP-76 subcellular localization and T cell function SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ADAPTER PROTEIN SLP-76; ANTIGEN RECEPTOR; DIFFERENTIAL REQUIREMENT; TYROSINE PHOSPHORYLATION; INTERLEUKIN-2 PRODUCTION; MEDIATED ACTIVATION; MOLECULAR-CLONING; LINKER PROTEIN; LIVING CELLS; LAT AB The adaptor protein Src homology (SH) 2 domain-containing and leukocyte-specific phosphoprotein of 76 kDa (SLP-76) is critical for signal transduction in multiple hematopoietic lineages. It links proximal and distal T cell receptor signaling events through its function as a molecular scaffold in the assembly of multimolecular signaling complexes. Here we studied the functional roles of sub-domains within the SLP-76 proline-rich region, specifically the Gads binding domain and the recently defined P1 domain. To gain a further understanding of the functions mediated by this region, we used three complementary approaches as follows: reconstitution of SLP-76-deficient cells with functional domain deletion mutants, blocking molecular associations through the expression of a dominant negative protein fragment, and directed localization of SLP-76 to assess the role of the domains in SLP-76 recruitment. We find the Gads binding domain and the P1 domain are both necessary for optimal SLP-76 function, and in the absence of these two regions, SLP-76 is functionally inert. Furthermore, we provide direct evidence that SLP-76 localization and, in turn, function are dependent upon association with Gads. C1 Univ Penn, Dept Pathol & Lab Med, Abramson Family Canc Res Inst, Signal Transduct Program, Philadelphia, PA 19104 USA. NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Koretzky, GA (reprint author), 421 Curie Blvd,415 BRB 2-3, Philadelphia, PA 19104 USA. EM koretzky@mail.med.upenn.edu FU NCI NIH HHS [P01-CA93615]; NIAMS NIH HHS [T32-AR07442]; NIDDK NIH HHS [F32-DK09969] NR 52 TC 55 Z9 57 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 APR 9 PY 2004 VL 279 IS 15 BP 15481 EP 15490 DI 10.1074/jbc.M313339200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 808UT UT WOS:000220594700119 PM 14722089 ER PT J AU Neufeld, EB Stonik, JA Demosky, SJ Knapper, CL Combs, CA Cooney, A Comly, M Dwyer, N Blanchette-Mackie, J Remaley, AT Santamarina-Fojo, S Brewer, HB AF Neufeld, EB Stonik, JA Demosky, SJ Knapper, CL Combs, CA Cooney, A Comly, M Dwyer, N Blanchette-Mackie, J Remaley, AT Santamarina-Fojo, S Brewer, HB TI The ABCA1 transporter modulates late endocytic trafficking - Insights from the correction of the genetic defect in Tangier Disease SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID APOLIPOPROTEIN-A-I; CHOLESTEROL EFFLUX; LIPID EFFLUX; CELLULAR CHOLESTEROL; PATHWAY; MEMBRANE; LOCALIZATION; REMOVAL; SURFACE; PHOSPHOLIPIDS AB We have previously established that the ABCA1 transporter, which plays a critical role in the lipidation of extracellular apolipoprotein acceptors, traffics between late endocytic vesicles and the cell surface (Neufeld, E. B., Remaley, A. T., Demosky, S. J., Jr., Stonik, J. A., Cooney, A. M., Comly, M., Dwyer, N. K., Zhang, M., Blanchette-Mackie, J., Santamarina-Fojo, S., and Brewer, H. B., Jr. (2001) J. Biol. Chem. 276, 27584-27590). The present study provides evidence that ABCA1 in late endocytic vesicles plays a role in cellular lipid efflux. Late endocytic trafficking was defective in Tangier disease fibroblasts that lack functional ABCA1. Consistent with a late endocytic protein trafficking defect, the hydrophobic amine U18666A retained NPC1 in abnormally tubulated, cholesterol-poor, Tangier disease late endosomes, rather than cholesterol-laden lysosomes, as in wild type fibroblasts. Consistent with a lipid trafficking defect, Tangier disease late endocytic vesicles accumulated both cholesterol and sphingomyelin and were immobilized in a perinuclear localization. The excess cholesterol in Tangier disease late endocytic vesicles retained massive amounts of NPC1, which traffics lysosomal cholesterol to other cellular sites. Exogenous apoA-I abrogated the cholesterol-induced retention of NPC1 in wild type but not in Tangier disease late endosomes. Adenovirally mediated ABCA1-GFP expression in Tangier disease fibroblasts corrected the late endocytic trafficking defects and restored apoA-I-mediated cholesterol efflux. ABCA1-GFP expression in wild type fibroblasts also reduced late endosome-associated NPC1, induced a marked uptake of fluorescent apoA-I into ABCA1-GFP-containing endosomes (that shuttled between late endosomes and the cell surface), and enhanced apoA-I-mediated cholesterol efflux. The combined results of this study suggest that ABCA1 converts pools of late endocytic lipids that retain NPC1 to pools that can associate with endocytosed apoA-I, and be released from the cell as nascent high density lipoprotein. C1 NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Light Microscopy Core Facil, Bethesda, MD 20892 USA. NIDDK, Lab Cellular Biol & Biochem, NIH, Bethesda, MD 20892 USA. RP Neufeld, EB (reprint author), NHLBI, Mol Dis Branch, NIH, 10-7N115,10 Ctr Dr, Bethesda, MD 20892 USA. EM neufelde@mail.nih.gov NR 39 TC 136 Z9 141 U1 1 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 APR 9 PY 2004 VL 279 IS 15 BP 15571 EP 15578 DI 10.1074/jbc.M314160200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 808UT UT WOS:000220594700129 PM 14747463 ER PT J AU Zheng, ZM Tao, MF Yamanegi, K Bodaghi, S Xiao, W AF Zheng, ZM Tao, MF Yamanegi, K Bodaghi, S Xiao, W TI Splicing of a cap-proximal human papillomavirus 16 E6E7 intron promotes E7 expression, but can be restrained by distance of the intron from its RNA 5 ' cap SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE papillomavirus; human papillomavirus type 16; alternative RNA splicing; RNA capping; oncogene expression ID HUMAN-PAPILLOMAVIRUS TYPE-16; CARCINOMA CELL-LINES; CERVICAL PREMALIGNANT LESIONS; PRE-MESSENGER-RNAS; OPEN READING FRAME; U-SNRNA EXPORT; BINDING COMPLEX; HUMAN KERATINOCYTES; TRANSLATION INITIATION; TRANSGENIC MICE AB Human papillomavirus 16 (HPV16) E6E7 pre-mRNA is bicistronic and has an intron in the E6 coding region with one 5' splice site and two alternative 3' splice sites, which produce E61 and E6*II, respectively. If this intron remains unspliced, the resulting E6E7 mRNA expresses oncogenic E6. We found for the first time that the E6E7 pre-mRNA was efficiently spliced in vitro only when capped and that cellular cap-binding factors were involved in the splicing. The cap-dependent splicing of the E6E7 pre-mRNA was extremely efficient in cervical cancer-derived cells, producing mostly E61, but inefficient in cells transfected with a common retrovirus expression vector, pLXSN16E6E7, due to the large size of this vector's exon 1. Further studies showed that efficient splicing of the E6E7 pre-mRNA depends on the distance of the cap-proximal intron from the RNA 5' cap, with an optimal distance of less than 307 nt in order to facilitate better association of U1 small nuclear RNA with the intron 5' splice site. The same was true for splicing of human P-globin RNA. Splicing of the E6E7 RNA provided more E7 RNA templates and promoted E7 translation, whereas a lack of RNA splicing produced a low level of E7 translation. Together, our data indicate that the distance between the RNA 5' cap and cap-proximal intron is rate limiting for RNA splicing. HPV16 E6E7 pre-mRNA takes advantage of its small cap-proximal exon to confer efficient splicing for better E7 expression. Published by Elsevier Ltd. C1 NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Zheng, ZM (reprint author), NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM zhengt@exchange.nih.gov FU PHS HHS [8340201] NR 72 TC 36 Z9 39 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 APR 9 PY 2004 VL 337 IS 5 BP 1091 EP 1108 DI 10.1016/j.jmb.2004.02.023 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 809RJ UT WOS:000220653500003 PM 15046980 ER PT J AU Marinissen, MJ Chiariello, M Tanos, T Bernard, O Narumiya, S Gutkind, JS AF Marinissen, MJ Chiariello, M Tanos, T Bernard, O Narumiya, S Gutkind, JS TI The small GTP-binding protein RhoA regulates c-Jun by a ROCK-JNK signaling axis SO MOLECULAR CELL LA English DT Article ID SERUM RESPONSE FACTOR; N-TERMINAL KINASE; ACTIN DYNAMICS; LIM-KINASE; ACTIVATION; TRANSFORMATION; PROMOTER; PATHWAY; GTPASES; SRF AB RhoA regulates the actin cytoskeleton and the expression of genes associated with cell proliferation. This includes c-fos and c-jun, which are members of the AP1 family of transcription factors that play a key role in normal and aberrant cell growth. Whereas RhoA stimulates the c-fos SRE by a recently elucidated mechanism that is dependent on actin treadmilling, how RhoA regulates c-jun is still poorly understood. We found that RhoA stimulates c-jun expression through ROCK, but independently from the ability of ROCK to promote actin polymerization. Instead, we found that ROCK activates JNK, which then phosphorylates c-Jun and ATF2 when bound to the c-jun promoter. Thus, ROCK represents a point of signal divergence downstream from RhoA, as it promotes actin reorganization and the consequent expression from the c-fos SRE, while a parallel pathway connects ROCK to JNK, thereby stimulating c-jun expression. Ultimately, these pathways converge in the nucleus to regulate AP1 activity. C1 Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. Univ Buenos Aires, Fac Ciencias Exactas, Buenos Aires, DF, Argentina. CNR, Ist Endocrinol & Oncol Sperimentale, I-80131 Naples, Italy. Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Parkville, Vic 3050, Australia. Kyoto Univ, Fac Med, Dept Pharmacol, Sakyo Ku, Kyoto 6068501, Japan. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Gutkind, J. Silvio/A-1053-2009; Chiariello, Mario/O-3642-2014 OI Chiariello, Mario/0000-0001-8434-5177 NR 38 TC 149 Z9 151 U1 0 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 APR 9 PY 2004 VL 14 IS 1 BP 29 EP 41 DI 10.1016/S1097-2765(04)00153-4 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 812HE UT WOS:000220829800003 PM 15068801 ER PT J AU LaBuda, CJ Dobolyi, A Usdin, TB AF LaBuda, CJ Dobolyi, A Usdin, TB TI Tuberoinfundibular peptide of 39 residues produces anxiolytic and antidepressant actions SO NEUROREPORT LA English DT Article DE anxiety; behavior; depression; immediate early gene; neuropeptide; parathyroid hormone 2 receptor ID C-FOS; NERVOUS-SYSTEM; RAT FOREBRAIN; PREOPTIC AREA; INDUCTION; RECEPTOR; LESIONS; RESPONSES; ANXIETY; STRESS AB Tuberoinfundibular peptide of 39 residues (TIP39) potently activates the parathyroid hormone-2 receptor (PTH2-R). A group of neurons in the posterior thalamus and one in the lateral pons synthesize TIP39. TIP39 projections reach most areas of PTH2-R density, including many within the limbic system and hypothalamus. We report that TIP39 induces Fos in the infralimbic cortex, lateral hypothalamus, preoptic area, lateral septum and paraventricular thalamic nucleus, areas believed to be important in anxiety and depression. TIP39 caused anxiolytic-like effects in the elevated plus-maze test and antidepressant-like effects in the forced-swim test. TIP39 did not change activity in the open field test. These findings point to a previously unknown role of the PTH2-R in the regulation of anxiety and depression. C1 NIMH, Genet Lab, Bethesda, MD 20892 USA. RP Usdin, TB (reprint author), NIMH, Genet Lab, Bldg 36,Rm 3D06,36 Convent Dr MSC 4094, Bethesda, MD 20892 USA. EM Usdint@mail.nih.gov RI Dobolyi, Arpad/B-9089-2008 NR 25 TC 20 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 APR 9 PY 2004 VL 15 IS 5 BP 881 EP 885 DI 10.1097/01.wnr.0000119731.93564.a1 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 871NK UT WOS:000225140200030 PM 15073536 ER PT J AU Blonder, J Rodriguez-Galan, MC Lucas, DA Young, HA Issaq, HJ Veenstra, TD Conrads, TP AF Blonder, J Rodriguez-Galan, MC Lucas, DA Young, HA Issaq, HJ Veenstra, TD Conrads, TP TI Proteomic investigation of natural killer cell microsomes using gas-phase fractionation by mass spectrometry SO BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS LA English DT Article DE gas-phase fractionation; mass spectrometry; natural killer cell; membrane proteomic; microsome ID PROTEIN IDENTIFICATION; GELS AB We have explored the utility of gas-phase fractionation by mass spectrometry (MS) in the mass-to-charge (m/z) dimension (GPF(m/z)) for increasing the effective number of protein identifications in cases where sample quantity limits the use of multi-dimensional chromatographic fractionation. A peptide digestate from proteins isolated from the membrane fraction of natural killer (NK) cells was analyzed by microcapillary reversed-phase liquid chromatography coupled online to an ion-trap (IT) mass spectrometer. Performing GPF(m/z). using eight narrow precursor ion scan m1z ranges enabled the identification of 340 NK cell proteins from 12 mug of digestate, representing more than a fivefold increase in the number of proteins identified as compared to the same experiment employing a standard precursor ion survey scan m/z range (i.e., m/z 400-2000). The results show that GPF(m/z) represents an effective technique for increasing protein identifications in global proteomic investigations especially when sample quantity is limited. (C) 2003 Elsevier B.V. All rights reserved. C1 NCI, SAIC Frederick Inc, Lab Proteom & Analyt Technol, Biomed Proteom Program, Frederick, MD 21702 USA. NCI, Expt Immunol Lab, Frederick, MD 21702 USA. RP Conrads, TP (reprint author), NCI, SAIC Frederick Inc, Lab Proteom & Analyt Technol, Biomed Proteom Program, POB B, Frederick, MD 21702 USA. EM Conrads@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 12 TC 20 Z9 22 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-9639 J9 BBA-PROTEINS PROTEOM JI BBA-Proteins Proteomics PD APR 8 PY 2004 VL 1698 IS 1 BP 87 EP 95 DI 10.1016/j.bbapap.2003.10.009 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 811FF UT WOS:000220757100008 PM 15063318 ER PT J AU Phue, JN Shiloach, J AF Phue, JN Shiloach, J TI Transcription levels of key metabolic genes are the cause for different glucose utilization pathways in E-coli B (BL21) and E-coli K (JM109) SO JOURNAL OF BIOTECHNOLOGY LA English DT Article; Proceedings Paper CT 2nd Symposium on Recombinant Protein Production with Prokaryotic and Eukrayotic Cells CY NOV, 2002 CL Cernobbio, ITALY DE E. coli; glucose; acetate; glyoxylate; northern blot ID GLYOXYLATE BYPASS OPERON; ESCHERICHIA-COLI BL21; ACETATE METABOLISM; ACETYL-COENZYME; DENSITY FERMENTATION; PROTEIN-PRODUCTION; GROWTH; CYCLE; ICLR; ACCUMULATION AB Acetate accumulation is a common problem observed in aerobic high cell density cultures of Escherichia coli. It has been hypothesized in previous reports that the glyoxylate shunt is active in E. coli BL21, the low acetate producer, and inactive in E. coli JM109, the high acetate producer. This hypothesis was further strengthened by incorporating (13) from uniformly labeled glucose into TCA cycle intermediates. Using northern blot analyses, the current report demonstrates that the reason for the inactivity of the glyoxylate pathway in E. coli JM109 is the no apparent transcription of isocitrate lyase (aceA) and malate synthase (aceB), and transcription of the isocitrate lyase repressor (OR). The reverse is seen in E. coli BL21 where the glyoxylate pathway is active due to constitutive transcription of aceA and aceB and no transcription of the OR. In addition, there is a difference between the two strains in the transcription of the acetyl-CoA synthetase (acs), phosphotransacetylase-acetate kinase (pta-ackA) pathway, and pyruvate oxidase (poxB), pathway. The transcript of acs is higher in E. coli BL21 and lower in the E. coli JM109, while the reverse is true for poxB transcription. Published by Elsevier B.V. C1 NIDDK, Biotechnol Unit, NIH, Bethesda, MD 20892 USA. RP Shiloach, J (reprint author), NIDDK, Biotechnol Unit, NIH, Bldg 14A Rm 173, Bethesda, MD 20892 USA. EM yossi@nih.gov NR 26 TC 61 Z9 64 U1 1 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1656 J9 J BIOTECHNOL JI J. Biotechnol. PD APR 8 PY 2004 VL 109 IS 1-2 BP 21 EP 30 DI 10.1016/j.jbiotec.2003.10.038 PG 10 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 813VJ UT WOS:000220934300004 PM 15063611 ER PT J AU Shi, ZD Wei, CQ Lee, KO Liu, HP Zhang, MC Araki, T Roberts, LR Worthy, KM Fisher, RJ Neel, BG Kelley, JA Yang, DJ Burke, TR AF Shi, ZD Wei, CQ Lee, KO Liu, HP Zhang, MC Araki, T Roberts, LR Worthy, KM Fisher, RJ Neel, BG Kelley, JA Yang, DJ Burke, TR TI Macrocyclization in the design of non-phosphorus-containing Grb2 SH2 domain-binding ligands SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PHOSPHATE-CONTAINING LIGANDS; AFFINITY; INHIBITION AB Macrocyclization from the phosphotyrosyl. (pTyr) mimetic's beta-position has previously been shown to enhance Grb2 SH2 domain-binding affinity of phosphonate-based analogues. The current study examined the effects of such macrocyclization using a dicarboxymethyl-based pTyr mimetic. In extracellular assays affinity was enhanced approximately 5-fold relative to an open-chain congener. Enhancement was also observed in whole-cell assays examining blockade of Grb2 binding to the erbB-2 protein-tyrosine kinase. C1 NCI, Med Chem Lab, CCR, NIH, Ft Detrick, MD 21702 USA. Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. SAIC, Prot Chem Lab, Frederick, MD 21702 USA. RP Burke, TR (reprint author), NCI, Med Chem Lab, CCR, NIH, Ft Detrick, MD 21702 USA. EM tburke@helix.nih.gov RI Fisher, Robert/B-1431-2009; Burke, Terrence/N-2601-2014 FU NCI NIH HHS [R01 CA 49152] NR 11 TC 29 Z9 29 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD APR 8 PY 2004 VL 47 IS 8 BP 2166 EP 2169 DI 10.1021/jm030510e PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 809MZ UT WOS:000220642100028 PM 15056012 ER PT J AU Lee, YS Krauss, M AF Lee, YS Krauss, M TI Structure and reaction in the active site of mammalian adenylyl cyclase SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID SUBSTRATE-ASSISTED CATALYSIS; MECHANISM; POTENTIALS; PROTEINS AB The reaction path for the catalytic conversion of adenosine triphosphate (ATP) to. cyclic adenosine monophosphate (cAMP) by the enzyme mammalian adenylyl cyclase has been calculated theoretically using the Hartree-Fock method. The crystal structure of a thiophosphate reactant analogue, ATPalphaS, provides the basic structure of the active site binding that is then leveraged into the native reaction path by energy gradient optimization of protein binding residues and the ATP. A two-metal cluster bound to two aspartate residues and the ATP is important both structurally and catalytically. Autocatalytic activation of the reacting ribose 3'OH group is calculated in the reactant conformation but the catalytic MgA divalent cation binds to the developing 3'O anion and stabilizes the formation of a five-coordinate intermediate with the cyclic phosphate already formed. Changes in the coordination of the metals in the complex and the H-bonding of arginines that bridge the phosphate groups stabilize the reaction path complex from reactive intermediate to the product. Final transfer of the 3'H proton to the oxygen bridging the alpha and beta phosphate groups yields the cAMP and pyrophosphate product still bound by many H-bonds in the active site. C1 NIST, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. NIH, Ctr Mol Modeling, CIT, Bethesda, MD 20892 USA. RP Krauss, M (reprint author), NIST, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. EM krauss@carb.nist.gov NR 19 TC 1 Z9 1 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD APR 8 PY 2004 VL 108 IS 14 BP 4508 EP 4515 DI 10.1021/jp036564h PG 8 WC Chemistry, Physical SC Chemistry GA 809MH UT WOS:000220640300042 ER PT J AU Guirland, C Suzuki, S Kojima, M Lu, B Zheng, JQ AF Guirland, C Suzuki, S Kojima, M Lu, B Zheng, JQ TI Lipid rafts mediate chemotropic guidance of nerve growth cones SO NEURON LA English DT Article ID MYELIN-ASSOCIATED GLYCOPROTEIN; PHOSPHOLIPASE C-GAMMA; PLASMA-MEMBRANE; NOGO RECEPTOR; SIGNAL-TRANSDUCTION; COMPLEX; LIGAND; CELLS; TRANSMEMBRANE; LOCALIZATION AB Axon guidance requires signal transduction of extracellular cues through the plasma membrane for directional motility. Here we present evidence that cholesterol- and sphingolipid-enriched membrane microdomains (lipid rafts) mediate specific guidance responses of nerve growth cones. Disruption of lipid rafts by various approaches targeting cholesterol or gangliosides selectively abolished growth cone attraction and repulsion in BDNF and netrin-1 gradients, respectively, without affecting glumamate-induced attraction. Interestingly, local raft disruption on one side of the growth cone in bath BDNF or netrin-1 produced opposite turning responses to that induced by the gradients. Raft manipulation also blocked Semaphorin 3A-induced growth cone repulsion, inhibition, and collapse. Finally, guidance responses appeared to involve raft-dependent activation of p42/p44 MAPK and ligand-induced receptor recruitment to lipid rafts. Together with the observation of asymmetric receptor-raft associations at the growth cone in guidance gradients, our findings indicate that localized signaling through membrane rafts plays a role in mediating guidance actions of extracellular cues on developing axons. C1 Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA. Natl Inst Adv Ind Sci & Technol, Div Life Sci Technol, Ikeda, Osaka 5638577, Japan. NICHHD, Sect Synapse Dev & Plast, NIH, Bethesda, MD 20892 USA. RP Zheng, JQ (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurosci & Cell Biol, Piscataway, NJ 08854 USA. EM james.zheng@umdnj.edu RI Lu, Bai/A-4018-2012 NR 51 TC 182 Z9 185 U1 1 U2 8 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD APR 8 PY 2004 VL 42 IS 1 BP 51 EP 62 DI 10.1016/S0896-6273(04)00157-6 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 821KF UT WOS:000221458400007 PM 15066264 ER PT J AU Zhang, RX La, LX Qiao, JT Malsnee, K Ruda, MA AF Zhang, RX La, LX Qiao, JT Malsnee, K Ruda, MA TI Endogenous and exogenous glucocorticoid suppresses up-regulation of preprodynorphin mRNA and hyperalgesia in rats with peripheral inflammation SO NEUROSCIENCE LETTERS LA English DT Article DE hyperalgesia; pain; gene expression; dexamethasone; spinal cord; dynorphin; rat ID NECROSIS-FACTOR-ALPHA; NF-KAPPA-B; SPINAL-CORD; GENE-EXPRESSION; PRODYNORPHIN GENE; C-FOS; DEXAMETHASONE; RECEPTOR; PAIN; INHIBITION AB Glucocorticoids (GC) play important roles in response to stressful stimuli, including pain. This study examined the effects of bilateral adrenalectomy (ADX) and dexamethasone (DEX) replacement on the hyperalgesia and spinal preprodynorphin (PPD) mRNA expression induced by injecting complete Freund's adjuvant (CFA) into rats' hind paws. The results demonstrated that CFA induced more intense hyperalgesia and upexpression of spinal PPD mRNA in ADX rats than in control rats, while both of these intensified reactions could be significantly suppressed by subcutaneous pretreatment with DEX. This leads to the conclusion that both exogenous (pharmacological) and endogenous (physiological) GC suppresses the behavioral hyperalgesia and the up-regulation of spinal PPD mRNA induced by sustained peripheral inflammation. The results also suggest that spinal PPD mRNA suppression may partially underlie the inhibition of behavioral hyperalgesia. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 Univ Maryland, Sch Med, Ctr Integrat Med, Baltimore, MD 21201 USA. Shanxi Med Univ, Dept Neurobiol, Shanxi 030001, Peoples R China. NIDCR, Pain & Neurosensory Mech Branch, Cellular Neurosci Sect, NIH, Bethesda, MD 20892 USA. RP Zhang, RX (reprint author), James Kernan Hosp Mans, 2200 Kernan Dr,3rd Floor, Baltimore, MD 21207 USA. EM rzhan001@umaryland.edu RI Lao, Lixing/I-7979-2013; OI Lao, Lixing/0000-0003-0198-9714 NR 34 TC 20 Z9 22 U1 0 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD APR 8 PY 2004 VL 359 IS 1-2 BP 85 EP 88 DI 10.1016/j.neulet.2004.02.014 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 811JS UT WOS:000220768800022 PM 15050718 ER PT J AU Vitiello, B Swedo, S AF Vitiello, B Swedo, S TI Antidepressant medications in children SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID ADOLESCENTS; DEPRESSION; FLUOXETINE; TRIAL C1 NIMH, Bethesda, MD 20892 USA. RP Vitiello, B (reprint author), NIMH, Bethesda, MD 20892 USA. NR 5 TC 62 Z9 62 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 8 PY 2004 VL 350 IS 15 BP 1489 EP 1491 DI 10.1056/NEJMp038248 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 810CI UT WOS:000220682000003 PM 15071123 ER PT J AU Brewer, HB AF Brewer, HB TI Increasing HDL cholesterol levels SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID HIGH-DENSITY-LIPOPROTEINS; ATHEROSCLEROSIS; TARGET C1 NHLBI, Bethesda, MD 20892 USA. RP Brewer, HB (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. NR 5 TC 88 Z9 93 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 APR 8 PY 2004 VL 350 IS 15 BP 1491 EP 1494 DI 10.1056/NEJMp048023 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 810CI UT WOS:000220682000004 PM 15071124 ER PT J AU Edison, RJ Muenke, M AF Edison, RJ Muenke, M TI Central nervous system and limb anomalies in case reports of first-trimester statin exposure SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NIH, Bethesda, MD 20892 USA. RP Edison, RJ (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM muenke@nih.gov NR 5 TC 103 Z9 107 U1 0 U2 9 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 APR 8 PY 2004 VL 350 IS 15 BP 1579 EP 1582 DI 10.1056/NEJM200404083501524 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 810CI UT WOS:000220682000032 PM 15071140 ER PT J AU Warming, S Suzuki, T Yamaguchi, TP Jenkins, NA Copeland, NG AF Warming, S Suzuki, T Yamaguchi, TP Jenkins, NA Copeland, NG TI Early B-cell factor-associated zinc-finger gene is a frequent target of retroviral integration in murine B-cell lymphomas SO ONCOGENE LA English DT Article DE EBFAZ; EVI3; B-cell lymphoma ID ACUTE LYMPHOBLASTIC-LEUKEMIA; PRE-B; PROTEIN; MOUSE; IDENTIFICATION; EXPRESSION; LAMBDA-5; STRAINS; CLONING; LOCUS AB The early B-cell factor (EBF)-associated zinc-finger protein (EBFAZ) binds to and negatively regulates EBF, a basic helix-loop-helix transcription factor required for B-cell lineage commitment and development of the olfactory epithelium. It also binds to SMA- and MAD-related protein 1 (SMAD1) and SMAD4 in response to bone morphogenic protein 2 (BMP2) signaling. It is highly related to ecotropic viral integration site 3 (EVI3), a protein that, like EBFAZ, contains 30 Kruppel-like zinc finger repeats. In previous studies, we showed that Evi3 is a frequent target of retroviral integration in AKXD27 B-cell lymphomas. Here, we show that EBFAZ is also a frequent target. Integrations at Ebfaz and Evi3 are mutually exclusive, suggesting that they function in the same tumor pathway. Lymphomas with integrations at Ebfaz or Evi3 express the pre-B-cell-specific marker immunoglobulin lambda chain 5, and contain immunoglobulin heavy-chain rearrangements, suggesting that they are blocked at an early B-cell stage. Unlike Evi3, which is expressed at low levels in normal B cells, or Ebfaz, which is not expressed in B cells, both genes are highly expressed following viral integration. Collectively, our results suggest that ectopic expression of Ebfaz can substitute for the upregulated expression of Evi3 in B-cell disease and highlight the importance of this gene family in hematopoietic cancer. C1 NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. NCI, Canc & Dev Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Copeland, NG (reprint author), NCI, Mouse Canc Genet Program, Ctr Canc Res, W 7th St & Ft Detrick, Frederick, MD 21702 USA. EM copeland@ncifcrf.gov NR 19 TC 17 Z9 18 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD APR 8 PY 2004 VL 23 IS 15 BP 2727 EP 2731 DI 10.1038/sj.onc.1207452 PG 5 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 810OZ UT WOS:000220714900014 PM 15048087 ER PT J AU Cho, SW Velikovsky, CA Swaminathan, CP Houtman, JCD Samelson, LE Mariuzza, RA AF Cho, SW Velikovsky, CA Swaminathan, CP Houtman, JCD Samelson, LE Mariuzza, RA TI Structural basis for differential recognition of tyrosine-phosphorylated sites in the linker for activation of T cells (LAT) by the adaptor Gads SO EMBO JOURNAL LA English DT Article DE Gads; Grb2; LAT; SH2 domain; tyrosine phosphorylation ID SRC SH2 DOMAIN; PHOSPHOTYROSINE RECOGNITION; PHOSPHOPEPTIDE BINDING; SIGNAL-TRANSDUCTION; ANTIGEN RECEPTOR; PROTEIN; SPECIFICITY; GRB2; ASSOCIATION; KINASE AB The transmembrane protein, linker for activation of T cells (LAT), is essential for T-cell activation and development. Phosphorylation of LAT at multiple tyrosines creates binding sites for the adaptors Gads and Grb2, leading to nucleation of multiprotein signaling complexes. Human LAT contains five potential binding sites for Gads, of which only those at Tyr171 and Tyr191 appear necessary for T-cell function. We asked whether Gads binds preferentially to these sites, as differential recognition could assist in assembling defined LAT-based complexes. Measured calorimetrically, Gads-SH2 binds LAT tyrosine phosphorylation sites 171 and 191 with higher affinities than the other sites, with the differences ranging from only several fold weaker binding to no detectable interaction. Crystal structures of Gads-SH2 complexed. with phosphopeptides representing sites 171, 191 and 226 were determined to 1.8-1.9 Angstrom resolutions. The structures reveal the basis for preferential recognition of specific LAT sites by Gads, as well as for the relatively greater promiscuity of the related adaptor Grb2, whose binding also requires asparagine at position + 2 C-terminal to the phosphorylated tyrosine. C1 Univ Maryland, Inst Biotechnol, Ctr Adv Res Biotechnol, WM Keck Lab Struct Biol, Rockville, MD 20850 USA. NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Mariuzza, RA (reprint author), Univ Maryland, Inst Biotechnol, Ctr Adv Res Biotechnol, WM Keck Lab Struct Biol, 9600 Gudelsky Dr, Rockville, MD 20850 USA. EM mariuzza@carb.nist.gov FU NIAID NIH HHS [AI36900, R01 AI036900, R37 AI036900] NR 45 TC 19 Z9 19 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0261-4189 J9 EMBO J JI Embo J. PD APR 7 PY 2004 VL 23 IS 7 BP 1441 EP 1451 DI 10.1038/sj.emboj.7600168 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 819QC UT WOS:000221328700004 PM 15029250 ER PT J AU Leitzmann, MF Platz, EA Stampfer, MJ Willett, WC Giovannucci, E AF Leitzmann, MF Platz, EA Stampfer, MJ Willett, WC Giovannucci, E TI Ejaculation frequency and subsequent risk of prostate cancer SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID SEXUAL-BEHAVIOR; SEMINAL PLASMA; INTRALUMINAL CRYSTALLOIDS; ERECTILE DYSFUNCTION; CIGARETTE-SMOKING; MEN; CARCINOMA; EPIDEMIOLOGY; QUESTIONNAIRE; METAANALYSIS AB Context Sexual activity has been hypothesized to play a role in the development of prostate cancer, but epidemiological data are virtually limited to case-control studies, which may be prone to bias because recall among individuals with prostate cancer could be distorted as a consequence of prostate malignancy or ongoing therapy. Objective To examine the association between ejaculation frequency, which includes sexual intercourse, nocturnal emission, and masturbation and risk of prostate cancer. Design, Setting, and Participants Prospective study using follow-up data from the Health Professionals Follow-up Study (February 1, 1992, through January 31, 2000) of 29342 US men aged 46 to 81 years, who provided information on history of ejaculation frequency on a self-administered questionnaire in 1992 and responded to follow-up questionnaires every 2 years to 2000. Ejaculation frequency was assessed by asking participants to report the average number of ejaculations they had per month during the ages of 20 to 29 years, 40 to 49 years, and during the past year (1991). Main Outcome Measure Incidence of total prostate cancer. Results During 222426 person-years of follow-up, there were 1449 new cases of total prostate cancer, 953 organ-confined cases, and 147 advanced cases of prostate cancer. Most categories of ejaculation frequency were unrelated to risk of prostate cancer. However, high ejaculation frequency was related to decreased risk of total prostate cancer. The multivariate relative risks for men reporting 21 or more ejaculations per month compared with men reporting 4 to 7 ejaculations per month at ages 20 to 29 years were 0.89 (95% confidence interval [CI], 0.73-1.10); ages 40 to 49 years, 0.68 (95% CI, 0.53-0.86); previous year, 0.49 (95% CI, 0.27-0.88); and averaged across a lifetime, 0.67(95% CI, 051-0.89). Similar associations were observed for organ-confined prostate cancer. Ejaculation frequency was not statistically significantly associated with risk of advanced prostate cancer. Conclusions Our results suggest that ejaculation frequency is not related to increased risk of prostate cancer. C1 NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Johns Hopkins Bloomerg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Channing Lab, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Leitzmann, MF (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, EPS-MSC 7232,6120 Execut Blvd, Bethesda, MD 20892 USA. EM leitzmann@mail.nih.gov FU NCI NIH HHS [5T32 CA09001-26, CA055075]; NHLBI NIH HHS [HL035464] NR 56 TC 45 Z9 46 U1 1 U2 20 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 APR 7 PY 2004 VL 291 IS 13 BP 1578 EP 1586 DI 10.1001/jama.291.13.1578 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 809PQ UT WOS:000220649000022 PM 15069045 ER PT J AU Hasan, RK Wulfkuhle, JD Liotta, LA Petricoin, EF AF Hasan, RK Wulfkuhle, JD Liotta, LA Petricoin, EF TI Molecular technologies for personalized cancer management SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PHASE PROTEIN MICROARRAYS; BREAST-CANCER; OVARIAN-CANCER; CHEMOTHERAPY; SURVIVAL; PROGRESSION; MUTATIONS; DNA C1 Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. NCI, Bethesda, MD 20892 USA. US FDA, Bethesda, MD 20014 USA. RP Hasan, RK (reprint author), Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. NR 20 TC 3 Z9 3 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 APR 7 PY 2004 VL 291 IS 13 BP 1644 EP 1645 DI 10.1001/jama.291.13.1644 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 809PQ UT WOS:000220649000033 PM 15069056 ER PT J AU Swain, SM Wilson, JW Mamounas, EP Bryant, J Wickerham, DL Fisher, B Paik, S Wolmark, N AF Swain, SM Wilson, JW Mamounas, EP Bryant, J Wickerham, DL Fisher, B Paik, S Wolmark, N TI Estrogen receptor status of primary breast cancer is predictive of estrogen receptor status of contralateral breast cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SURGICAL ADJUVANT BREAST; 20-YEAR FOLLOW-UP; RANDOMIZED-TRIAL; PREOPERATIVE CHEMOTHERAPY; HYSTERECTOMIZED WOMEN; POSTMENOPAUSAL WOMEN; RADICAL-MASTECTOMY; TAMOXIFEN; PREVENTION; TUMORS AB Background: Tamoxifen reduces the risk for contralateral breast cancer by approximately 30%-50%, with benefits probably limited to women with estrogen receptor (ER)-positive primary disease. In a retrospective analysis of data from National Surgical and Adjuvant Breast and Bowel Project trials B-18, B-22, and B-25, we determined whether the ER status of primary breast cancer predicts the ER status of a subsequent contralateral breast cancer and whether tamoxifen treatment affects this relationship. In these trials, tamoxifen at 20 mg/day had been administered only to women aged 50 years or older, rather than to those determined by the ER status of their primary tumor, allowing an assessment of the treatment's effects in ER-negative disease. Methods: Among the 5513 eligible patients, 176 patients developed a contralateral breast cancer. The ER status of the primary and contralateral tumor was determined and cross-classified for women who did not receive tamoxifen (i.e., those aged 49 years or younger) and for women who did (i.e., those aged 50 years or older). ER data were available for 110 evaluable invasive contralateral breast cancers. Results: Among patients who did not receive tamoxifen (n = 62), 89% with an ER-positive primary cancer had an ER-positive contralateral breast cancer and 70% with an ER-negative primary breast cancer had an ER-negative contralateral breast cancer (odds ratio for the association between primary and contralateral ER status = 14.8, 95% confidence interval = 3.8 to 74.3; P < .001). Among patients who received tamoxifen (n = 48), 56% with an ER-positive primary cancer had an ER-positive contralateral breast cancer and 78% with an ER-negative primary cancer had an ER-negative contralateral breast cancer (odds ratio = 3.4, 95% confidence interval = 0.53 to 39.2; P = .25). Conclusion: The ER status of the primary breast cancer was associated with that of the contralateral breast for patients not receiving tamoxifen. Patients with an ER-positive primary cancer who received tamoxifen had a lower concordance rate with fewer ER-positive contralateral breast cancers, which may be a result of tamoxifen treatment. C1 NCI, Bethesda, MD 20892 USA. Natl Surg & Adjuvant Breast & Bowel Project Biost, Pittsburgh, PA USA. Univ Pittsburgh, Pittsburgh, PA USA. Aultman Canc Ctr, Canton, OH USA. Natl Surg & Adjuvant Breast & Bower Project Opera, Pittsburgh, PA USA. Alleghany Gen Hosp, Alleghany, PA USA. RP Swain, SM (reprint author), 8901 Wisconsin Ave,Bldg 8,Rm 5101, Bethesda, MD 20889 USA. EM swains@mail.nih.gov OI Swain, Sandra/0000-0002-1320-3830 NR 39 TC 58 Z9 63 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD APR 7 PY 2004 VL 96 IS 7 BP 516 EP 523 DI 10.1093/jnci/djh097 PG 8 WC Oncology SC Oncology GA 810LF UT WOS:000220705100007 PM 15069113 ER PT J AU Carter, HB Metter, EJ Wright, J Landis, P Platz, E Walsh, PC AF Carter, HB Metter, EJ Wright, J Landis, P Platz, E Walsh, PC TI Prostate-specific antigen and all-cause mortality: Results from the Baltimore Longitudinal Study on Aging SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID AGE C1 Johns Hopkins Univ, Sch Med, Johns Hopkins Hosp, James Buchanan Brady Urol Inst,Dept Urol, Baltimore, MD 21287 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Carter, HB (reprint author), Johns Hopkins Univ, Sch Med, Johns Hopkins Hosp, James Buchanan Brady Urol Inst,Dept Urol, 403 Marburg,600 N Wolfe St, Baltimore, MD 21287 USA. EM hcarter@jhmi.edu FU NCI NIH HHS [CA58236] NR 7 TC 6 Z9 6 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 APR 7 PY 2004 VL 96 IS 7 BP 557 EP 558 DI 10.1093/jnci/djh111 PG 2 WC Oncology SC Oncology GA 810LF UT WOS:000220705100017 PM 15069122 ER PT J AU Halladay, AK Tessarollo, L Zhou, R Wagner, GC AF Halladay, AK Tessarollo, L Zhou, R Wagner, GC TI Neurochemical and behavioral deficits consequent to expression of a dominant negative EphA5 receptor SO MOLECULAR BRAIN RESEARCH LA English DT Article DE transgenic; Eph; behavior; striatum; mice ID TYROSINE KINASE RECEPTOR; CENTRAL-NERVOUS-SYSTEM; HIPPOCAMPAL-LESIONS; NEURITE OUTGROWTH; TOPOGRAPHIC PROJECTION; AVOIDANCE-BEHAVIOR; RETROGRADE-AMNESIA; NUCLEUS ACCUMBENS; CEREBRAL-CORTEX; RAT AB The Eph family tyrosine kinase receptors and their ligands have been linked to axon guidance and topographic mapping of the developing central nervous system. More specifically, the EphA5 receptor has been shown to play a role in development of hippocamposeptal, retinotectal and thalamocortical projections. Recently, a line of transgenic mice was developed which expresses a truncated EphA5 receptor lacking a functional tyrosine kinase domain. In a previous study, axonal tracing revealed that medial hippocampal axons in this strain projected laterally and ventrally away from their normal target area. In the current study, both transgenic and wild-type controls were evaluated in unconditioned (rotorod and locomotor activity) and conditioned (water maze and active avoidance) behavior tasks which tested hippocampal and striatal functioning. Compared to controls, the transgenic strain did not show differences in rotorod motor activity but did show a transient deficit in spatial navigation ability and a consistent impairment in active avoidance. The dominant-negative mutant receptor also resulted in a decrease in striatal dopamine and serotonin concentrations with no change in hippocampal monoamines. Collectively, these data suggest that animals expressing a truncated EphA5 receptor show deficits related to striatal functioning. (C) 2004 Elsevier B.V. All rights reserved. C1 Rutgers State Univ, Dept Psychol, Piscataway, NJ 08854 USA. Rutgers State Univ, Dept Pharmacol & Toxicol, Piscataway, NJ 08854 USA. NCI, Mouse Canc Genet Program, Neural Dev Grp, Bethesda, MD 20892 USA. Rutgers State Univ, Dept Biol Chem, Piscataway, NJ USA. RP Wagner, GC (reprint author), Rutgers State Univ, Dept Psychol, Piscataway, NJ 08854 USA. EM gcwagner@rci.rutgers.edu NR 53 TC 19 Z9 19 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 APR 7 PY 2004 VL 123 IS 1-2 BP 104 EP 111 DI 10.1016/j.molbrainres.2004.01.005 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 814BF UT WOS:000220949500012 ER PT J AU Thompson, C Gary, D Mattson, M Mackenzie, A Robertson, GS AF Thompson, C Gary, D Mattson, M Mackenzie, A Robertson, GS TI Kainic acid-induced naip expression in the hippocampus is blocked in mice lacking TNF receptors SO MOLECULAR BRAIN RESEARCH LA English DT Article DE apoptosis; neuroprotection; inflammation; hippocampus; epilepsy ID TUMOR-NECROSIS-FACTOR; APOPTOSIS INHIBITORY PROTEIN; NF-KAPPA-B; SPINAL MUSCULAR-ATROPHY; FOCAL CEREBRAL-ISCHEMIA; INDUCED CELL-DEATH; FACTOR-ALPHA; RAT-BRAIN; NEURONS; CASPASES AB Mice that lack tumor necrosis factor-alpha (TNF) receptors are more susceptible than wild-type animals to brain injury produced by kainic acid or transient focal ischemia suggesting that the rapid production of TNF that occurs after these insults serves a neuroprotective role. The mechanisms by which TNF reduces neuronal loss after brain injury may involve the up-regulation of proteins that maintain calcium homeostasis or reduce free radical generation. We report here that systemic administration of kainic acid rapidly elevates expression of mRNA encoding neuronal apoptosis inhibitor protein (NAIP) in the hippocampus and that this increase does not occur in mice that lack TNF receptors. Given that NAIP overexpression can reduce neuronal injury by blocking apoptosis, our findings suggest that induction of the naip gene may contribute to the neuroprotective properties of TNF. (C) 2004 Elsevier B.V. All rights reserved. C1 Dept Psychiat, Halifax, NS B3H 1X5, Canada. Dept Pharmacol, Halifax, NS B3H 1X5, Canada. Univ Ottawa, Fac Med, Ottawa Hosp Res Inst, Ottawa, ON K1H 8M5, Canada. Aegera Therapeut Inc, Ottawa, ON K1H 8M5, Canada. NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. Childrens Hosp Eastern Ontario, Mol Genet Res Lab, Ottawa, ON K1H 8L1, Canada. RP Robertson, GS (reprint author), Dept Psychiat, Sir Charles Tupper Med Bldg,5850 Coll St, Halifax, NS B3H 1X5, Canada. EM George.Robertson@dal.ca NR 44 TC 10 Z9 11 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD APR 7 PY 2004 VL 123 IS 1-2 BP 126 EP 131 DI 10.1016/j.molbrainres.2004.01.009 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 814BF UT WOS:000220949500015 ER PT J AU Padayatty, SJ Sun, H Wang, YH Riordan, HD Hewitt, SM Katz, A Wesley, RA Levine, M AF Padayatty, SJ Sun, H Wang, YH Riordan, HD Hewitt, SM Katz, A Wesley, RA Levine, M TI Vitamin C pharmacokinetics: Implications for oral and intravenous use SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID RECOMMENDED DIETARY ALLOWANCE; ASCORBIC-ACID; DISEASE PREVENTION; ADVANCED CANCER; CYTOTOXICITY; VOLUNTEERS; TRIAL AB Background: Vitamin C at high concentrations is toxic to cancer cells in vitro. Early clinical studies of vitamin C in patients with terminal cancer suggested clinical benefit, but 2 double-blind, placebo-controlled trials showed none. However, these studies used different routes of administration. Objective: To determine whether plasma vitamin C concentrations vary substantially with the route of administration. Design: Dose concentratior. studies and pharmacokinetic modeling. Setting: Academic medical center. Participants: 17 healthy hospitalized volunteers. Measurements: Vitamin C plasma and urine concentrations were measured after administration of oral and intravenous doses at a dose range of 0.015 to 1.25 g, and plasma concentrations were calculated for a dose range of 1 to 100 g. Results: Peak plasma vitamin C concentrations were higher after administration of intravenous doses than after administration of oral doses (P < 0.001), and the difference increased according to dose. Vitamin C at a dose of 1.25 g administered orally produced mean ( +/- SD) peak plasma concentrations of 134.8 +/- 20.6 mumol/L compared with 885 +/- 201.2 mumol/L for intravenous administration. For the maximum tolerated oral dose of 3 g every 4 hours, pharmacokinetic modeling predicted peak plasma vitamin C concentrations of 220 mumol/L and 13 400 mumol/L for a 50-g intravenous dose. Peak predicted urine concentrations of vitamin C from intravenous administration were 140-fold higher than those from maximum oral doses. Limitations: Patient data are not available to confirm pharmacokinetic modeling at high doses and in patients with cancer. Conclusions: oral vitamin C produces plasma concentrations that are tightly controlled. Only intravenous administration of vitamin C produces high plasma and urine concentrations that might have antitumor activity. Because efficacy of vitamin C treatment cannot be judged from clinical trials that use only oral dosing, the role of vitamin C in cancer treatment should be re-evaluated. C1 NIH, Mol & Clin Nutr Sect, Bethesda, MD 20892 USA. NCI, NIDDKD, Bethesda, MD 20892 USA. NIH, Clin Ctr, Bethesda, MD 20892 USA. Food & Drug Adm, Rockville, MD USA. Biocommun Res Inst, Wichita, KS USA. RP Levine, M (reprint author), NIH, Mol & Clin Nutr Sect, Bldg 10,Room 4D52-MSC 1372, Bethesda, MD 20892 USA. RI Padayatty, Sebastian/A-8581-2012; OI Padayatty, Sebastian/0000-0001-8758-3170; Hewitt, Stephen/0000-0001-8283-1788 FU NIDDK NIH HHS [Z01 DK 54506] NR 20 TC 245 Z9 255 U1 4 U2 20 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 APR 6 PY 2004 VL 140 IS 7 BP 533 EP 537 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 808OE UT WOS:000220577600005 PM 15068981 ER PT J AU Gea-Banacloche, J Johnson, RT Bagic, A Butman, JA Murray, PR Agrawal, AG AF Gea-Banacloche, J Johnson, RT Bagic, A Butman, JA Murray, PR Agrawal, AG TI West Nile Virus: Pathogenesis and therapeutic options SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID ST-LOUIS ENCEPHALITIS; REFRACTORY STATUS EPILEPTICUS; NEW-YORK-CITY; JAPANESE ENCEPHALITIS; RAPID DETECTION; UNITED-STATES; INFECTION; IMMUNOGLOBULIN; ANTIBODY; FEVER AB West Nile virus, a member of the family Flaviviridae, has spread throughout the United States. With more than 9000 cases and 200 deaths in 2003, West Nile virus has become the most common cause of viral encephalitis in several states. West Nile virus encephalitis is a zoonosis. The life cycle of the virus includes mainly birds as hosts and mosquitoes as vectors. Humans are accidental hosts, insufficient to support the life cycle of the virus because of low-grade, transient viremia. However, human-to-human transmission through blood, organ transplantation, and lactation has been documented. The frequency of severe neurologic disease in the current epidemic suggests a more neurovirulent strain of virus than the one classically associated with West Nile fever. Several neurologic manifestations have been described, but the most characteristic presentation is encephalitis with weakness. Magnetic resonance imaging scans may be normal initially, but a characteristic pattern of involvement of deep gray matter nuclei can be recognized. Although results of polymerase chain reaction may be positive in the cerebrospinal fluid early in the course of the disease, diagnosis is based on serologic tests. Possible cross-reactivity with other members of the genus flavivirus mandates caution when serologic testing results are interpreted. Thus far, no therapeutic intervention has shown consistent clinical efficacy in West Nile virus disease. Several approaches, including interferon-alpha2b and immunoglobulin with high titer against West Nile virus, offer promise based on animal models and limited clinical experience. New drugs with in vitro activity are being investigated, and a vaccine is being developed. C1 NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, NCI, NIH, Bethesda, MD USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Gea-Banacloche, J (reprint author), NCI, Expt Transplantat & Immunol Branch, 10 Ctr Dr,Room 12S227, Bethesda, MD 20892 USA. EM banacloj@mail.nih.gov RI Butman, John/A-2694-2008; OI Butman, John/0000-0002-1547-9195 NR 70 TC 59 Z9 63 U1 0 U2 7 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 APR 6 PY 2004 VL 140 IS 7 BP 545 EP 553 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 808OE UT WOS:000220577600007 PM 15068983 ER PT J AU Joseph, J Liu, ST Jablonski, SA Yen, TJ Dasso, M AF Joseph, J Liu, ST Jablonski, SA Yen, TJ Dasso, M TI The RanGAP1-RanBP2 complex is essential for microtubule-kinetochore interactions in vivo SO CURRENT BIOLOGY LA English DT Article ID NUCLEAR-PORE COMPLEX; GTPASE-ACTIVATING PROTEIN; SPINDLE CHECKPOINT; MITOTIC SPINDLE; MAMMALIAN-CELLS/; CENP-E; ATTACHMENT; CENTROSOME; LOCALIZATION; MITOSIS AB RanGAP1 is the activating protein for the Ran GTPase. Vertebrate RanGAP1 is conjugated to a small ubiquitin-like protein, SUMO-1 [1, 2]. This modification promotes association of RanGAP1 with the interphase nuclear pore complex (NPC) through binding to the nucleoporin RanBP2, also known as Nup358. During mitosis, RanGAP1 is concentrated at kinetochores in a microtubule- (MT) and SUMO-1-dependent fashion [3]. RanBP2 is also abundantly found on kinetochores in mitosis [3]. Here we show that ablation of proteins required for MT-kinetochore attachment (Hec1/Ndc80, Nuf2 [4-6]) disrupts RanGAP1 and RanBP2 targeting to kinetochores. No similar disruption was observed after ablation of proteins nonessential for MT-kinetochore interactions (CENP-I, Bub1, CENP-E [7-9]). Acquisition of RanGAP1 and RanBP2 by kinetochores is temporally correlated in untreated cells with MT attachment. These patterns of accumulation suggest a loading mechanism wherein the RanGAP1-RanBP2 complex may be transferred along the MT onto the kinetochore. Depletion of RanBP2 caused mislocalization of RanGAP1, Mad1, Mad2, CENP-E, and CENP-F, as well as loss of cold-stable kinetochore-MT interactions and accumulation of mitotic cells with multipolar spindles and unaligned chromosomes. Taken together, our observations indicate that RanBP2 and RanGAP1 are targeted as a single complex that is both regulated by and essential for stable kinetochore-MT association. C1 NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. Fox Chase Canc Ctr, Inst Canc Res, Philadelphia, PA 19111 USA. RP Dasso, M (reprint author), NICHHD, Lab Gene Regulat & Dev, NIH, Bldg 18,Room 106,18 Lib Drive,MSC-5431, Bethesda, MD 20892 USA. EM mdasso@helix.nih.gov OI Yen, Tim/0000-0003-2159-0997; Dasso, Mary/0000-0002-5410-1371 FU Intramural NIH HHS [Z01 HD008740-06]; NCI NIH HHS [CA75138, CA06927]; NIGMS NIH HHS [GM44762] NR 28 TC 171 Z9 179 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD APR 6 PY 2004 VL 14 IS 7 BP 611 EP 617 DI 10.1016/j.cub.2004.03.031 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 811ZN UT WOS:000220809900028 PM 15062103 ER PT J AU Ory, S Morrison, DK AF Ory, S Morrison, DK TI Signal transduction: IMPlications for Ras-dependent ERK signaling SO CURRENT BIOLOGY LA English DT Editorial Material ID KINASE SUPPRESSOR; PROTEIN; SCAFFOLD; ACTIVATION; LOCALIZATION; PATHWAY; BINDING; KSR1 AB Ras interacts with numerous downstream effectors to transmit a diverse array of cellular signals. A new study shows that a protein known as Impedes Mitogenic signal Propagation, IMP, is an E3 ubiquitin ligase that binds Ras and modulates MAP kinase signaling by regulating the scaffolding activity of KSR. C1 NCI, Lab Prot Dynam & Signaling, Frederick, MD 21702 USA. RP Ory, S (reprint author), NCI, Lab Prot Dynam & Signaling, Frederick, MD 21702 USA. EM dmorrison@ncifcrf.gov RI Ory, Stephane/E-9947-2010 OI Ory, Stephane/0000-0003-4359-1157 NR 16 TC 41 Z9 42 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD APR 6 PY 2004 VL 14 IS 7 BP R277 EP R278 DI 10.1016/j.cub.2004.03.023 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 811ZN UT WOS:000220809900014 PM 15062121 ER PT J AU Krasilnikov, OV Bezrukov, SM AF Krasilnikov, OV Bezrukov, SM TI Polymer partitioning from nonideal solutions into protein voids SO MACROMOLECULES LA English DT Article ID PROBING ALAMETHICIN CHANNELS; LIPID BILAYER-MEMBRANES; WATER-SOLUBLE POLYMERS; ION CHANNELS; ALPHA-TOXIN; FREE-ENERGY; FLEXIBLE POLYMERS; OSMOTIC-STRESS; PORE; MOLECULES AB Using the change in conductance of a single nanometer-wide protein pore of the alpha-hemolysin channel to detect pore occupancy by polymers, we measure the equilibrium partitioning of differently sized poly(ethylene glycol)s as a function of polymer concentration in the bulk solution. In the semidilute regime, increased polymer concentration results in a sharp increase in polymer partitioning. Quantifying solution nonideality by osmotic pressure and taking the free energy of polymer confinement by the pore at infinite dilution as an adjustable parameter allows us to describe polymer partitioning only at low polymer concentrations. At larger concentrations the increase in partitioning is much sharper than the model predictions. The nature of this sharp transition between strong exclusion and strong partitioning might be rationalized within the concepts of scaling theory predicting this kind of behavior whenever the correlation length of the monomer density in the semidilute bulk solution becomes smaller than the pore radius. Specific attractive interactions between the protein pore and the polymer that exist in addition to the entropic repulsion accounted for in the present study may also play a role. C1 NICHD, LPSB, NIH, Bethesda, MD 20892 USA. Univ Fed Pernambuco, Lab Membrane Biophys, Dept Biophys, BR-50670901 Recife, PE, Brazil. Univ Fed Pernambuco, Lab Membrane Biophys, Dept Radiobiol, BR-50670901 Recife, PE, Brazil. RP Bezrukov, SM (reprint author), NICHD, LPSB, NIH, Bldg 9,Room 1N-124B, Bethesda, MD 20892 USA. EM bezrukov@helix.nih.gov NR 49 TC 33 Z9 34 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0024-9297 J9 MACROMOLECULES JI Macromolecules PD APR 6 PY 2004 VL 37 IS 7 BP 2650 EP 2657 DI 10.1021/ma030374n PG 8 WC Polymer Science SC Polymer Science GA 808PT UT WOS:000220581700046 ER PT J AU Sodhi, A Montaner, S Patel, V Gomez-Roman, JJ Li, Y Sausville, EA Sawai, ET Gutkind, JS AF Sodhi, A Montaner, S Patel, V Gomez-Roman, JJ Li, Y Sausville, EA Sawai, ET Gutkind, JS TI Akt plays a central role in sarcomagenesis induced by Kaposi's sarcoma herpesvirus-encoded G protein-coupled receptor SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE human herpesvirus 8; Kaposi's sarcoma-associated herpesvirus; 7-hydroxystaurosporine ID A AVIAN-LEUKOSIS; NF-KAPPA-B; GENE-EXPRESSION; ANTITUMOR-ACTIVITY; SIGNALING PATHWAY; TUMOR-SUPPRESSOR; KINASE; CANCER; UCN-01; CYCLIN AB We have recently engineered an in vivo endothelial cell-specific retroviral gene transfer system and found that a single Kaposi's sarcoma (KS)-associated herpesvirus/human herpesvirus 8 gene encoding a G protein-coupled receptor (vGPCR), is sufficient to induce KS-like tumors in mice. By using this system, we show here that the Akt signaling pathway plays a central role in vGPCR oncogenesis. Indeed, a constitutively active Akt was sufficient to induce benign hemangiomas in mice, whereas heterozyogosity for PTEN (the phosphatase and tension homologue deleted on chromosome 10), modestly enhancing basal Akt activity, dramatically enhanced vGPCR sarcomagenesis. Examination of KS biopsies from AIDS patients revealed active Akt as a prominent feature, supportive of a role for Akt in human Kaposi's sarcomagenesis. By using a vGPCR agonist-dependent mutant, we further establish constitutive activity as a requirement for vGPCR sarcomagenesis, validating targeted inhibition of key vGPCR signaling pathways as an approach for preventing its oncogenic potential. These observations prompted us to explore the efficacy of inhibiting Akt activation as a molecular approach to KS treatment. Pharmacological inhibition of the Akt pathway with the chemotherapeutic agent 7-hydroxy-staurosporine prevented proliferation of vGPCR-expressing endothelial cells in vitro and inhibited their tumorigenic potential in vivo. Both were associated with a decrease in Akt activity. These results identify Akt as an essential player in vGPCR sarcomagenesis and demonstrate the therapeutic potential of drugs targeting this pathway in the treatment of KS. C1 NCI, Dev Therapeut Program, NIH, Rockville, MD 20852 USA. Baylor Coll Med, Breast Ctr, Houston, TX 77030 USA. Marques de Valdecilla Univ Hosp, Dept Anat & Pathol, Santander, Spain. Univ Calif Davis, Dept Med Pathol, Davis, CA 95616 USA. Univ Calif Davis, Comparat Pathol Grad Grp, Davis, CA 95616 USA. Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Gutkind, JS (reprint author), NIDR, 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; OI Li, Yi/0000-0002-9976-518X; Gomez-Roman, Jose Javier/0000-0002-2849-9435 FU NIAID NIH HHS [R0-1 AI46145-01A2, R01 AI046145] NR 53 TC 99 Z9 108 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 6 PY 2004 VL 101 IS 14 BP 4821 EP 4826 DI 10.1073/pnas.0400835101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 811GU UT WOS:000220761200020 PM 15047889 ER PT J AU Kashuba, VI Li, JF Wang, FL Senchenko, VN Protopopov, A Malyukova, A Kutsenko, AS Kadyrova, E Zabarovska, VI Muravenko, OV Zelenin, AV Kisselev, LL Kuzmin, I Minna, JD Winberg, G Ernberg, I Braga, E Lerman, MI Klein, G Zabarovsky, ER AF Kashuba, VI Li, JF Wang, FL Senchenko, VN Protopopov, A Malyukova, A Kutsenko, AS Kadyrova, E Zabarovska, VI Muravenko, OV Zelenin, AV Kisselev, LL Kuzmin, I Minna, JD Winberg, G Ernberg, I Braga, E Lerman, MI Klein, G Zabarovsky, ER TI RBSP3 (HYA22) is a tumor suppressor gene implicated in major epithelial malignancies SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN-CHROMOSOME 3P21.3; LUNG-CANCER; IDENTIFICATION; REGION; SEARCH; PATHOGENESIS; INACTIVATION; PROTEIN; RASSF1A; LOCUS AB Chromosome 3p21.3 region is frequently (>90%) deleted in lung and other major human carcinomas. We subdivided 3p21.3 into LUCA and AP20 subregions and discovered frequent homozygous deletions (10-18%) in both subregions. This finding strongly implies that they harbor multiple tumor suppressor genes involved in the origin and/or development of major epithelial cancers. In this study, we performed an initial analysis of RBSP3/HYA22, a candidate tumor suppressor genes located in the AP20 region. Two sequence splice variants of RBSP3/HYA22 (A and B) were identified, and we provide evidence for their tumor suppressor function. By sequence analysis RBSP3/HYA22 belongs to a gene family of small C-terminal domain phosphatases that may control the RNA polymerase 11 transcription machinery. Expression of the gene was drastically (>20-fold) decreased in 11 of 12 analyzed carcinoma cell lines and in three of eight tumor biopsies. We report missense and nonsense mutations in tumors where RBSP3/HYA22 was expressed, growth suppression with regulated transgenes in culture, suppression of tumor formation in severe combined immundeficient mice, and dephosphorylation of ppRB by RBSP3/HYA22, presumably leading to a block of the cell cycle at the G(1)/S boundary. C1 Karolinska Inst, Ctr Microbiol & Tumor Biol, S-17177 Stockholm, Sweden. Karolinska Inst, Ctr Genom & Bioinformat, S-17177 Stockholm, Sweden. Ukrainian Acad Sci, Inst Mol Biol & Genet, UA-252627 Kiev, Ukraine. Russian Acad Sci, Ctr Bioengn, Moscow 117312, Russia. Russian State Genet Ctr, Moscow 117545, Russia. Russian Acad Sci, VA Engelhardt Mol Biol Inst, Moscow 119991, Russia. NCI, Canc Causing Genes Sect, Immunobiol Lab, Canc Res Ctr, Frederick, MD 21702 USA. SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. Univ Texas, SW Med Ctr, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA. RP Zabarovsky, ER (reprint author), Karolinska Inst, Ctr Microbiol & Tumor Biol, S-17177 Stockholm, Sweden. EM eugzab@aki.se RI Zabarovsky, Eugene/A-6645-2010; Winberg, Gosta/I-5686-2013; Senchenko, Vera/C-8992-2014; Braga, Eleonora/P-5574-2016; OI Senchenko, Vera/0000-0002-3119-515X; Winberg, Gosta/0000-0002-3371-4056 FU NCI NIH HHS [P50 CA070907, R01 CA071618, CA71618, P50 CA70907] NR 22 TC 61 Z9 75 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 6 PY 2004 VL 101 IS 14 BP 4906 EP 4911 DI 10.1073/pnas.0401238101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 811GU UT WOS:000220761200035 PM 15051889 ER PT J AU Castilla, LH Perrat, P Martinez, NJ Landrette, SF Keys, R Oikemus, S Flanegan, J Heilman, S Garrett, L Dutra, A Anderson, S Pihan, GA Wolff, L Liu, PP AF Castilla, LH Perrat, P Martinez, NJ Landrette, SF Keys, R Oikemus, S Flanegan, J Heilman, S Garrett, L Dutra, A Anderson, S Pihan, GA Wolff, L Liu, PP TI Identification of genes that synergize with Cbfb-MYH11 in the pathogenesis of acute myeloid leukemia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID FETAL LIVER HEMATOPOIESIS; ZINC-FINGER PROTEIN; C-MYB; BINDING-FACTOR; IN-VIVO; TRANSCRIPTION FACTORS; EXPRESSION; MICE; VIRUS; ENHANCER AB Acute myeloid leukemia subtype M4 with eosinophilia is associated with a chromosome 16 inversion that creates a fusion gene CBFB-MYH11. We have previously shown that CBFB-MYH11 is necessary but not sufficient for leukemogenesis. Here, we report the identification of genes that specifically cooperate with CBfb-MYH11 in leukemogenesis. Neonatal injection of Cbfb-MYH11 knock-in chimeric mice with retrovinus 4070A led to the development of acute myeloid leukemia in 2-5 months. Each leukemia sample contained one or a few viral insertions, suggesting that alteration of one gene could be sufficient to synergize with Cbfb-MYH11. The chromosomal position of 67 independent retroviral insertion sites (RlSs) was determined, and 90% of the RISs mapped within 10 kb of a flanking gene. In total, 54 candidate genes were identified; six of them were common insertion sites (CISs). CIS genes included members of a zinc finger transcription factors family, Plag1 and Piagl2, with eight and two independent insertions, respectively. CIS genes also included Runx2, Myb, H2-T24, and D6Mm5e. Comparison of the remaining 48 genes with single insertion sites with known leukemia-associated RISs indicated that 18 coincide with known RISs. To our knowledge, this retroviral genetic screen is the first to identify genes that cooperate with a fusion gene important for human myeloid leukemia. C1 Univ Massachusetts, Sch Med, Program Gene Funct & Express, Worcester, MA 01605 USA. Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01605 USA. NIH, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Castilla, LH (reprint author), Univ Massachusetts, Sch Med, Program Gene Funct & Express, Worcester, MA 01605 USA. EM lucio.castilla@umassmed.edu RI Liu, Paul/A-7976-2012 OI Liu, Paul/0000-0002-6779-025X FU NCI NIH HHS [R01 CA096983, R01-CA096983] NR 43 TC 85 Z9 88 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 APR 6 PY 2004 VL 101 IS 14 BP 4924 EP 4929 DI 10.1073/pnas.0400930101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 811GU UT WOS:000220761200038 PM 15044690 ER PT J AU Katano, H Pesnicak, L Cohen, JI AF Katano, H Pesnicak, L Cohen, JI TI Simvastatin induces apoptosis of Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines and delays development of EBV lymphomas SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HMG-COA REDUCTASE; INTERCELLULAR-ADHESION MOLECULE-1; FUNCTION-ASSOCIATED ANTIGEN-1; LIPID RAFTS; I-DOMAIN; LYMPHOPROLIFERATIVE DISEASE; LEUKOCYTE ADHESION; ANTITUMOR-ACTIVITY; BURKITTS-LYMPHOMA; B-LYMPHOCYTES AB Simvastatin and pravastatin are inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase, and are used as antihypercholesterolemia drugs. Simvastatin, but not pravastatin, binds to the inserted domain of leukocyte function antigen (LFA)-1 and inhibits the function of LFA-1, including adhesion and costimulation of lymphocytes. Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) express high levels of LFA-1 on their surface and grow in tight clumps. Here we show that simvastatin (2 muM) inhibits clump formation and induces apoptosis of EBV-transformed LCLs. The apoptosis-inducing effect of simvastatin depends on binding to the inserted domain of LFA-1. Simvastatin, but not pravastatin, dissociates EBV latent membrane protein 1 from lipid rafts of LCLs, resulting in down-regulation of nuclear factor kappaB activity and induction of apoptosis. Analysis of multiple EBV-positive and -negative cell lines indicated that both LFA-1 and EBV latent membrane protein 1 expression were required for simvastatin's effects. Administration of simvastatin to severe combined immunodeficiency mice followed by inoculation with LCLs resulted in delayed development of EBV lymphomas and prolonged survival of animals. To our knowledge, this is the first report in which a drug that targets LFA-1 has been used to treat B cell lymphoma. These data suggest that simvastatin may have promise for treatment or prevention of EBV-associated lymphomas that occur in immunocompromised persons. C1 NIAID, Med Virol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Cohen, JI (reprint author), NIAID, Med Virol Sect, Lab Clin Infect Dis, NIH, 10 Ctr Dr,Bldg 10,Room 11N228, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov NR 47 TC 51 Z9 53 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 6 PY 2004 VL 101 IS 14 BP 4960 EP 4965 DI 10.1073/pnas.0305149101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 811GU UT WOS:000220761200044 PM 15041742 ER PT J AU Akassoglou, K Malester, B Xu, JX Tessarollo, L Rosenbluth, J Chao, MV AF Akassoglou, K Malester, B Xu, JX Tessarollo, L Rosenbluth, J Chao, MV TI Brain-specific deletion of neuropathy target esterase/swisscheese results in neurodegeneration SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cre/lox P; vacuolation; thalamus; hippocampus; Purkinje cells ID NERVOUS-SYSTEM; ESTERASE; ORGANOPHOSPHORUS; MICE; DROSOPHILA; APOPTOSIS; GENE AB Neuropathy target esterase (NTE) is a neuronal membrane protein originally identified for its property to be modified by organophosphates (OPs), which in humans cause neuropathy characterized by axonal degeneration. Drosophila mutants for the homolog gene of NTE, swisscheese (sws), indicated a possible involvement of sws in the regulation of axon-glial cell interaction during glial wrapping. However, the role of NTE/sws in mammalian brain pathophysiology remains unknown. To investigate NTE function in vivo, we used the cre/loxP site-specific recombination strategy to generate mice with a specific deletion of NTE in neuronal tissues. Here we show that loss of NTE leads to prominent neuronal pathology in the hippocampus and thalamus and also defects in the cerebellum. Absence of NTE resulted in disruption of the endoplasmic reticulum, vacuolation of nerve cell bodies, and abnormal reticular aggregates. Thus, these results identify a physiological role for NTE in the nervous system and indicate that a loss-of-function mechanism may contribute to neurodegenerative diseases characterized by vacuolation and neuronal loss. C1 NYU, Sch Med, Neurobiol Program, Skirball Inst Biomol Med, New York, NY 10016 USA. NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA. NYU, Sch Med, Dept Physiol & Neurosci, New York, NY 10016 USA. NYU, Sch Med, Rusk Inst, New York, NY 10016 USA. Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. NCI, Neural Dev Grp, Mouse Canc Genet Program, Frederick, MD 21701 USA. RP Chao, MV (reprint author), NYU, Sch Med, Neurobiol Program, Skirball Inst Biomol Med, RR7714, New York, NY 10016 USA. EM chao@saturn.med.nyu.edu OI Chao, Moses/0000-0002-6969-3744 FU NIMH NIH HHS [MH59904, R01 MH059904]; NINDS NIH HHS [NS37475, R01 NS037475] NR 19 TC 104 Z9 113 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 6 PY 2004 VL 101 IS 14 BP 5075 EP 5080 DI 10.1073/pnas.0401030101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 811GU UT WOS:000220761200064 PM 15051870 ER PT J AU Islami, F Kamangar, F Aghcheli, K Fahimi, S Semnani, S Taghavi, N Marjani, HA Merat, S Nasseri-Moghaddam, S Pourshams, A Nouraie, M Khatibian, M Abedi, B Brazandeh, MH Ghaziani, R Sotoudeh, M Dawsey, SM Abnet, CC Taylor, PR Malekzadeh, R AF Islami, F Kamangar, F Aghcheli, K Fahimi, S Semnani, S Taghavi, N Marjani, HA Merat, S Nasseri-Moghaddam, S Pourshams, A Nouraie, M Khatibian, M Abedi, B Brazandeh, MH Ghaziani, R Sotoudeh, M Dawsey, SM Abnet, CC Taylor, PR Malekzadeh, R TI Epidemiologic features of upper gastrointestinal tract cancers in Northeastern Iran SO BRITISH JOURNAL OF CANCER LA English DT Article DE oesophageal cancer; gastric cancer; Turkmen; Iran ID ESOPHAGEAL CANCER; GASTRIC CANCERS; RISK-FACTORS; INCIDENT ESOPHAGEAL; OPIUM; ADENOCARCINOMA; POPULATION; CARCINOMA; PYROLYSIS; MUTAGENS AB Previous studies have shown that oesophageal and gastric cancers are the most common causes of cancer death in the Golestan Province, Iran. In 2001, we established Atrak Clinic, a referral clinic for gastrointestinal (GI) diseases in Gonbad, the major city of eastern Golestan, which has permitted, for the first time in this region, endoscopic localisation and histologic examination of upper GI cancers. Among the initial 682 patients seen at Atrak Clinic, 370 were confirmed histologically to have cancer, including 223 (60%) oesophageal squamous cell cancers (ESCC), 22 (6%) oesophageal adenocarcinomas (EAC), 58 (16%) gastric cardia adenocarcinomas (GCA), and 58 (16%) gastric noncardia adenocarcinomas. The proportional occurrence of these four main site-cell type subdivisions of upper GI cancers in Golestan is similar to that seen in Linxian, China, another area of high ESCC incidence, and is markedly different from the current proportions in many Western countries. Questioning of patients about exposure to some known and suspected risk factors for squamous cell oesophageal cancer confirmed a negligible history of consumption of alcohol, little use of cigarettes or nass (tobacco, lime and ash), and a low intake of opium, suggesting that the high rates of ESCC seen in northeastern Iran must have other important risk factors that remain speculative or unknown. Further studies are needed to define more precisely the patterns of upper GI cancer incidence, to test other previously suspected risk factors, and to find new significant risk factors in this high-risk area. C1 Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Ctr, Tehran, Iran. NCI, Canc Prevent Studies Branch, Bethesda, MD 20892 USA. Golestan Univ Med Sci, Gorgan, Iran. RP Malekzadeh, R (reprint author), Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Ctr, N Kargar Ave, Tehran, Iran. EM malek@ams.ac.ir RI Abnet, Christian/C-4111-2015; Semnani, Shahryar/N-2270-2016; Abedi-Ardekani, Behnoush/O-7829-2016; OI Abnet, Christian/0000-0002-3008-7843; Semnani, Shahryar/0000-0002-8768-6142; Abedi-Ardekani, Behnoush/0000-0002-0980-0587; Malekzadeh, Reza/0000-0003-1043-3814 NR 24 TC 91 Z9 92 U1 1 U2 4 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 APR 5 PY 2004 VL 90 IS 7 BP 1402 EP 1406 DI 10.1038/sj.bjc.6601737 PG 5 WC Oncology SC Oncology GA 816QQ UT WOS:000221124800020 PM 15054463 ER PT J AU Mo, FM Offertaler, L Kunos, G AF Mo, FM Offertaler, L Kunos, G TI Atypical cannabinoid stimulates endothelial cell migration via a G(i)/G(o)-coupled receptor distinct from CB1, CB2 or EDG-1 SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE vascular endothelium; atypical cannabinoid receptor; cell migration ID PROTEIN-COUPLED RECEPTOR; IN-VIVO; MESENTERIC VASODILATION; K+ CHANNEL; INVOLVEMENT; SPHINGOSINE-1-PHOSPHATE; ACTIVATION; LIGANDS; AKT; ANGIOGENESIS AB The endothelium-dependent mesenteric vasorelaxant effect of anandamide has been attributed to stimulation of a G(i)/G(o)-coupled receptor, for which the nonpsychoactive analog abnormal cannabidiol (abn-cbd, (-)-4-(3-3,4-trans-p-menthadien-[1,8]-yl)olivetol) is a selective agonist and the compound O-1918 ((-)-4-(3-3,4-trans-p-menthadien-(1,8)-yl)-orcinol) is a selective antagonist. In human umbilical vein endothelial cells abn-cbd was reported to increase the phosphorylation of p44/42 mitogen activated protein kinase (MAPK) and protein kinase B/Akt, and these effects could be inhibited by pertussis toxin, by phosphatidylinositol 3-kinase (PI3K) inhibitors or by O-1918 [Mol. Pharmacol. 63 (2003) 699]. In the present experiments, abn-cbd caused a concentration-dependent increase in human umbilical vein endothelial cell migration, as quantified in a transwell chamber. This effect was antagonized by O-1918, by the PI3K inhibitor wortmannin, and by pertussis toxin, but not by the cannabinoid CB1 receptor antagonist AM251 or the cannabinoid CB2 receptor antagonist SR144528. The EDG-1 receptor agonist sphingosine-1-phosphate also increased human umbilical vein endothelial cell migration, but this response was unaffected by O-1918. In Chinese hamster ovary cells stably transfected with the gene encoding the EDG-1 receptor, p44/42 MAPK phosphorylation was unaffected by abn-cbd, but strongly induced by sphingosine-1-phosphate. These results indicate that an abn-cbd-sensitive endothelial receptor distinct from cannabinoid CB1, CB2 or EDG-1 receptors mediates not only vasorelaxation but also endothelial cell migration. (C) 2004 Elsevier B.V. All rights reserved. C1 NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. RP Kunos, G (reprint author), NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. EM gkunos@mail.nih.gov NR 35 TC 47 Z9 47 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD APR 5 PY 2004 VL 489 IS 1-2 BP 21 EP 27 DI 10.1016/j.ejphar.2004.02.034 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 811IY UT WOS:000220766800004 PM 15063151 ER PT J AU Xu, Y Keith, B Grem, JL AF Xu, Y Keith, B Grem, JL TI Measurement of the anticancer agent gemcitabine and its deaminated metabolite at low concentrations in human plasma by liquid chromatography-mass spectrometry SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE gemcitabine; 2 ',2-difluoro-2 '-deoxyuridine ID PHASE-I; 2',2'-DIFLUORODEOXYCYTIDINE 5'-TRIPHOSPHATE; CANCER; CELLS; PHARMACOLOGY; TRIAL; VIVO AB A liquid chromatography/mass spectrometry (LC-MS) method has been developed and validated for the determination of the anticancer agent gemcitabine (dFdC) and its metabolite 2',2'-difluoro-2'-deoxyuridine (dFdU) in human plasma. An Oasis(R) HLB solid phase extraction cartridge was used for plasma sample preparation. Separation of the analytes was achieved with a YMC ODS-AQ (5 mum, 120 A, 2.0 mm x 150 mm) column. The initial composition of the mobile phase was 2% methanol/98% 5 mM[ ammonium acetate at pH 6.8 (v/v), and the flow rate was 0.2 ml/min. An isocratic gradient was used for 3 min, followed by a linear gradient over 4 min to 30% methanol/70% 5 mM ammonium acetate at pH 6.8. The gradient returned to the initial conditions over 2 min and remained there for 6 min. The retention times of dFdC, dFdU, and the internal standard 5'-deoxy-5-fluorouridine (5'-DFUR) were 11.46, 12.63, and 13.58 min. The mass spectrometer was operated under negative electrospray ionization conditions. Single-ion-monitoring (SIM) mode was used for analyte quantitation at m/z 262 for LdFdC-H](-), m/z 263 for [dFdU-H](-), and m/z 245 for [5-DFUR-H](-). The average recoveries for dFdC, dFdU, and 5'-DFUR were 88.4, 84.6, and 99.3%, respectively. The linear calibration ranges were 5-1000 ng/ml for dFdC, and 5-5000 ng/ml for dFdU. The intra- and inter-assay precisions (%CV) were less than or equal to3 and less than or equal to7% at three concentration levels (50.0, 500, and 5000ng/ml). The limits of quantitation (defined as 10 times of signal-to-noise ratio) were 3.16ng/ml for dFdC, and 1.35 ng/ml for dFdU with 50-mul sample injections. This method has been used for measuring plasma concentrations of dFdC and dFdU in samples from adult cancer patients in a Phase I trial of weekly dFdC given as 150 (or lower) mg/(m(2) 24-h) infusion. The average plasma dFdC concentrations at 22- and 23-h into the infusion were 18.3 and 16.8 ng/ml at 150 and 100 mg/m(2), respectively; the values for dFdU averaged 2950 and 1372 ng/ml. (C) 2004 Elsevier B.V. All rights reserved. C1 Cleveland State Univ, Dept Chem, Cleveland, OH 44115 USA. NCI, Gastrointestinal Malignancies Sect, Canc Therapeut Branch, Ctr Canc Res, Bethesda, MD 20889 USA. RP Xu, Y (reprint author), Cleveland State Univ, Dept Chem, 2399 Euclid Ave, Cleveland, OH 44115 USA. EM y.xu@csuohio.edu NR 13 TC 20 Z9 20 U1 2 U2 3 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 APR 5 PY 2004 VL 802 IS 2 BP 263 EP 270 DI 10.1016/j.jchromb.2003.11.038 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 800TS UT WOS:000220051200004 PM 15018786 ER PT J AU Jovanovic, K Burke, RE AF Jovanovic, K Burke, RE TI Morphology of brachial segments in mudpuppy (Necturus maculosus) spinal cord studied with confocal and electron microscopy SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE interneurons; motoneurons; subpial plexus; central pattern generator for locomotion ID FIBRILLARY ACIDIC PROTEIN; PATTERN IN-VITRO; RADIAL GLIA; HORSERADISH-PEROXIDASE; AXIAL MUSCULATURE; NEURAL-NETWORKS; NERVOUS-SYSTEM; REGENERATION; MOTONEURONS; LOCOMOTION AB The isolated brachial spinal cord of Necturus maculosus is useful for studies of neural networks underlying forelimb locomotion, but information about its cellular morphology is scarce. We addressed this issue by using confocal and electron microscopy. Remarkably, the central region of gray matter was aneural and consisted exclusively of a tenuous meshwork of glial fibers and large extracellular spaces. Somata of motoneurons (MNs) and interneurons (INs), labeled by retrograde transport of fluorescent tracers from ventral roots and axons in the ventrolateral funiculus, respectively, were confined within a gray neuropil layer abutting the white matter borders, whereas their dendrites projected widely throughout the white matter. About one-third of labeled INs were found contralaterally, with axons crossing ventral to a thick layer of ependyma surrounding the central canal. Lateral MN dendrites proliferated under the pial surface to form a dense, thin (1-2 mum) plexus immediately beneath a thin layer of glial fibrillary acidic protein-positive glia limitans. The latter contained arrays of unusual tubular structures (diameter 200-400 nm, length 3 mum) that resembled mitochondria but lacked double membranes or cristae. Dorsal roots (DRs) produced dense presynaptic arbors within a wedge-shaped afferent termination zone medial to the dorsal root entry, within which dendrites of MNs and INs mingled with dense collections of synaptic boutons. Our data suggest that a major fraction of synaptic interactions takes place within the white matter. This study provides a detailed foundation for designing electrophysiological experiments to study the neural circuits involved in locomotor pattern generation. Published 2004 Wiley-Liss, Inc. C1 NINDS, Lab Neural Control, NIH, Bethesda, MD 20895 USA. RP Burke, RE (reprint author), NINDS, Lab Neural Control, NIH, Bethesda, MD 20895 USA. EM reburke@helix.nih.gov NR 57 TC 5 Z9 5 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD APR 5 PY 2004 VL 471 IS 3 BP 361 EP 385 DI 10.1002/cne.20044 PG 25 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 800ED UT WOS:000220010800008 PM 14991567 ER PT J AU Zeng, XM Negrete, GA Kasmer, C Yang, WW Gearhart, PJ AF Zeng, XM Negrete, GA Kasmer, C Yang, WW Gearhart, PJ TI Absence of DNA polymerase eta reveals targeting of C mutations on the nontranscribed strand in immunoglobulin switch regions SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE somatic hypermutation; activation-induced cytosine deaminase; xeroderma pigmentosum variant; gap-filling repair; translesion replication ID HEAVY-CHAIN SWITCH; MISMATCH REPAIR PROTEIN; CYTIDINE DEAMINASE AID; STIMULATED B-CELLS; S-GAMMA REGIONS; SOMATIC HYPERMUTATION; MICE DEFICIENT; VARIABLE GENES; MU-REGION; ANTIBODY DIVERSIFICATION AB Activation-induced cytosine deaminase preferentially deaminates C in DNA on the nontranscribed strand in vitro, which theoretically should produce a large increase in mutations of C during hypermutation of immunoglobulin genes. However, a bias for C mutations has not been observed among the mutations in variable genes. Therefore, we examined mutations in the mu and gamma switch regions, which can form stable secondary structures, to look for C mutations. To further simplify the pattern, mutations were studied in the absence of DNA polymerase (pol) eta, which may produce substitutions of nucleotides downstream of C. DNA from lymphocytes of patients with xeroderma pigmentosum variant (XP-V) disease, whose polymerase eta is defective, had the same frequency of switching to all four gamma isotypes and hypermutation in mu-gamma switch sites (0.5% mutations per basepair) as control subjects. There were fewer mutations of A and T bases in the XP-V clones, sin-tilar to variable gene mutations from these patients, which confirms that polymerase eta produces substitutions opposite A and T. Most importantly, the absence of polymerase eta revealed an increase in C mutations on the nontranscribed strand. This data shows for the first time that C is preferentially mutated in vivo and pol eta generates hypermutation in the mu and gamma switch regions. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Gearhart, PJ (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM gearhartp@grc.nia.nih.gov NR 56 TC 52 Z9 53 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD APR 5 PY 2004 VL 199 IS 7 BP 917 EP 924 DI 10.1084/jem.2003022 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 811GS UT WOS:000220761000004 PM 15051760 ER PT J AU Wolint, P Betts, MR Koup, RA Oxenius, A AF Wolint, P Betts, MR Koup, RA Oxenius, A TI Immediate cytotoxicity but not degranulation distinguishes effector and memory subsets of CD8(+) T cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE cytotoxic T cell; central memory; effector memory; lytic granules; virus ID CELLULAR IMMUNE-RESPONSES; NATURAL-KILLER-CELLS; IN-VIVO; CUTTING EDGE; VIRAL-INFECTION; DENDRITIC CELLS; LYMPHOCYTES; NAIVE; DIFFERENTIATION; EXPRESSION AB CD8(+) T cells play a central role in the resolution and containment of viral infections. A key effector function of CD8(+) T cells is their cytolytic activity toward infected cells. Here, we studied the regulation of cytolytic activity in naive, effector, and central versus effector memory CD8(+) T cells specific for the same glycoprotein-derived epitope of lymphocytic choriomeningitis virus. Our results show that the kinetics of degranulation, assessed by a novel flow cytometric based assay, were identical in effector and both subsets of memory CD8(+) T cells, but absent in naive CD8(+) T cells. However, immediate cytolytic activity was most pronounced in effector T cells, low in effector memory T cells, and absent in central memory T cells, correlating with the respective levels of cytolytic effector molecules present in lyric granules. These results indicate that an inherent program of degranulation is a feature of antigen-experienced cells as opposed to naive CD8(+) T cells and that the ability of CD8(+) T cells to induce target cell apoptosis/death is dependent on granule protein content rather than on the act of degranulation itself. Furthermore, these results provide a potential mechanism by which central memory CD8(+) T cell-mediated death of antigen-presenting cells within the lymph node is avoided. C1 ETH, Inst Microbiol, CH-8092 Zurich, Switzerland. NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Oxenius, A (reprint author), ETH, Inst Microbiol, LFV B31-1,Schmelzbergstr 7, CH-8092 Zurich, Switzerland. EM oxenius@micro.biol.ethz.ch RI Oxenius, Annette/G-7794-2015 NR 34 TC 164 Z9 166 U1 0 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD APR 5 PY 2004 VL 199 IS 7 BP 925 EP 936 DI 10.1084/jem.20031799 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 811GS UT WOS:000220761000005 PM 15051762 ER PT J AU Jolly, PS Bektas, M Olivera, A Gonzalez-Espinosa, C Proia, RL Rivera, J Milstien, S Spiegel, S AF Jolly, PS Bektas, M Olivera, A Gonzalez-Espinosa, C Proia, RL Rivera, J Milstien, S Spiegel, S TI Transactivation of sphingosine-1-phosphate receptors by Fc epsilon RI triggering is required for normal mast cell degranulation and chemotaxis SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE sphingosine kinase; SIP receptors; RBL-2H3 cells; motility ID AIRWAY SMOOTH-MUSCLE; AFFINITY IGE RECEPTOR; SPHINGOSINE KINASE TYPE-2; FUNCTIONAL-CHARACTERIZATION; MOLECULAR-CLONING; PROTEIN-KINASE; 1-PHOSPHATE; EDG-1; ACTIVATION; PHOSPHORYLATION AB Mast cells secrete various substances that initiate and perpetuate allergic responses, Cross-linking of the high-affinity receptor for IgE (FcepsilonRI) in RBL-2H3 and bone marrow-derived mast cells activates sphingosine kinase (SphK), which leads to generation and secretion of the potent sphingolipid mediator, sphingosine-1-phosphate (S1P). In turn, S1P activates its receptors S1P, and SIP, that are present in mast cells. Moreover, inhibition of SphK blocks FcepsilonRI-mediated internalization of these receptors and markedly reduces degranulation and chemotaxis. Although transactivation of S1P(1) and Gi signaling are important for cytoskeletal rearrangements and migration of mast cells toward antigen, they are dispensable for FcepsilonRI-triggered degranulation. However, SIP, whose expression is up-regulated by FcepsilonRI cross-linking, was required for degranulation and inhibited migration toward antigen. Together, our results suggest that activation of SphKs and consequently S1PRs by FcepsilonRI triggering plays a crucial role in mast cell functions and might be involved in the movement of mast cells to sites of inflammation. C1 Virginia Commonwealth Univ, Dept Biochem, Med Ctr, Richmond, VA 23298 USA. Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20007 USA. NIAMSD, Bethesda, MD 20892 USA. NIDDKD, Bethesda, MD 20892 USA. NIMH, NIH, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Virginia Commonwealth Univ, Dept Biochem, Med Ctr, Richmond, VA 23298 USA. EM sspiegel@vcu.edu RI Proia, Richard/A-7908-2012 FU NCI NIH HHS [P30 CA016059, P30 CA16059]; NIAID NIH HHS [AIS0094] NR 46 TC 210 Z9 215 U1 0 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD APR 5 PY 2004 VL 199 IS 7 BP 959 EP 970 DI 10.1084/jem.20030680 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 811GS UT WOS:000220761000008 PM 15067032 ER PT J AU Croitoru, N Inberg, A Ben-David, M Gannot, I AF Croitoru, N Inberg, A Ben-David, M Gannot, I TI Broad band and low loss mid-IR flexible hollow waveguides SO OPTICS EXPRESS LA English DT Article ID MECHANICAL-PROPERTIES; INFRARED RADIATION; FIBERS; TRANSMISSION AB This paper introduces a deposition method to create a multilayered waveguide with alternating layers of high index of refraction contrast. A very thin Ag layer, practically transparent in the mid-IR radiation wavelengths of CO2 and Er-YAG lasers, was created. This enabled a good contrast of the indices of refraction of silver/silver iodide. Theoretical calculations as well as experiments have shown that transmission was higher at these wavelengths for two pair layers, in comparison to one pair of silver/silver iodide. Windows of transmittance and small sensitivity to bending were demonstrated for those two pair layer waveguides. This method could be extended to an increased number of pairs to configure a true photonic band gap waveguide. (C) 2004 Optical Society of America. C1 Tel Aviv Univ, Fac Engn, Dept Phys Elect, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Fac Exact Sci, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Fac Engn, Dept Bioengn, IL-69978 Tel Aviv, Israel. NIH, Lab Integrat & Med Biophys, Bethesda, MD 20892 USA. RP Croitoru, N (reprint author), Tel Aviv Univ, Fac Engn, Dept Phys Elect, IL-69978 Tel Aviv, Israel. EM gannoti@mail.nih.gov NR 19 TC 10 Z9 11 U1 0 U2 2 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD APR 5 PY 2004 VL 12 IS 7 BP 1341 EP 1352 DI 10.1364/OPEX.12.001341 PG 12 WC Optics SC Optics GA 809MN UT WOS:000220640900019 PM 19474955 ER PT J AU Tron, EAM Wilke, HL Petermann, SR Rust, L AF Tron, EAM Wilke, HL Petermann, SR Rust, L TI Pseudomonas aeruginosa from canine otitis externa exhibit a quorum sensing deficiency SO VETERINARY MICROBIOLOGY LA English DT Article DE Pseudomonas aeruginosa; canine otitis externa; quorum sensing; bacterial gene regulation; elastase; matrix metalloproteinases ID TO-CELL COMMUNICATION; VIRULENCE FACTORS; CYSTIC-FIBROSIS; ELASTASE; EXPRESSION; GENES; LASR; INFECTIONS; PROTEASES; ACTIVATOR AB Pseudomonas aeruginosa LasB elastase gene (lasB) transcription depends on cell density-dependent quorum-sensing mechanisms of gene activation. Previously, we collected several non-mucoid P. aeruginosa veterinary isolates and showed that the total matrix protease phenotype was similar for isolates regardless of host and site of isolation. In contrast, isolates from chronic canine ear infections (otitis externa) were significantly more likely to exhibit less elastase activity as measured by elastin Congo red than from any other site [Clin. Diag. Lab. Immun. 8 (2001) 632]. In this study, we found that the elastase deficiency phenotype is stable upon passage in broth culture. Transcript amplification analyses indicated that the elastase deficiency appears to be strain-specific. with each isolate exhibiting a unique expression profile relative to strain PAO1. Although a number of strain-specific transcriptional differences were observed, the overall pattern that emerges is a quorum sensing deficiency among canine ear P aeruginosa isolates. (C) 2004 Elsevier B.V. All rights reserved. C1 N Dakota State Univ, Dept Vet & Microbiol Sci, Van Es Labs, Fargo, ND 58105 USA. Univ Connecticut, Ctr Excellence Vaccine Res, Storrs, CT 06269 USA. RP Rust, L (reprint author), NIAID, DHHS, NIH, Sci Review Program,Div Extramural Affairs, 6700B Rockledge Dr,MSC7616, Bethesda, MD 20892 USA. EM lr228v@nih.gov FU NIAID NIH HHS [1 R15 AI 46506-01] NR 45 TC 8 Z9 9 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1135 J9 VET MICROBIOL JI Vet. Microbiol. PD APR 5 PY 2004 VL 99 IS 2 BP 121 EP 129 DI 10.1016/j.vetmic.2003.12.005 PG 9 WC Microbiology; Veterinary Sciences SC Microbiology; Veterinary Sciences GA 801UI UT WOS:000220120400005 PM 15019103 ER PT J AU Kuribayashi, H Wakabayashi, A Shimizu, M Kaneko, H Norose, Y Nakagawa, Y Wang, J Kumagai, Y Margulies, DH Takahashi, H AF Kuribayashi, H Wakabayashi, A Shimizu, M Kaneko, H Norose, Y Nakagawa, Y Wang, J Kumagai, Y Margulies, DH Takahashi, H TI Resistance to viral infection by intraepithelial lymphocytes in HIV-1P18-110-specific T-cell receptor transgenic mice SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE HIV-1; mucosal immunity; transgenic mice; TCR; CTL; IELs; tetramer; alpha beta TCR; gamma delta TCR; vaccinia virus vector ID HUMAN-IMMUNODEFICIENCY-VIRUS; CLASS-I; IMMUNODOMINANT EPITOPE; ENVELOPE GLYCOPROTEIN; ANTIGEN PRESENTATION; MHC MOLECULE; PEPTIDE; MUCOSAL; PROTEIN; CTL AB For the analysis of mucosal immunity to HIV-1, we have recently established a line of transgenic (Tg) mice expressing the TCRalpha and TCRP genes of the murine CTL clone RT1 specific for P18-I10 (RGPGRAFVTI), an immunodominant gp160 envelope-derived epitope of IIIB isolate, restricted by the H-2D(d) MHC-I molecule. Here we examine those cells bearing specific TCR among the intraepithelial lymphocytes (IELs), with flow cytometric analysis using H-2D(d)/P18-I10 tetramers. We observed three distinct CD3(+), tetramer positive populations among the lELs: extra-thymic CD8alphaalpha(+), alphabetaTCR T-cells; CD8alphaalpha(+), gammadeltaTCR T-cells; and thymus-derived CD8alphabeta(+), alphabetaTCR T-cells. Challenge of these Tg mice with P18-I10 encoded by a vaccinia virus vector, either intrarectally (i.r.) or intraperitoneally (i.p.), revealed that the intraepithelial compartment seems to be a major site for prevention of the spread of viral infection. Such immunity appears due to the thymus-derived, CD8alphabeta(+) antigen-specific CTLs together with CD8alphaalpha(+) gammadelta cells, which regulate virus spread. This model system for studying CTL based immunity at mucosal sites should prove helpful in developing rational approaches for HIV control. (C) 2004 Elsevier Inc. All rights reserved. C1 Nippon Med Coll, Dept Microbiol & Immunol, Tokyo 1138602, Japan. Nippon Med Coll, Dept Joint Dis & Rheumat, Tokyo 1138602, Japan. NIAID, Mol Biol Sect, Lab Immunol, NIH, Bethesda, MD 20892 USA. RP Takahashi, H (reprint author), Nippon Med Coll, Dept Microbiol & Immunol, Tokyo 1138602, Japan. EM htkuhkai@nms.ac.jp RI Margulies, David/H-7089-2013 NR 29 TC 3 Z9 5 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD APR 2 PY 2004 VL 316 IS 2 BP 356 EP 363 DI 10.1016/j.bbrc.2004.02.058 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 804YE UT WOS:000220333200010 PM 15020225 ER PT J AU Yamada, S Nakajima, H Kuehn, MR AF Yamada, S Nakajima, H Kuehn, MR TI Novel testis- and embryo-specific isoforms of the phosphofructokinase-1 muscle type gene SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE phosphofructokinase-1, muscle type; PFK-M; 5 ' UTR; gene expression; testis; embryo ID MESSENGER-RNA; 2-PROMOTER SYSTEM; GENOMIC DNA; TRANSCRIPTION; EXPRESSION; RABBIT; REGION; DIFFERENTIATION; LIBRARIES; RAT AB We have identified novel transcriptional isoforms of the human and mouse genes encoding muscle type phosphofructokinase-1 (PFK-M). These isoforms are expressed specifically in the testis and in the mid-gestation embryo, and have been termed TE-PFK-M (testis- and embryo-specific PFK-M). The 5'UTR of TE-PFK-M is composed of three newly identified exons that lie much farther upstream of the PFK-M coding region than the previously characterized 5'UTR. In addition, this upstream region encodes a series of small polyadenylated transcripts, some of which share the same exons found in the 5'UTR of TE-PFK-M, and which may play some role in regulating TE-PFK-M expression. These findings indicate an even more complex level of control of PFK-M expression than previously thought. Published by Elsevier Inc. C1 NCI Frederick, Lab Prot Dynam & Signalling, Canc Res Ctr, Frederick, MD 21702 USA. Osaka Med Ctr Canc & Cardiovasc Dis, Dept Clin Lab, Higashinari Ku, Osaka 5378511, Japan. RP Kuehn, MR (reprint author), NCI Frederick, Lab Prot Dynam & Signalling, Canc Res Ctr, Frederick, MD 21702 USA. EM mkuehn@mail.nih.gov RI Kuehn, Michael/A-4573-2014 OI Kuehn, Michael/0000-0002-7703-9160 NR 28 TC 9 Z9 9 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD APR 2 PY 2004 VL 316 IS 2 BP 580 EP 587 DI 10.1016/j.bbrc.2004.02.089 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 804YE UT WOS:000220333200042 PM 15020257 ER PT J AU Hogg, T Mechold, U Malke, H Cashel, M Hilgenfeld, R AF Hogg, T Mechold, U Malke, H Cashel, M Hilgenfeld, R TI Conformational antagonism between opposing active sites in a bifunctional Re1A/SpoT homolog modulates (p)ppGpp metabolism during the stringent response SO CELL LA English DT Article ID DNA-POLYMERASE-BETA; STREPTOCOCCUS-EQUISIMILIS; RELA/SPOT HOMOLOGS; STATIONARY-PHASE; MECHANISM; RELA; SUPERFAMILY; EXPRESSION; STARVATION; SEQUENCES AB Enzymes of the Rel/Spo family enable bacteria to survive prolonged periods of nutrient limitation by producing an intracellular signaling alarmone, (p)ppGpp, which triggers the so-called stringent response. Both the synthesis of (p)ppGpp from ATP and GDP(GTP), and its hydrolysis to GDP(GTP) and pyrophosphate, are catalyzed by Rel/Spo proteins. The 2.1 Angstrom crystal structure of the bifunctional catalytic fragment of the Rel/Spo homolog from Streptococcus dysgalactiae subsp. equisimilis, Rel(Seq), reveals two conformations of the enzyme corresponding to known reciprocal activity states: (p)ppGpp-hydrolase-OFF/(p)ppGpp-synthetase-ON and hydrolase-ON/synthetase-OFF. The hydrolase and synthetase domains bear remarkable similarities to the catalytic domains of the cyclic phosphodiesterase and nucleotidyltransferase superfamilies, respectively. The active sites, separated by more than 30 Angstrom, contain bound nucleotides including an unusual (p)ppGpp derivative, GDP-2':3'-cyclic monophosphate. Reciprocal regulation of the antagonistic catalytic activities, suggested by the structure, is supported by mutagenesis experiments and appears to involve ligand-induced signal transmission between the two active sites. C1 Med Univ Lubeck, Inst Biochem, D-23538 Lubeck, Germany. Univ Jena, Inst Mol Biotechnol, D-07745 Jena, Germany. Univ Jena, Inst Mol Biol, D-07745 Jena, Germany. NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73190 USA. RP Hilgenfeld, R (reprint author), Med Univ Lubeck, Inst Biochem, Ratzeburger Allee 160, D-23538 Lubeck, Germany. EM hilgenfeld@biochem.uni-luebeck.de RI Hilgenfeld, Rolf/C-9675-2011 NR 43 TC 144 Z9 150 U1 2 U2 13 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD APR 2 PY 2004 VL 117 IS 1 BP 57 EP 68 DI 10.1016/S0092-8674(04)00260-0 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 821YV UT WOS:000221500300008 PM 15066282 ER PT J AU Vinogradova, TM Zhou, YY Maltsev, V Lyashkov, A Stern, M Lakatta, EG AF Vinogradova, TM Zhou, YY Maltsev, V Lyashkov, A Stern, M Lakatta, EG TI Rhythmic ryanodine receptor Ca2+ releases during diastolic depolarization of sinoatrial pacemaker cells do not require membrane depolarization SO CIRCULATION RESEARCH LA English DT Article DE sinoatrial node; ryanodine receptors; local Ca2+ release; permeabilized sinoatrial nodal cells ID NA+-CA2+ EXCHANGE CURRENT; SARCOPLASMIC-RETICULUM; CARDIAC MYOCYTES; VENTRICULAR MYOCYTES; CALCIUM-RELEASE; NODAL CELLS; STIMULATION; CONTRACTION; SPARKS; MUSCLE AB Localized, subsarcolemmal Ca2+ release (LCR) via ryanodine receptors (RyRs) during diastolic depolarization of sinoatrial nodal cells augments the terminal depolarization rate. We determined whether LCRs in rabbit sinoatrial nodal cells require the concurrent membrane depolarization, or are intrinsically rhythmic, and whether rhythmicity is linked to the spontaneous cycle length. Confocal linescan images revealed persistent LCRs both in saponin-permeabilized cells and in spontaneously beating cells acutely voltage-clamped at the maximum diastolic potential. During the initial stage of voltage clamp, the LCR spatiotemporal characteristics did not differ from those in spontaneously beating cells, or in permeabilized cells bathed in 150 nmol/L Ca2+. The period of persistent rhythmic LCRs during voltage clamp was slightly less than the spontaneous cycle length before voltage clamp. In spontaneously beating cells, in both transient and steady states, LCR period was highly correlated with the spontaneous cycle length; and regardless of the cycle length, LCRs occurred predominantly at a constant time, ie, 80% to 90% of the cycle length. Numerical model simulations incorporating LCRs reproduce the experimental results. We conclude that diastolic LCRs reflect rhythmic intracellular Ca2+ cycling that does not require the concomitant membrane depolarization, and that LCR periodicity is closely linked to the spontaneous cycle length. Thus, the biological clock of sinoatrial nodal pacemaker cells, like that of many other rhythmic functions occurring throughout nature, involves an intracellular Ca2+ rhythm. C1 NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Vinogradova, TM (reprint author), NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, Intramural Res Program,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM vinogradovat@grc.nia.nih.gov NR 33 TC 93 Z9 97 U1 0 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD APR 2 PY 2004 VL 94 IS 6 BP 802 EP 809 DI 10.1161/01.RES.0000122045.55331.0F PG 8 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 808SJ UT WOS:000220588500014 PM 14963011 ER PT J AU Rostovtseva, TK Antonsson, B Suzuki, M Youle, RJ Colombini, M Bezrukov, SM AF Rostovtseva, TK Antonsson, B Suzuki, M Youle, RJ Colombini, M Bezrukov, SM TI Bid, but not Bax, regulates VDAC channels SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MITOCHONDRIAL OUTER-MEMBRANE; CYTOCHROME-C RELEASE; DEPENDENT ANION CHANNEL; BCL-2 FAMILY-MEMBER; NEUROSPORA-CRASSA; CONTACT SITES; ION-CHANNEL; CONFORMATIONAL-CHANGE; ANTIAPOPTOTIC BCL-2; BRAIN MITOCHONDRIA AB During apoptosis, cytochrome c is released from mitochondria into the cytosol, where it participates in caspase activation. Various and often conflicting mechanisms have been proposed to account for the increased permeability of the mitochondrial outer membrane that is responsible for this process. The voltage-dependent anion channel (VDAC) is the major permeability pathway for metabolites in the mitochondrial outer membrane and therefore is a very attractive candidate for cytochrome c translocation. Here, we report that properties of VDAC channels reconstituted into planar phospholipid membranes are unaffected by addition of the pro-apoptotic protein Bax under a variety of conditions. Contrary to other reports (Shimizu, S., Narita, M., and Tsujimoto, Y. (1999) Nature 399, 483 - 487; Shimizu, S., Ide, T., Yanagida, T., and Tsujimoto, Y. (2000) J. Biol. Chem. 275, 12321 - 12325; Shimizu, S., Konishi, A., Kodama, T., and Tsujimoto, Y. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 3100 - 3105), we found no electrophysiologically detectable interaction between VDAC channels isolated from mammalian mitochondria and either monomeric or oligomeric forms of Bax. We conclude that Bax does not induce cytochrome c release by acting on VDAC. In contrast to Bax, another pro-apoptotic protein ( Bid) proteolytically cleaved with caspase-8 affected the voltage gating of VDAC by inducing channel closure. We speculate that by decreasing the probability of VDAC opening, Bid reduces metabolite exchange between mitochondria and the cytosol, leading to mitochondrial dysfunction. C1 NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. NICHD, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Serono Pharmaceut Res Inst, CH-1228 Geneva, Switzerland. Univ Maryland, Dept Biol, College Pk, MD 20742 USA. RP Rostovtseva, TK (reprint author), NICHD, Lab Phys & Struct Biol, NIH, Bldg 9,Rm 1E-106, Bethesda, MD 20892 USA. EM rostovts@helix.nih.gov RI Colombini, Marco/A-1540-2014 NR 69 TC 132 Z9 140 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 APR 2 PY 2004 VL 279 IS 14 BP 13575 EP 13583 DI 10.1074/jbc.M310593200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 807CB UT WOS:000220478500037 PM 14729675 ER PT J AU Lawson, VA Priola, SA Meade-White, C Lawson, M Chesebro, B AF Lawson, VA Priola, SA Meade-White, C Lawson, M Chesebro, B TI Flexible N-terminal region of prion protein influences conformation of protease-resistant prion protein isoforms associated with cross-species scrapie infection in vivo and in vitro SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; STRAUSSLER-SCHEINKER-DISEASE; TRANSMISSIBLE MINK ENCEPHALOPATHY; STRAIN VARIATION; AMYLOID PROTEIN; MOLECULAR-BASIS; PRP FRAGMENT; CONVERSION; REPLICATION; VARIANT AB Transmissible spongiform encephalopathy (TSE) diseases are characterized by the accumulation in brain of an abnormal protease-resistant form of the host-encoded prion protein (PrP), PrP-res. PrP-res conformation differs among TSE agents derived from various sources, and these conformational differences are thought to influence the biological characteristics of these agents. In this study, we introduced deletions into the flexible N-terminal region of PrP ( residues 34 - 124) and investigated the effect of this region on the conformation of PrP-res generated in an in vitro cell-free conversion assay. PrP deleted from residues 34 to 99 generated 12 - 16-kDa protease-resistant bands with intact C termini but variable N termini. The variable N termini were the result of exposure of new protease cleavage sites in PrP-res between residues 130 and 157, suggesting that these new cleavage sites were caused by alterations in the conformation of the PrP-res generated. Similarly truncated 12 - 16-kDa PrP bands were also identified in brain homogenates from mice infected with mouse-passaged hamster scrapie as well as in the cell-free conversion assay using conditions that mimicked the hamster/mouse species barrier to infection. Thus, by its effects on PrP-res conformation, the flexible N-terminal region of PrP seemed to influence TSE pathogenesis and cross-species TSE transmission. C1 NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Chesebro, B (reprint author), 903 S 4th St, Hamilton, MT 59840 USA. EM bchesebro@nih.gov OI Lawson, Victoria/0000-0002-7362-7176 NR 50 TC 48 Z9 52 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 APR 2 PY 2004 VL 279 IS 14 BP 13689 EP 13695 DI 10.1074/jbc.M303697200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 807CB UT WOS:000220478500051 PM 14736880 ER PT J AU Galkin, A Kulakova, L Sarikaya, E Lim, K Howard, A Herzberg, O AF Galkin, A Kulakova, L Sarikaya, E Lim, K Howard, A Herzberg, O TI Structural insight into arginine degradation by arginine deiminase, an antibacterial and parasite drug target SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PSEUDOMONAS-AERUGINOSA; CRYSTAL-STRUCTURE; AMIDINOTRANSFERASE; PROTEIN; ENZYME; IDENTIFICATION; BIOSYNTHESIS; EXPRESSION; SOFTWARE; CLONING AB L-Arginine deiminase (ADI) catalyzes the irreversible hydrolysis of arginine to citrulline and ammonia. ADI is involved in the first step of the most widespread anaerobic route of arginine degradation. ADI, missing in high eukaryotes, is a potential antimicrobial and antiparasitic drug target. We have determined the crystal structure of ADI from Pseudomonas aeruginosa by the multi-wavelength anomalous diffraction method at 2.45 Angstrom resolution. The structure exhibits similarity to other arginine-modifying or substituted arginine-modifying enzymes such as dimethylarginine dimethylaminohydrolase (DDAH), arginine: glycine amidinotransferase, and arginine: inosamine-phosphate amidinotransferase, despite the lack of significant amino acid sequence homology to these enzymes. The similarity spans a core domain comprising five betabetaalphabeta motifs arranged in a circle around a 5-fold pseudosymmetry axis. ADI contains an additional alpha-helical domain of novel topology inserted between the first and the second betabetaalphabeta modules. A catalytic triad, Cys-His-Glu/Asp ( arranged in a different manner from that of the thiol proteases), seen in the other arginine-modifying enzymes is also conserved in ADI, as well as many other residues involved in substrate binding. Based on this conservation pattern and the assumption that the substrate binding mode is similar to that of DDAH, an ADI catalytic mechanism is proposed. The main players are Cys-406, which mounts the nucleophilic attack on the carbon atom of the guanidinium group of arginine, and His-278, which serves as a general base. C1 Univ Maryland, Maryland Biotechnol Inst, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Argonne Natl Lab, Adv Photon Source, Argonne, IL 60439 USA. IIT, Chicago, IL 60616 USA. RP Herzberg, O (reprint author), Univ Maryland, Maryland Biotechnol Inst, Ctr Adv Res Biotechnol, 9600 Gudelsky Dr, Rockville, MD 20850 USA. EM osnat@carb.umbi.umd.edu RI ID, IMCACAT/D-5867-2014 FU NIGMS NIH HHS [P01 GM57890] NR 30 TC 54 Z9 57 U1 0 U2 9 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 APR 2 PY 2004 VL 279 IS 14 BP 14001 EP 14008 DI 10.1074/jbc.M313410200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 807CB UT WOS:000220478500088 PM 14701825 ER PT J AU Srichai, MB Konieczkowski, M Padiyar, A Konieczkowski, DJ Mukherjee, A Hayden, PS Kamat, S El-Meanawy, MA Khan, S Mundel, P Lee, SB Bruggeman, LA Schelling, JR Sedor, JR AF Srichai, MB Konieczkowski, M Padiyar, A Konieczkowski, DJ Mukherjee, A Hayden, PS Kamat, S El-Meanawy, MA Khan, S Mundel, P Lee, SB Bruggeman, LA Schelling, JR Sedor, JR TI A WT1 co-regulator controls podocyte phenotype by shuttling between adhesion structures and nucleus SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; TUMOR SUPPRESSOR WT1; DENYS-DRASH-SYNDROME; CONGENITAL NEPHROTIC SYNDROME; HIV-ASSOCIATED NEPHROPATHY; GLOMERULAR SLIT DIAPHRAGM; CELL-CELL ADHESION; WILMS-TUMOR; TRANSCRIPTIONAL ACTIVATION; CD2-ASSOCIATED PROTEIN AB Glomerular podocyte differentiation state is critical for filtration barrier function and is regulated by WT1, a zinc finger transcription factor. A yeast two-hybrid assay identified a novel, WT1-interacting protein (WTIP) that maps to human chromosome 19q13.1, a region with genes linked to familial focal segmental glomerulosclerosis. The domain structure of WTIP is similar to the zyxin subfamily of cytosolic LIM domain-containing proteins, which contain three carboxyl-terminal LIM protein-protein interaction domains and a proline-rich, pre-LIM region with a nuclear export signal. Other LIM domain-containing proteins ( zyxin and mouse muscle LIM protein) did not interact with WT1 in two-hybrid assays, and WTIP did not interact with an unrelated transcription factor, LMX1B. WTIP mRNA was detected in cultured podocytes and was developmentally regulated, with expression peaking in mouse kidney at embryonic day 15 - 16 (E15 - E16) in kidney but persisting into adulthood. In situ hybridization demonstrated WTIP expression in developing E15 glomeruli and in cultured podocytes. The partial WTIP clone, which interacted with WTIP in the two-hybrid assay, co-localized with WT1 in nuclei, co-precipitated with WT1, and inhibited WT1-dependent transcriptional activation of the amphiregulin promoter. In contrast, full-length WTIP was excluded from cell nuclei, but after the addition of leptomycin B, an inhibitor of Crm1-mediated nuclear export, it accumulated in the nucleus and co-precipitated with WT1 in whole cell lysates. Epitope-tagged WTIP co-localized with the adaptor protein CD2AP (CMS) in podocyte actin spots and with Mena at cell-cell junctions. We propose that WTIP monitors slit diaphragm protein assembly as part of a multiple protein complex, linking this specialized adhesion junction to the actin cytoskeleton, and shuttles into the nucleus after podocyte injury, providing a mechanism whereby changes in slit diaphragm structure modulate gene expression. C1 Case Western Reserve Univ, Sch Med, Dept Med, Cleveland, OH 44109 USA. Case Western Reserve Univ, Sch Med, Dept Physiol & Biophys, Cleveland, OH 44109 USA. Rammelkamp Ctr Res & Educ, Cleveland, OH 44109 USA. Albert Einstein Coll Med, Dept Anat, Bronx, NY 10461 USA. NIDDK, Dept Genet Dev, NIH, Bethesda, MD 20892 USA. RP Sedor, JR (reprint author), Metrohlth Med Ctr, Dept Med, BG 531, 2500 Metrohlth Dr, Cleveland, OH 44109 USA. EM jrs4@po.cwru.edu FU NIDDK NIH HHS [DK064719, DK07470, DK038558, P50 DK054178] NR 59 TC 54 Z9 59 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 APR 2 PY 2004 VL 279 IS 14 BP 14398 EP 14408 DI 10.1074/jbc.M314155200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 807CB UT WOS:000220478500136 PM 14736876 ER PT J AU Hargittai, MRS Gorelick, RJ Rouzina, L Musier-Forsyth, K AF Hargittai, MRS Gorelick, RJ Rouzina, L Musier-Forsyth, K TI Mechanistic insights into the kinetics of HIV-1 nucleocapsid protein-facilitated tRNA annealing to the primer binding site SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE chaperone activity; NC protein; zinc fingers; nucleic acid annealing; primer tRNA ID NUCLEIC-ACID-CHAPERONE; COMPLEMENTARY-DNA STRANDS; ZINC-FINGER STRUCTURES; STEM-LOOP SL2; REVERSE-TRANSCRIPTION; SECONDARY STRUCTURE; IN-VITRO; CONFORMATIONAL FLUCTUATIONS; PACKAGING SIGNAL; ORDERED AGGREGATION AB HIV-1 reverse transcriptase uses human tRNA(Lys,3) as a primer to initiate reverse transcription. Prior to initiation, the 3' 18 nucleotides of this tRNA are annealed to a complementary sequence on the RNA genome known as the primer binding site (PBS). Here, we show that the HIV-1 nucleocapsid protein (NC) enhances this annealing by approximately five orders of magnitude in vitro, decreasing the transition state enthalpy from approximately 20 kcal mol(-1) for the uncatalyzed reaction to 13 kcal mol-1 for the NC-catalyzed process. Moreover, the annealing follows second-order kinetics, consistent with the nucleation of the intermolecular duplex being the rate-limiting step. This nucleation is preceded by melting of a small duplex region within the original structure, and is followed by much faster zipping of the rest of the 18 base-pair (bp) duplex. A tRNA mutational analysis shows that destabilization of the tRNA acceptor stem has only a minor effect on the annealing rate. In contrast, addition of bases to the 5' end of tRNA that are complementary to its single-stranded 3' end interferes with duplex nucleation and therefore has a much larger effect on the net reaction rate. Assuming that the apparent transition free energy of the annealing reaction, DeltaG(double dagger), is a sum of the melting (DeltaG(m)) and nucleation (DeltaG(nuc)) free energies, we show that NC affects both DeltaG(m) and DeltaG(nuc). We estimate that ten to 100-fold of the overall rate enhancement is due to NC-induced destabilization of a 4 bp helix in the PBS, while the additional factor of 10(3)-10(4) rate enhancement is a result of NC-facilitated duplex nucleation. The apparently similar effectiveness of wild-type and SSHS NC, a mutant that lacks the zinc finger structures, in facilitating the tRNA annealing reaction is most likely the result of the mutual cancellation of two factors: SSHS NC is less effective than wild-type NC as a duplex destabilizer, but more effective as a duplex nucleating agent. (C) 2004 Elsevier Ltd. All rights reserved. C1 Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. NCI, SAIC Frederick, AIDS Vaccine Program, Frederick, MD 21702 USA. Univ Minnesota, Dept Chem, Minneapolis, MN 55455 USA. RP Musier-Forsyth, K (reprint author), Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. EM rouzina@cbs.umn.edu; musier@chem.umn.edu FU NCI NIH HHS [N01-CO-12400]; NIAID NIH HHS [AI43231]; NIGMS NIH HHS [T32 GM08277] NR 91 TC 84 Z9 86 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD APR 2 PY 2004 VL 337 IS 4 BP 951 EP 968 DI 10.1016/j.jmb.2004.01.054 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 807QH UT WOS:000220515500014 PM 15033363 ER PT J AU Pettit, GR Hoffmann, H Herald, DL McNulty, J Murphy, A Higgs, KC Hamel, E Lewin, NE Pearce, LV Blumberg, PM Pettit, RK Knight, JC AF Pettit, GR Hoffmann, H Herald, DL McNulty, J Murphy, A Higgs, KC Hamel, E Lewin, NE Pearce, LV Blumberg, PM Pettit, RK Knight, JC TI Antineoplastic agents 491. Synthetic conversion of aaptamine to isoaaptamine, 9-demethylaaptamine, and 4-methylaaptamine SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID ALPHA-BLOCKING ACTIVITY; SPONGE AAPTOS-AAPTOS; MARINE ALKALOIDS; NATURAL-PRODUCTS AB Aaptamine (1) was used as starting material for synthetic transformation to isoaaptamine (2), 9-demethylaaptamine (5), and 4-methylaaptamine (6). A general method for the selective O-demethylation of such 1H-benzo [de][1,6]-naphthyridine (1) marine sponge constituents at position C-9 has been developed. Selective O-demethylation of aaptamine (1) and 1-methylaaptamine (11) with 48% hydrobromic acid led to 9-demethylaaptamine (5) and isoaaptamine (2), respectively. A selection of other aaptamine derivatives were synthesized, and their structures were unambiguously determined by X-ray methods. In addition, their cancer cell growth inhibitory properties were evaluated against the murine P388 lymphocytic cell line and a minipanel of human cancer cell lines. Evaluation as inhibitors of the PKC signal transduction pathway and against a selection of microorganisms was also undertaken. Aaptamine derivatives 3 and 5 had broad-spectrum antimicrobial activities. C1 Arizona State Univ, Canc Res Inst, Tempe, AZ 85287 USA. Arizona State Univ, Dept Chem & Biochem, Tempe, AZ 85287 USA. NCI, Screening Technol Branch, DTP, DCTD,NIH, Ft Detrick, MD 21702 USA. NCI, Mol Mechanism Tumor Promot Sect, LCCTP, Bethesda, MD 20892 USA. RP Pettit, GR (reprint author), Arizona State Univ, Canc Res Inst, POB 872404, Tempe, AZ 85287 USA. RI McNulty, James/E-7871-2011 FU NCI NIH HHS [CA44344-05-12, R01 CA90441-01] NR 23 TC 23 Z9 23 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD APR 2 PY 2004 VL 69 IS 7 BP 2251 EP 2256 DI 10.1021/jo0300486 PG 6 WC Chemistry, Organic SC Chemistry GA 807MS UT WOS:000220506200004 PM 15049616 ER PT J AU Yanada, R Koh, Y Nishimori, N Matsumura, A Obika, S Mitsuya, H Fujii, N Takemoto, Y AF Yanada, R Koh, Y Nishimori, N Matsumura, A Obika, S Mitsuya, H Fujii, N Takemoto, Y TI Indium-mediated atom-transfer and reductive radical cyclizations of lodoalkynes: Synthesis and biological evaluation of HIV-protease inhibitors SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID 3-COMPONENT COUPLING REACTIONS; C BOND FORMATION; AQUEOUS-MEDIA; CARBONYL-COMPOUNDS; ELECTRON-TRANSFER; DEVELOPMENTAL TOXICITY; SEQUENTIAL GENERATION; TRIBUTYLTIN HYDRIDE; HEX-5-YNYL IODIDES; ACTIVATED OLEFINS AB Novel indium-mediated radical cyclization reactions of aliphatic iodoalkynes have been studied. Treatment of iodoalkynes with a catalytic amount of In (0.1 equiv) and I-2 (0.05 equiv) promotes atom-transfer 5-exo cyclization to give five-membered alkenyl iodides. In contrast, reaction with In (2 equiv) and I-2 (1 equiv) yields reductive 5-exo cyclization products via the same 5-exo cyclization. Both processes are most likely initiated by low-valent indium species. To demonstrate versatility of these reactions, optically active HIV protease inhibitors were synthesized by this reductive cyclization method. Among them, several products, which contain a hydroxyethylamine dipeptide isostere as a transition state-mimicking substructure, proved to possess potent activity (IC50 = 5-39 nM) against a wide spectrum of HIV strains, including multidrug-resistant variants. C1 Kyoto Univ, Grad Sch Pharmaceut Sci, Sakyo Ku, Kyoto 6068501, Japan. Kumamoto Univ, Sch Med, Dept Internal Med 2, Kumamoto 860, Japan. NCI, Expt Retrovirol Sect, Med Branch, Div Clin Sci,NIH, Bethesda, MD 20892 USA. RP Yanada, R (reprint author), Kyoto Univ, Grad Sch Pharmaceut Sci, Sakyo Ku, Kyoto 6068501, Japan. EM ryanada@pharm.kyoto-u.ac.jp; takemoto@pharm.kyoto-u.ac.jp RI Takemoto, Yoshiji/C-7099-2009 NR 70 TC 51 Z9 51 U1 1 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD APR 2 PY 2004 VL 69 IS 7 BP 2417 EP 2422 DI 10.1021/jo035482m PG 6 WC Chemistry, Organic SC Chemistry GA 807MS UT WOS:000220506200027 PM 15049639 ER PT J AU Cieslak, J Grajkowski, A Livengood, V Beaucage, SL AF Cieslak, J Grajkowski, A Livengood, V Beaucage, SL TI Thermolytic 4-methylthio-1-butyl group for phosphate/thiophosphate protection in solid-phase synthesis of DNA oligonucleotides SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID SULFUR-TRANSFER REAGENT; 3H-1,2-BENZODITHIOL-3-ONE 1,1-DIOXIDE; OLIGODEOXYRIBONUCLEOTIDE SYNTHESIS; PHOSPHATE PROTECTION; OXIDATION; PHOSPHITES; CHEMISTRY AB The thermolabile 4-methylthio-1-butyl phosphate/thiophosphate protecting group for DNA oligonucleotides has been investigated for its potential application to a "heat-driven" process for either oligonucleotide synthesis on diagnostic microarrays or, oppositely, to the large-scale preparation of therapeutic oligonucleotides. The preparation of phosphoramidites 10a-d is straightforward, and the incorporation of these amidites into oligonucleotides via solid-phase techniques proceeds as efficiently as that achieved with 2-cyanoethyl deoxyribonucleoside phosphoramidites. The versatility of the 4-methylthio-1-butyl phosphate/thiophosphate protecting group is exemplified by its facile removal from oligonucleotides upon heating for 30 min at 55 degreesC in an aqueous buffer under neutral conditions or within 2 h at 55 degreesC in concentrated NH4OH. The deprotection reaction occurs through an intramolecular cyclodeesterification mechanism leading to the formation of sulfonium salt 18. When mixed with deoxyribonucleosides and N-protected 2'-deoxyribonucleosides or with a model phosphorothioate diester under conditions approximating those of large-scale (>50 mmol) oligonucleotide deprotection reactions, the salt 18 did not significantly alter DNA nucleobases or desulfurize the phosphorothioate diester model to an appreciable extent. C1 US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Beaucage, SL (reprint author), US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, 8800 Rockville Pike, Bethesda, MD 20892 USA. EM beaucage@cber.fda.gov NR 28 TC 16 Z9 16 U1 1 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD APR 2 PY 2004 VL 69 IS 7 BP 2509 EP 2515 DI 10.1021/jo035861f PG 7 WC Chemistry, Organic SC Chemistry GA 807MS UT WOS:000220506200040 PM 15049652 ER PT J AU Pandit, SD Li, KCP AF Pandit, SD Li, KCP TI A primer on molecular biology for imagers: III. Proteins: Structure and function SO ACADEMIC RADIOLOGY LA English DT Article C1 NIH, Mol Imaging Lab, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. RP Pandit, SD (reprint author), NIH, Mol Imaging Lab, Dept Diagnost Radiol, Ctr Clin, 10-1N306,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 16 TC 6 Z9 6 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 APR PY 2004 VL 11 IS 4 BP 448 EP 461 DI 10.1016/j.acra.2004.02.002 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 807HC UT WOS:000220491600010 PM 15109017 ER PT J AU Dodd, LE Wagner, RF Armato, SG McNitt-Gray, MF Beiden, S Chan, HP Gur, D McLennan, G Metz, CE Petrick, N Sahiner, B Sayre, J AF Dodd, LE Wagner, RF Armato, SG McNitt-Gray, MF Beiden, S Chan, HP Gur, D McLennan, G Metz, CE Petrick, N Sahiner, B Sayre, J CA Lung Image Database Consortium Res TI Assessment methodologies and statistical issues for computer-aided diagnosis of lung nodules in computed tomography: Contemporary research topics relevant to the lung image database consortium SO ACADEMIC RADIOLOGY LA English DT Article DE computer-aided diagnosis (CAD); database development; lung cancer; lung nodule; MRMC; ROC ID OPERATING CHARACTERISTIC ANALYSIS; OF-VARIANCE MODELS; FINITE-SAMPLE SIZE; OBSERVER-PERFORMANCE; ROC ANALYSIS; CONDITIONAL DEPENDENCE; MULTIPLE-ABNORMALITIES; REGRESSION METHODOLOGY; DISEASE VERIFICATION; SELECTION BIAS AB Cancer of the lung and bronchus is the leading fatal malignancy in the United States. Five-year survival is low, but treatment of early stage disease considerably improves chances of survival. Advances in multidetector-row computed tomography technology provide detection of smaller lung nodules and offer a potentially effective screening tool. The large number of images per exam, however, requires considerable radiologist time for interpretation and is an impediment to clinical throughput. Thus, computer-aided diagnosis (CAD) methods are needed to assist radiologists with their decision making. To promote the development of CAD methods, the National Cancer Institute formed the Lung Image Database Consortium (LIDC). The LIDC is charged with developing the consensus and standards necessary to create an image database of multidetector-row computed tomography lung images as a resource for CAD researchers. To develop such a prospective database, its potential uses must be anticipated. The ultimate applications will influence the information that must be included along with the images, the relevant measures of algorithm performance, and the number of required images. In this article we outline assessment methodologies and statistical issues as they relate to several potential uses of the LIDC database. We review methods for performance assessment and discuss issues of defining "truth" as well as the complications that arise when truth information is not available. We also discuss issues about sizing and populating a database. (C) AUR, 2004. C1 NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. US FDA, Ctr Devices & Radiol Hlth, Rockville, MD 20857 USA. Univ Chicago, Dept Radiol, Chicago, IL 60637 USA. Univ Calif Los Angeles, Dept Radiol, David Geffen Sch Med, Los Angeles, CA 90024 USA. Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. Univ Pittsburgh, Dept Radiol, Pittsburgh, PA 15260 USA. Univ Iowa, Dept Med, Iowa City, IA 52242 USA. Univ Calif Los Angeles, Dept Biostat, Sch Publ Hlth, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Radiol, Sch Publ Hlth, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Radiol, Sch Med, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Biostat, Sch Med, Los Angeles, CA 90024 USA. RP NCI, Biometr Res Branch, Div Canc Treatment & Diag, 6130 Execut Blvd,MSC 7434, Bethesda, MD 20892 USA. EM doddl@mail.nih.gov FU NCI NIH HHS [U01CA091103, U01CA091099, U01CA091090, U01CA091100, U01CA091085] NR 85 TC 51 Z9 52 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD APR PY 2004 VL 11 IS 4 BP 462 EP 475 DI 10.1016/S1076-6332(03)00814-6 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 807HC UT WOS:000220491600011 PM 15109018 ER PT J AU Saxena, AK Saul, A Garboczi, DN AF Saxena, AK Saul, A Garboczi, DN TI Crystallization and preliminary X-ray analysis of the Plasmodium vivax sexual stage 25 kDa protein Pvs25, a transmission-blocking vaccine candidate for malaria SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID OOKINETE SURFACE; ANTIBODIES AB The Plasmodium vivax sexual stage 25 kDa protein Pvs25 is expressed on the surface of the ookinete form of the parasite. Monoclonal antibodies directed against Pvs25 block the development of P. vivax oocysts in the mosquito host. Thus, Pvs25 is a potential vaccine candidate for eliciting transmission-blocking immunity in individuals living in malaria-epidemic regions. Pvs25 which was expressed and purified for clinical trials was crystallized using polyethylene glycol as the precipitating agent and diffracts X-rays to 2.3 Angstrom. The orthorhombic Pvs25 crystal form belongs to space group P2(1)2(1)2(1), with unit-cell parameters a=42.6, b=59.8, c=66.8 Angstrom and one molecule in the asymmetric unit. Reductively methylated Pvs25 crystallized in two forms: an orthorhombic P2(1)2(1)2(1) form with unit-cell parameters a=43.4, b=62.9, c=66.9 Angstrom and one molecule in the asymmetric unit and a monoclinic P2(1) form with unit-cell parameters a=53.5, b=43.3, c=65.3 Angstrom, beta=104.0degrees which was predicted to have one or two molecules in the asymmetric unit. Several native and heavy-atom data sets have been collected from Pvs25 and methylated Pvs25 crystals for use in MAD or MIR techniques. C1 NIAID, Struct Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. NIAAA, Malaria Vaccine Dev Branch, NIH, Rockville, MD 20852 USA. RP Garboczi, DN (reprint author), NIAID, Struct Biol Sect, Immunogenet Lab, NIH, Twinbrook 2,12441 Parklawn Dr, Rockville, MD 20852 USA. EM dgarboczi@niaid.nih.gov RI Saul, Allan/I-6968-2013 OI Saul, Allan/0000-0003-0665-4091 NR 17 TC 6 Z9 7 U1 0 U2 0 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 APR PY 2004 VL 60 BP 706 EP 708 DI 10.1107/S0907444904001398 PN 4 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 805LR UT WOS:000220368300012 PM 15039560 ER PT J AU Klosek, MM AF Klosek, MM TI Multiscale analysis of effects of additive and multiplicative noise on delay differential equations near a bifurcation point SO ACTA PHYSICA POLONICA B LA English DT Article; Proceedings Paper CT 16th Marian Smoluchowski Symposium on Statistical Physics CY SEP 06-11, 2003 CL Zakopane, POLAND SP Marian Smoluchowski Inst Phys, Silesian Univ Technol, Dept Phys Chem, Silesian Univ, Inst Phys, Warsaw Univ, Dept Phys ID STOCHASTIC RESONANCE; SYSTEM AB We study effects of noisy and deterministic perturbations on oscillatory solutions to delay differential equations. We develop the multiscale technique and derive amplitude equations for noisy oscillations near a critical delay. We investigate effects of additive and multiplicative noise. We show that if the magnitudes of noise and deterministic perturbations are balanced, then the oscillatory behavior persists for long times being sustained by the noise. We illustrate the technique and its results on linear and logistic delay equations. C1 NCI, Lab Computat & Expt Biol, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Klosek, MM (reprint author), NCI, Lab Computat & Expt Biol, NIH, Dept Hlth & Human Serv, 12B S Dr, Bethesda, MD 20892 USA. EM klosek@nih.gov NR 22 TC 3 Z9 4 U1 0 U2 0 PU ACTA PHYSICA POLONICA B, JAGELLONIAN UNIV, INST PHYSICS PI KRAKOW PA REYMONTA 4, 30-059 KRAKOW, POLAND SN 0587-4254 J9 ACTA PHYS POL B JI Acta Phys. Pol. B PD APR PY 2004 VL 35 IS 4 BP 1387 EP 1405 PG 19 WC Physics, Multidisciplinary SC Physics GA 822LE UT WOS:000221540600007 ER PT J AU Terracciano, A Costa, PT AF Terracciano, A Costa, PT TI Smoking and the Five-Factor Model of personality SO ADDICTION LA English DT Article DE conscientiousness; five-factor model; health risk behavior; impulsivity; interaction effect; neuroticism; personality traits; smoking ID EXPERT-SYSTEM INTERVENTION; CIGARETTE-SMOKING; NICOTINE DEPENDENCE; HEALTH BEHAVIOR; NEGATIVE AFFECT; BIG-5 FACTORS; YOUNG-ADULTS; 5 CULTURES; CESSATION; SMOKERS AB Aims Investigating the association between personality traits and smoking status using a comprehensive model of personality, the Five-Factor Model (FFM). Design Cross-sectional survey. Setting Baltimore. MD, USA. Participants Adult elderly Americans (n= 1638). Measurements A self-administered survey on cigarette smoking and the Revised NEO Personality Inventory (NEO-PI-R). Findings Current smokers scored higher than never smokers on neuroticism and lower on agreeableness and conscientiousness; former smokers scored intermediate on these higher-order dimensions. Neuroticism was related to smoking particularly among individuals with low conscientiousness. as indicated by an interaction effect between the two factors. There were no differences on extraversion and openness to experience. At the lower-order facet level, smokers were characterized by inability to resist cravings (high impulsiveness), search for stimulation (high excitement-seeking), lack of perseverance (low self-discipline) and lack of careful consideration of the consequences of their actions (low deliberation). Conclusions At the higher-order factor level, this study replicates and extends previous studies using a comprehensive model of personality (FFM). The greater specificity provided by the facet-level analysis appears to explain some of the conflicting results in the literature, and the use of an older sample provides insight especially into the former smokers group. Personality research may lead to a deeper understanding of cigarette smoking and can potentially contribute to policies and programs of smoking prevention and cessation. C1 NIA, Lab Personal & Cognit, NIH, DHHS, Baltimore, MD 21224 USA. RP Terracciano, A (reprint author), NIA, Lab Personal & Cognit, NIH, DHHS, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM TerraccianoA@grc.nia.nih.gov RI terracciano, antonio/B-1884-2008; OI Costa, Paul/0000-0003-4375-1712 FU Intramural NIH HHS [Z99 AG999999, ZIA AG000183-22, ZIA AG000183-23, ZIA AG000197-03, ZIA AG000197-04] NR 71 TC 178 Z9 181 U1 6 U2 33 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0965-2140 J9 ADDICTION JI Addiction PD APR PY 2004 VL 99 IS 4 BP 472 EP 481 DI 10.1111/j.1360-0443.2004.00687.x PG 10 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 813BH UT WOS:000220882100016 PM 15049747 ER PT J AU Butler, RN Warner, HR Williams, TF Austad, SN Brody, JA Campisi, J Cerami, A Cohen, G Cristofalo, VJ Drachman, DA Finch, CE Fridovich, I Harley, CB Havlik, RJ Martin, GM Miller, RA Olshansky, SJ Pereira-Smith, OM Smith, JR Sprott, RL West, MD Wilmoth, JR Wright, WE AF Butler, RN Warner, HR Williams, TF Austad, SN Brody, JA Campisi, J Cerami, A Cohen, G Cristofalo, VJ Drachman, DA Finch, CE Fridovich, I Harley, CB Havlik, RJ Martin, GM Miller, RA Olshansky, SJ Pereira-Smith, OM Smith, JR Sprott, RL West, MD Wilmoth, JR Wright, WE TI The aging factor in health and disease: The promise of basic research on aging SO AGING CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article ID LIFE-SPAN; CAENORHABDITIS-ELEGANS; HUMAN-CELLS; LONGEVITY; MICE; POPULATION; TELOMERASE; SENESCENCE; EXTENSION; SEQUENCE C1 Int Longev Ctr USA, Alliance Hlth & Future, New York, NY 10028 USA. Mt Sinai Med Ctr, Dept Geriatr, New York, NY 10029 USA. NIA, Biol Aging Program, Bethesda, MD 20892 USA. Univ Rochester, Monroe Community Hosp, Rochester, NY USA. RP Int Longev Ctr USA, Alliance Hlth & Future, 60 E 86th St, New York, NY 10028 USA. NR 36 TC 15 Z9 15 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1594-0667 EI 1720-8319 J9 AGING CLIN EXP RES JI Aging Clin. Exp. Res. PD APR PY 2004 VL 16 IS 2 BP 104 EP 111 PG 8 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 822DI UT WOS:000221515200002 PM 15195984 ER PT J AU Leng, SX Cappola, AR Andersen, RE Blackman, MR Koenig, K Blair, M Walston, JD AF Leng, SX Cappola, AR Andersen, RE Blackman, MR Koenig, K Blair, M Walston, JD TI Serum levels of insulin-like growth factor-I (IGF-I) and dehydroepiandrosterone sulfate (DHEA-S), and their relationships with serum interleukin-6, in the geriatric syndrome of frailty SO AGING CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article ID HEALTHY OLDER MEN; BODY-COMPOSITION; TESTOSTERONE LEVELS; FUNCTIONAL DECLINE; TRANSGENIC MICE; MUSCLE STRENGTH; ELDERLY-PEOPLE; HORMONE; WOMEN; AGE AB Background and aims: The geriatric syndrome of frailty has been conceptualized as a loss of physiologic reserve associated with endocrine dysregulation and immune dysfunction. Our prior studies suggest that the frailty syndrome is associated with elevated serum IL-6 levels. In the present study, our aim is to evaluate the possible role of endocrine dysregulation and its relationship with serum IL-6 in the pathogenesis of this syndrome. Methods: Using a recently validated screening algorithm for frailty, we identified 18 frail and 33 non-frail community-dwelling older adults for inclusion in this study. Serum levels of insulin-like growth factor-I (IGF-I), DHEA-S, and IL-6 were measured by immunoassays. The inter-relationships among serum levels of IL-6, DHEA-S. and IGF-I were determined by linear regression analysis. Results: Age-adjusted serum levels of IGF-I (88 +/- 49 us 122 +/- 47 [ng/mL], p<0.023) and DHEA-S (0.30 +/- 0.21 us 0.53 +/- 0.25 [pg/mL], p=0.016) were significantly lower in frail us non-frail individuals, respectively. There was a trend for IL-6 to be inversely correlated with IGF-1 in the frail (r=-0.42; p=0.082) but not the non-frail group (r=0.12, p=0.521). Conclusions: Frail subjects have lower levels of serum IGF-I and DHEA-S and higher levels of IL-6 than do non-frail, age-matched individuals. The trend toward an inverse correlation between IGF-I and IL-6 in the frail, but not the non-frail group., suggests potential interaction between endocrine and immune/cytokine dysregulation that requires further study in larger cohorts, ((C))2004, Editrice Kurtis. C1 Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. NIH, Natl Ctr Complementary & Alternat Med, Clin Invest Lab, Bethesda, MD USA. RP Walston, JD (reprint author), Johns Hopkins Asthma & Allergy Ctr, Rm 5A 24,5501 Hopkins Bayview Circle, Baltimore, MD 21224 USA. EM jwalston@jhmi.edu FU NCRR NIH HHS [M01RR-02719] NR 30 TC 104 Z9 108 U1 1 U2 4 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 APR PY 2004 VL 16 IS 2 BP 153 EP 157 PG 5 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 822DI UT WOS:000221515200010 PM 15195991 ER PT J AU Martin, SC Wolters, PL Klaas, PA Perez, L Wood, LV AF Martin, SC Wolters, PL Klaas, PA Perez, L Wood, LV TI Coping styles among families of children with HIV infection SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article ID SEROPOSITIVE WOMEN; SOCIAL SUPPORT; ADJUSTMENT; DISEASE; IMPACT; STRESS; ADOLESCENTS; STRATEGIES; AVOIDANCE; CANCER AB The primary aim of this study was to examine coping strategies among families of HIV-infected children and how they relate to medical, central nervous system (CNS) and family environment factors. Caregivers of HIV-positive children (N = 52) completed a family coping measure (F-COPES) and provided information regarding family environment. Data regarding medical and CNS status were obtained from patient records. Results indicated that families' passive coping and spiritual support were among the coping techniques used most often, and social support was used least often. Medical variables were unrelated to any coping styles. Families of children with CNS impairment endorsed more passive coping techniques than families of children with no apparent deficits. A trend was found for non-biological caregivers to seek out more community resources and support than biological caregivers. Findings suggest the need to target families least likely to utilize resources, and to teach them to effectively seek out and benefit from social and community supports. C1 NCI, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. Med Illness Counseling Ctr, Chevy Chase, MD USA. Westat Corp, Bethesda, MD USA. RP Martin, SC (reprint author), 9030 Old Georgetown Rd,107, Bethesda, MD 20892 USA. EM martins@mail.nih.gov NR 34 TC 8 Z9 9 U1 0 U2 4 PU CARFAX PUBLISHING PI BASINGSTOKE PA RANKINE RD, BASINGSTOKE RG24 8PR, HANTS, ENGLAND SN 0954-0121 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids/Hiv PD APR PY 2004 VL 16 IS 3 BP 283 EP 292 DI 10.1080/09540120410001665295 PG 10 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Respiratory System; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychology; Respiratory System; Biomedical Social Sciences GA 811XB UT WOS:000220803500002 PM 15203422 ER PT J AU Mossman, SP Pierce, CC Watson, AJ Robertson, MN Montefiori, DC Kuller, L Richardson, BA Bradshaw, JD Munn, RJ Hu, SL Greenberg, PD Benveniste, RE Haigwood, NL AF Mossman, SP Pierce, CC Watson, AJ Robertson, MN Montefiori, DC Kuller, L Richardson, BA Bradshaw, JD Munn, RJ Hu, SL Greenberg, PD Benveniste, RE Haigwood, NL TI Protective immunity to SIV challenge elicited by vaccination of macaques with multigenic DNA vaccines producing virus-like particles SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CYTOTOXIC T-LYMPHOCYTES; COMBINATION IMMUNIZATION; NEUTRALIZING ANTIBODIES; PRIMATE MODELS; VIRAL LOAD; INFECTION; AIDS; RESPONSES; ENVELOPE AB We utilized SIVmne infection of Macaca fascicularis to assess the efficacy of DNA vaccination alone, and as a priming agent in combination with subunit protein boosts. All SIVmne structural and regulatory genes were expressed using the human cytomegalovirus Immediate Early-1 promoter in plasmids that directed the formation of virus-like particles in vitro. Macaques (n=4) were immunized intradermally and intramuscularly four times over 36 weeks with 3 mg plasmid DNA. A second group (n=4) received two DNA priming inoculations followed by two intramuscular boosts consisting of 250 mug recombinant Env gp160 and 250 mug recombinant Gag-Pol particles in MF-59 adjuvant. These regimens elicited modest cellular immunity prior to challenge. Humoral immune responses to Env gp160 were elicited and sustained by both vaccine protocols, and as expected antibody titers were higher in the protein subunit-boosted animals. Neutralizing antibodies prior to challenge were measurable in two of four subunit-boosted macaques. The two vaccine regimens elicited comparable helper T cell responses at the time of challenge. Vaccinees and mock-immunized controls (n=4) were challenged intrarectally at week 38 with uncloned SIVmne. Following challenge all macaques became infected, but both vaccine regimens resulted in reduced peak virus loads (p=0.07) and significantly improved maintenance of peripheral CD4(+) T cell counts postchallenge (p=0.007, DNA alone and p=0.01, all vaccinees). There was no significant difference between the two vaccine groups in levels of plasma viremia or maintenance of CD4(+) T cell counts postchallenge. C1 Seattle Biomed Res Inst, Seattle, WA 98109 USA. Univ Washington, Reg Primate Res Ctr, Seattle, WA 98195 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. Duke Univ, Med Ctr, Durham, NC 27710 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Univ Calif Davis, Dept Pathol, Davis, CA 95616 USA. NCI, Viral Carcinogenesis Lab, Frederick, MD 21702 USA. Univ Washington, Dept Pathobiol, Seattle, WA 98195 USA. RP Haigwood, NL (reprint author), Seattle Biomed Res Inst, 307 Westlake Ave N,Suite 500, Seattle, WA 98109 USA. EM nancy.haigwood@sbri.org RI Hu, Shiu-Lok/A-3196-2008 OI Hu, Shiu-Lok/0000-0003-4336-7964 FU NIAID NIH HHS [AI-26503] NR 32 TC 18 Z9 18 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 APR PY 2004 VL 20 IS 4 BP 425 EP 434 DI 10.1089/088922204323048177 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 818KI UT WOS:000221243600010 PM 15157361 ER PT J AU Zhang, XC Li, SY Brown, RA Ren, J AF Zhang, XC Li, SY Brown, RA Ren, J TI Ethanol and acetaldehyde in alcoholic cardiomyopathy: from bad to ugly en route to oxidative stress SO ALCOHOL LA English DT Review DE ethanol; acetaldchyde; alcoholic cardiomyopathy; oxidative stress ID ACTIVATED PROTEIN-KINASE; HEPATIC STELLATE CELLS; N-TERMINAL KINASE; VENTRICULAR MYOCYTES; LIPID-PEROXIDATION; GENE-EXPRESSION; ALDEHYDE DEHYDROGENASE; IN-VIVO; CARDIAC OVEREXPRESSION; CONTRACTILE DEFECT AB Alcoholic cardiomyopathy is characterized by cardiomegaly, disruptions of myofibrillary architecture, reduced myocardial contractility, decreased ejection fraction, and enhanced risk of stroke and hypertension. Although several mechanisms have been postulated for alcoholic cardiomyopathy, including oxidative damage, accumulation of triglycerides, altered fatty acid extraction, decreased myofilament Ca2+ sensitivity, and impaired protein synthesis, neither the mechanism nor the ultimate toxin has been unveiled. Primary candidates acting as specific toxins of myocardial tissue are ethanol; its first and major metabolic product, acetaldehyde; and fatty acid ethyl esters. Acetaldehyde has been demonstrated to impair directly cardiac contractile function, disrupt cardiac excitation-contractile coupling, and contribute to oxidative damage and lipid peroxidation. Acetaldehyde-elicited cardiac dysfunction may be mediated through cytochrome P450 oxidase, xanthine oxidase, and the stress-signaling cascade. Unfortunately, the most direct approach that can be used to examine toxicity is hampered by the fact that direct intake of acetaldehyde is highly toxic and unsuitable for long-term study. To overcome this obstacle, transgenic mice have been used to alter artificially ethanol/acetaldehyde metabolism, resulting in elevated acetaldehyde concentrations after ethanol ingestion. In this review, we summarize results obtained with the use of transgenic animal models to elucidate the role of acetaldehyde in the mechanism of action in alcoholic cardiomyopathy. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Wyoming, Coll Hlth Sci, Grad Program Neurosci, Div Pharmaceut Sci, Laramie, WY 82071 USA. Univ Wyoming, Coll Hlth Sci, Ctr Cardiovasc Res & Alternat Med, Laramie, WY 82071 USA. NIAAA, Biomed Res Branch, Div Basic Res, NIH, Bethesda, MD 20892 USA. RP Ren, J (reprint author), Univ Wyoming, Coll Hlth Sci, Grad Program Neurosci, Div Pharmaceut Sci, Laramie, WY 82071 USA. EM jren@uwyo.edu FU NCRR NIH HHS [P20 RR15640, RR-16474]; NIAAA NIH HHS [1R01 AA013412-01, R15 AA13575-01] NR 100 TC 62 Z9 70 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0741-8329 J9 ALCOHOL JI Alcohol PD APR PY 2004 VL 32 IS 3 BP 175 EP 186 DI 10.1016/j.alcohol.2004.01.005 PG 12 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA 846CG UT WOS:000223291800001 PM 15282111 ER PT J AU Lowy, FD Waldhausen, JA Miller, M Sopko, G Rosenberg, Y Skarlatos, SI AF Lowy, FD Waldhausen, JA Miller, M Sopko, G Rosenberg, Y Skarlatos, SI TI Report of the national heart, lung and blood institute-National Institute of Allergy and Infectious Diseases Working Group on antimicrobial strategies and cardiothoracic surgery SO AMERICAN HEART JOURNAL LA English DT Article ID RESISTANT STAPHYLOCOCCUS-AUREUS; BINDING PROTEIN-A; INTRANASAL MUPIROCIN; VETERANS-AFFAIRS; CARDIAC-SURGERY; ENDOCARDITIS; FIBRONECTIN; MORTALITY; ADHERENCE; MULTIPLE AB Infections related to cardiac surgery increase morbidity and mortality, and increase cost and use of health resources. With the widespread use of synthetic materials, whether in prosthetic valves or vascular conduits, bacterial infection and, more rarely, fungal complications can be devastating, requiring prolonged antimicrobial therapy and, at times, re-operations with high morbidity and mortality rates. With the US population aging and living longer, cardiac surgery is applied to an older population with significant comorbidities, making the threat from infectious complications significant. The dwindling armamentarium of existing antimicrobial agents, a limited pharmaceutical pipeline of future therapies, and the emergence of antimicrobial-resistant bacteria have increased the challenge of treating cardiothoracic infections. Thus, there is critical need for addressing the existing and emerging issues in this area to develop new safe and effective strategies to address the clinical challenges facing cardiothoracic surgeons.As a result of this need, the National Heart, Lung, and Blood Institute and the National Institute of Allergy and Infectious Diseases convened a Working Group on April 4 and 5, 2002, in Bethesda, Md, which explored both basic science and clinical research opportunities in the prevention and treatment of major infections after cardiac surgery. Because of its importance as the most common pathogen in this set-, ting, the focus of discussions was on the prevention and treatment of Staphylococcus aureus infections. This report summarizes the 5 main areas that the Working Group targeted (epidemiology of infections, molecular mechanisms of infections and complications, current pharmacotherapy, new frontiers, and clinical trial design) and highlights the recommendations that were set forth by the Working Group. C1 NHLBI, Div Heart & Vasc Dis, Rockledge Ctr 2, NIH, Bethesda, MD 20892 USA. Columbia Univ, Coll Phys & Surg, New York, NY 10027 USA. Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Hershey, PA 17033 USA. NIAID, Bacteriol & Mycol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. RP Skarlatos, SI (reprint author), NHLBI, Div Heart & Vasc Dis, Rockledge Ctr 2, NIH, 6701 Rockledge Dr,Room 10198,MSC 7956, Bethesda, MD 20892 USA. EM skarlats@nhlbi.nih.gov NR 32 TC 3 Z9 3 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 APR PY 2004 VL 147 IS 4 BP 575 EP 581 DI 10.1016/j.ahj.2003.08.016 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 895XG UT WOS:000226896900004 PM 15077070 ER PT J AU Robbins, JB Schneerson, R Horwith, G Naso, R Fattom, A AF Robbins, JB Schneerson, R Horwith, G Naso, R Fattom, A TI Staphylococcus aureus types 5 and 8 capsular polysaccaride-protein conjugate vaccines SO AMERICAN HEART JOURNAL LA English DT Article ID HUMAN POLYMORPHONUCLEAR LEUKOCYTES; RECOMBINANT EXOPROTEIN-A; ANTIBODY-RESPONSE; WOUND INFECTIONS; CARDIAC-SURGERY; CARRIER STATE; EXOTOXIN-A; POLYSACCHARIDE; MICE; PHAGOCYTOSIS AB Background Staphylococcus aureus, the first or second most common pathogen isolated from patients, is capsulated; there are at least 12 capsular types, and types 5 and 8 comprise approximately 85% of blood. Types 5 and 8, composed of a trisaccharicle repeat unit including a mannose uronic acid and 2 fucoses, are non-immunogenic. As protein conjugates, they induce opsonophagoctyic antibodies that confer type-specific active and passive protection in mice. Methods A phase II study of patients with end-stage renal disease showed that these conjugates induced approximately one third of the immunoglobulin G antibody of healthy individuals. Increasing the dose to 100 mug of polysaccharide induced levels similar to that in healthy individuals injected with 25 mug. Results In a double-blinded randomized and controlled study of patients undergoing renal dialysis, the conjugates induced statistically significant protection against bacteremia for as long as 10 months after immunization. The estimated protective level was 80 mug Ab/mL. At re-injection approximately 2 years later, 83 of 83 recipients responded with protective levels. Conclusions Conjugate vaccine-induced antibodies to the types 5 and 8 capsular polysaccharide antibodies of S aureus prevent bacteremia caused by this pathogen. The extent and duration of conjugate-induced immunity can be extended by re-immunization approximately 1 year later. Studies of patients undergoing cardiovascular surgery who would be immunized with the staphylococcus conjugates when they are immunologically intact are planned. C1 NICHHD, NIH, Bethesda, MD 20892 USA. Nobi Biopharmaceut, Rockville, MD USA. RP Robbins, JB (reprint author), NICHHD, NIH, Bldg 6,Room 424, Bethesda, MD 20892 USA. EM robbinsjo@mail.nih.gov NR 60 TC 21 Z9 22 U1 0 U2 1 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 APR PY 2004 VL 147 IS 4 BP 593 EP 598 DI 10.1016/j.ahj.2004.01.012 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 895XG UT WOS:000226896900007 PM 15077073 ER PT J AU Ivy, DD Doran, A Claussen, L Bingaman, D Yetman, A AF Ivy, DD Doran, A Claussen, L Bingaman, D Yetman, A TI Weaning and discontinuation of Epoprostenol in children with idiopathic, pulmonary arterial hypertension receiving concomitant bosentan SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID THERAPY; PROSTACYCLIN; ENDOTHELIN-1; SURVIVAL AB In 7 of 8 children with idiopathic pulmonary arterial hypertension treated with intravenous epoprostenol for >1 year, concomitant use of bosentan allowed a reduction of epoprostenol and decreased its associated side effects without deterioration of clinical and hemodynamic parameters. In 3 children with normal or near-normal pulmonary artery pressure on epoprostenol, the addition of bosentan allowed discontinuation of epoprostenol and stabilization of hemodynamics for up to 1 year. (C) 2004 by Excerpta Medica, Inc. C1 Univ Colorado, Childrens Hosp, Dept Pediat, Pediat Heart Lung Ctr,Pediat Pulm Hypertens Progr, Denver, CO 80218 USA. NIH, Gen Clin Res Ctr Program, Natl Ctr Res Resources, Bethesda, MD USA. RP Ivy, DD (reprint author), Univ Colorado, Childrens Hosp, Dept Pediat, Pediat Heart Lung Ctr,Pediat Pulm Hypertens Progr, 1056 E 19th Ave, Denver, CO 80218 USA. EM ivy.dunbar@ichden.org FU NCRR NIH HHS [M01 RR000069, M01 RR000069-457038, M01RR00069] NR 11 TC 42 Z9 44 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD APR 1 PY 2004 VL 93 IS 7 BP 943 EP 946 DI 10.1016/j.amjcard.2003.12.031 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 807HW UT WOS:000220493600028 PM 15050507 ER PT J AU Rastogi, T Reddy, KS Vaz, M Spiegelman, D Prabhakaran, D Willett, WC Stampfer, MJ Ascherio, A AF Rastogi, T Reddy, KS Vaz, M Spiegelman, D Prabhakaran, D Willett, WC Stampfer, MJ Ascherio, A TI Diet and risk of ischemic heart disease in India SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE diet; nutrition; ischemic heart disease; India; foods; vegetables; green leafy vegetables; fats; oils ID TRANS-FATTY-ACIDS; ACUTE MYOCARDIAL-INFARCTION; PLASMA HOMOCYSTEINE CONCENTRATIONS; CORONARY-ARTERY DISEASE; ALPHA-LINOLENIC ACID; CARDIOVASCULAR-DISEASE; CONTROLLED TRIAL; FOLLOW-UP; WOMEN; MEN AB Background: Ischemic heart disease (IHD) is a leading cause of death in India. Dietary changes could reduce risk, but few studies have addressed the association between diet and IHD risk in India. Objective: The goal was to address the association between diet and IHD risk among Indians in New Delhi (northern India) and Bangalore (southern India). Design: We collected data from 350 cases of acute myocardial infarction and 700 controls matched on the basis of age, sex, and hospital as part of a hospital-based case-control study in 8 hospitals. Long-term dietary intake was assessed by using food-frequency questionnaires developed for New Delhi and Bangalore. We used conditional logistic regression to control for the matching factors and other predictors of risk. Results: We observed a significant and dose-dependent inverse association between vegetable intake and IHD risk. The inverse association was stronger for green leafy vegetables; in multivariate analysis, persons consuming a median of 3.5 servings/wk had a 67% lower relative risk (RR: 0.33; 95% CI: 0.17, 0.64; P for trend = 0.0001) than did those consuming 0.5 servings/wk. Controlling for other dietary covariates did not alter the association. Cereal intake was also associated with a lower risk. Use of mustard oil, which is rich in alpha-linolenic acid, was associated with a lower risk than was use of sunflower oil [for use in cooking: RR: 0.49 (95% CI: 0.24, 0.99); for use in frying, RR: 0.29 (95% CI: 0.13, 0.64)]. Conclusion: Diets rich in vegetables and use of mustard oil could contribute to the lower risk of IHD among Indians. C1 Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. All India Inst Med Sci, Dept Cardiol, New Delhi, India. St Johns Med Coll, Div Nutr, Bangalore, Karnataka, India. RP Rastogi, T (reprint author), Natl Canc Inst, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, 6120 Execut Blvd,EPS 320, Rockville, MD 20852 USA. EM trastogi@post.harvard.edu NR 42 TC 83 Z9 86 U1 0 U2 2 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD APR PY 2004 VL 79 IS 4 BP 582 EP 592 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 807IZ UT WOS:000220496500010 PM 15051601 ER PT J AU Coss, A Cantor, KP Reif, JS Lynch, CF Ward, MH AF Coss, A Cantor, KP Reif, JS Lynch, CF Ward, MH TI Pancreatic cancer and drinking water and dietary sources of nitrate and nitrite SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE diet; nitrates; nitrites; pancreatic neoplasms; water; water pollution ID N-NITROSO COMPOUNDS; CURED MEAT-PRODUCTS; BLADDER-CANCER; RISK; ETIOLOGY; NITROSAMINES; POPULATION; EXPOSURE; SMOKERS; TRENDS AB N-Nitroso compounds, known animal carcinogens, are formed endogenously from drinking water and dietary sources of nitrate and nitrite. The authors conducted a population-based case-control study of pancreatic cancer in Iowa to determine whether increased consumption of nitrate and nitrite from drinking water and dietary sources was associated with risk. They linked detailed water source histories to nitrate measurements for Iowa community water supplies. After exclusions for insufficient data, 1,244 controls and 189 pancreatic cancer cases were available for analysis. Among controls, the median average nitrate level (1960-1987) was 1.27 (interquartile range, 0.6-2.8) mg of nitrate nitrogen per liter of water. No association was observed between pancreatic cancer risk and increasing quartiles of the community water supplies' nitrate level. Increasing intake of dietary nitrite from animal sources was associated with an elevated risk of pancreatic cancer among men and women (highest quartile odds ratios = 2.3, 95% confidence interval: 1.1, 5.1, for men and 3.2, 95% confidence interval: 1.6, 6.4, for women). In contrast, dietary nitrate intake showed an inverse association with risk among women and no association among men. This study suggests that long-term exposure to drinking water nitrate at levels below the maximum contaminant level of nitrate nitrogen (10 mg/liter) is not associated with pancreatic cancer; however, the consumption of dietary nitrite from animal products may increase risk. C1 NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept HHS, Bethesda, MD 20892 USA. Colorado State Univ, Dept Environm & Radiol Hlth Sci, Ft Collins, CO 80523 USA. Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. RP Ward, MH (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept HHS, 6120 Execut Blvd,EPS 8104, Bethesda, MD 20892 USA. EM wardm@mail.nih.gov NR 39 TC 43 Z9 45 U1 1 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD APR 1 PY 2004 VL 159 IS 7 BP 693 EP 701 DI 10.1093/aje/kwh081 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 807EN UT WOS:000220484900008 PM 15033647 ER PT J AU Tucker, MA AF Tucker, MA TI Re: "Childhood cancer and population mixing" SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter ID LEUKEMIA C1 NCI, Genet Epidemiol Branch, Rockville, MD 20852 USA. RP Tucker, MA (reprint author), NCI, Genet Epidemiol Branch, Rockville, MD 20852 USA. RI Tucker, Margaret/B-4297-2015 NR 3 TC 2 Z9 2 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 APR 1 PY 2004 VL 159 IS 7 BP 716 EP 717 DI 10.1093/aje/kwh099 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 807EN UT WOS:000220484900012 PM 15033650 ER PT J AU Sass, DA Schoen, RE Weissfeld, JL Weissfeld, L Thaete, L Kuller,LH McAdams, M Lanza, E Schatzkin, A AF Sass, DA Schoen, RE Weissfeld, JL Weissfeld, L Thaete, L Kuller,LH McAdams, M Lanza, E Schatzkin, A TI Relationship of visceral adipose tissue to recurrence of adenomatous polyps SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID BODY-FAT DISTRIBUTION; COLORECTAL-CANCER; COMPUTED-TOMOGRAPHY; COLON-CANCER; PHYSICAL-ACTIVITY; HIGH-FIBER; BINDING-PROTEINS; DIETARY FIBER; WEIGHT-LOSS; WOMEN AB OBJECTIVES: Insulin is a growth factor for colorectal cancer. Visceral adipose tissue (VAT) is strongly associated with insulin levels, and insulin and visceral obesity have been associated in cohort studies with colorectal cancer. The aim of this investigation was to determine whether VAT is associated with recurrence of adenomatous polyps, the precursor to colorectal cancer. METHODS: As an ancillary study to the Polyp Prevention Trial, a randomized clinical trial that evaluated the effect of a low-fat, high-fiber, high vegetable and fruit diet on adenomatous polyp recurrence, subjects at one clinical center underwent measurement of VAT with a single-slice CT scan through the L4-L5 interspace. The scan was performed around the time of the subject's year 4 colonoscopy that determined adenoma recurrence. RESULTS: Of 119 subjects, 44 of 84 men (52%) and 16 of 35 women (46%) had a recurrent adenoma (p 0.51). Body mass index (BMI) and weight at baseline and at year 4 colonoscopy were unrelated to adenoma recurrence. In a multivariate model including visceral fat quartile, remote history of polyps, gender, age, and randomization group, only remote history of polyps was statistically significantly associated with recurrent adenoma with a relative risk of 4.6 (95% Cl 1.7, 12.4, p 0.001). There was no consistent monotonic trend of increased or decreased risk of recurrence as one ascended quartiles of adipose tissue for visceral, subcutaneous, or total abdominal fat. CONCLUSION: In this study, no association between visceral adipose tissue and adenomatous polyp recurrence was observed. Further study and exploration of the role of VAT in adenoma progression is required. C1 Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Sch Med, Dept Epidemiol, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Sch Med, Dept Biostat, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Sch Med, Dept Radiol, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15260 USA. Informat Management Serv Inc, Rockville, MD USA. Natl Canc Inst, Bethesda, MD USA. RP Sass, DA (reprint author), Div Gastroenterol & Hepatol, Mezzanine Level,C Wing,PUH,200 Lothrop St, Pittsburgh, PA 15213 USA. FU NCI NIH HHS [K07-CA72561] NR 44 TC 33 Z9 33 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD APR PY 2004 VL 99 IS 4 BP 687 EP 693 DI 10.1111/j.1572-0241.2004.04136.x PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 816KF UT WOS:000221108100021 PM 15089903 ER PT J AU Wooding, S Kim, UK Bamshad, MJ Larsen, J Jorde, LB Drayna, D AF Wooding, S Kim, UK Bamshad, MJ Larsen, J Jorde, LB Drayna, D TI Natural selection and molecular evolution in PTC, a bitter-taste receptor gene SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID MITOCHONDRIAL-DNA SEQUENCES; POPULATION-GROWTH; GEOGRAPHIC SUBDIVISION; PAIRWISE COMPARISONS; NATIVE-AMERICANS; HUMAN ORIGINS; PLEISTOCENE; COALESCENT; PATTERNS; LOCUS AB The ability to taste phenylthiocarbamide (PTC) is a classic phenotype that has long been known to vary in human populations. This phenotype is of genetic, epidemiologic, and evolutionary interest because the ability to taste PTC is correlated with the ability to taste other bitter substances, many of which are toxic. Thus, variation in PTC perception may reflect variation in dietary preferences throughout human history and could correlate with susceptibility to diet-related diseases in modern populations. To test R. A. Fisher's long-standing hypothesis that variability in PTC perception has been maintained by balancing natural selection, we examined patterns of DNA sequence variation in the recently identified PTC gene, which accounts for up to 85% of phenotypic variance in the trait. We analyzed the entire coding region of PTC ( 1,002 bp) in a sample of 330 chromosomes collected from African (n=62), Asian (n=138), European (n=110), and North American (n=20) populations by use of new statistical tests for natural selection that take into account the potentially confounding effects of human population growth. Two intermediate-frequency haplotypes corresponding to "taster" and "nontaster" phenotypes were found. These haplotypes had similar frequencies across Africa, Asia, and Europe. Genetic differentiation between the continental population samples was low (F-ST = 0.056) in comparison with estimates based on other genes. In addition, Tajima's D and Fu and Li's D and F statistics demonstrated a significant deviation from neutrality because of an excess of intermediate-frequency variants when human population growth was taken into account (P<.01). These results combine to suggest that balancing natural selection has acted to maintain " taster" and " nontaster" alleles at the PTC locus in humans. C1 Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA. NIDCD, NIH, Rockville, MD USA. RP Wooding, S (reprint author), Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA. EM swooding@genetics.utah.edu FU NIEHS NIH HHS [ES12125, F32 ES012125]; NIGMS NIH HHS [GM59290, R01 GM059290]; PHS HHS [Z01-000046-04] NR 62 TC 170 Z9 175 U1 14 U2 137 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 APR PY 2004 VL 74 IS 4 BP 637 EP 646 DI 10.1086/383092 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 804EA UT WOS:000220280800004 PM 14997422 ER PT J AU Cabral, WA Marini, JC AF Cabral, WA Marini, JC TI High proportion of mutant osteoblasts is compatible with normal skeletal function in mosaic carriers of osteogenesis imperfecta SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article; Proceedings Paper CT 24th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 20-24, 2002 CL SAN ANTONIO, TX SP Amer Soc Bone & Mineral Res ID MESENCHYMAL STEM-CELLS; MARROW STROMAL CELLS; COLLAGEN MUTATION DATABASE; I COLLAGEN; SOMATIC MOSAICISM; BONE-MARROW; GENE-THERAPY; NONHEMATOPOIETIC TISSUES; VARIABLE EXPRESSIVITY; PARENTAL MOSAICISM AB Individuals with mosaicism for the autosomal dominant bone dysplasia osteogenesis imperfecta (OI) are generally identified by having more than one affected child. The mosaic carriers have both normal and mutant cell populations in somatic and germline tissues but are unaffected or minimally affected by the type I collagen mutation that manifests clinically in their heterozygous offspring. We determined the proportion of mutant osteoblasts in skeletal tissue of two mosaic carriers who each have a COL1A1 mutation in a high proportion of dermal fibroblasts. Both carriers had normal height and bone histology; the first carrier had normal lumbar spine measurements (L1 - L4), as determined by dual-energy x-ray absorptiometry (Z = +1.17). In cultured cells from the first carrier, studied by labeled PCR and single-cell PCR over successive passages, the collagen mutation was present in 85% of fibroblasts and 50% and 75% of osteoblasts from her right iliac crest and left patella, respectively, with minimal selection. The second carrier was studied by PCR amplification of DNA from autopsy paraffin blocks. The proportion of heterozygous cells was 40% in calvarium, 65% in tracheal ring, and 70% in aorta. Thus, in OI, substantially normal skeletal growth, density, and histology are compatible with a 40% - 75% burden of osteoblasts heterozygous for a COL1A1 mutation. These data are encouraging for mesenchymal stem-cell transplantation, since mosaic carriers are a naturally occurring model for cell therapy. C1 NICHHD, Bone & Extracellular Matrix Branch, Sect Heritable Disorders Bone, NIH, Bethesda, MD 20892 USA. RP Marini, JC (reprint author), NICHHD, Bone & Extracellular Matrix Branch, Sect Heritable Disorders Bone, NIH, Bldg 10,Room 9S239,9000 Rockville Pike, Bethesda, MD 20892 USA. EM oidoc@helix.nih.gov NR 36 TC 24 Z9 26 U1 0 U2 2 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 APR PY 2004 VL 74 IS 4 BP 752 EP 760 DI 10.1086/383252 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 804EA UT WOS:000220280800015 PM 15024692 ER PT J AU Stewart, KJ Sung, JD Silber, HA Fleg, JL Kelemen, MD Turner, KL Bacher, AC Dobrosielski, DA DeRegis, JR Shapiro, EP Ouyang, P AF Stewart, KJ Sung, JD Silber, HA Fleg, JL Kelemen, MD Turner, KL Bacher, AC Dobrosielski, DA DeRegis, JR Shapiro, EP Ouyang, P TI Exaggerated exercise blood pressure is related to impaired endothelial vasodilator function SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE hypertension; exercise; blood pressure; pulse pressure; endothelium; aortic stiffness; stress test ID FLOW-MEDIATED VASODILATION; ESSENTIAL-HYPERTENSION; FUTURE HYPERTENSION; RISK; DYSFUNCTION; MEN; ARTERIES; ATHEROSCLEROSIS; DILATION; WOMEN AB Background: Persons with high normal blood pressure (BP) or mild hypertension who also have an exaggerated BP response to exercise are at risk for worsening hypertension. The mechanisms that explain this relationship are unknown. We examined the relationships of endothelial vasodilator function and of aortic stiffness with exercise BP. Methods: Subjects were 38 men and 44 women, aged 55 to 75 years, with untreated high normal BP or mild hypertension but otherwise healthy. Exercise was performed on a treadmill. Endothelial vasodilator function was assessed as brachial artery flow-mediated vasodilation (FMD) during reactive hyperemia. Aortic stiffness was measured as pulse wave velocity (PWV). Results: Among men, resting systolic BP explained 34% of the variance (P < .01) in maximal exercise systolic BP and FMD explained an additional 11% (P < .01); resting systolic BP explained 23% of the variance in maximal pulse pressure (PP) (P < .01), and FMD explained an additional 10% (P < .01). Among women, resting systolic BP was the only independent correlate of maximal systolic BP (R-2 = 0. 12, P < .03) and FMD correlated negatively with maximal PP (R-2 = 0.12, P < .03). Among men, FMD was the only independent correlate of the difference between resting and maximal systolic BP (R-2 = 0.20, P < .02). The FMD was the only independent correlate of the difference between resting and maximal PP among men (R-2 = 0.17, P < .03) and among women (R-2 = 0.12, P < .03). The PWV did not correlate with exercise BP responses. Conclusions: These results suggest that impaired endothelial vasodilator function may be a mechanism contributing to exercise hypertension and may also be one link between exaggerated exercise BP and worsening hypertension. 0 2004 American Journal of Hypertension, Ltd. C1 Johns Hopkins Univ, Sch Med, Div Cardiol, Dept Med, Baltimore, MD USA. NIA, Ctr Gerontol Res, NIH, Baltimore, MD 21224 USA. RP Stewart, KJ (reprint author), Johns Hopkins Bayview Med Ctr, 4940 Eastern Ave, Baltimore, MD 21224 USA. EM kstewart@mail.jhmi.edu FU NHLBI NIH HHS [R01HL59164] NR 30 TC 89 Z9 93 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD APR PY 2004 VL 17 IS 4 BP 314 EP 320 DI 10.1016/S0895-7061(03)01003-3 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 809UE UT WOS:000220660800005 PM 15062884 ER PT J AU Kramer, H Cooper, R Jacobs, D Bild, D Post, W Saad, M Liu, K AF Kramer, H Cooper, R Jacobs, D Bild, D Post, W Saad, M Liu, K TI Association between increased urine albumin excretion and measures of subclinical cardiovascular disease: The multi-ethnic study of atherosclerosis SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Meeting Abstract CT Annual Clinical Meeting of the National-Kidney-Foundation CY APR 28-MAY 02, 2004 CL Chicago, IL SP Natl Kidney Fdn C1 Loyola Med Ctr, Chicago, IL USA. Univ Minnesota, Minneapolis, MN USA. NHLBI, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Univ Calif Los Angeles, Los Angeles, CA USA. Northwestern Univ, Chicago, IL 60611 USA. NR 0 TC 0 Z9 0 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 APR PY 2004 VL 43 IS 4 MA 57 BP A29 EP A29 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 811RR UT WOS:000220789500083 ER PT J AU Klabunde, CN Riley, GF Mandelson, MT Frame, PS Brown, ML AF Klabunde, CN Riley, GF Mandelson, MT Frame, PS Brown, ML TI Health plan policies and programs for colorectal cancer screening: A national profile SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID ASYMPTOMATIC ADULTS; GUIDELINES; INSURANCE; RATIONALE; SERVICES; COVERAGE AB Background: A consensus has emerged that average-risk adults 50 years of age or older should be screened for colorectal cancer (CRC). Objectives: To describe health plans' coverage policies, guidelines, and organized programs to promote CRC screening. Study Design and Methods: Review of data from the National Cancer Institute Survey of Colorectal Cancer Screening Practices, administered to a national sample of health plans in 1999-2000. The survey inquired about coverage policies for fecal occult blood testing, sigmoidoscopy, colonoscopy, and double-contrast barium enema; the nature of any guidelines the plan had issued to its providers on CRC screening; and systems for recruiting patients into screening and for tracking and reporting the results of screening and follow-up procedures. Results: Of 346 eligible health plans, 180 (52%) responded. Nearly all health plans covered at least 1 CRC screening modality. Plans were most likely to cover fecal occult blood testing (97%) and least likely to cover colonoscopy (57%). Sixty-five percent had issued guidelines on CRC screening to providers. One quarter had a mechanism to remind patients that they are due for CRC screening, but fewer had systems for prompting providers, contacting noncompliant patients, or tracking completion of screening. Conclusions: Health plans have the ability to provide organizational infrastructure for a broad range of preventive services to well-defined populations. However, few health plans had all 3 essential CRC screening delivery components-coverage, guidelines, and tracking systems-in place in 1999-2000. C1 NCI, Appl Res Program, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Off Res Dev & Informat, Ctr Medicare, Baltimore, MD USA. Off Res Dev & Informat, Medicaid Serv, Baltimore, MD USA. Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, Seattle, WA USA. Tri County Family Med, Cohocton, NY USA. Univ Rochester, Sch Med & Dent, Dept Family Med, Rochester, NY USA. RP Klabunde, CN (reprint author), NCI, Appl Res Program, Execut Plaza N Room 4005,6130 Execut Blvd, Bethesda, MD 20892 USA. EM ck97b@nih.gov FU NCI NIH HHS [N01-PC-85169] NR 30 TC 42 Z9 43 U1 0 U2 1 PU AMER MED PUBLISHING, M W C COMPANY PI JAMESBURG PA 241 FORSGATE DR, STE 102, JAMESBURG, NJ 08831 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD APR PY 2004 VL 10 IS 4 BP 273 EP 279 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 811SO UT WOS:000220791800005 PM 15124504 ER PT J AU Sullivan, PF Neale, BM van den Oord, E Miles, MF Neale, MC Bulik, CM Joyce, PR Straub, RE Kendler, KS AF Sullivan, PF Neale, BM van den Oord, E Miles, MF Neale, MC Bulik, CM Joyce, PR Straub, RE Kendler, KS TI Candidate genes for nicotine dependence via linkage, epistasis, and bioinformatics SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE affected sibling pair; MAPK; cigarette smoking; genetics; genome scan; epistasis ID FALSE DISCOVERY RATE; GENOME-WIDE SEARCH; COMPLEX TRAITS; CHROMOSOMES 2; RAT; MICROARRAYS; EXPRESSION; RECEPTOR; ALCOHOL; COCAINE AB Many smoking-related phenotypes are substantially heritable. One genome scan of nicotine dependence (ND) has been published and several others are in progress and should be completed in the next 5 years. The goal of this hypothesis-generating study was two-fold. First, we present further analyses of our genome scan data for ND published by Straub et al. [1999: Mol Psychiatry 4:129-144] (PMID: 10208445). Second, we used the method described by Cox et al. [1999: Nat Genet 21:213-215] (PMID: 9988276) to search for epistatic loci across the markers used in the genome scan. The overall results of the genome scan nearly reached the rigorous Lander and Krugylak [1995: Nat Genet 11:241-247] criteria for "significant" linkage with the best findings on chromosomes 10 and 2. We then looked for correspondence between genes located in the 10 regions implicated in affected sibling pair (ASP) and epistatic linkage analyses with a list of genes suggested by microarray studies of experimental nicotine exposure and candidate genes from the literature. We found correspondence between linkage and microarray/candidate gene studies for genes involved with the mitogen-activated protein kinase (MAPK) signaling system, nuclear factor kappa B (NFKB) complex, neuropeptide Y (NPY) neurotransmission, a nicotinic receptor subunit (CHRNA2), the vesicular monoamine transporter (SLC18A2), genes in pathways implicated in human anxiety (HTR7, TDO2, and the endozepine-related protein precursor, DKFZP434A2417), and the mu1-opioid receptor (OPRM1). Although the hypotheses resulting from these linkage and bioinformatic analyses are plausible and intriguing, their ultimate worth depends on replication in additional linkage samples and in future experimental studies. (C) 2003 Wiley-Liss, Inc. C1 Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA 23284 USA. Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23284 USA. Christchurch Sch Med, Dept Psychol Med, Christchurch, New Zealand. NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. RP Sullivan, PF (reprint author), Univ N Carolina, FRANZCP Dept Genet, CB No 7264, Chapel Hill, NC 27599 USA. EM pfsulliv@hsc.vcu.edu RI Neale, Michael/B-1418-2008 FU NCI NIH HHS [CA 85739]; NIDA NIH HHS [DA 10228]; NIMH NIH HHS [MH 01458, MH 59160, MH 65332] NR 52 TC 53 Z9 55 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD APR 1 PY 2004 VL 126B IS 1 BP 23 EP 36 DI 10.1002/ajmg.b.20138 PG 14 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 808ZP UT WOS:000220607300006 PM 15048644 ER PT J AU DeClerck, YA Mercurio, AM Stack, MS Chapman, HA Zutter, MM Muschel, RJ Raz, A Matrisian, LM Sloane, BF Noel, A Hendrix, MJ Coussens, L Padarathsingh, M AF DeClerck, YA Mercurio, AM Stack, MS Chapman, HA Zutter, MM Muschel, RJ Raz, A Matrisian, LM Sloane, BF Noel, A Hendrix, MJ Coussens, L Padarathsingh, M TI Review - Proteases, extracellular matrix, and cancer - A workshop of the path B study section SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Review ID PLASMINOGEN-ACTIVATOR INHIBITOR-1; ENDOTHELIAL GROWTH-FACTOR; BREAST-CARCINOMA CELLS; ALPHA-6-BETA-4 INTEGRIN; IN-VIVO; CHEMOTACTIC MIGRATION; VASCULOGENIC MIMICRY; IMAGING PROTEOLYSIS; AGGRESSIVE MELANOMA; ORAL KERATINOCYTES AB The role of the extracellular matrix (ECM) in the tumor microenvironment is not limited to being a barrier against tumor invasion. The ECM is a reservoir of cell binding proteins and growth factors that affect tumor cell behavior. it is also substantially modified by proteases produced by tumor cells or stroma cells. As a result of the activity of these proteases, cell-cell and cell-ECM interactions are altered, new biologically active ECM molecules are generated, and the bioavailability and activity of many growth factors, growth factor receptors, and cytokines are modified. ECM-degrading proteases also play a critical role in angiogenesis, where they can act as positive as well as negative regulators of endothelial cell proliferation and vascular morphogenesis. This review article summarizes some of the most relevant findings made over the recent years that were discussed at a workshop organized by the Path B Study Section of the National institutes of Health in October 2002. C1 Childrens Hosp Los Angeles, Div Hematol Oncol, Saban Res Inst, Los Angeles, CA 90027 USA. Univ So Calif, Keck Sch Med, Dept Pediat & Biochem, Los Angeles, CA USA. Univ So Calif, Keck Sch Med, Dept Biol Mol, Los Angeles, CA USA. Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. Northwestern Univ, Sch Med, Dept Cell & Mol Biol, Chicago, IL 60611 USA. Univ Calif San Francisco, Dept Med, Sch Med, San Francisco, CA 94143 USA. Vanderbilt Univ, Sch Med, Dept Cellular & Mol Pathol, Nashville, TN 37212 USA. Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. Wayne State Univ, Sch Med, Karmanos Canc Inst, Dept Pathol, Detroit, MI USA. Wayne State Univ, Sch Med, Karmanos Canc Inst, Dept Radiat Oncol, Detroit, MI USA. Vanderbilt Univ, Sch Med, Dept Canc Biol, Nashville, TN USA. Wayne State Univ, Sch Med, Dept Pharmacol, Detroit, MI 48201 USA. Univ Liege, Dept Tumor & Dev Biol, Liege, Belgium. Univ Iowa, Holden Comprehens Canc Ctr, Dept Anat & Cell Biol, Iowa City, IA USA. Univ Calif San Francisco, Sch Med, Inst Canc Res, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Med, Dept Pathol, San Francisco, CA 94143 USA. NIH, Ctr Sci Review, Bethesda, MD 20892 USA. RP DeClerck, YA (reprint author), Childrens Hosp Los Angeles, Div Hematol Oncol, Saban Res Inst, MS 54,4650 Sunset Blvd, Los Angeles, CA 90027 USA. EM declerck@hsc.usc.edu RI Sloane, Bonnie/A-1050-2009; OI Noel, Agnes/0000-0002-7670-6179 FU NCI NIH HHS [R01 CA080789] NR 48 TC 144 Z9 153 U1 1 U2 4 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 APR PY 2004 VL 164 IS 4 BP 1131 EP 1139 DI 10.1016/S0002-9440(10)63200-2 PG 9 WC Pathology SC Pathology GA 806CB UT WOS:000220410900002 PM 15039201 ER PT J AU Lugassy, C Kleinman, HK Engbring, JA Welch, DR Harms, JF Rufner, R Ghanem, G Patierno, SR Barnhill, RL AF Lugassy, C Kleinman, HK Engbring, JA Welch, DR Harms, JF Rufner, R Ghanem, G Patierno, SR Barnhill, RL TI Pericyte-like location of GFP-tagged melanoma cells - Ex vivo and in vivo studies of extravascular migratory metastasis SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID IMMUNOHISTOCHEMICAL OBSERVATIONS; VASCULOGENIC MIMICRY; CUTANEOUS MELANOMA; PROGNOSTIC FACTOR; TUMOR-CELLS; ANGIOGENESIS; LAMININ; MATRIX; MODEL; INVASION AB Previous studies have demonstrated that some tumor cells occupy a pericyte-like location in melanoma, forming angio-tumoral complexes. We hypothesized that these tumor cells are migrating along the abluminal surface of the endothelium, a mechanism termed "extravascular migratory metastasis." In the present study, we have used human and murine melanoma cells that stably express enhanced green fluorescence protein (GFP) to examine, in an ex vivo co-culture model, melanoma cell interactions with vessels that have sprouted from rat aortic rings. We also used in vivo tumor growth on the chick chorioallantoic membrane (CAM) to observe the dissemination pathway of melanoma cells. In the ex vivo rat aorta system, we observed a pericyte-like location of tumor cells that were spreading along the vascular channels. For examination of the CAM in vivo, we have used the Lugassy preparation, allowing one to obtain striking images of the relationship between fluorescent GFP cells and microvessels. Melanoma cells were found cuffing; the outside of vessels around the tumor. Tumor cells were observed along the vessels several centimeters from the tumor. Confocal microscopy and histopathology confirmed the peri-cyte-like location of tumor cells, without any observable intravasation. The results indicate that melanoma cells; can migrate along the abluminal surface of vessels. This study also demonstrates that these models can provide quantitation analysis that may prove useful in elucidating the molecular interactions involved in extravascular migratory metastasis. C1 George Washington Univ, Med Ctr, Dept Dermatol, Washington, DC USA. George Washington Univ, Med Ctr, Dept Pharmacol, Washington, DC USA. George Washington Univ, Med Ctr, Program Mol & Cellular Oncol, Washington, DC USA. George Washington Univ, Med Ctr, Ctr Microscopy & Image Anal, Washington, DC USA. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. Univ Alabama, Ctr Comprehens Canc, Birmingham, AL 35294 USA. Penn State Univ, Coll Med, Jake Gittlen Canc Res Inst, Hershey, PA USA. Free Univ Brussels, Brussels, Belgium. RP Barnhill, RL (reprint author), Univ Miami, Dept Pathol, 1611 NW 12th Ave,Holtz Bldg 2044 R-5, Miami, FL 33136 USA. EM rlbarnhill@aol.com NR 38 TC 25 Z9 28 U1 0 U2 1 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 APR PY 2004 VL 164 IS 4 BP 1191 EP 1198 DI 10.1016/S0002-9440(10)63207-5 PG 8 WC Pathology SC Pathology GA 806CB UT WOS:000220410900009 PM 15039208 ER PT J AU Petermann, A Hiromura, K Pippin, J Blonski, M Couser, WG Kopp, J Mundel, P Shankland, SJ AF Petermann, A Hiromura, K Pippin, J Blonski, M Couser, WG Kopp, J Mundel, P Shankland, SJ TI Differential expression of D-type cyclins in podocytes in vitro and in vivo SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID EXPERIMENTAL MEMBRANOUS NEPHROPATHY; HIV-ASSOCIATED NEPHROPATHY; GLOMERULAR-DISEASE; DEPENDENT KINASES; GLOMERULOSCLEROSIS; PROLIFERATION; INHIBITORS; PROGRESSION; MYOBLASTS; PROTEIN AB The proliferative response of podocytes to injury determines the histological phenotype. Moreover, an apparent lack of podocyte proliferation may underlie the development of glomerulosclerosis. Podocyte proliferation is closely linked with its state of differentiation. However, the mechanisms regulating these processes are not fully elucidated. Because D-type cyclins have been shown to be important in the regulation of proliferation and differentiation, we examined their expression in podocytes in vitro and in vivo. The glomerular expression of cyclins D1 and D3 was examined in vitro in cultured immortalized podocytes by immunostaining and Western blot analysis, and in embryonic mice and rats, the passive Heymann nephritis model of experimental membranous nephropathy in rats, and human immunodeficiency virus (HIV)-transgenic mice. Kidneys from cyclin D1 knockout mice were also examined. Cyclin D1 was abundant in cultured proliferating podocytes, but not in quiescent differentiated podocytes. In contrast, cyclin D3 was abundant in differentiated, but not proliferating podocytes. Cyclin D1 was expressed in embryonic mouse and rat glomeruli during the S- and comma-shaped stages, and was absent in podocytes at the capillary loop stage and in mature rodent glomeruli. Cvclin D1 protein increased after injury in passive Heymann nephritis rats and in HIV-transgenic mice. Cyclin D3 was constitutively and specifically expressed in podocytes in normal rodent glomeruli, and decreases during dedifferentiation and proliferation in HIV-transgenic mice. Kidneys from cyclin D1-/- mice were normal with the podocytes expressing specific differentiation markers. Cyclin D1 is not necessary for the terminal differentiation of podocytes, and expression coincides with cell-cycle entry. In contrast, cyclin D3 expression coincides with podocyte differentiation and quiescence. C1 Univ Washington, Sch Med, Div Nephrol, Dept Med, Seattle, WA 98195 USA. Rhein Westfal TH Aachen, Univ Klinikum, D-5100 Aachen, Germany. NIH, Bethesda, MD 20892 USA. Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. Albert Einstein Coll Med, Dept Anat, Bronx, NY 10467 USA. RP Shankland, SJ (reprint author), Univ Washington, Sch Med, Div Nephrol, Dept Med, Box 356521, Seattle, WA 98195 USA. EM stuartjs@u.washington.edu OI Kopp, Jeffrey/0000-0001-9052-186X FU NIDDK NIH HHS [DK34198, DK47659, DK51096, DK52121, DK56799, R01 DK051096, R01 DK052121, R01 DK056799] NR 29 TC 23 Z9 23 U1 1 U2 1 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 APR PY 2004 VL 164 IS 4 BP 1417 EP 1424 DI 10.1016/S0002-9440(10)63228-2 PG 8 WC Pathology SC Pathology GA 806CB UT WOS:000220410900030 PM 15039229 ER PT J AU Cui, XZ Moayeri, M Li, Y Li, XM Haley, M Fitz, Y Correa-Araujo, R Banks, SM Leppla, SH Eichacker, PQ AF Cui, XZ Moayeri, M Li, Y Li, XM Haley, M Fitz, Y Correa-Araujo, R Banks, SM Leppla, SH Eichacker, PQ TI Lethality during continuous anthrax lethal toxin infusion is associated with circulatory shock but not inflammatory cytokine or nitric oxide release in rats SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE Bacillus anthracis; sepsis; pathogenesis; model ID BACILLUS-ANTHRACIS; PROTECTIVE ANTIGEN; INHALATIONAL ANTHRAX; SEPTIC SHOCK; MONOCLONAL-ANTIBODIES; ESCHERICHIA-COLI; FACTOR CLEAVES; TNF-ALPHA; MACROPHAGES; EXPOSURE AB Although circulatory shock related to lethal toxin (LeTx) may play a primary role in lethality due to Bacillus anthracis infection, its mechanisms are unclear. We investigated whether LeTx-induced shock is associated with inflammatory cytokine and nitric oxide ( NO) release. Sprague-Dawley rats with central venous and arterial catheters received 24-h infusions of LeTx ( lethal factor 100 mug/kg; protective antigen 200 mug/kg) that produced death beginning at 9 h and a 7-day mortality rate of 53%. By 9 h, mean arterial blood pressure, heart rate, pH, and base excess were decreased and lactate and hemoglobin levels were increased in LeTx nonsurvivors compared with LeTx survivors and controls ( diluent only) ( P less than or equal to 0.05 for each comparing the 3 groups). Despite these changes, arterial oxygen and circulating leukocytes and platelets were not decreased and TNF-alpha, IL-1beta, IL-6, and IL-10 levels were not increased comparing either LeTx nonsurvivors or survivors to controls. Nitrate/nitrite levels and tissue histology also did not differ comparing LeTx animals and controls. In additional experiments, although 24-h infusions of LeTx and Esherichia coli LPS produced similar mortality rates ( 54 and 56%, respectively) and times to death (13.2 +/- 0.8 vs. 11.0 +/- 1.7 h, respectively) compared with controls, only LPS reduced circulating leukocytes, platelets, and IL-2 levels and increased TNF-alpha, IL-1alpha and - 1beta, IL-6, IL-10, interferon-gamma, granulocyte macrophage-colony stimulating factor, RANTES, migratory inhibitory protein-1alpha, - 2, and - 3, and monocyte chemotactic protein-1, as well as nitrate/nitrite levels ( all P less than or equal to 0.05 for the effects of LPS). Thus, in contrast to LPS, excessive inflammatory cytokine and NO release does not appear to contribute to the circulatory shock and lethality occurring with LeTx in this rat model. Although therapies to modulate these host mediators may be applicable for shock caused by LPS or other bacterial toxins, they may not with LeTx. C1 NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Cui, XZ (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bldg 10,Rm 7D43, Bethesda, MD 20892 USA. EM cxizhong@mail.cc.nih.gov NR 42 TC 95 Z9 96 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD APR 1 PY 2004 VL 286 IS 4 BP R699 EP R709 DI 10.1152/ajpregu.00593.2003 PG 11 WC Physiology SC Physiology GA 800UV UT WOS:000220054100013 PM 14715494 ER PT J AU Yonkers, KA Wisner, KL Stowe, Z Leibenluft, E Cohen, L Miller, L Manber, R Viguera, A Suppes, T Altshuler, L AF Yonkers, KA Wisner, KL Stowe, Z Leibenluft, E Cohen, L Miller, L Manber, R Viguera, A Suppes, T Altshuler, L TI Management of bipolar disorder during pregnancy and the postpartum period SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Review ID VALPROIC ACID; ANTIEPILEPTIC DRUGS; SPINA-BIFIDA; DOUBLE-BLIND; IN-UTERO; NEONATAL PHARMACOKINETICS; CALCIUM-ANTAGONISTS; MAJOR MALFORMATIONS; BENZODIAZEPINE USE; PLACENTAL-TRANSFER AB Objective: Bipolar disorder affects 0.5%-1.5% of individuals in the United States. The typical age at onset is late adolescence or early adulthood, placing women at risk for episodes throughout their reproductive years. General guidelines for the treatment of bipolar disorder are available from the American Psychiatric Association, but additional issues arise when these guidelines are applied in the treatment of peripartum women. The authors summarize knowledge regarding the management of bipolar disorder during pregnancy and the postpartum period, with a focus on managing mania, hypomania, and the psychotic components of the illness. Method: An expert panel reviewed articles that address the management of bipolar disorder and the consequences of the use of mood stabilizers during pregnancy, and a consensus document was generated. Results: The treatment of bipolar disorder in pregnant women involves significant challenges. Some mood stabilizers, e.g., sodium valproate and carbamazepine, are human teratogens. On the other hand, the teratogenicity associated with lithium may have been overestimated in the past. Conclusions: Since treatment can be managed most effectively if pregnancy is planned, clinicians should discuss the issue of pregnancy and its management with every bipolar disorder patient who has childbearing potential, regardless of future reproductive plans. Additional research should address the risks of disturbed sleep to pregnant and postpartum women with bipolar disorder, as well as structural and behavioral consequences to offspring when mood stabilizers are used during pregnancy. Longitudinal and cohort studies can promote these efforts. Given the rate of bipolar disorder in the general population, research efforts will need to be broad based and include multiple collaborating centers. C1 Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06510 USA. Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Obstet & Gynecol, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Pediat, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. NIMH, Pediat & Dev Neuropsychiat Branch, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA. Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat, Los Angeles, CA 90024 USA. RP Yonkers, KA (reprint author), Yale Univ, Sch Med, Dept Psychiat, 142 Temple St,Suite 301, New Haven, CT 06510 USA. EM kimberly.yonkers@yale.edu NR 103 TC 171 Z9 179 U1 1 U2 11 PU AMER PSYCHIATRIC PRESS, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD APR PY 2004 VL 161 IS 4 BP 608 EP 620 DI 10.1176/appi.ajp.161.4.608 PG 13 WC Psychiatry SC Psychiatry GA 818WW UT WOS:000221276200003 PM 15056503 ER PT J AU Bremner, JD Vythilingam, M Vermetten, E Vaccarino, V Charney, DS AF Bremner, JD Vythilingam, M Vermetten, E Vaccarino, V Charney, DS TI Deficits in hippocampal and anterior cingulate functioning during verbal declarative memory encoding in midlife major depression SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; CORTICOTROPIN-RELEASING HORMONE; CEREBRAL BLOOD-FLOW; EPISODIC MEMORY; GERIATRIC DEPRESSION; PREFRONTAL CORTEX; FRONTAL-CORTEX; CORTISOL HYPERSECRETION; MATERNAL-DEPRIVATION; PSYCHOSOCIAL STRESS AB Objective: Prior studies showed that subjects with major depression have deficits in hippocampal-based verbal declarative memory (e.g., recall of a paragraph) and in hippocampal and prefrontal cortical functioning and structure. The purpose of the present study was to assess hippocampal and prefrontal functioning during performance of a verbal declarative memory task in subjects with midlife major depression. Method: Subjects with midlife major depression (N = 18) and healthy subjects (N = 9) underwent positron emission tomography imaging during a control task and verbal encoding of a paragraph. Results: During the verbal memory encoding task the comparison subjects, but not the subjects with depression, activated the right hippocampus and prefrontal cortex (anterior cingulate), as well as the cuneus and cerebellum. Conclusions: These results are consistent with a failure of hippocampal and anterior cingulate activation in depression, and they support the hypothesis of deficits in hippocampal and anterior cingulate functioning in depression. C1 Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA USA. Emory Univ, Sch Med, Dept Radiol, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Dept Internal Med Cardiol, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Emory Ctr Positron Emiss Tomog, Atlanta, GA 30322 USA. Atlanta VA Med Ctr, Decatur, GA USA. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Bremner, JD (reprint author), Emory Univ Hosp, PET Ctr Nucl Med, 1364 Clifton Rd NE, Atlanta, GA 30322 USA. EM jdbremn@emory.edu RI Bremner, James/B-1632-2013; OI Vermetten, Eric/0000-0003-0579-4404 FU NIMH NIH HHS [MH-56120] NR 109 TC 93 Z9 97 U1 6 U2 15 PU AMER PSYCHIATRIC PRESS, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD APR PY 2004 VL 161 IS 4 BP 637 EP 645 DI 10.1176/appi.ajp.161.4.637 PG 9 WC Psychiatry SC Psychiatry GA 818WW UT WOS:000221276200009 PM 15056509 ER PT J AU Fee, E Brown, TM AF Fee, E Brown, TM TI Factory injuries and progressive reform SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 NIH, Natl Lib Med, Hist Med Div, Bethesda, MD USA. Univ Rochester, Dept Hist, Rochester, NY USA. Univ Rochester, Dept Community & Prevent Med, Rochester, NY USA. RP Fee, E (reprint author), Bldg 38,Room 1E21,8600 Rockville Pike, Bethesda, MD 20894 USA. EM elizabeth_fee@nlm.nih.gov NR 3 TC 1 Z9 1 U1 0 U2 1 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD APR PY 2004 VL 94 IS 4 BP 540 EP 540 DI 10.2105/AJPH.94.4.540 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 807IC UT WOS:000220494200009 PM 15053997 ER PT J AU Kalantaridou, SN Makrigiannakis, A Zoumakis, E Chrousos, GP AF Kalantaridou, SN Makrigiannakis, A Zoumakis, E Chrousos, GP TI Reproductive functions of corticotropin-releasing hormone. Research and potential clinical utility of antalarmins (CRH receptor type 1 antagonists) SO AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Article; Proceedings Paper CT 1st Brown-Linkoping Conference on Basic and Clinical Aspects of Reproductive Immunology CY NOV 15-17, 2002 CL Providence, RI DE implantation; ovarian CRH; parturition; placental CRH; uterine CRH ID ENDOMETRIAL STROMAL CELLS; PITUITARY-ADRENAL AXIS; HUMAN-PLACENTA; BINDING PROTEIN; FETAL MEMBRANES; HUMAN-PREGNANCY; PRETERM BIRTH; IN-VITRO; EXPRESSION; GENE AB BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis exerts a complex, mostly inhibitory, effect on the female reproductive system. In addition, the principal regulator of this axis, the hypothalamic neuropeptide corticotropin-releasing hormone (CRH) and its receptors have been identified in most female reproductive tissues, including the ovary, uterus, and placenta. Furthermore, CRH is secreted in peripheral inflammatory sites where it exerts strong inflammatory actions. Antalarmins (CRH receptor type I antagonists) have been used to elucidate the roles of CRH in stress, inflammation and reproduction. METHOD OF STUDY: We review existing data on the effects of CRH in the female reproductive system. RESULTS: Ovarian CRH participates in female sex steroid production, follicular maturation, ovulation and luteolysis. Uterine CRH participates in decidualization, implantation, and early maternal tolerance. Placental CRH participates in the physiology of pregnancy and the onset of parturition. Circulating placental CRH is secreted mostly during the latter half of pregnancy and is responsible for the concurrently increasing physiologic hypercortisolism of this period. After labor and delivery, this hypercortisolism is ensued by a transient suppression of hypothalamic CRH secretion, which may explain the postpartum blues and depression and the increased autoimmune manifestations depression of period, the postpartum period. CONCLUSIONS: These data show that CRH is present in female reproductive tissues, and is regulating key reproductive functions with an inflammatory component, such as ovulation, luteolysis, implantation, and parturition. C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Univ Ioannina, Sch Med, Dept Obstet & Gynecol, Div Reprod Endocrinol, GR-45110 Ioannina, Greece. Univ Crete, Sch Med, Dept Obstet & Gynecol, Iraklion, Greece. RP Chrousos, GP (reprint author), NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bldg 10,Room 9D42, Bethesda, MD 20892 USA. EM chrousog@mail.nih.gov NR 44 TC 20 Z9 20 U1 1 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 8755-8920 J9 AM J REPROD IMMUNOL JI Am. J. Reprod. Immunol. PD APR PY 2004 VL 51 IS 4 BP 269 EP 274 DI 10.1111/j.1600-0897.2004.00155.x PG 6 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA 813HY UT WOS:000220899400002 PM 15212679 ER PT J AU Abrahams, VM Kim, YM Straszewski, SL Romero, R Mor, G AF Abrahams, VM Kim, YM Straszewski, SL Romero, R Mor, G TI Macrophages and apoptotic cell clearance during pregnancy SO AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Article; Proceedings Paper CT 1st Brown-Linkoping Conference on Basic and Clinical Aspects of Reproductive Immunology CY NOV 15-17, 2002 CL Providence, RI DE apoptosis; cytokines; decidua; implantation; trophoblast ID FAS/FAS LIGAND SYSTEM; INDUCED PRETERM LABOR; PLACENTAL APOPTOSIS; TROPHOBLAST CELLS; HUMAN DECIDUA; CYTOKINE EXPRESSION; EMBRYO IMPLANTATION; GROWTH RESTRICTION; ALTERED EXPRESSION; SPIRAL ARTERIES AB BACKGROUND: During implantation, apoptosis is critical for the appropriate tissue remodeling of the maternal decidua and invasion Of the developing embryo, yet the regulation of apoptosis is also imperative for a successful pregnancy. The quick and effective removal of apoptotic cells by tissue macrophages represents an essential process, which prevents the release of self-antigens, and in the case of pregnancy, paternal alloantigens. METHODS OF STUDY: Recent studies have shown that the process of apoptotic cell clearance is not a neutral event, but rather an active one that induces macrophage production of anti-inflammatory cytokines and survival factors. Apoptotic cell clearance is, therefore, necessary for the resolution of inflammatory conditions, which during pregnancy could have lethal consequences. CONCLUSIONS: The function of the maternal immune system during implantation and throughout pregnancy is, therefore, an important area of investigation. This review will discuss the role of decidual macrophages in apoptotic cell clearance during pregnancy. C1 Yale Univ, Sch Med, Dept Obstet & Gynecol, New Haven, CT 06520 USA. NICHD, Perinatal Res Branch, NIH, Detroit, MI USA. RP Mor, G (reprint author), Yale Univ, Sch Med, Dept Obstet & Gynecol, 333 Cedar St,FMB 301, New Haven, CT 06520 USA. EM gil.mor@yale.edu FU NCI NIH HHS [R01-CA092435-01]; NICHD NIH HHS [R01HD37137] NR 55 TC 141 Z9 163 U1 0 U2 5 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 8755-8920 J9 AM J REPROD IMMUNOL JI Am. J. Reprod. Immunol. PD APR PY 2004 VL 51 IS 4 BP 275 EP 282 DI 10.1111/j.1600-0897.2004.00156.x PG 8 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA 813HY UT WOS:000220899400003 PM 15212680 ER PT J AU Duan, WZ Guo, ZH Jiang, HY Ladenheim, B Xu, XG Cadet, JL Mattson, MP AF Duan, WZ Guo, ZH Jiang, HY Ladenheim, B Xu, XG Cadet, JL Mattson, MP TI Paroxetine retards disease onset and progression in huntingtin mutant mice SO ANNALS OF NEUROLOGY LA English DT Article ID DIETARY RESTRICTION; RESPONSE ELEMENT; BINDING PROTEIN; METABOLISM; INCREASES; DEFICITS; NEURONS; CREB; RAT AB We report that administration of paroxetine, a widely prescribed antidepressant drug that acts by inhibiting re-uptake of the neurotransmitter serotonin, suppresses the neurodegenerative process and increases the survival of huntingtin mutant mice, an animal model of Huntington's disease (HD). Paroxetine attenuated motor dysfunction and body weight loss and improved glucose metabolism in the HD mice. Paroxetine was beneficial when treatment was initiated before or after the onset of motor dysfunction, suggesting a potential for such antidepressant drugs in the treatment of presymptomatic and symptomatic HD patients. C1 NIA, Neurosci Lab, Res Ctr, Intramural Res Program, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD USA. NIDA, Mol Neuropsychiat Branch, Baltimore, MD USA. RP Duan, WZ (reprint author), NIA, Neurosci Lab, Res Ctr, Intramural Res Program, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM duanwe@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 NR 20 TC 49 Z9 50 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 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD APR PY 2004 VL 55 IS 4 BP 590 EP 594 DI 10.1002/ana.20075 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 806ME UT WOS:000220437200019 PM 15048901 ER PT J AU Kromhout, H Fransman, W Vermeulen, R Roff, M Van Hemmen, JJ AF Kromhout, H Fransman, W Vermeulen, R Roff, M Van Hemmen, JJ TI Variability of task-based dermal exposure measurements from a variety of workplaces SO ANNALS OF OCCUPATIONAL HYGIENE LA English DT Article DE dermal exposure; tasks; variability; industry; hospitals ID MODEL AB Introduction: The RISKOFDERM project collected task-based estimates of potential dermal exposure from a wide range of industries and services from around Europe. A formal statistical analysis was carried out to explore the main components of variability in dermal exposure levels. The central research question was to what extent dermal exposure levels could be explained by generic grouping variables like 'exposure scenarios' and 'dermal exposure operation units' (DEOs) (grouping of scenarios on the basis of similarity in exposure patterns). Methods: Mixed effect linear models were used to estimate variance components of potential dermal exposure for DEOs or scenarios and for factories, workers and time. In addition within-and between-worker variance components were estimated for single groups of workers performing a specific scenario in a specific location with potential dermal exposure to a specific agent. Results: Variability in potential dermal exposure is very large. Differences in geometric mean potential dermal exposure can range over 3-5 orders of magnitude both for DEOs and scenarios. The range depends on how dermal exposure is expressed (amount or rate). Both DEOs and scenarios explain a considerable amount of variability, but large differences in dermal exposure still existed within DEOs and scenarios. In contrast, between-worker variability in mean potential dermal exposure is minimal for a given scenario carried out within a specific location with exposure to a particular agent. Temporal variability, however, is considerable, most likely due to the event-based nature of the dermal exposure process. Conclusion: The classification of tasks in DEOs and scenarios has proven to be useful since large differences in average dermal exposure estimates exist between DEOs and between scenarios. However, large differences also exist between scenarios within a DEO and even within a scenario. These differences are governed by local conditions determined by the actual handling of the agent, the agent's physical and chemical properties, its intrinsic toxicity, control measures taken and training and attitude of workers. For the time being, actual dermal exposure measurements and a better understanding of actual determinants of dermal exposure seem to be a necessity in order to evaluate dermal exposure hazards properly. C1 Univ Utrecht, Inst Risk Assessment Sci, Environm & Occupat Hlth Div, Utrecht, Netherlands. Natl Canc Inst, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, Rockville, MD USA. Hlth & Safety Lab, Sheffield S3 7HQ, S Yorkshire, England. TNO Nutr & Food Res, Dept Chem Exposure Assessment, Zeist, Netherlands. RP Kromhout, H (reprint author), Univ Utrecht, Inst Risk Assessment Sci, Environm & Occupat Hlth Div, Utrecht, Netherlands. EM h.kromhout@iras.uu.nl RI Kromhout, Hans/A-9159-2008; Vermeulen, Roel/F-8037-2011 OI Vermeulen, Roel/0000-0003-4082-8163 NR 7 TC 16 Z9 17 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0003-4878 J9 ANN OCCUP HYG JI Ann. Occup. Hyg. PD APR PY 2004 VL 48 IS 3 BP 187 EP 196 DI 10.1093/annhyg/meh030 PG 10 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA 815VU UT WOS:000221070600002 PM 15059794 ER PT J AU Fransman, W Vermeulen, R Kromhout, H AF Fransman, W Vermeulen, R Kromhout, H TI Occupational dermal exposure to cyclophosphamide in Dutch hospitals: A pilot study SO ANNALS OF OCCUPATIONAL HYGIENE LA English DT Article DE antineoplastic drugs; cleaning personnel; cyclophosphamide; dermal exposure; hospital; nurses; pharmacy technicians ID HANDLING ANTINEOPLASTIC DRUGS; SISTER CHROMATID EXCHANGES; CYTOSTATIC DRUGS; ENVIRONMENTAL CONTAMINATION; CHROMOSOMAL-ABERRATIONS; PHARMACY TECHNICIANS; NURSES; AGENTS; URINE; EXCRETION AB Introduction: Several studies have shown that exposure to antineoplastic drugs can cause reproductive toxic effects as well as carcinogenic effects. Presence of these drugs in the urine of hospital personnel has been widely studied and some work has been done on exposure by inhalation. So far, assessment of dermal exposure to antineoplastic drugs has not been extensively studied. In this pilot study we assessed potential and actual dermal exposure for several common hospital tasks. Results were used to derive an optimal measurement strategy for a currently ongoing exposure survey. Methods: Dermal exposure to cyclophosphamide was determined in three Dutch hospitals during five tasks (preparation, decanting urine, washing the patient, removing bed sheets and cleaning the toilet) using pad samples on 10 body locations. In addition, protective medical gloves (worn during the performance of these activities) were collected to estimate potential exposure of the hands. Subsequently, hands were washed to measure actual exposure of the hands. Bulk samples (i.e. application and body fluids) were collected and possible contact surfaces were monitored to assess the amount of cyclophosphamide potentially available for exposure. Results: The results show that hospital personnel (i.e. pharmacy technicians and oncology nurses) are dermally exposed to cyclophosphamide during performance of their daily duties. Exposure occurred predominantly on the hands and sporadically on other body locations (i.e. forehead and forearms). Gloves used during preparation of cyclophosphamide were more contaminated than gloves used in other tasks, however, actual exposure of the hands (underneath the gloves) was highest during decanting of urine of treated patients. Glove samples correlated significantly with handwash samples (r = 0.57, P = 0.03, n = 15). The level of protection from gloves varied between tasks, being highest for gloves used during preparation (median = 98 %) and lowest for gloves used during decanting urine (median = 19 %). Conclusion: This pilot study demonstrated that dermal exposure to cyclophosphamide is common among hospital personnel. The results showed that hands, forearms and forehead accounted for 87% of the cyclophosphamide total body exposure. Glove samples together with handwash samples enabled estimation of glove efficiency, which appeared to vary strongly between tasks observed. C1 Univ Utrecht, Inst Risk Assessment Sci, Environm & Occupat Hlth Grp, NL-3508 TD Utrecht, Netherlands. NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, Rockville, MD USA. RP Kromhout, H (reprint author), Univ Utrecht, Inst Risk Assessment Sci, Environm & Occupat Hlth Grp, POB 80176, NL-3508 TD Utrecht, Netherlands. EM h.kromhout@iras.uu.nl RI Kromhout, Hans/A-9159-2008; Vermeulen, Roel/F-8037-2011 OI Vermeulen, Roel/0000-0003-4082-8163 NR 29 TC 50 Z9 57 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0003-4878 J9 ANN OCCUP HYG JI Ann. Occup. Hyg. PD APR PY 2004 VL 48 IS 3 BP 237 EP 244 DI 10.1093/annhyg/meh017 PG 8 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA 815VU UT WOS:000221070600008 PM 15059800 ER PT J AU Childs, RW AF Childs, RW TI Evolving trends in hematopoietic cell transplantation for solid tumors: tempering enthusiasm with clinical reality SO ANNALS OF ONCOLOGY LA English DT Editorial Material ID BONE-MARROW TRANSPLANTATION; METASTATIC BREAST-CANCER; HIGH-DOSE CHEMOTHERAPY; MULTIPLE-MYELOMA; LEUKEMIA; BLOOD C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Childs, RW (reprint author), NHLBI, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM childsr@nih.gov NR 13 TC 2 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD APR PY 2004 VL 15 IS 4 BP 543 EP 544 DI 10.1093/annonc/mdh159 PG 2 WC Oncology SC Oncology GA 811FS UT WOS:000220758400001 PM 15033656 ER PT J AU Kim, YH Lee, HS Lee, HJ Hur, K Kim, WH Bang, YJ Kim, SJ Lee, KU Choe, KJ Yang, HK AF Kim, YH Lee, HS Lee, HJ Hur, K Kim, WH Bang, YJ Kim, SJ Lee, KU Choe, KJ Yang, HK TI Prognostic significance of the expression of Smad4 and Smad7 in human gastric carcinomas SO ANNALS OF ONCOLOGY LA English DT Article DE gastric carcinoma; prognostic factor; Smad4; Smad7; transforming growth factor-beta ID TUMOR-SUPPRESSOR GENE; GROWTH-FACTOR-BETA; HUMAN-CHROMOSOME 18Q21.1; SQUAMOUS-CELL CARCINOMA; DPC4 GENE; CANCER; FAMILY; MODULATORS; PATHWAY; PROTEIN AB Background: Transforming growth factor-beta (TGF-beta) modulates the growth and function of many cells, including those with malignant transformation. Smad proteins have been identified as major components in the intracellular signaling of TGF-beta family members. Patients and methods: To clarify the correlations between clinicopathologic profiles and the patient's survival, the expression of common mediator Smad (Smad4) and inhibitory Smad (Smad7) were evaluated immunohistochemically in 304 consecutive gastric carcinomas using the tissue array method. Results: Positive Smad4 expression was observed in 266 (87.5%) tumors and positive Smad7 expression in 98 (32.2%) tumors. The prognosis of patients with a Smad4-positive tumor was significantly better than that of the patients with a negative tumor. The survival rate was significantly higher in patients with negative Smad7 expression than those with positive Smad7 expression. In subgroup analysis according to TNM (tumour-node-metastasis) stage, both Smad4 and Smad7 showed most significant prognostic differences in stage I gastric cancer patients. Multivariate analysis indicated that tumor size, depth of invasion, lymph node metastasis and Smad7 expression were independent prognostic factors. Conclusion: Enhanced expression of the TGF-beta signaling inhibitor Smad7 may present one of the novel mechanisms of TGF-beta resistance in human gastric carcinomas. C1 Seoul Natl Univ, Coll Med, Dept Surg, Seoul 110744, South Korea. Seoul Natl Univ, Coll Med, Dept Pathol, Seoul 110744, South Korea. Seoul Natl Univ, Coll Med, Natl Res Lab Canc Epigenet, Seoul 110744, South Korea. Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110744, South Korea. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Yang, HK (reprint author), Seoul Natl Univ, Coll Med, Dept Surg, 28 Yongon Dong, Seoul 110744, South Korea. EM hkyang@plaza.snu.ac.kr RI Kim, Wooho/G-3703-2011; Hur, Keun/G-9513-2011; Seoul National University, Pathology/B-6702-2012; Yang, Han-Kwang/J-2767-2012; Lee, Hyuk-Joon/J-2782-2012; Bang, Yung Jue/J-2759-2012; Lee, Hye Seung/G-6419-2011; OI Lee, Hye Seung/0000-0002-1667-7986; Hur, Keun/0000-0002-6944-2718 NR 30 TC 40 Z9 54 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD APR PY 2004 VL 15 IS 4 BP 574 EP 580 DI 10.1093/annonc/mdh131 PG 7 WC Oncology SC Oncology GA 811FS UT WOS:000220758400006 PM 15033661 ER PT J AU Hira, PR Al-Ali, F Shweiki, HM Abdella, NA Johny, M Francis, I Iqbal, J Thompson, R Neva, F AF Hira, PR Al-Ali, F Shweiki, HM Abdella, NA Johny, M Francis, I Iqbal, J Thompson, R Neva, F TI Strongyloidiasis: challenges in diagnosis and management in non-endemic Kuwait SO ANNALS OF TROPICAL MEDICINE AND PARASITOLOGY LA English DT Article ID LINKED IMMUNOSORBENT-ASSAY; LARVAL ANTIGENS; STERCORALIS; INFECTIONS; SERODIAGNOSIS; EFFICACY; ELISA AB Among immunocompromised individuals, hyper-infection with Strongyloides stercoralis may occur and lead to fatal strongyloidiasis. To clinicians and laboratory diagnosticians in non-endemic countries such as Kuwait, this severe infection poses a particular problem. The clinical histories and signs and symptoms of four Kuwaiti cases of S. stercoralis hyper-infection were reviewed. Each of the four was found not only to have lived in an area where S. stercoralis was endemic but also to have been treated with immunosuppressive steroids (for medical problems unrelated to the nematode infection). When they presented with undiagnosed hyper-infections their clinical features were confusing. Three of the cases, all with low eosinophil counts, died but the other, who was treated with thiabendazole, survived. In the light of these observations, healthy medical examinees who had recently moved from endemic zones were checked for asymptomatic S. stercoralis infection, both by stool examination and ELISA-based serology. Of 381 stool samples investigated over a 3-month period, 183 (48%) were found positive for helminths, 7% for S. stercoralis. Of 198 individuals from endemic zones who were screened after another medical examination, 71 (35.8%) were found positive for intestinal helminth parasites, including one (1.45%) infected with S. stercoralis. Although ELISA appear reliable in making a presumptive diagnosis of strongylodiasis, the results of such assays are not very specific and are best interpreted in conjunction with the patient's clinical status. The concurrent administration of anthelminthics to patients prescribed steroids who, because they live or have lived in an area where S. stercoralis is endemic, are at risk of infection with the nematode, should be considered. C1 Kuwait Univ, Fac Med, Dept Microbiol, Safat 13110, Kuwait. Farwania Hosp, Microbiol Labs, Farwaniya 81004, Kuwait. Jahra Hosp, Dept Lab, Jahra 01753, Kuwait. Kuwait Univ, Fac Med, Dept Med, Safat 13110, Kuwait. NIH, Parasitol Lab, Bethesda, MD 20892 USA. Amiri Hosp, Microbiol Labs, Safat 13041, Kuwait. Kuwait Univ, Fac Med, Dept Pathol, Safat 13110, Kuwait. RP Hira, PR (reprint author), Kuwait Univ, Fac Med, Dept Microbiol, POB 24923, Safat 13110, Kuwait. EM hira@hsc.kuniv.edu.kw NR 22 TC 9 Z9 9 U1 0 U2 0 PU MANEY PUBLISHING PI LEEDS PA HUDSON RD, LEEDS LS9 7DL, ENGLAND SN 0003-4983 J9 ANN TROP MED PARASIT JI Ann. Trop. Med. Parasitol. PD APR PY 2004 VL 98 IS 3 BP 261 EP 270 DI 10.1179/000349804225003299 PG 10 WC Public, Environmental & Occupational Health; Parasitology; Tropical Medicine SC Public, Environmental & Occupational Health; Parasitology; Tropical Medicine GA 820KO UT WOS:000221387800005 PM 15119971 ER PT J AU Burger, AM Fiebig, HH Stinson, SF Sausville, EA AF Burger, AM Fiebig, HH Stinson, SF Sausville, EA TI 17-(Allylamino)-17-demethoxygeldanamycin activity in human melanoma models SO ANTI-CANCER DRUGS LA English DT Article DE ansamycin; c-Raf-1; Hsp90; melanoma; cancer treatment ID TYROSINE-KINASE; ANTITUMOR AGENT; GELDANAMYCIN; EXPRESSION; INHIBITION; PROTEINS; COMPLEX; HSP90; DESTABILIZATION; ASSOCIATION AB 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) is a semisynthetic antitumor agent, which has entered phase I/II clinical trials. Melanoma cell lines in the NCI in vitro screen (mean G1(50) = 84 nM) were relatively sensitive to the agent, which was therefore tested in vivo in four s.c. growing human melanoma xenografts; (MEXF 276, 989,462 and 514) in athymic mice. 17-AAG markedly inhibited tumor growth at doses of 80 (maximum tolerated dose) and 60 mg/kg/day in a qd x 5 (h: 0, 6; i.p.) schedule in two of four xenograft models. Cell lines derived from the 17-AAG-sensitive MEXF 276 and -resistant MEXF 514 melanomas, MEXF 276L and 514L, were chosen to study the effects of 17-AAG on its target Hsp90 as well as the Hsp90 'client' protein c-Raf-1 in vitro. Cells were exposed to drug concentrations which just cause total growth inhibition (total growth inhibition = 375 nM in MEXF 276L and 10 muM in MEXF 514L). Pharmacokinetic determinations confirmed that 17-AAG concentrations producing growth inhibition in vitro are readily achievable in vivo at the MTD (AUC(0-infinity) 1068 muM(.)min). Whilst 17-AAG treatment did not affect Hsp90 expression in the relatively resistant MEXF 514L cells, it caused a rapid transient decline in the markedly sensitive MEXF 276L cell line. In contrast, Hsp72 expression increased. Following Hsp90 depletion at 2-8h in MEXF 276L cells, down-regulation of c-Raf-1 was seen starting at 16 h after drug addition. In MEXF 276 xenograft tissues treated with effective dose levels, loss of Hsp90 was seen and was associated with occurrence of apoptotic figures. The apoptotic index rose from 9% after 48 h, greater than 12% at 72 h to 45% at 10 days. These data support the hypothesis that in some melanoma models, a very good response (e.g. with tumor regressions) to 17-AAG may be associated with modulation of Hsp90 expression. The expression of this target should be followed in clinical studies with 17-AAG. (C) 2004 Lippincott Williams Wilkins. C1 NCI, Dev Therapeut Program, Div Canc Treatment & Diagnost, Bethesda, MD USA. Univ Freiburg, Tumor Biol Ctr, Freiburg, Germany. RP Sausville, EA (reprint author), EPN, NCI, Dev Therapeut Program, Room 8018,6130 Execut Blvd, Rockville, MD 20852 USA. EM sausville@nih.gov NR 32 TC 72 Z9 74 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4973 J9 ANTI-CANCER DRUG JI Anti-Cancer Drugs PD APR PY 2004 VL 15 IS 4 BP 377 EP 387 DI 10.1097/01.cad.0000124496.74538.e4 PG 11 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 814VF UT WOS:000221001500011 PM 15057143 ER PT J AU Petraitiene, R Petraitis, V Lyman, CA Groll, AH Mickiene, D Peter, J Bacher, J Roussillon, K Hemmings, M Armstrong, D Avila, NA Walsh, TJ AF Petraitiene, R Petraitis, V Lyman, CA Groll, AH Mickiene, D Peter, J Bacher, J Roussillon, K Hemmings, M Armstrong, D Avila, NA Walsh, TJ TI Efficacy, safety, and plasma pharmacokinetics of escalating dosages of intravenously administered ravuconazole lysine phosphoester for treatment of experimental pulmonary aspergillosis in persistently neutropenic rabbits SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID INVASIVE FUNGAL-INFECTIONS; TRIAZOLE ANTIFUNGAL AGENTS; IN-VITRO SUSCEPTIBILITIES; AMPHOTERICIN-B; FILAMENTOUS FUNGI; ORAL TRIAZOLE; VORICONAZOLE; BMS-207147; ITRACONAZOLE; THERAPY AB Ravuconazole is a new antifungal triazole with broad-spectrum activity and a long half-life in plasma. We studied the antifungal efficacy, safety, and pharmacokinetics of ravuconazole lysine phosphoester in escalating dosages for the treatment of invasive pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits. Treatment groups consisted of rabbits treated with ravuconazole at 2.5 (RVC2.5), 5 (RVC5), and 10 (RVC10) mg/kg of body weight/day, rabbits treated with amphotericin B (AMB) at 1 mg/kg/day, or untreated controls. There was a dose-dependent reduction of pulmonary residual fungal burden (CFU per gram) in RVC5-, RVC10-, and AMB-treated rabbits in comparison to untreated controls (P<0.01, P<0.001, and P<0.01, respectively). These findings correlated with progressive galactomannan antigenemia in untreated controls and the RVC2.5-treated rabbits, a lower galactomannan index (GMI) in RVC5- and RVC10-treated rabbits, and a similarly low GMI in AMB-treated rabbits (P<0.01). Rabbits treated with RVC5, RVC10, and AMB also showed a reduction of organism-mediated pulmonary injury, as measured by infarct scores and lung weights, in comparison to untreated controls (P<0.001). These results were supported by decreased pulmonary infiltrates detected by computed tomography in RVC5- and RVC10-treated rabbits in comparison to untreated controls (P<0.05). Survival throughout the entire study was achieved in 95% of RVC5-treated rabbits (P<0.001), 85% of RVC10-treated rabbits (P<0.001), and 50% of AMB-treated rabbits (P<0.05) in comparison to none of the untreated controls. Ravuconazole showed linear plasma pharmacokinetics and a large volume of distribution while maintaining concentrations in plasma above the MIC throughout the dosing interval. There was no evidence of hepatotoxicity or nephrotoxicity among ravuconazole-treated animals. Intravenously administered ravuconazole lysine phosphoester showed dose-dependent efficacy and an excellent safety profile for the treatment of invasive pulmonary aspergillosis in persistently neutropenic rabbits. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NIH, Surg Serv, Vet Resources Program, Off Res Serv, Bethesda, MD 20892 USA. NIH, Dept Radiol, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bldg 10,Rm 13N240,10 Ctr Dr, Bethesda, MD 20892 USA. EM walsht@mail.nih.gov NR 49 TC 25 Z9 27 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD APR PY 2004 VL 48 IS 4 BP 1188 EP 1196 DI 10.1128/AAC.48.4.1188-1196.2004 PG 9 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 809TI UT WOS:000220658600016 PM 15047519 ER PT J AU Nayeem, MA AF Nayeem, MA TI Sublethal simulated ischemia promotes delayed resistance against ischemia via ATP-Sensitive (K+) channels in murine myocytes: Role of PKC and NOS SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID PROTEIN-KINASE-C; NITRIC-OXIDE SYNTHASE; CONSCIOUS RABBITS; MYOCARDIAL PROTECTION; CORONARY ANGIOPLASTY; ADENOSINE A(1); SMOOTH-MUSCLE; LATE-PHASE; RECEPTOR; HEART AB In this study, we examined whether sublethal simulated ischemia (SSI) induces delayed cellular protection in mouse cardiac myocytes, and whether the delayed cellular protection depends on the activation of protein kinase C-epsilon (PKC-epsilon), inducible nitric oxide synthase (iNOS), and ATP-sensitive K+ (K-ATP) channels against subsequent sustained simulated ischemia (SI). The following groups of mouse cardiac myocytes were studied: (a) SI: incubation with SI buffer for 1 h; (b) SSI: incubation with SSI buffer for 30 min; (c) SSI + PKC inhibitor, chelerythrine chloride (CCI): SSI and 1 muM CCI; (d) SSI + iNOS inhibitor, S-methylthiourea (SMT): SSI and 100 nM SMT; (e) SSI + K-ATP channel blocker, glibenclamide (Glb): SSI and 50 muM Glb; (f) SSI + mitochondrial K-ATP channel blocker, 5-hydroxydecanoate (5-HD): SSI and 50 muM 5-HD. The release of lactate dehydrogenase into the medium and the amount remaining in the cells was measured, and A, adenosine receptor, PKC-epsilon, and NOS were detected through western blot analysis. The delayed cellular protection acquired due to SSI showed a decreased release of lactate dehydrogenase (%) from 46.51 +/- 1.60 to 37.00 +/- 1.34 (p < 0.001) and was blocked by CCI (47.08 +/- 0.95), SMT (48.08 +/- 1.18), Glb (45.88 +/- 1.31), and 5-HD (47.20 +/- 1.56). Simultaneously, SSI-induced up-regulation of A, adenosine receptor, PKC-epsilon, iNOS, and opening of both membrane and mitochondrial K-ATP channels also was observed compared with controls. C1 NIEHS, DIR, ETP,LPC, MEM,NIH, Res Triangle Pk, NC 27709 USA. RP NIEHS, DIR, ETP,LPC, MEM,NIH, Bldg Rm 101,C340,MD C3-10,POB 12233, Res Triangle Pk, NC 27709 USA. EM nayeem@nichs.nih.gov RI Nayeem, Mohammed/A-3949-2017 OI Nayeem, Mohammed/0000-0002-7827-4760 NR 37 TC 3 Z9 3 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD APR PY 2004 VL 6 IS 2 BP 375 EP 383 DI 10.1089/152308604322899440 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 802ZG UT WOS:000220200800019 PM 15025939 ER PT J AU Thierry, KL Spence, MJ AF Thierry, KL Spence, MJ TI A real-life event enhances the accuracy of preschoolers' recall SO APPLIED COGNITIVE PSYCHOLOGY LA English DT Article ID EYEWITNESS MEMORY; CHILDRENS MEMORY; DEVELOPMENTAL DIFFERENCES; SUGGESTIBILITY; IMITATION; TESTIMONY; MISINFORMATION; PARTICIPATION; EXPERIENCE; TELEVISION AB Children's memory and susceptibility to misinformation about a real-life and video event were examined. Eighty-six three- to four-year-olds and five- to six-year-olds observed an event either in real life or on video. Immediately afterward, they freely recalled the event and answered misleading questions about central and descriptive information. Three- to four-year-olds in the video condition were less likely to accurately recall descriptive information than three- to four-year-olds in the live condition and five- to six-year-olds in either condition. Children in the video condition were less accurate in response to misleading questions than nose in the live condition. When video condition three- to four-year-olds in Experiment 2 were asked nonmisleading questions that prompted them for descriptive information, they recalled descriptors less accurately than those in the live condition. These results have particularly important implications for studies that utilize video events when investigating children's eyewitness memory. Copyright (C) 2004 John Wiley Sons, Ltd. C1 Natl Inst Child Hlth & Human Dev, Sect Social & Emot Dev, Bethesda, MD 20892 USA. Univ Texas, Sch Behav & Brain Sci, Richardson, TX USA. RP Thierry, KL (reprint author), Natl Inst Child Hlth & Human Dev, Sect Social & Emot Dev, Rockledge 1 Ctr,6705 Rockledge Dr,Suite 8048, Bethesda, MD 20892 USA. EM thierryk@mail.nih.gov NR 34 TC 12 Z9 12 U1 1 U2 3 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0888-4080 J9 APPL COGNITIVE PSYCH JI Appl. Cogn. Psychol. PD APR PY 2004 VL 18 IS 3 BP 297 EP 309 DI 10.1002/acp.965 PG 13 WC Psychology, Experimental SC Psychology GA 810MB UT WOS:000220707300004 ER PT J AU Papadopoulos, EJ Jaffe, ES Elgart, GW Raffeld, M Turner, ML AF Papadopoulos, EJ Jaffe, ES Elgart, GW Raffeld, M Turner, ML TI Periodic fever with atypical dyshidrosis - Leukemic mycosis fungoides. SO ARCHIVES OF DERMATOLOGY LA English DT Article ID SEZARY-SYNDROME C1 NIH, Bethesda, MD 20892 USA. RP Papadopoulos, EJ (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD APR PY 2004 VL 140 IS 4 BP 479 EP + DI 10.1001/archderm.140.4.479-a PG 2 WC Dermatology SC Dermatology GA 922BU UT WOS:000228811600014 PM 15096381 ER PT J AU Grant, BF Stinson, FS Dawson, DA Chou, SP Ruan, J Pickering, RP AF Grant, BF Stinson, FS Dawson, DA Chou, SP Ruan, J Pickering, RP TI Co-occurrence of 12-month alcohol and drug use disorders and personality disorders in the united states - Results from the national epidemiologic survey on alcohol and related conditions SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID DSM-III-R; INTERVIEW SCHEDULE AUDADIS; SUBSTANCE USE DISORDERS; GENERAL-POPULATION SAMPLE; IV ALCOHOL; ANTISOCIAL PERSONALITY; PSYCHIATRIC-DISORDERS; COCAINE DEPENDENCE; ICD-10 ALCOHOL; NOSOLOGICAL COMPARISONS AB Background: Very little information is available on the co-occurrence of different personality disorders (PDs) and alcohol and drug use disorders in the US population. Objective: To present national data on sex differences in the co-occurrence of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) alcohol and drug use disorders and 7 of the 10 DSM-IV PDs. Design: Face-to-face interviews conducted in the 200 1 2002 National Epidemiologic Survey on Alcohol and Related Conditions (N=43093). Setting: The United States and the District of Columbia, including Alaska and Hawaii. Participants: Household and group-quarters residents, aged 18 years and older. Results: Among individuals with a current alcohol use disorder, 28.6% (95% confidence interval [CI], 26.7-30.6) had at least 1 PD, whereas 47.7% (95% Cl, 43.951.6) of those with a current drug use disorder had at least I PD. Further 16.4% (95% Cl, 15.1-17.6) of individuals with at least I PD had a current alcohol use disorder and 6.5% (95% Cl, 5.7-7.3) had a current drug use disorder. Associations between PDs and alcohol and drug use disorders were overwhelmingly positive and significant (P < .05). Overall, alcohol use disorders were most strongly related to antisocial (odds ratio [ OR], 4.8; 95% Cl, 4.1-5.6), histrionic (OR, 4.7; 95% Cl, 3.8-5.8), and dependent (OR, 3.0; 95% Cl, 1.9-4.8) PDs. Drug use disorders also were more highly associated with antisocial (OR, 11.8; 95% Cl, 9.7-14.3), histrionic (OR, 8.0; 95% Cl, 6.0-10.7), and dependent (OR, 11.6; 95% Cl, 7.119. 1) PDs. Associations between obsessive-compulsive, histrionic, schizoid, and antisocial PDs and specific alcohol and drug use disorders were significantly stronger (P < .04) among women than men, whereas the association between dependent PD and drug dependence was significantly greater (P < .04) among men than women. Conclusions: The co-occurrence of PDs with alcohol and drug use disorders is pervasive in the US population. Results highlight the need for further research on the underlying structure of these disorders and the treatment implications of these disorders when comorbid. C1 NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, Dept HHS,NIH, Bethesda, MD 20892 USA. RP Grant, BF (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, Dept HHS,NIH, MS 9304,5635 Fishers Ln, Bethesda, MD 20892 USA. EM bgrant@willco.niaaa.nih.gov NR 83 TC 401 Z9 411 U1 5 U2 14 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD APR PY 2004 VL 61 IS 4 BP 361 EP 368 DI 10.1001/archpsyc.61.4.361 PG 8 WC Psychiatry SC Psychiatry GA 811CD UT WOS:000220749100005 PM 15066894 ER PT J AU Ferris, FL Tielsch, JM AF Ferris, FL Tielsch, JM TI Blindness and visual impairment - A public health issue for the future as well as today SO ARCHIVES OF OPHTHALMOLOGY LA English DT Editorial Material C1 NEI, Div Epidemiol & Clin Res, Bethesda, MD 20892 USA. RP Ferris, FL (reprint author), NEI, Div Epidemiol & Clin Res, Bldg 31,Room 6A52,31 Ctr Dr,MSC 2510, Bethesda, MD 20892 USA. NR 6 TC 15 Z9 15 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD APR PY 2004 VL 122 IS 4 BP 451 EP 452 DI 10.1001/archopht.122.4.451 PG 2 WC Ophthalmology SC Ophthalmology GA 812GT UT WOS:000220828700001 PM 15078660 ER PT J AU Csaky, K Baffi, J Chan, CC Byrnes, GA AF Csaky, K Baffi, J Chan, CC Byrnes, GA TI Clinicopathologic correlation of progressive fibrovascular proliferation associated with occult choroidal neovascularization in age-related macular degeneration SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article C1 NEI, NIH, Bethesda, MD 20895 USA. RP Csaky, K (reprint author), NEI, NIH, Bldg 10,Room 10N119,9000 Rockville Pike, Bethesda, MD 20895 USA. EM kcsaky@helix.nih.gov NR 5 TC 6 Z9 6 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD APR PY 2004 VL 122 IS 4 BP 650 EP 652 DI 10.1001/archopht.122.4.650 PG 3 WC Ophthalmology SC Ophthalmology GA 812GT UT WOS:000220828700027 PM 15078686 ER PT J AU Lu, JH Dveksler, G Kaplan, GG AF Lu, JH Dveksler, G Kaplan, GG TI Rescue of Hepatitis A virus from cDNA-transfected but not virion RNA-transfected mouse Ltk-cells SO ARCHIVES OF VIROLOGY LA English DT Article ID COMPLETE NUCLEOTIDE-SEQUENCE; CAP-INDEPENDENT TRANSLATION; MONKEY KIDNEY-CELLS; WILD-TYPE VIRUS; CULTURE; ADAPTATION; MUTATIONS; GROWTH; REPLICATION; IDENTIFICATION AB Hepatitis A virus (HAV) has stringent replication requirements and a restricted host-range. Mouse Ltk-cells do not support growth of HAV upon infection or transfection of virion RNA. However, low levels of HAV were rescued from Ltk- cells transiently transfected with its infectious cDNA. Ltk- stable transfectants that expressed HAV antigens and produced infectious HAV were selected and termed Ltk-pJH15 cells. After a few serial passages, HAV became undetectable in the Ltk-pJH15 cells. Multiple rounds of single cell cloning of HAV antigen positive Ltk-pJH15 cells resulted in the isolation of clone E8 that produced higher levels of HAV for at least 5 passages. HAV produced in E8 cells was similar to the parental virus as shown by infectivity assays. Luciferase assays using a bi-cistronic construct containing the HAV 5' noncoding region showed similar levels of HAV IRES-dependent translation in Ltk- and Ltk-pJH15 cells, which suggested that HAV IRES-dependent translation was not a limiting factor for HAV growth in these cells. The availability of the Ltk-pHJ15 cells will allow the identification of cellular factors required for HAV growth, which could lead to the development of a mouse model to study pathogenesis of HAV. C1 US FDA, Ctr Biol Evaluat & Res, Hepatatis Lab, Bethesda, MD USA. Uniformed Serv Univ Hlth Sci, Dept Pathol, Bethesda, MD 20814 USA. RP Kaplan, GG (reprint author), 8800 Rockville Pike,Bldg 29-NIH,Rm 225,HFM-325, Bethesda, MD 20892 USA. EM gk@helix.nih.gov NR 27 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER-VERLAG WIEN PI VIENNA PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 VIENNA, AUSTRIA SN 0304-8608 J9 ARCH VIROL JI Arch. Virol. PD APR PY 2004 VL 149 IS 4 BP 759 EP 772 DI 10.1007/s00705-003-0226-2 PG 14 WC Virology SC Virology GA 812NN UT WOS:000220846300007 PM 15045562 ER PT J AU Atreya, CD Kulkarni, S Mohan, KVK AF Atreya, CD Kulkarni, S Mohan, KVK TI Rubella virus P90 associates with the cytokinesis regulatory protein Citron-K kinase and the viral infection and constitutive expression of P90 protein both induce cell cycle arrest following S phase in cell culture SO ARCHIVES OF VIROLOGY LA English DT Article ID VIRUS-INDUCED APOPTOSIS; BINDING PROTEIN; RUBELLA; RHO; IDENTIFICATION; REPLICATION; INTERACTS; TARGET; RB AB In utero infection of developing fetus by Rubella virus (RV) causes cell division inhibition of critical precursor cells in organogenesis, CNS-associated birth defects and induction of apoptosis in cell culture. The underlying mechanisms of RV-induced congenital abnormalities are not known. Here, we identified a novel interaction between RV replicase P90 protein and a cytokinesis-regulatory protein, the Citron-K kinase (CK), in a yeast two-hybrid cDNA library screen. Aberrations in cytokinesis and subsequent apoptosis do occur in specific cell types when the CK gene is knocked out or, its regulatory function is perturbed. Our analysis found that full-length P90 binds CK and in RV-infected cells P90 colocalizes with CK in the cytoplasm. Furthermore, during RN infection as well as cellular expression of P90 alone, we identified a discrete subpopulation of cells containing 4N DNA content, indicating that these cells are arrested in the cell cycle following S phase, suggesting that cellular expression of viral P90 during RV infection perturbs cytokinesis. Previous reports by others established that RV infection leads to apoptosis in cell culture. These observations together taken to the fetal organogenesis level, favor the idea that RV P90, by binding to cellular CK, invokes cell cycle aberrations resulting in the cell-and organ-specific growth inhibition and programmed cell death during RV infection in utero, which commonly is referred to as RV-induced teratogenesis. C1 US FDA, Ctr Biol Evaluat & Res, Sect Viral Pathogenesis & Adverse React, Lab Pediat & Resp Viral Dis, Bethesda, MD 20892 USA. RP Atreya, CD (reprint author), US FDA, Ctr Biol Evaluat & Res, Sect Viral Pathogenesis & Adverse React, Lab Pediat & Resp Viral Dis, HFM-460,Bldg 29A,2C-11,NIH Campus,8800 Rockville, Bethesda, MD 20892 USA. EM Atreya@cber.fda.gov NR 31 TC 11 Z9 11 U1 1 U2 3 PU SPRINGER-VERLAG WIEN PI VIENNA PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 VIENNA, AUSTRIA SN 0304-8608 J9 ARCH VIROL JI Arch. Virol. PD APR PY 2004 VL 149 IS 4 BP 779 EP 789 DI 10.1007/s00705-003-0267-6 PG 11 WC Virology SC Virology GA 812NN UT WOS:000220846300009 PM 15045564 ER PT J AU Maini, RN Breedveld, FC Kalden, JR Smolen, JS Furst, D Weisman, MH St Clair, EW Keenan, GF van der Heijde, D Marsters, PA Lipsky, PE AF Maini, RN Breedveld, FC Kalden, JR Smolen, JS Furst, D Weisman, MH St Clair, EW Keenan, GF van der Heijde, D Marsters, PA Lipsky, PE CA Anti-Tumor Necrosis Factor Trial R TI Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate SO ARTHRITIS AND RHEUMATISM LA English DT Article ID NECROSIS-FACTOR-ALPHA; QUALITY-OF-LIFE; HEALTH SURVEY SF-36; MONOCLONAL-ANTIBODY; RADIOLOGIC DAMAGE; HODGKINS-DISEASE; RELIABILITY; DISABILITY; SHARP/VAN; CAPACITY AB Objective. To evaluate the efficacy and safety of repeated administration of infliximab plus methotrexate (MTX) over a 2-year period in patients with rheumatoid arthritis (RA) who previously experienced an incomplete response to MTX. Methods. Four hundred twenty-eight patients were randomly assigned to receive MTX plus placebo or infliximab at a dose of 3 or 10 mg/kg plus MTX for 54 weeks, with an additional,year of followup. The protocol was later amended to allow for continued treatment during the second year. Of 259 patients who entered the second year of treatment, 216 continued to receive infliximab plus MTX for 102 weeks. Ninety-four of these 259 patients experienced a gap in therapy of > 8 weeks before continuing therapy. Infusions were administered at weeks 0; 2, and 6, followed by treatment every 4 weeks or every 8 weeks (alternating with placebo infusions in the interim 4-week visits) at a dose of 3 or 10 mg/kg for a total of 102 weeks (including the gap in therapy). For safety and efficacy assessments, data on the patients who were randomized to receive treatment, irrespective of whether treatment was administered for 102 weeks, were evaluated using all actual observations available. The efficacy measures included the Health Assessment Questionnaire (HAQ) (physical function), Short Form 36 health survey (SF-36) (health-related quality of life), total radiographic scores (structural damage), and the American College of Rheumatology 20% improvement criteria (ACR20) (signs and symptoms). Results. The infliximab plus MTX regimens resulted in significantly greater improvement in HAQ scores (P less than or equal to 0.006) and SF-36 physical component summary scores (P less than or equal to 0.011) compared with the MTX-only group. There also was stability in the SF-36 mental component summary score among patients who received the infliximab plus MTX regimens. Median changes from baseline to week 102 in the total radiographic score were 4.25 for patients who received the MTX-only regimen and 0.50 for patients who received the infliximab plus MTX regimen. The proportion of patients achieving an ACR20 response at week 102 varied from 40% to 48% for the infliximab plus MTX groups compared with 16% for the MTX-only group. Conclusion. Throughout 102 weeks of therapy, infliximab plus MTX provided significant, clinically relevant improvement in physical function and quality of life, accompanied by inhibition of progressive joint damage and sustained improvement in the signs and symptoms of RA among patients who previously had an incomplete response to MTX alone. C1 NIAMS Intramural Res Program, NIH, Bethesda, MD 20892 USA. Kennedy Inst, London, England. Leiden Univ Hosp, Leiden, Netherlands. Inst Clin Immunol & Rheumatol, Erlangen, Germany. Lainz Hosp, A-1130 Vienna, Austria. Ludwig Boltzmann Inst Rheumatol, A-1130 Vienna, Austria. Virginia Mason Hosp, Seattle, WA USA. Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. Duke Univ Hosp S, Durham, NC USA. Centocor Inc, Malvern, PA USA. Univ Hosp, Maastricht, Netherlands. RP Lipsky, PE (reprint author), NIAMS Intramural Res Program, NIH, 9000 Rockville Pike,Bldg 10,Room 9N228, Bethesda, MD 20892 USA. EM LipskyP@mail.nih.gov NR 34 TC 340 Z9 366 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 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD APR PY 2004 VL 50 IS 4 BP 1051 EP 1065 DI 10.1002/art.20159 PG 15 WC Rheumatology SC Rheumatology GA 811HS UT WOS:000220763600006 PM 15077287 ER PT J AU Ward, MM AF Ward, MM TI Decreases in rates of hospitalizations for manifestations of severe rheumatoid arthritis, 1983-2001 SO ARTHRITIS AND RHEUMATISM LA English DT Article ID MODIFYING ANTIRHEUMATIC DRUGS; POPULATION-BASED ASSESSMENT; FOLLOW-UP; ORTHOPEDIC-SURGERY; CONTROLLED TRIAL; DOUBLE-BLIND; LONG-TERM; DISEASE; THERAPY; PREVALENCE AB Objective. To determine whether the rates of hospitalization for 4 manifestations of severe rheumatoid arthritis (RA), which are used as indicators of long-term health outcomes, have changed from 1983 to 2001. Methods. Data on all patients with RA who were hospitalized with rheumatoid vasculitis or to undergo splenectomy for Felty's syndrome, cervical spine fusion for myelopathy, or total knee arthroplasty at hospitals in California were abstracted from a state hospitalization database. Changes in rates of hospitalization from 1983 to 2001 were examined in this serial cross-sectional study. Results. Rates of hospitalization for rheumatoid vasculitis and splenectomy in Felty's syndrome decreased progressively over time. The risk of hospitalization for rheumatoid vasculitis was one-third lower in 1998-2001 than in 1983-1987. The risk of hospitalization for splenectomy in Felty's syndrome was 71% lower in 1998-2001 than in 1983-1987. There were no significant decreases in the rates of hospitalization for cervical spine surgery or total knee arthroplasty (primary and revision), although in 1998-2001 there was a reversal of the trend of increasing rates of total knee arthroplasty. The risk of hospitalization for primary total knee arthroplasty was significantly lower in 1998-2001 than in 1990-1993 (rate ratio 0.90, 95% confidence interval 0.86-0.95; P < 0.0001). Conclusion. Rates of hospitalization for rheumatoid vasculitis and splenectomy in Felty's syndrome have decreased over the past 19 years, and there has been a recent decrease in the rates of primary total knee arthroplasty in patients with RA. Although several factors may account for these decreases, these findings suggest that since the early 1980s, the long-term health outcomes of patients with RA have improved. 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 42 TC 59 Z9 60 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD APR PY 2004 VL 50 IS 4 BP 1122 EP 1131 DI 10.1002/art.20158 PG 10 WC Rheumatology SC Rheumatology GA 811HS UT WOS:000220763600013 PM 15077294 ER PT J AU McClain, MT Arbuckle, MR Heinlen, LD Dennis, GJ Roebuck, J Rubertone, MV Harley, JB James, JA AF McClain, MT Arbuckle, MR Heinlen, LD Dennis, GJ Roebuck, J Rubertone, MV Harley, JB James, JA TI The prevalence, onset, and clinical significance of antiphospholipid antibodies prior to diagnosis of systemic lupus erythematosus SO ARTHRITIS AND RHEUMATISM LA English DT Article ID CONNECTIVE-TISSUE DISEASES; ANTICARDIOLIPIN ANTIBODIES; ANTIPROTHROMBIN ANTIBODIES; VENOUS THROMBOSIS; REVISED CRITERIA; COHORT; RISK; ASSOCIATIONS; CLASSIFICATION; CARDIOLIPIN AB Objective. To determine whether antiphospholipid antibodies (aPL) occur before the diagnosis of systemic lupus erythematosus (SLE) and before initial clotting events, and whether their presence early in the disease course influences clinical outcome. Methods. Serum samples obtained from 130 lupus patients before and after SLE diagnosis were screened for IgG and IgM aPL using an anticardiolipin (aCL) enzyme-linked immunosorbent assay. Medical records of all patients were carefully reviewed for data on the time of onset of SLE features meeting clinical criteria and on disease manifestations. Results. Twenty-four patients (18.5%) were positive for IgG and/or IgM aCL prior to SLE diagnosis. Anticardiolipin antibodies appeared from 7.6 years prior to SLE diagnosis to within the same month as SLE diagnosis, with a mean onset occurring 3.0 years before SLE diagnosis. Additionally, aCL presence early in the disease process seemed to predict a more severe clinical outcome; these patients eventually met an average of 6.1 of the 11 classification criteria for SLE, compared with 4.9 criteria for other patients (P < 0.001). The early aCL-positive population also had more frequent renal disease, central nervous system disease, thrombocytopenia, and clotting events. In this population, aCL preceded initial thrombotic events by a mean of 3.1 years. Conclusion. Anticardiolipin antibodies in SLE patients tend to precede initial clotting events by several years. Furthermore, the presence of early, prediagnosis aPL seems to herald a more varied, severe clinical course with earlier onset in patients with SLE. C1 Oklahoma Med Res Fdn, Arthritis & Immunol Program, Oklahoma City, OK 73104 USA. Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. NIAMSD, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Bethesda, MD 20892 USA. USA, Ctr Hlth Promot & Prevent Med, Washington, DC USA. Univ Oklahoma, Oklahoma Med Res Fdn, Hlth Sci Ctr, Oklahoma City, OK USA. Dept Vet Affairs, Oklahoma City, OK USA. RP James, JA (reprint author), Oklahoma Med Res Fdn, Arthritis & Immunol Program, 825 NE 13th St, Oklahoma City, OK 73104 USA. EM jamesj@omrf.ouhsc.edu FU NCRR NIH HHS [RR-15577, RR-14467]; NIAID NIH HHS [AI-24717, AI-31584]; NIAMS NIH HHS [AR-45231, AR-45084, AR-48940, AR-42460] NR 33 TC 95 Z9 103 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 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD APR PY 2004 VL 50 IS 4 BP 1226 EP 1232 DI 10.1002/art.20120 PG 7 WC Rheumatology SC Rheumatology GA 811HS UT WOS:000220763600024 PM 15077305 ER PT J AU Nowak, M Carrasquillo, JA Yarboro, CH Bacharach, SL Whatley, M Valencia, X Takada, K Brust, DG Illei, GG AF Nowak, M Carrasquillo, JA Yarboro, CH Bacharach, SL Whatley, M Valencia, X Takada, K Brust, DG Illei, GG TI A pilot study of the use of 2-[F-18]-fluoro-2-deoxy-D-glucose-positron emission tomography to assess the distribution of activated lymphocytes in patients with systemic lupus erythematosus SO ARTHRITIS AND RHEUMATISM LA English DT Article ID MYASTHENIA-GRAVIS; THYMOMA; THYMUS; CELLS; THYMECTOMY AB Objective. The 2-[F-18]-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) technique provides information on uptake and metabolism of glucose in various tissues. Compared with resting cells, activated lymphocytes take up radioactively labeled glucose analog at a higher rate, which makes it possible to identify lymphoid organs with higher concentrations of activated lymphocytes. This study was undertaken to compare the pattern of PET images and quantitative FDG uptake in lymphoid organs of patients with active systemic lupus erythematosus (SLE) versus patients with inactive SLE and to correlate these findings with peripheral blood lymphocyte phenotypes. Methods. Ten patients with active SLE and 9 patients with inactive SLE were studied. FDG-PET images were obtained from the inguinal region to above the ear, starting at 60 minutes after injection of FDG. Standardized uptake values using lean body mass were determined over areas of interest. Results. Both patients with active lupus and those with inactive lupus had increased FDG uptake in lymph nodes when compared with healthy volunteers, and there was no statistically significant difference between the 2 groups of lupus patients. Thymic uptake was demonstrated in 5 of 10 patients with active lupus compared with 0 of 9 patients with inactive disease. Three of the 5 patients with active SLE who were over 29 years of age had thymic uptake. Of the activation markers tested, only the CD3/CD71 population of cells was significantly different between the patient groups, with an increased percentage in the active disease group (P = 0.0247). Conclusion. Increased FDG uptake in lymph nodes of both patients with active SLE and patients with inactive SLE suggests that metabolic, and probably immunologic, activity is enhanced not only in active, but also in clinically quiescent, disease. The increased thymic uptake observed only in patients with active disease suggests that the thymus plays an important role during periods of disease activity. C1 NIAMSD, Arthritis & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Illei, GG (reprint author), NIAMSD, Arthritis & Rheumatism Branch, NIH, 10 Ctr Dr,Bldg 10 Room 9S205, Bethesda, MD 20892 USA. EM illeig@mail.nih.gov RI Carrasquillo, Jorge/E-7120-2010; OI Carrasquillo, Jorge/0000-0002-8513-5734 NR 21 TC 10 Z9 11 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD APR PY 2004 VL 50 IS 4 BP 1233 EP 1238 DI 10.1002/art.20150 PG 6 WC Rheumatology SC Rheumatology GA 811HS UT WOS:000220763600025 PM 15077306 ER PT J AU Fox, CS Parise, H Vasan, RS Levy, D O'Donnell, CJ D'Agostino, RB Plehn, JF Benjamin, EJ AF Fox, CS Parise, H Vasan, RS Levy, D O'Donnell, CJ D'Agostino, RB Plehn, JF Benjamin, EJ TI Mitral annular calcification is a predictor for incident atrial fibrillation SO ATHEROSCLEROSIS LA English DT Article DE mitral annular calcification; epidemiology; atrial fibrillation; echocardiography; cohort study; prognosis ID ANULUS CALCIFICATION; RISK-FACTORS; FRAMINGHAM; DISEASE; CALCIUM; STROKE; PREVALENCE; COHORT; OLDER; SIZE AB Background Mitral annular calcification (MAC) has been associated with adverse cardiovascular disease outcomes and stroke in longitudinal and community-based cohorts. Prospective data are limited on its association with atrial fibrillation (AF). Methods: We examined the association between MAC and the long-term risk of AF over 16 years of follow-up in participants in the original cohort of the Framingham Heart Study who attended a routine examination between 1979 and 1981. MAC was assessed by M-mode echocardiography. Cox proportional-hazards models were used to estimate hazard ratios (HR) for incident AF. Results: Of 1126 subjects who had adequate echocardiographic assessment and were AF-free at baseline, 149 (13%) had MAC. There were 217 cases of incident AF (42 in subjects with MAC). The age- and sex-adjusted incidence rate was 362 per 10,000 person-years in subjects with MAC compared with 185 per 10,000 person-years in those without MAC. In multivariable-adjusted analyses, MAC was associated with an increased risk of AF (HR 1.6, 95% Cl 1.1-2.2). This association was attenuated upon further adjustment for left atrial size (HR 1.4, 95% Cl 0.9-2.0). Conclusions: The association between MAC and incident AF may be mediated partially through left atrial enlargement. These data suggest the importance of better understanding the mechanisms involved in cardiac valvular calcification. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 NHLBI, Framington Heart Study, Framingham, MA 01702 USA. Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. Boston Univ, Sch Med, Cardiol Sect, Dept Med & Prevent Med Sect, Boston, MA 02215 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Benjamin, EJ (reprint author), NHLBI, Framington Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM emelia@fram.nhlbi.nih.gov OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [K24 HL 04334, N01-HC-25195]; NINDS NIH HHS [5R01-NS-17950] NR 19 TC 44 Z9 45 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD APR PY 2004 VL 173 IS 2 BP 291 EP 294 DI 10.1016/j.athersclerosis.2003.12.018 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 825KL UT WOS:000221755700016 PM 15064104 ER PT J AU Pantin-Jackwood, MJ Brown, TP Kim, Y Huff, GR AF Pantin-Jackwood, MJ Brown, TP Kim, Y Huff, GR TI Proventriculitis in broiler chickens: Effects of immunosuppression SO AVIAN DISEASES LA English DT Article DE proventriculitis; immunosuppression; IBDV ID INFECTIOUS BURSAL DISEASE; PATHOGEN-FREE CHICKENS; CYCLOSPORINE-A; MALABSORPTION-SYNDROME; VIRUS; COPPER; CELL; CYCLOPHOSPHAMIDE; MEGABACTERIA; LYMPHOCYTES AB Proventriculitis in broilers causes carcass condemnation when swollen proventriculi tear during evisceration. The cause of this proventriculitis is unknown, but several infectious agents have been associated with it. One such agent, infectious bursal disease virus (IBDV), has been implicated as a cause of proventriculitis, but a direct effect of this virus on the proventriculus has not been proven. The role of IBDV in proventriculitis may be indirect as a result of its ability to cause immunosuppression. The objective of this study was to understand how immunosuppression affects the incidence of proventriculitis in broiler chickens. Immunosuppression was induced in commercial and specific-pathogen-free broiler chickens using chemicals (cyclophosphamide and cyclosporin) or virus (IBDV). All groups were then exposed to a proventricular homogenate produced from diseased birds. At 7 and 14 days postinoculation, the incidence of proventriculitis in these groups was compared to that produced by homogenate exposure in immunocompetent broilers. All birds exposed to the proventricular homogenate from diseased birds developed proventriculitis. Cyclophosphamide and IBDV, both B cell suppressors, did not significantly affect the incidence or characteristics of the proventriculitis observed, although they did have an effect on the size of the proventriculus at 7 days postinoculation. Chickens inimunosuppressed with cyclosporin, a T cell suppressor, developed more severe lesions and had a higher incidence of proventriculitis. These findings indicate that both B and T cells are involved in the immune response against proventriculitis, but cell-mediated immunity appears to have a more important role in controlling the disease. IBDV affects both Immoral and cellular immunity in the chicken, so although under experimental conditions it didn't have a major effect on proventriculitis, it may explain why control of IBDV in the field seems to reduce the incidence of proventriculitis. C1 Univ Georgia, Coll Vet Med, Dept Avian Med, Athens, GA 30602 USA. Univ Georgia, Coll Vet Med, Dept Vet Pathol, Athens, GA 30602 USA. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. USDA ARS, Poultry Prod & Prod Safety Res, Ctr Excellence Poultry Sci, Fayetteville, AR 72701 USA. RP Pantin-Jackwood, MJ (reprint author), Univ Georgia, Coll Vet Med, Dept Avian Med, Athens, GA 30602 USA. NR 41 TC 11 Z9 13 U1 1 U2 5 PU AMER ASSOC AVIAN PATHOLOGISTS PI ATHENS PA 953 COLLEGE STATION RD, ATHENS, GA 30602-4875 USA SN 0005-2086 J9 AVIAN DIS JI Avian Dis. PD APR-JUN PY 2004 VL 48 IS 2 BP 300 EP 316 DI 10.1637/7099 PG 17 WC Veterinary Sciences SC Veterinary Sciences GA 937IF UT WOS:000229917100009 PM 15283417 ER PT J AU Butts, CL Sternberg, EM AF Butts, CL Sternberg, EM TI Different approaches to understanding autoimmune rheumatic diseases: the neuroimmunoendocrine system SO BEST PRACTICE & RESEARCH IN CLINICAL RHEUMATOLOGY LA English DT Article DE neuroendocrine; hormones and immunity ID CENTRAL-NERVOUS-SYSTEM; LUPUS-ERYTHEMATOSUS; MULTIPLE-SCLEROSIS; GLUCOCORTICOID-RECEPTOR; T-CELL; NOD MICE; CLINICAL IMPLICATIONS; TRANSGENIC MICE; GENETIC-CONTROL; IMMUNE-SYSTEM AB Rheumatic autoimmune diseases are characterized by dysregulation of the immune response that leads to inflammation, pain, disease and stiffness and have been shown to have differences in disease pattern, depending on the gender and age of an individual. The majority of these conditions predominantly affect females of all species and also show increased severity of disease in female animal models. In addition to the gender differences in disease development, persons are often more susceptible at specific stages of life. This review will discuss some of the data indicating age and gender differences in development of these diseases and will review hormonal and other factors that may contribute to disease expression and severity. C1 NIMH, Bethesda, MD 20892 USA. RP Sternberg, EM (reprint author), NIMH, 2601A23,36 Convent Dr, Bethesda, MD 20892 USA. EM ems@codon.nih.gov NR 61 TC 12 Z9 13 U1 1 U2 2 PU BAILLIERE TINDALL PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1521-6942 J9 BEST PRACT RES CL RH JI Best Pract. Res. Clin. Rheumatol. PD APR PY 2004 VL 18 IS 2 BP 125 EP 139 DI 10.1016/j.berh.2004.02.002 PG 15 WC Rheumatology SC Rheumatology GA 825NM UT WOS:000221765200003 PM 15121035 ER PT J AU Radaeva, S Jaruga, B Kim, WH Heller, T Liang, TJ Gao, B AF Radaeva, S Jaruga, B Kim, WH Heller, T Liang, TJ Gao, B TI Interferon-gamma inhibits interferon-alpha signalling in hepatic cells: evidence for the involvement of STAT1 induction and hyperexpression of STAT1 in chronic hepatitis C SO BIOCHEMICAL JOURNAL LA English DT Article DE Hep3B; hepatitis; interferon (IFN); liver; signal transducers and activators of transcription factor (STAT) ID STIMULATED JAK/STAT PATHWAY; PRIMARY HUMAN HEPATOCYTES; NECROSIS-FACTOR-ALPHA; INTRAHEPATIC EXPRESSION; TARGETED DISRUPTION; ISGF3 COMPONENTS; VIRUS-INFECTION; MELANOMA-CELLS; RESISTANCE; RECEPTOR AB IFN-gamma (interferon-gamma) modulates IFN-alpha therapy in chronic hepatitis C infection: however, the underlying mechanism remains unclear. Here we demonstrate that long-term (3-6 days) but not short-term (up to 1 day) IFN-gamma treatment of human hepatoma Hep3B cells attenuates IFN-alpha activation of STAT1 (signal transducers and activators of transcription factor 1), STAT2 and STAT3. but enhances IFN-gamma and interleukin 6 activation of STATs. Prolonged exposure to IFN-gamma also significantly induces STAT1 protein expression without affecting,STAT2,STAT3 and ERK (extracellular-signal-regulated kinase) 1/2 protein expression. To determine the role of STAT1 protein overexpression ill regulation of IFN-alpha signalling, Hep3B cells were stably transfected with wild-type STAT1. Over-expression of STAT1 via stable transfection enhances IFN-gamma activation of STAT1, but surprisingly attenuates IFN-alpha activation of STAT1, STAT2 and STAT3 without affecting Janus kinase activation. This STAT1-mediated inhibition does not require STAT1 tyrosine phosphorylation because overexpression of dominant-negative STAT1 with a mutation on tyrosine residue 701 also blocks IFN-alpha activation of STAT1, STAT2 and STAT3. Moreover, overexpression of STAT1 blocks IFN-alpha-activated STAT2 translocation from IFN-alpha receptor 2 to IFN-alpha receptor 1, a critical step in IFN-alpha signalling activation. Finally, significantly higher levels of STAT1 protein expression, which is probably induced by IFN-gamma are detected in the majority of hepatitis C virus-infected livers compared with healthy controls. In conclusion, long-term IFN-gamma treatment inhibits IFN-alpha-activated signals most probably, at least in part, through the induction of STAT1 protein expression, which could partly contribute to IFN-alpha treatment failure in hepatitis C patients. C1 NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. NIDDKD, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. RP Gao, B (reprint author), NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, 12420 Parklawn Dr,MSC 8115, Bethesda, MD 20892 USA. EM bgao@mail.nih.gov NR 42 TC 29 Z9 30 U1 0 U2 1 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD APR 1 PY 2004 VL 379 BP 199 EP 208 DI 10.1042/BJ20031495 PN 1 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 814PL UT WOS:000220986500023 PM 14690454 ER PT J AU Barr, CS Newman, TK Shannon, C Parker, C Dvoskin, RL Becker, ML Schwandt, M Champoux, M Lesch, KP Goldman, D Suomi, SJ Higley, JD AF Barr, CS Newman, TK Shannon, C Parker, C Dvoskin, RL Becker, ML Schwandt, M Champoux, M Lesch, KP Goldman, D Suomi, SJ Higley, JD TI Rearing condition and rh5-HTTLPR interact to influence limbic-hypothalamic-pituitary-adrenal axis response to stress in infant macaques SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Nonhuman primate; serotonin transporter; stress; adrenocorticotropic hormone; cortisol; hypothalamic-pituitary-adrenal axis ID SEROTONIN TRANSPORTER GENE; CORTICOSTEROID RECEPTOR-BINDING; CSF MONOAMINE METABOLITE; NONHUMAN PRIMATE MODEL; ANXIETY-RELATED TRAITS; PROMOTER POLYMORPHISM; MAJOR DEPRESSION; EARLY EXPERIENCE; ALLOSTATIC LOAD; RHESUS-MONKEYS AB Background. In humans and macaques, a promoter polymorphism that decreases transcription of the serotonin transporter gene is associated with anxiety. Serotonin transporter gene disruption in rodents produces anxious animals with exaggerated limbic-hypothalamic-pituitary-adrenal (LHPA) responses to stress. We wanted to determine whether serotonin transporter gene promoter variation (rh-5HTTLPR) and rearing condition would interact to influence endocrine responses to stress in infant rhesus macaques. Methods: Animals were reared with their mothers (MR, n = 141) or in peer-only groups (PR, n = 67). At 6 months of age, adrenocorticotropic hormone (ACTH) and cortisol levels were determined at baseline and during separation stress. Serotonin transporter genotype (1/1 and 1/s) was determined with polymerase chain reaction followed by gel electrophoresis. Results: Cortisol levels increased during separation, and there was a mar. n effect of rearing condition, with decreased cortisol levels among PR macaques. Animals with 1/s rh5-HTTLPR genotypes bad higher ACTH levels than did 1/1 animals. Adrenocorticotropic hormone levels increased during separation, and there was a separation X rearing X rh5-HTTLPR interaction, such that PR4/s animals bad higher ACTH levels during separation than did other animals studied affects LHPA axis activity and that the influence Conclusions: These data demonstrate that serotonin transporter gene variation of rh5-HTTLPR on hormonal responses during stress is modulated by early experience. C1 NIAAA, Primate Unit, NIHAC, NIH,Lab Clin Studies, Poolesville, MD 20837 USA. NIAAA, NIH, Neurogenet Lab, Poolesville, MD 20837 USA. NICHHD, NIH, Poolesville, MD USA. Univ Wurzburg, Dept Clin & Mol Psychobiol, Dept Psychiat & Psychotherapy, Wurzburg, Germany. RP Barr, CS (reprint author), NIAAA, Primate Unit, NIHAC, NIH,Lab Clin Studies, POB 529, Poolesville, MD 20837 USA. RI Goldman, David/F-9772-2010; Schwandt, Melanie/L-9866-2016; Lesch, Klaus-Peter/J-4906-2013 OI Goldman, David/0000-0002-1724-5405; Lesch, Klaus-Peter/0000-0001-8348-153X NR 52 TC 253 Z9 255 U1 6 U2 22 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 1 PY 2004 VL 55 IS 7 BP 733 EP 738 DI 10.1016/j.biopsych.2003.12.008 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 806ON UT WOS:000220443300010 PM 15039002 ER PT J AU Yallampalli, C Kondapaka, SB Lanlua, P Wimalawansa, SJ Gangula, PRR AF Yallampalli, C Kondapaka, SB Lanlua, P Wimalawansa, SJ Gangula, PRR TI Female sex steroid hormones and pregnancy regulate receptors for calcitonin gene-related peptide in rat mesenteric arteries, but not in aorta SO BIOLOGY OF REPRODUCTION LA English DT Article DE estradiol; polypeptide receptors; pregnancy; progesterone; steroid hormones ID DEOXYCORTICOSTERONE-SALT HYPERTENSION; ESTER-INDUCED HYPERTENSION; INDUCED VASODILATION; CORONARY-ARTERIES; CGRP RECEPTOR; VAS-DEFERENS; NITRIC-OXIDE; SPINAL-CORD; K+ CHANNELS; UTERINE AB Calcitonin gene-related peptide (CGRP) is a potent vasodilator neuropeptide known to be involved in the regulation of vascular tone. Results of previous studies from our laboratory and others suggest that vascular sensitivity to CGRP is enhanced during pregnancy and that the female sex steroid hormones estradiol-17beta (E-2) and progesterone (P-4) may be involved in this process. We hypothesized that CGRP receptors in the mesenteric artery are increased during pregnancy and with sex steroid hormone treatments. In the present study, we investigated whether pregnancy and female sex steroid hormones modulate the CGRP-receptors CGRP-A and CGRP-B in the mesenteric artery in the rat. The CGRP-A receptor consists of calcitonin receptor-like receptor (CRLR) and receptor activity-modifying protein 1 (RAMP(1)); however, the CGRP-B receptor needs to be further characterized. Messenger RNA levels for CRLR and RAMP, were assessed by reverse transcription-polymerase chain reaction, and CGRP-B receptor proteins levels were determined by Western blot analysis. In addition, [I-125]CGRP binding was measured by Scatchard analysis. Both mRNA for CGRP-A (CRLR and RAMP(1)) and the protein for CGRP-B receptors in mesenteric arteries were increased with pregnancy compared to nonpregnant, diestrous animals. A P-4 antagonist, RU-486, downregulated and P-4 upregulated these receptors in mesenteric arteries (P < 0.05) in pregnant rats. In adult ovariectomized rats, P-4 upregulated CRLR and RAMP, mRNA levels as well as [I-125]CGRP-binding sites. The CGRP-B-receptor protein levels were significantly (P < 0.05) elevated by P-4 and by combined E-2 and P-4 treatment. Together with earlier findings, these data suggest that increases in the expression of CGRP-A (CRLR and RAMP(1)) and CGRP-B receptors in mesenteric arteries may be important in reducing vascular resistance and in vascular adaptations that occur during pregnancy; in addition, P-4 may be involved in this process. C1 Univ Texas, Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. NCI, Div Canc Treatment & Diagnosis, NIH, Bethesda, MD 20892 USA. Mahidol Univ, Dept Anat, Nakhon Pathom 73170, Thailand. Univ Med & Dent New Jersey, Dept Endocrinol Metab & Nutr, New Brunswick, NJ 08903 USA. RP Yallampalli, C (reprint author), Univ Texas, Med Branch, Dept Obstet & Gynecol, 301 Univ Blvd,Med Res Bldg,Rm 11 138, Galveston, TX 77555 USA. EM chyallam@utmb.edu OI Wimalawansa, Prof. Sunil/0000-0003-1096-8595 FU NHLBI NIH HHS [HL 58144, HL72650]; NICHD NIH HHS [HD40828] NR 38 TC 22 Z9 23 U1 0 U2 2 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD APR PY 2004 VL 70 IS 4 BP 1055 EP 1062 DI 10.1095/biolreprod.103.022467 PG 8 WC Reproductive Biology SC Reproductive Biology GA 806OU UT WOS:000220444000023 PM 14668209 ER PT J AU Wu, XW Brooks, BR AF Wu, XW Brooks, BR TI beta-hairpin folding mechanism of a nine-residue peptide revealed from molecular dynamics simulations in explicit water SO BIOPHYSICAL JOURNAL LA English DT Article ID FREE-ENERGY LANDSCAPE; AQUEOUS-SOLUTION; FORCE-FIELD; PROTEIN-G; MODEL; THERMODYNAMICS; CONFORMATIONS; FRAGMENT; SOLVENT; HELIX AB The beta-hairpin fold mechanism of a nine-residue peptide, which is modified from the beta-hairpin of alpha-amylase inhibitor tendamistat (residues 15-23), is studied through direct folding simulations in explicit water at native folding conditions. Three 300-nanosecond self-guided molecular dynamics (SGMD) simulations have revealed a series of beta-hairpin folding events. During these simulations, the peptide folds repeatedly into a major cluster of beta-hairpin structures, which agree well with nuclear magnetic resonance experimental observations. This major cluster is found to have the minimum conformational free energy among all sampled conformations. This peptide also folds into many other beta-hairpin structures, which represent some local free energy minimum states. In the unfolded state, the N-terminal residues of the peptide, Tyr-1, Gln-2, and Asn-3, have a confined conformational distribution. This confinement makes beta-hairpin the only energetically favored structure to fold. The unfolded state of this peptide is populated with conformations with non-native intrapeptide interactions. This peptide goes through fully hydrated conformations to eliminate non-native interactions before folding into a beta-hairpin. The folding of a beta-hairpin starts with side-chain interactions, which bring two strands together to form interstrand hydrogen bonds. The unfolding of the beta-hairpin is not simply the reverse of the folding process. Comparing unfolding simulations using MD and SGMD methods demonstrate that SGMD simulations can qualitatively reproduce the kinetics of the peptide system. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Wu, XW (reprint author), NHLBI, Biophys Chem Lab, NIH, Bldg 50,Rm 3308,50 South Dr, Bethesda, MD 20892 USA. EM wuxw@nhlbi.nih.gov NR 32 TC 32 Z9 33 U1 2 U2 8 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD APR PY 2004 VL 86 IS 4 BP 1946 EP 1958 PG 13 WC Biophysics SC Biophysics GA 808KI UT WOS:000220567600005 PM 15041639 ER PT J AU Maltsev, VA Vinogradova, TM Bogdanov, KY Lakatta, EG Stern, MD AF Maltsev, VA Vinogradova, TM Bogdanov, KY Lakatta, EG Stern, MD TI Diastolic calcium release controls the beating rate of rabbit sinoatrial node cells: Numerical modeling of the coupling process SO BIOPHYSICAL JOURNAL LA English DT Article ID RETICULUM CA2+ RELEASE; SARCOPLASMIC-RETICULUM; RYANODINE RECEPTORS; PACEMAKER ACTIVITY; CARDIAC-MUSCLE; SPARKS; FLUO-3 AB Recent studies employing Ca2+ indicators and confocal microscopy demonstrate substantial local Ca2+ release beneath the cell plasma membrane (subspace) of sinoatrial node cells (SANCs) occurring during diastolic depolarization. Pharmacological and biophysical experiments have suggested that the released Ca2+ interacts with the plasma membrane via the ion current (I-NaCa) produced by the Na+/Ca2+ exchanger and constitutes an important determinant of the pacemaker rate. This study provides a numerical validation of the functional importance of diastolic Ca2+ release for rate control. The subspace Ca2+ signals in rabbit SANCs were measured by laser confocal microscopy, averaged, and calibrated. The time course of the subspace [Ca2+] displayed both diastolic and systolic components. The diastolic component was mainly due to the local Ca2+ releases; it was numerically approximated and incorporated into a SANC cellular electrophysiology model. The model predicts that the diastolic Ca2+ release strongly interacts with plasma membrane via I-NaCa and thus controls the phase of the action potential upstroke and ultimately the final action potential rate. C1 NIA, Gerontol Res Ctr, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Stern, MD (reprint author), NIA, Gerontol Res Ctr, Intramural Res Program, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM stemm@grc.nia.nih.gov NR 24 TC 49 Z9 50 U1 0 U2 4 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD APR PY 2004 VL 86 IS 4 BP 2596 EP 2605 PG 10 WC Biophysics SC Biophysics GA 808KI UT WOS:000220567600061 PM 15041695 ER PT J AU Katano, H Afione, S Schmidt, M Chiorini, JA AF Katano, H Afione, S Schmidt, M Chiorini, JA TI Identification of adeno-associated virus contamination in cell and virus stocks by PCR SO BIOTECHNIQUES LA English DT Article ID BOVINE PAPILLOMAVIRUS; DNA-REPLICATION; GENE-THERAPY; REP GENE; INHIBITION; TRANSDUCTION; ADENOVIRUS; TRANSFORMATION; SPECIFICITY; EFFICIENT AB To further understand the biology of adeno-associated virus (AAV) and identify the presence of AAV in laboratory samples, we have developed a sensitive PCR-based assay using degenerate primers based on the sequence of seven diverse AAV isolates. Using these primers, we can detect free virus in viral stocks, cleared cell lysate, as well as in latently infected cells. The method can detect as little as 10 viral copies/muL of sample and can be adapted for high-throughput screening technology. With this method, we have also detected a new AAV isolate from a stock of bovine adenovirus. C1 NIH, Bethesda, MD 20892 USA. RP Chiorini, JA (reprint author), NIH, 10-1N113,10 Ctr Dr,MSC 1190, Bethesda, MD 20892 USA. EM jchiorini@dir.nidcr.nih.gov NR 23 TC 7 Z9 7 U1 1 U2 1 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD APR PY 2004 VL 36 IS 4 BP 676 EP + PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 811VC UT WOS:000220798400016 PM 15088385 ER PT J AU Tsang, S Sun, ZH Stewart, C Lum, N Frankenberger, C Subleski, M Rasmussen, L Munroe, DJ AF Tsang, S Sun, ZH Stewart, C Lum, N Frankenberger, C Subleski, M Rasmussen, L Munroe, DJ TI Development of multiplex DNA electronic microarrays using a universal adaptor system for detection of single nucleotide polymorphisms SO BIOTECHNIQUES LA English DT Article ID MICROELECTRONIC CHIP ARRAY; HYBRIDIZATION; AMPLIFICATION; MICROCHIPS; DEVICES AB The NanoChip(R) electronic microarray is designed for the rapid detection of genetic variation in research and clinical diagnosis. We have developed a multiplex electronic microarray assay, specific for single nucleotide polymorphism (SNP) genotyping and mutation detection, using universal adaptor sequences tailed to the 5' end of PCR primers specific to each target. PCR products, amplified by primers directed to the universal adaptor sequence, are immobilized on the microarray either directly or via capture oligonucleotides complementary to the universal adaptor sequence. This simple modification results in a significant increase infidelity with improved specificity and accuracy. In addition, the multiplexing of genetic variant detection allows increased throughput and significantly reduced cost per assay. This general schema can also be applied to other microarray and macroarray formats. C1 Natl Canc Inst, SAIC Frederick, Frederick, MD USA. RP Tsang, S (reprint author), Lab Mol Technol, 915 Toll House Ave,Suite 211, Frederick, MD 21702 USA. EM shirleytsang@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 16 TC 3 Z9 4 U1 0 U2 2 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD APR PY 2004 VL 36 IS 4 BP 682 EP 688 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 811VC UT WOS:000220798400017 PM 15088386 ER PT J AU Jackson, LW Correa-Villasenor, A Lees, PSJ Dominici, F Stewart, PA Breysse, PN Matanoski, G AF Jackson, LW Correa-Villasenor, A Lees, PSJ Dominici, F Stewart, PA Breysse, PN Matanoski, G TI Parental lead exposure and total anomalous pulmonary venous return SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Article DE congenital heart defects; lead; occupational exposure ID LOW-BIRTH-WEIGHT; CONGENITAL HEART-DISEASE; OCCUPATIONAL EXPOSURES; SPONTANEOUS-ABORTION; SEMEN QUALITY; MALE-FERTILITY; SPERM COUNT; MEN; WORKERS; RISK AB Investigators from the Baltimore-Washington Infant Study (BWIS) reported an association between self-reported maternal lead exposure and total anomalous pulmonary venous return (TAPVR) in their offspring. This association was further evaluated in the BWIS population using a more sensitive exposure estimate. METHODS: Cases included 54 live-born infants with TAPVR; controls were a stratified random sample of 522 live-born infants from the BWIS control group. Parental lead exposure was based on three assessment methods, including: an industrial hygiene assessment, an a priori job exposure matrix, and self-reported exposures. A parent was classified as exposed to lead if he/she was classified as exposed by any one of the assessment methods. RESULTS: Approximately 17% of case mothers and 11% of control mothers were classified as exposed to lead during the three months prior to conception through the first trimester (odds ratio [OR], 1.57; 95% confidence interval [CI], 0.64-3.47). Among fathers, 61% of case fathers and 46% of control fathers were classified as exposed to lead during the six months prior to conception (paternal critical period) (OR, 1.83; 95% Cl, 1.00-3.42). During the paternal critical period, when only the father was exposed compared to neither parent exposed, the OR for any lead exposure and TAPVR was 1.65 (95% Cl, 0.84-3.25). CONCLUSIONS: This study supports a possible association between paternal lead exposure and TAPVR. Further studies are warranted using validated assessment methods for occupational and nonoccupational lead exposures to corroborate this association and to elucidate the possible biological mechanism. (C) 2004 Wiley-Liss, Inc. C1 NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. CDCP, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, Rockville, MD USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Jackson, LW (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, NIH, 6100 Executive Blvd,Room 7B03, Rockville, MD 20852 USA. EM jacksole@mail.nih.gov FU NIEHS NIH HHS [R29-ES06218] NR 54 TC 18 Z9 19 U1 2 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1542-0752 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD APR PY 2004 VL 70 IS 4 BP 185 EP 193 DI 10.1002/bdra.20014 PG 9 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 817JZ UT WOS:000221175100005 PM 15108245 ER PT J AU Jahnke, GD Price, CJ Marr, MC Myers, CB George, JD AF Jahnke, GD Price, CJ Marr, MC Myers, CB George, JD TI Developmental toxicity evaluation of emodin in rats and mice SO BIRTH DEFECTS RESEARCH PART B-DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY LA English DT Article DE emodin; development; birth defects; rats; mice; pregnancy; herbal remedy ID ANESTHESIA AB BACKGROUND: Emodin, a widely available herbal remedy, was evaluated for potential effects on pregnancy outcome. METHODS: Emodin was administered in feed to timed-mated Sprague-Dawley (CD) rats (0, 425, 850, and 1700 ppm; gestational day [GD] 6-20), and Swiss Albino (CD-1) mice (0, 600, 2500 or 6000 ppm; GD 6-17). Ingested dose was 0, 31, 57, and similar to 80-144 mg emodin/kg/day (rats) and 0, 94, 391, and 1005 mg emodin/kg/day (mice). Timed-mated animals (23-25/group) were monitored for body weight, feed/water consumption, and clinical signs. At termination (rats: GD 20 ; mice: GD 17), confirmed pregnant dams (21-25/group) were evaluated for clinical signs: body, liver, kidney, and gravid uterine weights, uterine contents, and number of corpora lutea. Fetuses were weighed, sexed, and examined for external, visceral, and skeletal malformations /variations. RESULTS: There were no maternal deaths. In rats, maternal body weight, weight gain during treatment, and corrected weight gain exhibited a decreasing trend. Maternal body weight gain during treatment was significantly reduced at the high dose. In mice, maternal body weight and weight gain was decreased at the high dose. CONCLUSIONS: Prenatal mortality, live litter size, fetalsex ratio, and morphological development were unaffected in both rats and mice. At the high dose, rat average fetal body weight per litter was unaffected, but was significantly reduced in mice. The rat maternal lowest observed;adverse effect level (LOAEL) was 1700 ppm; the no observed adverse effect level (NOAEL) was 850 ppm. The rat developmental toxicity NOAEL was greater than or equal to 1700ppm. A LOAEL was not established. In mice, the maternal toxicity LOAEL was 6000ppm and the NOAEL was 2500ppm. The developmental toxicity LOAEL was 6000ppm (reduced fetal body weight) and the NOAEL was 2500 ppm. (C) 2004 Wiley-Liss, Inc. C1 Sci Int Inc, Alexandria, VA USA. RTI Int, Res Triangle Pk, NC USA. RP Jahnke, GD (reprint author), NIEHS, MC EC-32,POB 12233,Alexander Dr, Res Triangle Pk, NC 27709 USA. EM jahnke@niehs.nih.gov FU NIEHS NIH HHS [N01-ES-65405] NR 44 TC 16 Z9 17 U1 1 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1542-9733 J9 BIRTH DEFECTS RES B JI Birth Defects Res. Part B-Dev. Reprod. Toxicol. PD APR PY 2004 VL 71 IS 2 BP 89 EP 101 DI 10.1002/bdrb.20002 PG 13 WC Oncology; Genetics & Heredity; Toxicology SC Oncology; Genetics & Heredity; Toxicology GA 819LB UT WOS:000221315300004 PM 15098202 ER PT J AU Sierra, MD Yang, FQ Narazaki, M Salvucci, O Davis, D Yarchoan, R Zhang, HWH Fales, H Tosato, G AF Sierra, MD Yang, FQ Narazaki, M Salvucci, O Davis, D Yarchoan, R Zhang, HWH Fales, H Tosato, G TI Differential processing of strornal-derived factor-1 alpha and strornal-derived factor-1 beta explains functional diversity SO BLOOD LA English DT Article ID CHEMOKINE RECEPTOR CXCR4; CD26/DIPEPTIDYL PEPTIDASE-IV; STEM-CELL MOBILIZATION; BONE-MARROW; LYMPHOCYTE CHEMOATTRACTANT; CHROMOSOMAL LOCALIZATION; MOLECULAR-CLONING; ARMILLARIA-MELLEA; B-LYMPHOPOIESIS; HIV-1 ENTRY AB The chemokine stromal-derived factor-1 (SDF-1), which is constitutively expressed in most tissues as SDF-1alpha and SDF-1beta resulting from alternative gene splicing, regulates hematopoiesis, lymphocyte homing, B-lineage cell growth, and angiogenesis. Because SDIF-1alpha and SDF-1beta are constitutively and ubiquitously expressed, their degradation must serve an important regulatory role. Here we show that SDF-1alpha and SDF-1beta are secreted as full-length molecules. When exposed to human serum, full-length SDF-1alpha (1-68) undergoes processing first at the COOH terminus to produce SDF-1alpha 1-67 and then at the NH2 terminus to produce SDF-1alpha 3-67. By contrast, full-length SDF-1beta (1-72) Is processed only at the NH2 terminus to produce SDF-1beta 3-72. CD26/dipeptidyl peptidase is responsible for serum cleavage of SDF-1alpha and SDF-1beta at the NH2 terminus. Serum processing of SDF-1alpha at the COOH terminus, which has not been previously reported, reduces the ability of the polypeptide to bind to heparin and to cells and to stimulate B-cell proliferation and chemotaxis. The additional processing at the NH2 terminus renders both forms of SDF-1 unable to bind to heparin and to activate cells. The differential processing of SDF-1alpha and SDF-1beta provides biologic significance to the existence of 2 splice forms of the chemokine and adds a tool to precisely regulate SDF-1's biologic activity by changes in specific activity. (C) 2004 by The American Society of Hematology. C1 NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, HIV, NIH, Bethesda, MD 20892 USA. NCI, AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD USA. NIAID, Clin Invest Lab, NIH, Bethesda, MD USA. RP Tosato, G (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, Bldg 10,Rm 12N226,MSC 1907, Bethesda, MD 20892 USA. EM tosatog@mail.nih.gov NR 48 TC 89 Z9 91 U1 1 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD APR 1 PY 2004 VL 103 IS 7 BP 2452 EP 2459 PG 8 WC Hematology SC Hematology GA 830ZR UT WOS:000222163200012 ER PT J AU Shimizu, R Ohneda, K Engel, JD Trainor, CD Yamamoto, M AF Shimizu, R Ohneda, K Engel, JD Trainor, CD Yamamoto, M TI Transgenic rescue of GATA-1-deficient mice with GATA-1 lacking a FOG-1 association site phenocopies patients with X-linked thrombocytopenia SO BLOOD LA English DT Article ID TRANSCRIPTION FACTOR GATA-1; PROTEIN-PROTEIN INTERACTION; ZINC-FINGER PROTEIN; DNA-BINDING; GENE-EXPRESSION; ERYTHROID LINEAGE; IN-VIVO; DIFFERENTIATION; COFACTOR; MUTATION AB Association of GATA-1 and its cofactor Friend of GATA-1 (FOG-1) is essential for erythroid and megakaryocyte development. To assess functions of GATA-1-FOG-1 association during mouse development, we used the GATA-1 hematopoietic regulatory domain to generate transgenic mouse lines expressing a mutant GATA-1, which contains a substitution of glycine 205 for valine (V205G) that abrogates its association with FOG-1. We examined whether the transgenic expression of mutant GATA-1 rescues GATA-1 germ line mutants from embryonic lethality. In high-expressor lines we observed that the GATA-1(V205G) rescues GATA-1-deficient mice from embryonic lethality at the expected frequency, revealing that excess GATA-1V205G can eliminate the lethal anemia that is due to GATA-1 deficiency. In contrast, transgene expression comparable to the endogenous GATA-1 level resulted in much lower frequency of rescue, indicating that the GATA-1-FOG-1 association is critical for normal embryonic hematopoiesis. Rescued mice in these analyses exhibit thrombocytopenia and display dysregulated proliferation and impaired cytoplasmic maturation of megakaryocytes. Although anemia is not observed under steady-state conditions, stress erythropoiesis is attenuated in the rescued mice. Our findings reveal an indispensable role for the association of GATA-1 and FOG-1 during late-stage megakaryopoiesis and provide a unique model for X-linked thrombocytopenia with inherited GATA-1 mutation. (C) 2004 by The American Society of Hematology. C1 Univ Tsukuba, Ctr TARA, Tsukuba, Ibaraki 3058577, Japan. Univ Tsukuba, Inst Basic Med Sci, Tsukuba, Ibaraki 3058577, Japan. Univ Tsukuba, Japan Sci & Technol Corp, Yamamoto Environm Response Project ERATO, Tsukuba, Ibaraki 3058577, Japan. Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. RP Yamamoto, M (reprint author), Univ Tsukuba, Ctr TARA, 1-1-1 Tennoudai, Tsukuba, Ibaraki 3058577, Japan. EM masi@tara.tsukuba.ac.jp RI Yamamoto, Masayuki/A-4873-2010 NR 37 TC 34 Z9 34 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 APR 1 PY 2004 VL 103 IS 7 BP 2560 EP 2567 DI 10.1182/blood-2003-07-2514 PG 8 WC Hematology SC Hematology GA 830ZR UT WOS:000222163200026 PM 14656885 ER PT J AU Decker, T Oelsner, M Kreitman, RJ Salvatore, G Wang, QC Pastan, I Peschel, C Licht, T AF Decker, T Oelsner, M Kreitman, RJ Salvatore, G Wang, QC Pastan, I Peschel, C Licht, T TI Induction of caspase-dependent programmed cell death in B-cell chronic lymphocytic leukemia by anti-CD22 immunotoxins SO BLOOD LA English DT Article ID STABILIZED FV FRAGMENT; DRUG-INDUCED APOPTOSIS; NON-HODGKINS-LYMPHOMA; RECOMBINANT IMMUNOTOXIN; CYTOTOXIC ACTIVITY; PSEUDOMONAS EXOTOXIN; CLL CELLS; HEMATOLOGIC MALIGNANCIES; CANCER-CELLS; IN-VITRO AB B cells of chronic lymphocytic leukemia (CLL) are long-lived in vivo, possibly because of defects in apoptosis. We investigated BL22, an immunotoxin composed of the Fv portion of anti-CD22 antibody fused to a 38-kDa Pseudomonas exotoxin-A fragment. B cells from 22 patients with CLL were immunomagnetically enriched (96% purity) and were cultured with BL22 or an immunotoxin that does not recognize hematopoietic cells. The antileukemic activity of BL22 was correlated with CD22 expression, as determined by flow cytometry. BL22 induced caspase-9 and caspase-3 activation, poly(adenosine diphosphate [ADP]ribose)polymerase (PARP) cleavage, DNA fragmentation, and membrane flipping. Cell death was associated with the loss of mitochondrial membrane potential and the down-regulation of Mcl-1 and X-chromosomal inhibitor of apoptosis protein (XIAP). Furthermore, BL22 induced a proapoptotic 18-kDa Bax protein and conformational changes of Bax. Z-VAD.fmk abrogated apoptosis, confirming that cell death was executed by caspases. Conversely, Interleukin-4, a survival factor, inhibited spontaneous death in culture but failed to prevent immuno-toxin-induced apoptosis. BL22 cytotoxicity was markedly enhanced when combined with anticancer drugs including vincristine. We also investigated HA22, a newly engineered immunotoxin, in which BL22 residues are mutated to improve target binding. HA22 was more active than BL22. In conclusion, these immunotoxins induce caspase-mediated apoptosis involving mitochondrial damage. Combination with chemotherapy is expected to improve the efficacy of immunotoxin treatment. (C) 2004 by The American Society of Hematology. C1 Tech Univ Munich, Klinikum Rechts Isar, Med Klin 3, D-81675 Munich, Germany. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Decker, T (reprint author), Tech Univ Munich, Klinikum Rechts Isar, Med Klin 3, Ismaninger Str 22, D-81675 Munich, Germany. EM t.decker@lrz.tu-muenchen.de NR 60 TC 48 Z9 52 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 APR 1 PY 2004 VL 103 IS 7 BP 2718 EP 2726 DI 10.1182/blood-2003-04-1317 PG 9 WC Hematology SC Hematology GA 830ZR UT WOS:000222163200049 PM 14525789 ER PT J AU Goldfarb, LG Vicart, P Goebel, HH Dalakas, MC AF Goldfarb, LG Vicart, P Goebel, HH Dalakas, MC TI Desmin myopathy SO BRAIN LA English DT Review DE alpha B-crystallin; cardiomyopathy; desmin; desmin myopathy; desmin-related myopathy; myofibrillar myopathy ID ALPHA-B-CRYSTALLIN; MICE LACKING DESMIN; DOMINANT DISTAL MYOPATHY; HELICAL COILED COILS; HEAT-SHOCK PROTEINS; MYOFIBRILLAR MYOPATHY; INTERMEDIATE-FILAMENTS; SKELETAL MYOPATHY; FAMILIAL CARDIOMYOPATHY; ELECTRON-MICROSCOPY AB Desmin myopathy is a recently identified disease associated with mutations in desmin or alphaB-crystallin. Typically, the illness presents with lower limb muscle weakness slowly spreading to involve truncal, neck-flexor, facial, bulbar and respiratory muscles. Skeletal myopathy is often combined with cardiomyopathy manifested by conduction blocks and arrhythmias resulting in premature sudden death. Sections of the affected skeletal and cardiac muscles show abnormal fibre areas containing amorphous eosinophilic deposits seen as granular or granulofilamentous material on electron microscopic examination. Immuno-staining for desmin is positive in each region containing abnormal structures. The inheritance pattern in familial desmin myopathy is autosomal dominant or autosomal recessive, but many cases have no family history. At least some, and probably most, non-familial desmin myopathy cases are associated with de novo desmin mutations. Age of disease onset and rate of progression may vary depending on the type of inheritance and location of the causative mutation. Multiple mutations have been identified in the desmin gene: point substitutions, insertion, small in-frame deletions and a larger exon-skipping deletion. The majority of these mutations are located in conserved alpha-helical segments of desmin. Many of the missense mutations result in changing the original amino acid into proline, which is known as a helix breaker. Studies of transfected cell cultures indicate that mutant desmin is assembly-incompetent and able to disrupt a pre-existing filamentous network in dominant-negative fashion. Disease-associated desmin mutations in humans or transgenic mice cause accumulation of chimeric intracellular aggregates containing desmin and other cytoskeletal proteins. alphaB-crystallin serves in the muscle as a chaperone preventing desmin aggregation under various forms of stress. If mutated, alphaB-crystallin may cause a myopathy similar to those resulting from desmin mutations. Routine genetic testing of patients for mutations in desmin and alphaB- crystallin genes is now available and necessary for establishing an accurate diagnosis and providing appropriate genetic counselling. Better understanding of disease pathogenesis would stimulate research focused on developing specific treatments for these conditions. C1 NINDS, NIH, Bethesda, MD 20892 USA. Univ Paris 06, CNRS, UMR 7000, Lab Cytosquelette & Dev, Paris, France. Univ Mainz, Med Ctr, Dept Neuropathol, D-6500 Mainz, Germany. RP Goldfarb, LG (reprint author), NINDS, NIH, Bldg 10,Room 4B37,10 Ctr Dr,MSC 1361, Bethesda, MD 20892 USA. EM goldfarbl@ninds.nih.gov NR 87 TC 138 Z9 149 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD APR PY 2004 VL 127 BP 723 EP 734 DI 10.1093/brain/awh033 PN 4 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 807ET UT WOS:000220485500006 PM 14724127 ER PT J AU Fridman, EA Hanakawa, T Chung, M Hummel, F Leiguarda, RC Cohen, LG AF Fridman, EA Hanakawa, T Chung, M Hummel, F Leiguarda, RC Cohen, LG TI Reorganization of the human ipsilesional premotor cortex after stroke SO BRAIN LA English DT Article DE stroke; motor cortex; rehabilitation; pre-motor cortex; reaction time ID TRANSCRANIAL MAGNETIC STIMULATION; SIMPLE REACTION-TIME; MOTOR HAND AREA; POSTERIOR PARIETAL CORTEX; MOVEMENT-RELATED ACTIVITY; SILENT PERIOD; HUMAN BRAIN; FUNCTIONAL REORGANIZATION; CORTICOSPINAL PROJECTIONS; SOMATOSENSORY STIMULI AB The substrates that mediate recovery of motor function after stroke are incompletely understood. Several primate and human studies proposed the involvement of the premotor cortex of the lesioned hemisphere. Here, we studied four chronic stroke patients with focal subcortical lesions affecting the corticospinal outflow originating in the primary motor cortex (M1) and good motor recovery. We tested the hypothesis that, in these patients, disruption of activity in the premotor cortex of the lesioned hemisphere by transcranial magnetic stimulation (TMS) would result in degraded behaviour in the paretic hand. TMS was applied to the primary motor cortex, dorsal premotor cortex (PMd) and ventral premotor cortex (PMv) of the affected (M1(AH), PMdAH, PMv(AH)) and intact (M1(IH), PMdIH, PMv(IH)) hemispheres of patients and healthy controls in the setting of a simple reaction time (SRT) paradigm performed with the hand contralateral to the stimulated hemisphere. TMS applied to M1 led to substantial contralateral SRT delays in both groups. TMS applied to PMdAH of patients elicited clear delays in contralateral SRT in the paretic hand, whereas TMS applied to PMdIH of patients or healthy volunteers did not. Motor evoked potentials after stimulation of PMdAH were, on average, larger and had, on average, shorter latency than after stimulation of M1(AH). These results indicate that PMdAH participates as a substrate mediating functional recovery of executive motor function in patients with focal lesions of corticospinal outflow originating in M1 and good motor recovery. Our results are consistent with the hypothesis that the dorsal premotor cortex of the affected hemisphere can reorganize to control basic parameters of movement usually assigned to M1 function. C1 NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. FLENI, Dept Neurol, Buenos Aires, DF, Argentina. Kyoto Univ, Grad Sch Med, Human Brain Res Ctr, Kyoto, Japan. RP Cohen, LG (reprint author), NINDS, Human Cort Physiol Sect, NIH, Bldg 10,Room 5N226,10 Ctr Dr,MSC-1430, Bethesda, MD 20892 USA. EM CohenL@ninds.nih.gov OI Fridman, Esteban/0000-0001-7879-8874 NR 87 TC 249 Z9 254 U1 1 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD APR PY 2004 VL 127 BP 747 EP 758 DI 10.1093/brain/awh082 PN 4 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 807ET UT WOS:000220485500008 PM 14749291 ER PT J AU Singleton, A Gwinn-Hardy, K Sharabi, Y Li, ST Holmes, C Dendi, R Hardy, J Singleton, A Crawley, A Goldstein, DS AF Singleton, A Gwinn-Hardy, K Sharabi, Y Li, ST Holmes, C Dendi, R Hardy, J Singleton, A Crawley, A Goldstein, DS TI Association between cardiac denervation and parkinsonism caused by alpha-synuclein gene triplication SO BRAIN LA English DT Article DE fluorodopamine; norepinephrine; orthostatic hypotension; alpha-synuclein; baroreflex ID SYMPATHETIC NEUROCIRCULATORY FAILURE; AUTONOMIC DYSFUNCTION; DISEASE; 6-FLUORODOPAMINE; DISORDERS AB Parkinson's disease patients frequently have symptoms and signs of autonomic nervous dysfunction that are the source of considerable disability. Recent studies have revealed that most patients with Parkinson's disease, and all with Parkinson's disease-associated orthostatic hypotension, have a loss of cardiac sympathetic innervation. Familial Parkinson's disease, caused by mutation of the gene encoding alpha-synuclein, also features orthostatic hypotension, sympathetic neurocirculatory failure and cardiac sympathetic denervation. We have recently described a whole-gene triplication of alpha-synuclein causing Lewy body parkinsonism in a large, well characterized family called the 'Iowa kindred'. Here we report the results of cardiac PET scanning using the sympathoneural imaging agent, 6-[F-18]fluorodopamine in affected and unaffected members of this kindred. Four family members were studied, two with parkinsonism, one clinically normal and one with benign essential tremor alone. Both affected members had obvious loss of cardiac sympathetic innervation; the unaffected member had normal innervation, as did the member with isolated essential tremor. The results indicate that, in this family, where disease is caused by overexpression of normal alpha-synuclein, cardiac sympathetic denervation cosegregates with parkinsonism. Post-mortem studies have demonstrated synuclein-positive Lewy body formation in the brains of individuals with parkinsonism who were also in the family described here and who also carry this triplication. These results indicate that both parkinsonism and cardiac sympathetic denervation can result from an excess of normal synuclein. C1 NINDS, Parkinsons Unit, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Gwinn-Hardy, K (reprint author), 6001 Execut Blvd,NSC 2142, Bethesda, MD 20892 USA. EM gwinnk@ninds.nih.gov; gwinnk@ninds.nih.gov RI Gwinn, Katrina/C-2508-2009; Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; OI Gwinn, Katrina/0000-0002-8277-651X NR 17 TC 73 Z9 74 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD APR PY 2004 VL 127 BP 768 EP 772 DI 10.1093/brain/awh081 PN 4 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 807ET UT WOS:000220485500010 PM 14736756 ER PT J AU Goel, V Shuren, J Sheesley, L Grafman, J AF Goel, V Shuren, J Sheesley, L Grafman, J TI Asymmetrical involvement of frontal lobes in social reasoning SO BRAIN LA English DT Article DE reasoning; frontal lobes; Wason selection task; social knowledge ID WASON SELECTION TASK; HUMAN PREFRONTAL CORTEX; BRAIN; EXPERIENCE; MINDS; LOGIC AB The frontal lobes are widely implicated in logical reasoning. Recent neuroimaging studies suggest that frontal lobe involvement in reasoning is asymmetric (L>R) and increases with the presence of familiar, meaningful content in the reasoning situation. However, neuroimaging data can only provide sufficiency criteria. To determine the necessity of prefrontal involvement in logical reasoning, we tested 19 patients with focal frontal lobe lesions and 19 age- and education-matched normal controls on the Wason Card Selection Task, while manipulating social knowledge. Patients and controls performed equivalently on the arbitrary rule condition. Normal controls showed the expected improvement in the social knowledge conditions, but frontal lobe patients failed to show this facilitation in performance. Furthermore, left hemisphere patients were more affected than right hemisphere patients, suggesting that frontal lobe involvement in reasoning is asymmetric (L>R) and necessary for reasoning about social situations. C1 York Univ, Dept Psychol, Toronto, ON M3J 1P3, Canada. NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. US FDA, Off Policy, Rockville, MD 20857 USA. RP Goel, V (reprint author), York Univ, Dept Psychol, Toronto, ON M3J 1P3, Canada. EM vgoel@yorku.ca OI Grafman, Jordan H./0000-0001-8645-4457 NR 39 TC 28 Z9 32 U1 4 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD APR PY 2004 VL 127 BP 783 EP 790 DI 10.1093/brain/awh086 PN 4 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 807ET UT WOS:000220485500012 PM 14976069 ER PT J AU Teipel, SJ Alexander, GE Schapiro, MB Moller, HJ Rapoport, SI Hampel, H AF Teipel, SJ Alexander, GE Schapiro, MB Moller, HJ Rapoport, SI Hampel, H TI Age-related cortical grey matter reductions in non-demented Down's syndrome adults determined by MRI with voxel-based morphometry SO BRAIN LA English DT Article DE Alzheimer's disease; Down's syndrome; grey matter; neocortex; neurodegeneration ID CEREBRAL GLUCOSE-UTILIZATION; POSITRON-EMISSION-TOMOGRAPHY; ALZHEIMERS-DISEASE; CORPUS-CALLOSUM; NEUROFIBRILLARY TANGLES; COGNITIVE FUNCTION; ENTORHINAL CORTEX; REGIONAL-ANALYSIS; HUMAN BRAINS; MIDDLE-AGE AB Ageing in Down's syndrome is accompanied by amyloid and neurofibrillary pathology the distribution of which replicates pathological features of Alzheimer's disease. With advancing age, an increasing proportion of Down's syndrome subjects >40 years old develop progressive cognitive impairment, resembling the cognitive profile of Alzheimer's disease. Based on these findings, Down's syndrome has been proposed as a model to study the predementia stages of Alzheimer's disease. Using an interactive anatomical segmentation technique and volume-of-interest measurements of MRI, we showed recently that non-demented Down's syndrome adults had significantly reduced hippocampus, entorhinal cortex and corpus callosum sizes with increasing age. In this study, we applied the automated and objective technique of voxel-based morphometry, implemented in SPM99, to the analysis of structural MRI from 27 non-demented Down's syndrome adults (mean age 41.1 years, 15 female). Regional grey matter volume was decreased with advancing age in bilateral parietal cortex (mainly the precuneus and inferior parietal lobule), bilateral frontal cortex with left side predominance (mainly middle frontal gyrus), left occipital cortex (mainly lingual cortex), right precentral and left postcentral gyrus, left transverse temporal gyrus, and right parahippocampal gyrus. The reductions were unrelated to gender, intracranial volume or general cognitive function. Grey matter volume was relatively preserved in subcortical nuclei, periventricular regions, the basal surface of the brain (bilateral orbitofrontal and anterior temporal) and the anterior cingulate gyrus. Our findings suggest grey matter reductions in allocortex and association neocortex in the predementia stage of Down's syndrome. The most likely substrate of these changes is alterations or loss of allocortical and neocortical neurons due to Alzheimer's disease-type pathology. C1 Univ Munich, Alzheimer Mem Ctr, D-80336 Munich, Germany. Univ Munich, Dept Psychiat, Geriatr Psychiat Branch, Dementia & Neuroimaging Sect, D-80336 Munich, Germany. Arizona State Univ, Dept Psychol, Neuroimage Anal Lab, Tempe, AZ 85287 USA. Arizona Alzheimers Res Ctr, Phoenix, AZ USA. Arizona Alzheimers Dis Core Ctr, Phoenix, AZ USA. Cincinnati Childrens Hosp Med Ctr, Div Neurol, Cincinnati, OH USA. NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Teipel, SJ (reprint author), Univ Munich, Alzheimer Mem Ctr, Nussbaumstr 7, D-80336 Munich, Germany. EM stefan.teipel@med.uni-muenchen.de NR 78 TC 75 Z9 77 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD APR PY 2004 VL 127 BP 811 EP 824 DI 10.1093/brain/awh101 PN 4 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 807ET UT WOS:000220485500015 PM 14985261 ER PT J AU Yamamoto, J Ikeda, A Satow, T Matsuhashi, M Baba, K Yamane, F Miyamoto, S Mihara, T Hori, T Taki, W Hashimoto, N Shibasaki, H AF Yamamoto, J Ikeda, A Satow, T Matsuhashi, M Baba, K Yamane, F Miyamoto, S Mihara, T Hori, T Taki, W Hashimoto, N Shibasaki, H TI Human eye fields in the frontal lobe as studied by epicortical recording of movement-related cortical potentials SO BRAIN LA English DT Article DE human eye field; frontal lobe; movement-related cortical potential (MRCP); horizontal saccade; epicortical recording ID SUPPLEMENTARY MOTOR AREA; ELECTRICAL-STIMULATION; SENSORIMOTOR AREA; CINGULATE CORTEX; FUNCTIONAL-ANATOMY; VOLUNTARY MOVEMENT; NEURONAL-ACTIVITY; CEREBRAL-CORTEX; SACCADES; LOCATION AB We studied the generator location of premovement subcomponents of movement-related cortical potentials (MRCPs) [Bereitschaftspotential (BP), negative slope (NS') and motor potential (MP)] associated with voluntary, self-paced horizontal saccade in the human frontal lobe. Self-paced horizontal saccade, wrist (or middle finger) extension and foot dorsiflexion were employed in 10 patients (lateral surface of the frontal lobe in seven and mesial in three) as part of the presurgical evaluation, and data of five patients (lateral in four and mesial in three) were used in the final analysis. On the lateral frontal lobe, the maximum BP, NS' or MP with horizontal saccade was seen at or 1-2 cm rostral to the hand, arm or face area of the primary motor cortex (MI) in all four subjects investigated. This area exactly corresponded to the frontal eye field (FEF) identified by electrical stimulation. The amplitude of MRCPs with saccade was smaller than that with hand movements. On the mesial surface, within the supplementary motor area (SMA) proper, BP and/or NS' for horizontal saccade was located 1-2 cm rostral to that for hand and foot movements. BP and/or NS' delineated the supplementary eye field (SEF) at the rostral part of the SMA proper, and SEF partly overlapped with the hand and foot areas of the SMA proper. At the area just rostral to the vertical anterior commissure line and/or the pre-SMA defined by electrical stimulation, BP and/or NS' was seen invariably, regardless of the sites of movements, and in contrast with the SMA proper, there was no somatotopic representation. No clear MPs were elicited by eye movements on the mesial surface. In one of the two subjects whose MRCPs with horizontal saccade were recorded simultaneously from the lateral and mesial surfaces of the frontal lobe, BP from the SEF and pre-SMA preceded that from the FEF. It is concluded that MRCPs with horizontal saccade are useful for defining the FEF, SEF and pre-SMA, and that the SEF and pre-SMA become active in preparation for horizontal saccade earlier than the FEF. C1 Kyoto Univ, Grad Sch Med, Dept Neurol, Sakyo Ku, Kyoto 6068507, Japan. Kyoto Univ, Grad Sch Med, Dept Neurosurg, Sakyo Ku, Kyoto 6068507, Japan. Kyoto Univ, Grad Sch Med, Human Brain Res Ctr, Sakyo Ku, Kyoto 6068507, Japan. Shizuoka Med Inst Neurol Disorders, Shizuoka, Japan. Tokyo Womens Med Univ, Dept Neurosurg, Shinjuku Ku, Tokyo, Japan. Mie Univ, Sch Med, Dept Neurosurg, Tsu, Mie 514, Japan. NINDS, NIH, Bethesda, MD 20892 USA. RP Ikeda, A (reprint author), Kyoto Univ, Grad Sch Med, Dept Neurol, Sakyo Ku, Kyoto 6068507, Japan. EM akio@kuhp.kyoto-u.ac.jp OI Ikeda, Akio/0000-0002-0790-2598 NR 55 TC 31 Z9 31 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD APR PY 2004 VL 127 BP 873 EP 887 DI 10.1093/brain/awh110 PN 4 PG 15 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 807ET UT WOS:000220485500021 PM 14960503 ER PT J AU Funakoshi, T Ishibe, Y Okazaki, N Miura, K Liu, R Nagai, S Minami, Y AF Funakoshi, T Ishibe, Y Okazaki, N Miura, K Liu, R Nagai, S Minami, Y TI Effect of re-expansion after short-period lung collapse on pulmonary capillary permeability and pro-inflammatory cytokine gene expression in isolated rabbit lungs SO BRITISH JOURNAL OF ANAESTHESIA LA English DT Article DE gene, expression; lung, pulmonary capillary permeability; lung, re-expansion; polypeptides, inflammatory cytokine ID TUMOR-NECROSIS-FACTOR; SPIROMETRA-ERINACEIEUROPAEI SUPPRESS; EXCRETORY/SECRETORY PRODUCTS; REPERFUSION INJURY; FACTOR-ALPHA; TNF-ALPHA; INTERLEUKIN-8; EDEMA; MACROPHAGES; ISCHEMIA AB Background. Re-expansion pulmonary oedema is a rare complication caused by rapid re-expansion of a chronically collapsed lung. Several cases of pulmonary oedema associated with one-lung ventilation (OLV) have been reported recently. Elevated levels of pro-inflammatory cytokines in pulmonary oedema fluid are suggested to play important roles in its development. Activation of cytokines after re-expansion of collapsed lung during OLV has not been thoroughly investigated. Here we investigated the effects of re-expansion of the collapsed lung on pulmonary oedema formation and pro-inflammatory cytokine expression. Methods. Lungs isolated from female white Japanese rabbits were perfused and divided into a basal (BAS) group (n=7, baseline measurement alone), a control (CONT) group (n=9, ventilated without lung collapse for 120 min) and an atelectasis (ATEL) group (n=9, lung collapsed for 55 min followed by re-expansion and ventilation for 65 min). Pulmonary vascular resistance (PVR) and the coefficient of filtration (Kfc) were measured at baseline and 60 and 120 min. At the end of perfusion, bronchoalveolar lavage fluid/plasma protein ratio (B/P), wet/dry lung weight ratio (W/D) and mRNA expressions of tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and myeloperoxidase (MPO) were determined. Results. TNF-alpha and IL-1beta mRNA were significantly up-regulated in lungs of the ATEL group compared with BAS and CONT, though no significant differences were noted in PVR, Kfc, B/P and W/D within and between groups. MPO increased at 120 min in CONT and ATEL groups. Conclusion. Pro-inflammatory cytokines were up-regulated upon re-expansion and ventilation after short-period lung collapse, though no changes were noted in pulmonary capillary permeability. C1 Tottori Univ, Fac Med, Dept Surg, Div Anesthesiol & Crit Care Med, Tottori 6838504, Japan. NIAID, Malaria Vaccine Dev Unit, Parasit Dis Lab, NIH, Rockville, MD USA. Univ Penn, Dept Anesthesia, Philadelphia, PA 19104 USA. RP Ishibe, Y (reprint author), Tottori Univ, Fac Med, Dept Surg, Div Anesthesiol & Crit Care Med, 36-1 Nishi Cho, Tottori 6838504, Japan. EM ishibe@grape.med.tottori-u.ac.jp NR 27 TC 31 Z9 43 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0007-0912 J9 BRIT J ANAESTH JI Br. J. Anaesth. PD APR PY 2004 VL 92 IS 4 BP 558 EP 563 DI 10.1093/bja/aeh101 PG 6 WC Anesthesiology SC Anesthesiology GA 802RK UT WOS:000220180400018 PM 14977797 ER PT J AU Tohen, M Chengappa, KNR Suppes, T Baker, RW Zarate, CA Bowden, CL Sachs, GS Kupfer, DJ Ghaemi, SN Feldman, PD Risser, RC Evans, AR Calabrese, JR AF Tohen, M Chengappa, KNR Suppes, T Baker, RW Zarate, CA Bowden, CL Sachs, GS Kupfer, DJ Ghaemi, SN Feldman, PD Risser, RC Evans, AR Calabrese, JR TI Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone SO BRITISH JOURNAL OF PSYCHIATRY LA English DT Article ID TARDIVE-DYSKINESIA; RATING-SCALE; RECOVERY; MANIA; SCHIZOPHRENIA; RECURRENCE; PSYCHOSIS; EFFICACY; 6-MONTH; LITHIUM AB Background Few controlled studies have examined the use of atypical antipsychotic drugs for prevention of relapse in patients with bipolar I disorder Aims To evaluate whether olanzapine plus either lithium or valproate reduces the rate of relapse, compared with lithium or valproate alone. Method Patients achieving syndromic remission after 6 weeks' treatment with olanzapine plus either lithium (0.6- 1.2 mmol/l) or valproate (50-125 mug/ml) received lithium or valproate plus either olanzapine 5-20 mg/day (combination therapy) or placebo (monotherapy), and were followed in a double-masked trial for 18 months. Results The treatment difference in time to relapse into either mania or depression was not significant for syndromic relapse (median time to relapse: combination therapy 94 days, monotherapy 40.5 days; P=0.742), but was significant for symptomatic relapse (combination therapy 163 days, monotherapy 42 days; P=0.023). Conclusions Patients taking. olanzapine added to lithium or valproate experienced sustained symptomatic remission but not syndromic remission, for longer than those receiving lithium or valproate monotherapy. Declaration of interest M.T., R.W.B., P.D.F., A.R.E. and R.C.R. are stockholders in Eli Lilly & Company, the sponsor of this study. C1 Lilly Res Labs, Indianapolis, IN 46285 USA. Harvard Univ, McLean Hosp, Sch Med, Belmont, MA 02178 USA. Univ Pittsburgh, Western Psychiat Inst & Clin, Pittsburgh, PA USA. Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX USA. Lilly Res Labs, Indianapolis, IN USA. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, Dept Psychiat, San Antonio, TX 78284 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Univ Pittsburgh, Med Ctr, Western Psychiat Inst & Clin, Pittsburgh, PA USA. Harvard Univ, Cambridge Hosp, Sch Med, Dept Psychiat, Cambridge, MA USA. Lilly Res Labs, Indianapolis, IN USA. Case Western Reserve Univ, Dept Psychiat, Cleveland, OH 44106 USA. RP Tohen, M (reprint author), Lilly Res Labs, Indianapolis, IN 46285 USA. EM m.tohen@lilly.com RI Ghaemi, Nassir/J-4934-2013 NR 23 TC 213 Z9 217 U1 1 U2 4 PU ROYAL COLLEGE OF PSYCHIATRISTS PI LONDON PA BRITISH JOURNAL OF PSYCHIATRY 17 BELGRAVE SQUARE, LONDON SW1X 8PG, ENGLAND SN 0007-1250 J9 BRIT J PSYCHIAT JI Br. J. Psychiatry PD APR PY 2004 VL 184 BP 337 EP 345 DI 10.1192/bjp.184.4.337 PG 9 WC Psychiatry SC Psychiatry GA 811EC UT WOS:000220754200011 PM 15056579 ER PT J AU MacDonald, IM Reed, GF Wakeman, BJ AF MacDonald, IM Reed, GF Wakeman, BJ TI Strabismus after regional anesthesia for cataract surgery SO CANADIAN JOURNAL OF OPHTHALMOLOGY-JOURNAL CANADIEN D OPHTALMOLOGIE LA English DT Article DE cataract surgery; diplopia; strabismus; anesthesia ID EXTRAOCULAR-MUSCLE REGENERATION; PERIOCULAR ANESTHESIA; DIPLOPIA; CLUSTER AB Background: An adult strabismus clinic in a regional eye centre provided an opportunity to estimate the risk of postoperative diplopia from regional anesthesia after cataract surgery and to describe the management of these patients. Methods: Retrospective cohort analysis. All cases were referred over a 22-month period (November 1997 to September 1999) for investigation of postoperative diplopia after cataract surgery. The surgical and anesthetic records were reviewed to determine the number and location of injections, and the volume and type of regional anesthesia. The evolution and management of patients' diplopia was studied prospectively. Results: Twenty-one patients (12 women and 9 men aged 63 to 88 [median 76] years) were ascertained with postoperative diplopia. In I I cases the right eye was affected, and in 10 cases, the left eye. Vertical diplopia occurred most commonly from inferior rectus restriction (16 cases). Three cases resolved without treatment, which indicated that the diplopia was transient. Four patients declined treatment, five required prism in eyeglasses only, and nine required strabismus surgery. One patient required surgery and prism in eyeglasses. Two patients required more than one strabismus operation to relieve the diplopia. For the period of data collection, we estimate the risk of nontransient postoperative diplopia from regional anesthesia as 2.6 cases per 1000 cataract procedures (95% confidence interval 1.9-4.7). Interpretation: Patients should be forewarned of the risk of diplopia after cataract surgery with regional anesthesia. The treatment of the diplopia may require prism in eyeglasses or strabismus surgery or both. C1 Univ Alberta, Dept Ophthalmol, Edmonton, AB, Canada. NEI, Biometry Branch, NIH, Bethesda, MD USA. RP MacDonald, IM (reprint author), Univ Alberta, Royal Alexandra Hosp, Dept Ophthalmol, Rm 2319,10240 Kingsway Ave, Edmonton, AB T5H 3V9, Canada. OI MacDonald, Ian/0000-0001-7472-8385 NR 12 TC 4 Z9 5 U1 0 U2 0 PU CANADIAN OPHTHAL SOC PI OTTAWA PA 1525 CARLING AVE SUITE 610, OTTAWA, ONTARIO K1Z 8R9, CANADA SN 0008-4182 J9 CAN J OPHTHALMOL JI Can. J. Opthalmol.-J. Can. Opthalmol. PD APR PY 2004 VL 39 IS 3 BP 267 EP 271 PG 5 WC Ophthalmology SC Ophthalmology GA 818UW UT WOS:000221271000009 PM 15180144 ER PT J AU Chen, YJ Vortmeyer, A Zhuang, ZP Gibril, F Jensen, RT AF Chen, YJ Vortmeyer, A Zhuang, ZP Gibril, F Jensen, RT TI X-chromosome loss of heterozygosity frequently occurs in gastrinomas and is correlated with aggressive tumor growth SO CANCER LA English DT Article DE pancreatic endocrine tumors; Zollinger-Ellison syndrome; prognosis; loss of heterozygosity ID ZOLLINGER-ELLISON-SYNDROME; PANCREATIC ENDOCRINE TUMORS; COMPARATIVE GENOMIC HYBRIDIZATION; NEUROENDOCRINE TUMORS; SUPPRESSOR GENE; ALLELIC LOSS; METASTATIC GASTRINOMAS; PROGNOSTIC-FACTORS; NEOPLASIA TYPE-1; OVARIAN-CANCER AB BACKGROUND. Recent studies have shown that tumor growth, rather than hormone overproduction, is the leading cause of death among patients with gastrinomas and other malignant gastrointestinal endocrine tumors. No patient/laboratory characteristics accurately predict which tumors will exhibit aggressive growth. Furthermore, little is known regarding the molecular pathogenesis of these tumors. X-chromosome loss of heterozygosity (LOH) occurs in some nonendocrine tumors, and its presence can be associated with aggressive growth/decreased survival. Data on X-chromosome LOH in gastrointestinal endocrine tumors are conflicting. Therefore, the purpose of the current study was to determine whether X-chromosome LOH occurred in gastrinomas and, if so, whether it was correlated with tumor growth, tumor behavior, and/or prognosis. METHODS. X chromosome allelotyping was performed using 12 microsatallite markers spaced throughout the chromosome using DNA from leukocytes and microdissected gastrinoma specimens from 16 female patients. The presence of X-chromosome LOH was analyzed for correlations with clinical and laboratory tumor characteristics as well as tumor growth characteristics. RESULTS. Nine gastrinoma specimens (56%) had X-chromosome LOH, ranging from 6% to 23% at the 12 different loci studied. X-chromosome LOH was significantly associated with aggressive postoperative tumor growth, increased primary tumor size, and pancreatic primaries. In 6 tumor specimens, LOH occurred on Xp22.1-22.3 over a 28.4-centimorgan region. CONCLUSIONS. X-chromosome LOH was common in gastrinoma specimens from female patients, and its presence was found to be a potentially useful molecular/genetic prognostic factor for aggressive growth. Published 2004 by the American Cancer Society.*. C1 NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. NINDS, Mol Pathogenesis Unit, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Jensen, RT (reprint author), NIDDKD, Digest Dis Branch, NIH, Bldg 10,Room 9C-103,10 Ctr Dr,MSC 1804, Bethesda, MD 20892 USA. EM robertj@bdg10.niddk.nih.gov NR 53 TC 16 Z9 17 U1 1 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD APR 1 PY 2004 VL 100 IS 7 BP 1379 EP 1387 DI 10.1002/cncr.20104 PG 9 WC Oncology SC Oncology GA 805BE UT WOS:000220341000009 PM 15042671 ER PT J AU Milenic, DE Brechbiel, MW AF Milenic, DE Brechbiel, MW TI Targeting of radio-isotopes for cancer therapy SO CANCER BIOLOGY & THERAPY LA English DT Review DE radio immunotherapy; radioimmunoconsurjgates; monoclonal antibody; bifunctional chelating agent ID NON-HODGKINS-LYMPHOMA; PHASE-I TRIAL; STEM-CELL TRANSPLANTATION; ANTIBODY 81C6 TREATMENT; DIAGNOSED MALIGNANT GLIOMAS; METASTATIC COLON-CANCER; ALPHA-PARTICLE-EMITTER; REFRACTORY LOW-GRADE; HIGH-DOSE THERAPY; MONOCLONAL-ANTIBODY AB Treatment of patients with therapeutic monoclonal antibodies (mAbs) such cis rituximab (Rituxan), an anti-CD20 mAb, or trastuzumab (Herceptin), an anti-HER2 mAb, have shown efficacy in clinical trials and have gained approval from the Food and Drug Administration (FDA). Mylotarg, an anti-CD33 mAb conjugated with the antibiotic calicheamicin has proven efficacious in the treatment of patients with acute myeloid leukemia and has also received FDA approval. However, the use of radionuclides to either augment inherent activity or to exploit the specific targeting properties has been a major development in mAb therapeutics. Radionuclide- bearing mAbs have recently been approved by the FDA; Zevalin, an anti-CD20 mAb armed with Y-90 and Bexxar, an anti-CD20 mAb armed with I-131. This overview presents some background ond some of the strategies pertaining to radiolabeled monoclonal antibody therapies with a focus on experiences reported for radiolabeled mAbs as evaluated in clinical trials. C1 NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Brechbiel, MW (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, Ctr Canc Res,NIH, 10 Ctr Dr,Bldg 10,Room B3B69, Bethesda, MD 20892 USA. EM martinwb@mail.nih.gov NR 89 TC 27 Z9 30 U1 0 U2 1 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD APR PY 2004 VL 3 IS 4 BP 361 EP 370 PG 10 WC Oncology SC Oncology GA 837LP UT WOS:000222637200001 PM 14976424 ER PT J AU Retter, AS Gulley, JL Dahut, WL AF Retter, AS Gulley, JL Dahut, WL TI Novel therapeutic strategies in prostate cancer SO CANCER BIOLOGY & THERAPY LA English DT Review DE prostate; novel; vaccine; angiogenesis; cancer ID RANDOMIZED PHASE-II; PLACEBO-CONTROLLED TRIAL; BONE METASTASES; DENDRITIC CELLS; VACCINE TRIAL; SCID MICE; VITAMIN-D; THALIDOMIDE; ANGIOGENESIS; PROGRESSION AB Prostate cancer is the most common noncutaneous cancer in American men and the second most common cause of death. It is estimated that in 2003, 220,900 new cases will be diagnosed and 28,900 men will die from the disease. 1 Hormonal therapy via surgical or chemical castration is the mainstay of treatment for metastatic prostate cancer. While this is quite effective initially, with time patients become refractory to this treatment and may require additional therapy. There have been a substantial number of novel agents that have been developed in the last 10 years that show promise in the treatment of patients with prostate cancer, when used alone or when combined with current approaches (Table 1). C1 NCI, Genitourinary Branch, Med Oncol Clin Res Unit, NIH, Bethesda, MD 20892 USA. RP Retter, AS (reprint author), NCI, Genitourinary Branch, Med Oncol Clin Res Unit, NIH, 10 Ctr Dr,Bldg 10,Room 12N226, Bethesda, MD 20892 USA. EM rettera@mail.nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 64 TC 11 Z9 11 U1 0 U2 0 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD APR PY 2004 VL 3 IS 4 BP 371 EP 376 PG 6 WC Oncology SC Oncology GA 837LP UT WOS:000222637200002 PM 14726702 ER PT J AU Szakacs, G Chen, GK Gottesman, MM AF Szakacs, G Chen, GK Gottesman, MM TI The molecular mysteries underlying P-glycoprotein-mediated multidrug resistance SO CANCER BIOLOGY & THERAPY LA English DT Editorial Material DE multidrug resistance; P-glycoprotein; MDR1; ZNRD1; transcriptional regulation ID REGENERATING RAT-LIVER; MDR1 GENE; 12-O-TETRADECANOYLPHORBOL-13-ACETATE ACTIVATION; TRANSCRIPTIONAL REGULATION; EXPRESSION; PROMOTER; TRANSPORTERS; MODULATION; REGION; CELLS C1 NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 1A07, Bethesda, MD 20892 USA. EM mgottesman@nih.gov RI Szakacs, Gergely/A-2580-2009; Chen, Kevin/D-6769-2011 OI Szakacs, Gergely/0000-0002-9311-7827; Chen, Kevin/0000-0003-2983-6330 NR 21 TC 9 Z9 9 U1 1 U2 1 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD APR PY 2004 VL 3 IS 4 BP 382 EP 384 PG 3 WC Oncology SC Oncology GA 837LP UT WOS:000222637200004 PM 14976423 ER PT J AU Steeg, PS AF Steeg, PS TI The gift of absorption SO CANCER BIOLOGY & THERAPY LA English DT Editorial Material ID BREAST-CARCINOMA CELLS; NM23/NUCLEOSIDE DIPHOSPHATE KINASE; IN-VITRO; ADENOCARCINOMA CELLS; ENZYMATIC-ACTIVITY; MELANOMA-CELLS; ALPHA-ISOFORM; CANCER-CELLS; METASTASIS; NM23-H1 C1 NCI, Mol Therapeut Program, Womens Canc Sect, Lab Pathol,Ctr Canc Res, Bethesda, MD 20892 USA. RP Steeg, PS (reprint author), NCI, Mol Therapeut Program, Womens Canc Sect, Lab Pathol,Ctr Canc Res, Bldg 10,Room 2A33, Bethesda, MD 20892 USA. EM steegp@mail.nih.gov NR 26 TC 0 Z9 0 U1 0 U2 0 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD APR PY 2004 VL 3 IS 4 BP 415 EP 418 PG 4 WC Oncology SC Oncology GA 837LP UT WOS:000222637200012 PM 15020848 ER PT J AU Milenic, D Garmestani, K Dadachova, E Chappell, L Albert, P Hill, D Schlom, J Brechbiel, M AF Milenic, D Garmestani, K Dadachova, E Chappell, L Albert, P Hill, D Schlom, J Brechbiel, M TI Radioimmunotherapy of human colon carcinoma xenografts using a Bi-213-labeled domain-deleted humanized monoclonal antibody SO CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS LA English DT Article DE radioimmunotherapy; alpha-particle; bismuth; Bi-213; HuCC49 Delta CH2 ID ALPHA-PARTICLE-EMITTER; SINGLE-CHAIN-FV; VASCULAR-TARGETED RADIOIMMUNOTHERAPY; IN-VIVO; RADIOLABELED ANTIBODIES; IMMUNOGLOBULIN FORMS; LABELED-ANTIBODY; TUMOR XENOGRAFT; SOLID TUMORS; RENAL UPTAKE AB The data presented within this paper is the first report of a humanized domain-deleted monoclonal antibody (HuCC49DeltaCH2) to be utilized in a radioimmunotherapeutic (RIT) application with Bi-213. An initial study indicated that In-111-HuCC49DeltaCH2 targets the subcutaneously implanted human colon carcinoma xenograft, LS-174T, when injected via a peritoneal route. The HuCC49DeltaCH2 was then radiolabeled with 213 Bi, an a-emitting radionuclide with a half-life of 45.6 minutes, and evaluated for therapeutic efficacy. Dose titration studies indicated that a single dose of 500-1000 muCi, when injected by an intraperitoneal route, resulted in the growth inhibition or regression of the tumor xenograft. The radioimmunotherapeutic effect was found to be dose-dependent. Specificity of the therapeutic efficacy was confirmed in a subsequent experiment with athymic mice bearing TAG-72 negative MIP (human colorectal) xenografts. A preliminary study was also performed to assess a multiple-dose administration of Bi-213-HuCC49DeltaCH2. Doses (500 muCi) were administered at 14-day intervals after tumor implantation. A reduction in volume and/or delay in tumor growth was evident following the second and third injections of Bi-213-HuCC49DeltaCH2. As further validation of the use of Bi-213-HuCC49DeltaCH2 for RIT, a study using I-131 was conducted. The overall survival of mice receiving Bi-213-HuCC49DeltaCH2 was greater than those that received I-131-HuCC49DeltaCH2. C1 NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, Bethesda, MD 20892 USA. NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. RP Brechbiel, M (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, 10 Ctr Dr,MSC-1002,Room B3B69, Bethesda, MD 20892 USA. EM Martinwb@mail.nih.gov RI Dadachova, Ekaterina/I-7838-2013 NR 46 TC 34 Z9 34 U1 1 U2 3 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1084-9785 J9 CANCER BIOTHER RADIO JI Cancer Biother. Radiopharm. PD APR PY 2004 VL 19 IS 2 BP 135 EP 147 DI 10.1089/108497804323071904 PG 13 WC Oncology; Medicine, Research & Experimental; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Research & Experimental Medicine; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging GA 821XV UT WOS:000221497600001 PM 15186593 ER PT J AU Platz, EA Leitzmann, MF Hollis, BW Willett, WC Giovannucci, E AF Platz, EA Leitzmann, MF Hollis, BW Willett, WC Giovannucci, E TI Plasma 1,25-dihydroxy- and 25-hydroxyvitamin D and subsequent risk of prostate cancer SO CANCER CAUSES & CONTROL LA English DT Article DE cohort study; prostate cancer; risk; vitamin D ID VITAMIN-D METABOLITES; RECEPTOR EXPRESSION; UNITED-STATES; CELL-LINES; D-3; CALCIUM; 1-ALPHA,25-DIHYDROXYVITAMIN-D-3; RADIOIMMUNOASSAY; PROLIFERATION; PHOSPHORUS AB Objective: The hormone 1,25-dihydroxyvitamin D (1,25(OH)(2)D) promotes prostate epithelial cell differentiation in vitro and thus, several groups have hypothesized that men who systemically have lower levels of 1,25( OH) 2D may be at increased risk for prostate cancer. To address this hypothesis, we evaluated the association of circulating concentrations of 1,25(OH)(2)D and its precursor 25-hydroxyvitamin D (25(OH)D) with subsequent risk of prostate cancer. Methods: Prostate cancer cases were 460 men in the Health Professionals Follow-up Study who were diagnosed through 1998 after providing a blood specimen in 1993/95. 90.2% of the cases were organ confined or had minimal extraprostatic extension. An equal number of controls who had had a screening PSA test after blood draw were individually matched to cases on age, history of a PSA test before blood draw, and time of day, season, and year of blood draw. Plasma 1,25(OH)(2)D and 25( OH) D concentrations were determined by radio-immunosorbant assay blindly to case - control status. Odds ratios ( OR) of prostate cancer and 95% confidence intervals (CI) were estimated from conditional logistic regression models mutually adjusting for quartiles of 1,25(OH)(2)D and 25( OH) D concentrations and for suspected prostate cancer risk factors. Quartile cutpoints were determined separately by season of blood draw using the distributions among controls. Results: Mean concentrations of 1,25(OH)(2)D and 25(OH) D were slightly, but not statistically significantly (p = 0.06 and 0.20, respectively), higher in cases (34.3 +/- 7.1 pg/ml and 24.6 +/- 7.7 ng/ml, respectively) than in controls (33.5 +/- 7.1 pg/ml and 23.9 +/- 8.2 ng/ml, respectively). The OR of prostate cancer comparing men in the top to bottom quartile of 1,25(OH)(2)D was 1.25 (95% CI: 0.82 - 1.90, p-trend = 0.16). For 25(OH) D the OR of prostate cancer comparing the top and bottom quartiles was 1.19 ( 95% CI: 0.79 - 1.79, p- trend = 0.59). These findings did not vary by level of the other metabolite, age at diagnosis, family history of prostate cancer, or factors that are thought to influence 25(OH) D levels. Conclusion: In this prospective study, we did not observe an inverse association between plasma concentrations of 1,25(OH)(2)D or 25(OH) D and incident prostate cancer, although we cannot rule out potential effects at later stages of the disease. C1 Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA. NCI, Div Canc Etiol & Prevent, Rockville, MD USA. Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Channing Lab, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Channing Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Platz, EA (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Room E6138,615 N Wolfe St, Baltimore, MD 21205 USA. EM eplatz@jhsph.edu FU NCI NIH HHS [CA55075, CA72036]; NHLBI NIH HHS [HL35464] NR 28 TC 164 Z9 166 U1 1 U2 4 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD APR PY 2004 VL 15 IS 3 BP 255 EP 265 DI 10.1023/B:CACO.0000024245.24880.8a PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 812WC UT WOS:000220868600004 PM 15090720 ER PT J AU Rahman, L Voeller, D Rahman, M Lipkowitz, S Allegra, C Barrett, JC Kaye, FJ Zajac-Kaye, M AF Rahman, L Voeller, D Rahman, M Lipkowitz, S Allegra, C Barrett, JC Kaye, FJ Zajac-Kaye, M TI Thymidylate synthase as an oncogene: A novel role for an essential DNA synthesis enzyme SO CANCER CELL LA English DT Article ID MAMMALIAN RIBONUCLEOTIDE REDUCTASE; C-MYC; NEOPLASTIC TRANSFORMATION; PROGNOSTIC IMPORTANCE; PROTEIN EXPRESSION; GENE-EXPRESSION; R2 COMPONENT; IN-VITRO; S-PHASE; CANCER AB Thymidylate synthase (TS) is an E2F1-regulated enzyme that is essential for DNA synthesis and repair. TS protein and mRNA levels are elevated in many human cancers, and high TS levels have been correlated with poor prognosis in patients with colorectal, breast, cervical, bladder, kidney, and non-small cell lung cancers. In this study, we show that ectopic expression of catalytically active TS is sufficient to induce a transformed phenotype in mammalian cells as manifested by foci formation, anchorage independent growth, and tumor formation in nude mice. In contrast, comparable levels of two TS mutants carrying single point mutations within the catalytic domain had no transforming activity. In addition, we show that overexpression of TS results in apoptotic cell death following serum removal. These data demonstrate that TS exhibits oncogene-like activity and suggest a link between TS-regulated DNA synthesis and the induction of a neoplastic phenotype. C1 NCI, NIH, Ctr Canc Res, Basic Res Lab, Bethesda, MD 20892 USA. NCI, NIH, Ctr Canc Res, Mol Therapeut Program, Bethesda, MD 20892 USA. NCI, NIH, Ctr Canc Res, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. NCI, NIH, Ctr Canc Res, Lab Biosyst & Canc, Bethesda, MD 20892 USA. NCI, NIH, Ctr Canc Res, Dept Genet, Bethesda, MD 20892 USA. RP Zajac-Kaye, M (reprint author), NCI, NIH, Ctr Canc Res, Basic Res Lab, Bethesda, MD 20892 USA. EM kayem@exchange.nih.gov RI kaye, frederic/E-2437-2011 NR 55 TC 114 Z9 116 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD APR PY 2004 VL 5 IS 4 BP 341 EP 351 DI 10.1016/S1535-6108(04)00080-7 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 817DG UT WOS:000221157600009 PM 15093541 ER PT J AU Chiu, BCH Weisenburger, DD Zahm, SH Cantor, KP Gapstur, SM Holmes, F Burmeister, LF Blair, A AF Chiu, BCH Weisenburger, DD Zahm, SH Cantor, KP Gapstur, SM Holmes, F Burmeister, LF Blair, A TI Agricultural pesticide use, familial cancer, and risk of non-Hodgkin lymphoma SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID UNITED-STATES; T(14/18) SUBTYPES; EXPOSURE; HISTORY; LEUKEMIA; FARMERS; WORKERS; DISEASE; HEALTH; MEN AB To investigate whether the association between agricultural pesticide use and the risk of non-Hodgkin's lymphoma (NHL) is modified by a family history of hematopoietic cancer, including leukemia, myeloma, and lymphoma, we analyzed pooled data on white men from three population-based, case-control studies of NHL conducted in Iowa/Minnesota, Kansas, and Nebraska. Information on the agricultural use of insecticides, fungicides, and herbicides; a family history of cancer; and other risk factors was obtained by interviewing 973 cases and 2,853 controls or, if deceased, their next-of-kin (37% of cases, 43% of controls). The NHL risk was estimated by odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for age, state of residence, type of respondent, and use of hair dye. Compared to men with no family history of cancer, the ORs (95% CIs) of NHL was 1.5 (1.3-1.8) for men with a family history of nonhematopoietic cancer, and 2.7 (1.9-3.7) for those with a history of hematopoietic cancer among first-degree relatives. This positive association was noted for each group of NHL defined according to the Working Formulation, and was most pronounced for small lymphocytic NHL. Among direct respondents, farmers who used pesticides and had a positive family history of cancer or hematopoietic cancer were not at elevated risk of NHL, compared to nonfarmers who had no family cancer history. However, among proxy respondents, ORs were elevated for farmers who had a positive family history of hematopoietic cancer and used animal insecticides (OR = 4.6; 1.9-11.2), crop insecticides (OR = 4.7; 1.6-13.4), or herbicides (OR = 4.9; 1.7-14.2), although the interaction of family history of cancer and agricultural pesticide use was not statistically significant. In summary, the joint effects of the family cancer history and pesticide use were limited to proxy respondents with wide CIs and, thus, provide little evidence that a family history of cancer modifies the association of agricultural exposures with NHL. C1 Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. Northwestern Univ, Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. NCI, Div Canc Epidemiol & Genet, DHHS, NIH, Bethesda, MD 20892 USA. Univ Kansas, Med Ctr, Dept Internal Med, Kansas City, KS 66103 USA. Univ Iowa, Dept Biostat, Iowa City, IA 52240 USA. RP Chiu, BCH (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, 680 N Lake Shore Dr,Suite 1102, Chicago, IL 60611 USA. EM bchiu@northwestern.edu RI Zahm, Shelia/B-5025-2015 NR 46 TC 39 Z9 41 U1 2 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2004 VL 13 IS 4 BP 525 EP 531 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 810SQ UT WOS:000220724400005 PM 15066915 ER PT J AU Peters, U Hayes, RB Chatterjee, N Shao, W Schoen, RE Pinsky, P Hollis, BW McGlynn, KA AF Peters, U Hayes, RB Chatterjee, N Shao, W Schoen, RE Pinsky, P Hollis, BW McGlynn, KA CA Prostate, Lung, Colorectal Ovarian TI Circulating vitamin D metabolites, polymorphism in vitamin D receptor, and colorectal adenoma risk SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HEALTHY POSTMENOPAUSAL WOMEN; CANCER SCREENING TRIAL; COLON-CANCER; MESSENGER-RNA; UNITED-STATES; 25-HYDROXYVITAMIN D-3-1-ALPHA-HYDROXYLASE; SERUM 25-HYDROXYVITAMIN-D; ESTROGEN; CALCIUM; EXPRESSION AB Objective: Vitamin D is a potential agent for the prevention of colorectal cancer possibly through mechanisms mediated by the vitamin D receptor (VDR). We investigated the association of circulating vitamin D metabolites and a genetic variant of the VDR gene with advanced colorectal adenoma, a precursor lesion of colorectal cancer. Methods: Cases with advanced adenoma of the distal large bowel and gender- and ethnicity-matched controls with a negative sigmoidoscopy were randomly selected from participants in the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial. Genotype analysis of the VDR TaqI polymorphism was completed on 763 cases and 774 controls. Serum levels of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] were measured in a subset of 394 cases and 397 controls. Results: Serum levels of 25(OH)D were inversely associated with advanced adenoma risk in women but not in men. Comparing those in the highest quintile with those in the lowest quintile, the risk for advanced adenoma decreased by 73% in women [odds ratio (OR) = 0.27, 95% confidence interval (95% CI) = 0.11-0.69; P for trend = 0.0002], while the risk did not decrease in men (OR = 1.10, 95% Cl = 0.60-2.05; P for trend = 0.85). In women, 25(OH)D levels were significantly higher in current users of hormone replacement therapy (HRT) than in former or never HRT users. Neither serum 1,25(OH)(2)D nor VDR TaqI genotype was associated with advanced adenoma risk. Conclusion: Higher serum 25(OH)D levels were associated with decreased adenoma risk. Serum 1,25(OH)(2)D and VDR TaqI genotype were not associated with adenoma risk. C1 NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Dept HHS,NIH, Rockville, MD 20852 USA. NCI, Nutr Epidemiol Branch, Div Canc Prevent, Dept HHS,NIH, Rockville, MD 20852 USA. Sci Applicat Int Corp, NCI, Frederick, MD USA. Univ Pittsburgh, Dept Med & Epidemiol, Pittsburgh, PA USA. Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Biochem, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Biol Mol, Charleston, SC 29425 USA. RP Peters, U (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Dept HHS,NIH, 6120 Execut Blvd,EPS 3024, Rockville, MD 20852 USA. EM petersu@mail.nih.gov NR 48 TC 61 Z9 63 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2004 VL 13 IS 4 BP 546 EP 552 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 810SQ UT WOS:000220724400008 PM 15066918 ER PT J AU Lacey, JV Potischman, N Madigan, MP Berman, ML Mortel, R Twiggs, LB Barrett, RJ Wilbanks, GD Lurain, JR Fillmore, CM Sherman, ME Brinton, LA AF Lacey, JV Potischman, N Madigan, MP Berman, ML Mortel, R Twiggs, LB Barrett, RJ Wilbanks, GD Lurain, JR Fillmore, CM Sherman, ME Brinton, LA TI Insulin-like growth factors, insulin-like growth factor-binding proteins, and endometrial cancer in postmenopausal women: Results from a US case-control study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID FACTOR-I; IGF-I; ENDOGENOUS HORMONES; CIGARETTE-SMOKING; MESSENGER-RNA; FACTOR SYSTEM; RISK-FACTORS; EXPRESSION; ESTROGENS; CELLS AB Objective: To assess whether circulating insulin-like growth factor-1 (IGF-1), IGF-2, insulin-like growth factor-binding protein-1 (IGFBP-1), or IGFBP-3 were associated with endometrial cancer in postmenopausal women. Study Design: Between 1987 and 1990, we conducted a case-control study of 405 women with endometrial cancer and 297 matched population-based controls. This analysis included 174 postmenopausal cases and 136 controls. Results: In logistic regression models adjusted for potential confounders, higher IGF-1 levels were not positively associated with endometrial cancer odds ratio (OR) for the highest tertile versus the lowest tertile = 0.63, 95% confidence interval (0) = 0.30-1.32. Endometrial cancer was inversely associated with IGF-2 (OR for the highest tertile = 0.35, 95% CI = 0.18-0.69) and IGFBP-3 (OR for the highest tertile = 0.40, 95% CI = 0.21-0.77), and not associated with IGFBP-1. Conclusion: Serum IGF-1, IGF-2, and IGFBP-3, but not IGFBP-1, were inversely associated with endometrial cancer in postmenopausal women. These associations and the potential role of the IGF system in endometrial proliferation and carcinogenesis warrant further research. C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. NCI, Appl Res Branch, Rockville, MD 20852 USA. Univ Calif Irvine, Med Ctr, Dept Obstet & Gynecol, Irvine, CA USA. Penn State Univ, Milton S Hershey Med Ctr, Hershey, PA 17033 USA. Univ Minnesota, Hlth Sci Ctr, Dept Obstet & Gynecol, Minneapolis, MN 55455 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Obstet & Gynecol, Winston Salem, NC USA. Rush Med Coll, Dept Obstet & Gynecol, Chicago, IL USA. Northwestern Univ, Dept Obstet & Gynecol, Sch Med, Chicago, IL USA. RP Lacey, JV (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,MSC 7234, Rockville, MD 20852 USA. EM jimlacey@nih.gov RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 28 TC 25 Z9 28 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2004 VL 13 IS 4 BP 607 EP 612 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 810SQ UT WOS:000220724400016 PM 15066926 ER PT J AU Newcomb, PA Bush, AC Stoner, GL Lampe, JW Potter, JD Bigler, J AF Newcomb, PA Bush, AC Stoner, GL Lampe, JW Potter, JD Bigler, J TI No evidence of an association of JC virus and colon neoplasia SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; GASTROINTESTINAL-TRACT; POLYOMAVIRUS JCV; COMPLETE GENOMES; DNA SEQUENCES; T-ANTIGEN; EXPRESSION; PROTEIN; CANCER; AGNOPROTEIN AB JC virus (JCV) is an ubiquitous human polyomavirus that frequently resides in the kidneys of healthy individuals and is excreted in the urine of a large proportion of the adult population. Polyomaviruses are associated with disease largely in immunocompromised individuals (progressive multifocal leukoence-phalopathy). Colorectal cancers can show chromosome instability and it was hypothesized that JCV may account for some of this instability. We screened urine from 45 healthy donors and 233 colorectal cancer/ normal tissue pairs for the presence of JCV sequences using a Taqman assay. This assay could detect 1 virus genome in 10 human genomes. In the urine samples, we found an infection rate of approximately 70%. The JCV isolates in these samples could be categorized into four JCV types (213, 4, 7, and 8), none of which had a rearranged regulatory region. Among the colon tissues, one normal tissue (<0.5%) and none of the matched tumors tested positive for JCV. There is no evidence in these data to indicate that JCV is the cause of genetic instability in colorectal cancer. C1 Fred Hutchinson Canc Res Ctr, Canc Prevent Res Program, Seattle, WA 98109 USA. Natl Inst Neurol Disorders & Stroke, Neurotoxicol Sect, NIH, Bethesda, MD USA. RP Bigler, J (reprint author), Fred Hutchinson Canc Res Ctr, Canc Prevent Res Program, 1100 Fairview Ave N,DE-320,POB 19024, Seattle, WA 98109 USA. EM jbigler@fhcrc.org OI Potter, John/0000-0001-5439-1500 FU NCI NIH HHS [CA 95011, U01 CA 074794, CA 15704, U01 CA074794] NR 23 TC 41 Z9 44 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2004 VL 13 IS 4 BP 662 EP 666 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 810SQ UT WOS:000220724400025 PM 15066935 ER PT J AU Fergenbaum, JH Garcia-Closas, M Hewitt, SM Lissowska, J Sakoda, LC Sherman, ME AF Fergenbaum, JH Garcia-Closas, M Hewitt, SM Lissowska, J Sakoda, LC Sherman, ME TI Loss of antigenicity in stored sections of breast cancer tissue microarrays SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID PARAFFIN SLIDES; IMMUNOHISTOCHEMISTRY; SPECIMENS AB Immunohistochemical characterization of tumor tissues in epidemiological studies is a promising approach to identify breast cancer subtypes with distinct etiology. The recent development of the tissue microarray (TMA) technique allows for standardized, rapid, and cost-effective immunohistochemical characterization of many cases, which is critical in epidemiological studies. Sectioning paraffin blocks at different times results in loss of material, which can be reduced by preparing many sections each time a block is cut. However, data suggest that staining intensity declines in whole sections prepared from conventional paraffin blocks with storage time, resulting in false-negative results. This problem would be accentuated in TMAs because of the limited tissue representation of each case. To evaluate this concern, we prepared a single TMA block from 125 invasive breast carcinomas collected in a population-based case-control study conducted in Poland and compared estrogen receptor (ER-alpha), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression in sections cut and stored for 6 months at room temperature with sections cut from the same TMA block and stained on the same day. Percentage of positive cases for stored versus fresh sections was similar for ER (59.0%) but significantly higher in fresh sections for PR (56.3% versus 64.1%, P = 0.01) and HER2 (45.5% versus 64.4%, P < 0.001). Among cases positive in both stored and fresh sections, the median percentage of immunoreactive cells was significantly reduced and the staining intensity was consistently lower in stored compared with fresh sections. We conclude that loss of immunoreactivity is an important problem in TMAs of breast cancer. Improved methods for sectioning TMAs and storing tissue sections aimed at reducing loss of immunoreactivity are critical for the use of TMAs in epidemiological studies. C1 NCI, Div Canc Epidemiol & Genet, NIH, Dept HHS, Rockville, MD 20852 USA. NCI, Tissue Array Res Program, Pathol Lab, Canc Res Ctr, Bethesda, MD USA. Ctr Canc, Div Canc Epidemiol & Prevent, Warsaw, Poland. M Sklodowska Curie Inst Oncol, Warsaw, Poland. RP Sherman, ME (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept HHS, 6120 Execut Blvd,Execut Plaza S,Room 7080,MSC 723, Rockville, MD 20852 USA. EM shermanm@mail.nih.gov RI Garcia-Closas, Montserrat /F-3871-2015; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Hewitt, Stephen/0000-0001-8283-1788; Lissowska, Jolanta/0000-0003-2695-5799 NR 10 TC 79 Z9 83 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2004 VL 13 IS 4 BP 667 EP 672 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 810SQ UT WOS:000220724400026 PM 15066936 ER PT J AU Nikitin, AY Alcaraz, A Anver, MR Bonson, RT Cardiff, RD Dixon, D Fraire, AE Gabrielson, EW Gunning, WT Haines, DC Kaufman, MH Linnoila, RI Maronpot, RR Rabson, AS Reddick, RL Rehm, S Rozengurt, N Schuller, HM Shmidt, EN Travis, WD Ward, JM Jacks, T AF Nikitin, AY Alcaraz, A Anver, MR Bonson, RT Cardiff, RD Dixon, D Fraire, AE Gabrielson, EW Gunning, WT Haines, DC Kaufman, MH Linnoila, RI Maronpot, RR Rabson, AS Reddick, RL Rehm, S Rozengurt, N Schuller, HM Shmidt, EN Travis, WD Ward, JM Jacks, T TI Classification of proliferative pulmonary lesions of the mouse: Recommendations of the mouse models of human cancers consortium SO CANCER RESEARCH LA English DT Review ID LARGE T-ANTIGEN; STRAIN-A MICE; INDUCED LUNG-TUMORS; CLARA CELL ANTIGEN; TRANSGENIC MICE; K-RAS; HISTOLOGIC CHARACTERIZATION; CONDITIONAL EXPRESSION; N-NITROSOETHYLUREA; II CELLS AB Rapid advances in generating new mouse genetic models for lung neoplasia provide a continuous challenge for pathologists and investigators. Frequently, phenotypes of new models either have no precedents or are arbitrarily attributed according to incongruent human and mouse classifications. Thus, comparative characterization and validation of novel models can be difficult. To address these issues, a series of discussions was initiated by a panel of human, veterinary, and experimental pathologists during the Mouse Models of Human Cancers Consortium (NIH/National Cancer Institute) workshop on mouse models of lung cancer held in Boston on June 20-22, 2001. The panel performed a comparative evaluation of 78 cases of mouse and human lung proliferative lesions, and recommended development of a new practical classification scheme that would (a) allow easier comparison between human and mouse lung neoplasms, (b) accommodate newly emerging mouse neoplasms, and (c) address the interpretation of benign and preinvasive lesions of the mouse lung. Subsequent discussions with additional experts in pulmonary pathology resulted in the current proposal of a new classification. It is anticipated that this classification, as well as the complementary digital atlas of virtual histological slides, will help investigators and pathologists in their characterization of new mouse models, as well as stimulate further research aimed at a better understanding of proliferative lesions of the lung. C1 Cornell Univ, Dept Biomed Sci, Coll Vet Med, Ithaca, NY 14853 USA. NCI, Vet Pathol Sect, Pathol Histotechnol Lab, Sci Applicat Int Corp, Frederick, MD 21701 USA. Tufts Univ, Sch Vet Med, Dept Biomed Sci, North Grafton, MA 01536 USA. Univ Calif Davis, Ctr Comparat Med, Davis, CA 95616 USA. Natl Inst Environm Hlth Sci, Lab Expt Pathol, Res Triangle Pk, NC USA. Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01605 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. Med Coll Ohio, Dept Pathol, Toledo, OH 43699 USA. Univ Edinburgh, Dept Anat, Edinburgh, Midlothian, Scotland. NCI, Canc Res Ctr, Cell & Canc Biol Dept, NIH, Rockville, MD USA. NCI, NIH, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, Dept Pathol, San Antonio, TX 78284 USA. GlaxoSmithKline, King Of Prussia, PA USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA USA. Univ Tennessee, Coll Vet Med, Dept Pathol, Expt Oncol Lab, Knoxville, TN USA. Armed Forces Inst Pathol, Dept Pulm & Mediastinal Pathol, Washington, DC 20306 USA. NCI, Vet & Tumor Pathol Sect, Ctr Canc Res, NIH, Frederick, MD 21701 USA. MIT, Dept Biol, Cambridge, MA 02139 USA. MIT, Ctr Canc Res, Howard Hughes Med Inst, Cambridge, MA 02139 USA. RP Nikitin, AY (reprint author), Cornell Univ, Dept Biomed Sci, Coll Vet Med, VRT T2014A,Campus Rd, Ithaca, NY 14853 USA. EM an58@cornell.edu RI Gunning, William/E-4681-2010 FU NCI NIH HHS [CA84241, CA84242]; NCRR NIH HHS [RR017595]; PHS HHS [N01-C0-124000] NR 82 TC 198 Z9 202 U1 1 U2 7 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 APR 1 PY 2004 VL 64 IS 7 BP 2307 EP 2316 DI 10.1158/0008-5472.CAN-03-3376 PG 10 WC Oncology SC Oncology GA 808RP UT WOS:000220586500001 PM 15059877 ER PT J AU Hussain, SP Amstad, P He, PJ Robles, A Lupold, S Kaneko, I Ichimiya, M Sengupta, S Mechanic, L Okamura, S Hofseth, LJ Moake, M Nagashima, M Forrester, KS Harris, CC AF Hussain, SP Amstad, P He, PJ Robles, A Lupold, S Kaneko, I Ichimiya, M Sengupta, S Mechanic, L Okamura, S Hofseth, LJ Moake, M Nagashima, M Forrester, KS Harris, CC TI p53-induced up-regulation of MnSOD and GPx but not catalase increases oxidative stress and apoptosis SO CANCER RESEARCH LA English DT Article ID MANGANESE SUPEROXIDE-DISMUTASE; MOUSE EPIDERMAL-CELLS; PROTECTS HEPG2 CELLS; GLUTATHIONE-PEROXIDASE; CYTOCHROME-C; HYDROGEN-PEROXIDE; CU,ZN-SUPEROXIDE DISMUTASE; P53-DEPENDENT APOPTOSIS; TRANSCRIPTIONAL TARGET; MALIGNANT PHENOTYPE AB p53-mediated apoptosis may involve the induction of redox-controlling genes, resulting in the production of reactive oxygen species. Microarray expression analysis of doxorubicin exposed, related human lymphoblasts, p53 wild-type (WT) Tk6, and p53 mutant WTK1 identified the p53-dependent up-regulation of manganese superoxide dismutase (MnSOD) and glutathione peroxidase 1 (GPx). Consensus p53 binding sequences were identified in human MnSOD and GPx promoter regions. A 3-fold increase in the MnSOD promoter activity was observed after the induction of p53 in Li-Fraumeni syndrome (LFS) fibroblast, TR9-7, expressing p53 under the control of a tetracycline-regulated promoter. An increased protein expression of endogenous MnSOD and GPx also positively correlated with the level of p53 induction in TR9-7 cells. However, catalase (CAT) protein expression remained unaltered after p53 induction. We also examined the expression of MnSOD, GPx, and CAT in a panel of normal or LFS fibroblasts, containing either WT or mutant p53. We found increased MnSOD enzymatic activity, MnSOD mRNA expression, and MnSOD and GPx protein in LFS fibroblasts carrying a WT p53 allele when compared with homozygous mutant p53 isogenic cells. The CAT protein level was unchanged in these cells. We observed both the release of cytochrome C and Ca2+ from the mitochondria into the cytoplasm and an increased frequency of apoptotic cells after p53 induction in the TR9-7 cells that coincided with an increased expression of MnSOD and GPx, and the level of reactive oxygen species. The increase in apoptosis was reduced by the antioxidant N-acetylcysteine. These results identify a novel mechanism of p53-dependent apoptosis in which p53-mediated up-regulation of MnSOD and GPx, but not CAT, produces an imbalance in antioxidant enzymes and oxidative stress. C1 NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bldg 37,Room 3068, Bethesda, MD 20892 USA. EM Curtis_Harris@nih.gov OI Sengupta, Sagar/0000-0002-6365-1770 NR 62 TC 204 Z9 211 U1 2 U2 9 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 APR 1 PY 2004 VL 64 IS 7 BP 2350 EP 2356 DI 10.1158/0008-5472.CAN-2287-2 PG 7 WC Oncology SC Oncology GA 808RP UT WOS:000220586500009 PM 15059885 ER PT J AU Xi, ZJ Klokk, TI Korkmaz, K Kurys, P Elbi, C Risberg, B Danielsen, H Loda, M Saatcioglu, F AF Xi, ZJ Klokk, TI Korkmaz, K Kurys, P Elbi, C Risberg, B Danielsen, H Loda, M Saatcioglu, F TI Kallikrein 4 is a predominantly nuclear protein and is overexpressed in prostate cancer SO CANCER RESEARCH LA English DT Article ID GENE FAMILY; MOLECULAR-CLONING; SERINE-PROTEASE; GENOMIC ORGANIZATION; HOMEOBOX GENE; EXPRESSION; ANTIGEN; LOCALIZATION; FORMS; CELLS AB Kallikreins (KLKs) are highly conserved serine proteases that play key roles in a variety of physiological and pathological processes. KLKs are secreted proteins that have extracellular substrates and function. For example, prostate-specific antigen (or KLK3) is a secreted protein that is widely used as a diagnostic marker for prostate cancer. KLK4 is a recently identified member of the kallikrein family that is regulated by androgens and is highly specific to prostate for expression. Here, we show that the gene product of KLK4, hK4, is the first member of the KLK family that is intracellularly localized. We provide strong evidence that the previously assigned first exon that was predicted to code for a signal peptide that would target hK4 for secretion is not part of the physiologically relevant form of KLK4 mRNA. In addition to detailed mapping of the KLK4 mRNA 5' end by RT-PCR, this conclusion is supported by predominantly nuclear localization of the hK4 protein in the cell, documented by both immunofluorescence and cell fractionation experiments. Furthermore, in addition to androgens, hK4 expression is regulated by estrogen and progesterone in prostate cancer cells. Finally, in situ hybridization on normal and hyperplastic prostate samples in tissue microarrays indicate that KLK4 is predominantly expressed in the basal cells of the normal prostate gland and overexpressed in prostate cancer. These data suggest that KLK4 has a unique structure and function compared with other members of the KLK family and may have a role in the biology and characterization of prostate cancer. C1 Univ Oslo, Dept Biol, N-0316 Oslo, Norway. NCI, Lab Receptor Biol & Gene Express, Bethesda, MD 20892 USA. Norwegian Radium Hosp, Dept Pathol, Oslo, Norway. Univ Sheffield, Div Gen Med, Sheffield S10 2TN, S Yorkshire, England. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA. RP Saatcioglu, F (reprint author), Univ Oslo, Dept Biol, PB1050, N-0316 Oslo, Norway. EM fahris@bio.uio.no RI Risberg, Bjorn/A-6447-2008; Danielsen, Havard/A-7540-2014 NR 34 TC 83 Z9 84 U1 1 U2 1 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 APR 1 PY 2004 VL 64 IS 7 BP 2365 EP 2370 DI 10.1158/0008-5472.CAN-03-2025 PG 6 WC Oncology SC Oncology GA 808RP UT WOS:000220586500011 PM 15059887 ER PT J AU Oh, S Terabe, M Pendleton, CD Bhattacharyya, A Bera, TK Epel, M Reiter, Y Phillips, J Linehan, WM Kasten-Sportes, C Pastan, I Berzofsky, JA AF Oh, S Terabe, M Pendleton, CD Bhattacharyya, A Bera, TK Epel, M Reiter, Y Phillips, J Linehan, WM Kasten-Sportes, C Pastan, I Berzofsky, JA TI Human CTLs to wild-type and enhanced epitopes of a novel prostate and breast tumor-associated protein, TARP, lyse human breast cancer cells SO CANCER RESEARCH LA English DT Article ID HUMAN RECOMBINANT ANTIBODIES; CYTOTOXIC T-LYMPHOCYTES; COMPLEX-RESTRICTED SPECIFICITY; ALTERNATE READING FRAME; IN-SITU DETECTION; DENDRITIC CELLS; PHENOTYPIC ANALYSIS; CROSS-RECOGNITION; PEPTIDE COMPLEXES; HIV-1 GP160 AB Vaccine therapy for prostate and breast cancer may have potential for treating these major causes of death in males and females, respectively. Critical to the development of tumor-specific vaccines is finding and characterizing novel antigens to be recognized by CD8(+) T cells. To define new CD8(+) T-cell tumor antigens, we determined two wild-type HLA-A2 epitopes from a recently found tumor-associated protein, TARP (T-cell receptor gamma alternate reading frame protein), expressed in prostate and breast cancer cells. We were also able to engineer epitope-enhanced peptides by sequence modifications. Both wild-type and enhanced epitopes induced peptide-specific CD8(+) T-cell responses in A2K(b) transgenic mice. In vitro restimulation of human CD8(+) T cells from a prostate cancer patient resulted in CD8(+) T cells reactive to the peptide epitopes that could lyse HLA-A2(+) human breast cancer cells (MCF-7) expressing TARP. Epitope-specific human CD8(+) T cells were also enumerated in patients' peripheral blood by tetramer staining. Our data suggest that HLA-A2-binding TARP epitopes and enhanced epitopes discovered in this study could be incorporated into a potential vaccine for both breast and prostate cancer. C1 NCI, Ctr Canc Res, Vaccine Branch, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. Technion Israel Inst Technol, Haifa, Israel. Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Immunizat Res, Baltimore, MD USA. RP Berzofsky, JA (reprint author), NCI, Ctr Canc Res, Vaccine Branch, NIH, Bldg 10,Room 6B-12,MSC-1578, Bethesda, MD 20892 USA. EM berzofsk@helix.nih.gov NR 51 TC 49 Z9 50 U1 0 U2 4 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 APR 1 PY 2004 VL 64 IS 7 BP 2610 EP 2618 DI 10.1158/0008-5472.CAN-03-2183 PG 9 WC Oncology SC Oncology GA 808RP UT WOS:000220586500042 PM 15059918 ER PT J AU Klein, AP Brune, KA Petersen, GM Goggins, M Tersmette, AC Offerhaus, GJA Griffin, C Cameron, JL Yeo, CJ Kern, S Hruban, RH AF Klein, AP Brune, KA Petersen, GM Goggins, M Tersmette, AC Offerhaus, GJA Griffin, C Cameron, JL Yeo, CJ Kern, S Hruban, RH TI Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds SO CANCER RESEARCH LA English DT Article ID GENE-EXPRESSION; MUTATIONS; AGGREGATION; STRATEGIES; CARCINOMA; RELATIVES; BROTHERS; HISTORY; BRCA2 AB Individuals with a family history of pancreatic cancer have an increased risk of developing pancreatic cancer. Quantification of this risk provides a rational basis for cancer risk counseling and for screening for early pancreatic cancer. In a prospective registry-based study, we estimated the risk of pancreatic cancer in individuals with a family history of pancreatic cancer. Standardized incidence ratios were calculated by comparing the number of incident pancreatic cancers observed with those expected using Surveillance, Epidemiology and End Results (SEER) rates. Familial pancreatic cancer (FPC) kindreds were defined as kindreds having at least one pair of first-degree relatives with pancreatic cancer, and sporadic pancreatic cancer (SPC) kindreds as families without such an affected pair. Nineteen incident pancreatic cancers developed among 5,179 individuals from 838 kindreds (at baseline, 370 FPC kindreds and 468 SPC kindreds). Of these 5,179 individuals, 3,957 had at least one first-degree relative with pancreatic cancer and contributed 10,538 person-years of follow-up. In this group, the observed-to-expected rate of pancreatic cancer was significantly elevated in members of FPC kindreds [9.0; 95% confidence interval (CI), 4.5-16.1], but not in the SPC kindreds (1.8; 95% CI., 0.22-6.4). This risk in FPC kindreds was elevated in individuals with three (32.0; 95% CI, 10.2-74.7), two (6.4; CI, 1.8-16.4), or one (4.6; CI, 0.5-16.4) first-degree relative(s) with pancreatic cancer. Risk was not increased among 369 spouses and other genetically unrelated relatives. Risk was higher in smokers than in nonsmokers. Individuals with a strong family history of pancreatic cancer have a significantly increased risk of developing pancreatic cancer. C1 Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21205 USA. NHGRI, Stat Genet Sect, Inherited Dis Res Branch, NIH, Baltimore, MD USA. Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. Univ Amsterdam, Acad Med Ctr, Dept Pathol, NL-1105 AZ Amsterdam, Netherlands. RP Hruban, RH (reprint author), Johns Hopkins Med Inst, Dept Pathol, Weinberg 2242,401 N Broadway, Baltimore, MD 21231 USA. EM rhruban@jhmi.edu FU NCI NIH HHS [CA62924, R01 CA097075, R01 CA97075] NR 30 TC 247 Z9 255 U1 0 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 APR 1 PY 2004 VL 64 IS 7 BP 2634 EP 2638 DI 10.1158/0008-5472.CAN-03-3823 PG 5 WC Oncology SC Oncology GA 808RP UT WOS:000220586500045 PM 15059921 ER PT J AU Sills, RC Hong, HL Flake, G Moomaw, C Clayton, N Boorman, GA Dunnick, J Devereux, TR AF Sills, RC Hong, HL Flake, G Moomaw, C Clayton, N Boorman, GA Dunnick, J Devereux, TR TI o-Nitrotoluene-induced large intestinal tumors in B6C3F1 mice model human colon cancer in their molecular pathogenesis SO CARCINOGENESIS LA English DT Article ID BETA-CATENIN GENE; HEREDITARY COLORECTAL-CANCER; RAS PROTOONCOGENE ACTIVATION; DELETIONS INVOLVING EXON-3; INDUCED LUNG-TUMORS; SUPPRESSOR GENE; CYCLIN D1; K-RAS; PROTEIN ACCUMULATION; METHYLENE-CHLORIDE AB In the previous 500 2-year chemical bioassays within the National Toxicology Program, large intestinal tumors (cecal carcinomas) related to chemical exposure have not been observed in B6C3F1 mice. The recently completed o-nitrotoluene study provided the first cecal tumor response and an opportunity to evaluate the morphology and molecular profile of oncogenes and tumor suppressor genes that are relevant to humans. Morphologically, the carcinomas were gland-forming tumors lined by tall columnar epithelial cells that were positive for cytokeratin 20 and negative for cytokeratin 7. Using immunohistochemistry beta-catenin (encoded by Catnb) protein accumulation was detected in 80% (8/10) of the cecal carcinomas, while increased cyclin D1 and p53 protein expression was detected in 73% (8/11), respectively. There was no difference in adenomatous polyposis protein expression between normal colon and cecal carcinomas. All tumors examined exhibited mutations in exon 2 (corresponds to exon 3 in humans) in the Catnb gene. Mutations in p53 were identified in nine of 11 carcinomas, and all were in exon 7. Analysis of the K-ras gene revealed mutations in 82% (9/11) of carcinomas; all had specific G --> T transversions (Gly --> Val) at codons 10 or 12. The alterations in cancer genes and proteins found in the mouse large intestinal tumors included mutations that activate signal transduction pathways (K-ras and Catnb) and changes that disrupt the cell-cycle and bypass G(1) arrest (p53, cyclin D1). These alterations, which are hallmarks of human colon cancer, probably contributed to the pathogenesis of the large intestinal carcinomas in mice following o-nitrotoluene exposure. C1 NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Gen Toxicol, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Sills, RC (reprint author), NIEHS, Lab Expt Pathol, POB 12233, Res Triangle Pk, NC 27709 USA. EM sills@niehs.nih.gov NR 51 TC 13 Z9 13 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD APR PY 2004 VL 25 IS 4 BP 605 EP 612 DI 10.1093/carcin/bgh044 PG 8 WC Oncology SC Oncology GA 807EV UT WOS:000220485700017 PM 14688030 ER PT J AU Podjarny, A Cachau, RE Schneider, T Van Zandt, M Joachimiak, A AF Podjarny, A Cachau, RE Schneider, T Van Zandt, M Joachimiak, A TI Subatomic and atomic crystallographic studies of aldose reductase: implications for inhibitor binding SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Article DE aldose reductase inhibition; subatomic resolution crystallography ID HIGH-RESOLUTION; PROTEIN CRYSTALLOGRAPHY; CRAMBIN; MODEL AB The determination of several of aldose reductase-inhibitor complexes at subatomic resolution has revealed new structural details, including the specific interatomic contacts involved in inhibitor binding. In this article, we review the structures of the complexes of ALR2 with IDD 594 (resolution: 0.66 Angstrom, IC50 (concentration of the inhibitor that produced half-maximal effect): 30 nM, space group: P2(1)), IDD 393 (resolution: 0.90 Angstrom, IC50: 6 nM, space group: P1), fidarestat (resolution: 0.92 Angstrom, IC50: 9 nM, space group: P2(1)) and minalrestat (resolution: 1.10 Angstrom, IC50: 73 nM, space group: P1). The structures are compared and found to be highly reproductible within the same space group (root mean square (RMS) deviations: 0.15 similar to 0.3 Angstrom). The mode of binding of the carboxylate inhibitors IDD 594 and IDD 393 is analysed. The binding of the carboxylate head can be accurately determined by the subatomic resolution structures, since both the protonation states and the positions of the atoms are very precisely known. The differences appear in the binding in the specificity pocket. The high-resolution structures explain the differences in IC50, which are confirmed both experimentally by mass spectrometry measures of VC50 and theoretically by free energy perturbation calculations. The binding of the cyclic imide inhibitors fidarestat and minalrestat is also described, focusing on the observation of a Cl- ion which binds simultaneously with fidarestat. The presence of this anion, binding also to the active site residue His110, leads to a mechanism in which the inhibitor can bind in a neutral state and then become charged inside the active site pocket. This mechanism can explain the excellent in vivo properties of cyclic imide inhibitors. In summary, the complete and detailed information supplied by the subatomic resolution structures can explain the differences in binding energy of the different inhibitors. C1 IGBMC, CNRS, UMR 7104, Lab Genom & Biol Struct, F-67404 Illkirch Graffenstaden, France. NCI, Adv Biomed Comp Ctr, SAIC, Frederick, MD USA. Univ Gottingen, Dept Struct Chem, D-37077 Gottingen, Germany. Inst Diabet Discovery Inc, Branford, CT USA. Argonne Natl Lab, Struct Biol Ctr, Biosci Div, Argonne, IL 60439 USA. RP Podjarny, A (reprint author), IGBMC, CNRS, UMR 7104, Lab Genom & Biol Struct, 1 Rue Laurent Fries,BP 163, F-67404 Illkirch Graffenstaden, France. EM podjarny@titus.u-strasbg.fr RI Schneider, Thomas/B-7442-2011 OI Schneider, Thomas/0000-0001-6955-7374 FU NCI NIH HHS [N01-CO-12400] NR 26 TC 37 Z9 38 U1 0 U2 0 PU BIRKHAUSER VERLAG AG PI BASEL PA VIADUKSTRASSE 40-44, PO BOX 133, CH-4010 BASEL, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD APR PY 2004 VL 61 IS 7-8 BP 763 EP 773 DI 10.1007/s00018-003-3404-1 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 814NU UT WOS:000220982200004 PM 15095001 ER PT J AU Papp, H Czifra, G Bodo, E Lazar, J Kovacs, I Aleksza, M Juhasz, I Acs, P Sipka, S Kovacs, L Blumberg, PM Biro, T AF Papp, H Czifra, G Bodo, E Lazar, J Kovacs, I Aleksza, M Juhasz, I Acs, P Sipka, S Kovacs, L Blumberg, PM Biro, T TI Opposite roles of protein kinase C isoforms in proliferation, differentiation, apoptosis, and tumorigenicity of human HaCaT keratinocytes SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Article DE human keratinocyte; HaCaT; protein kinase C; isoenzyme; recombinant overexpression; proliferation; differentiation; tumorigenesis ID RADIATION-INDUCED APOPTOSIS; EPIDERMAL-KERATINOCYTES; NIH 3T3-CELLS; HUMAN SKIN; BETA-II; EXPRESSION; DELTA; ALPHA; ISOZYMES; MICE AB We have previously shown that the protein kinase C (PKC) system plays a pivotal role in regulation of proliferation and differentiation of the human keratinocyte line HaCaT which is often used to assess processes of immortalization, transformation, and tumorigenesis in human skin. In this paper, using pharmacological and molecular biology approaches, we investigated the isoform-specific roles of certain PKC isoenzymes (conventional cPKCalpha and beta; novel nPKCdelta and epsilon) in the regulation of various keratinocyte functions. cPKCalpha and nPKCdelta stimulated cellular differentiation and increased susceptibility of cells to actions of inducers of apoptosis, and they markedly inhibited cellular proliferation and tumor growth in immunodeficient mice. In marked contrast, cPKCbeta and nPKCepsilon increased both in vitro and in vivo growth of cells and inhibited differentiation and apoptosis. Our data present clear evidence for the specific, antagonistic roles of certain cPKC and nPKC isoforms in regulating the above processes in human HaCaT keratinocytes. C1 Hungarian Acad Sci, Dept Physiol, H-1051 Budapest, Hungary. Hungarian Acad Sci, Cell Physiol Res Grp, H-1051 Budapest, Hungary. Univ Debrecen, Dept Dermatol, Med & Hlth Sci Ctr, Res Ctr Mol Med, H-4012 Debrecen, Hungary. Kenezy Hosp, Dept Pathol, H-4031 Debrecen, Hungary. NCI, Mol Mech Tumor Promot Sect, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. RP Biro, T (reprint author), Hungarian Acad Sci, Dept Physiol, H-1051 Budapest, Hungary. EM biro@phys.dote.hu NR 40 TC 34 Z9 35 U1 2 U2 3 PU BIRKHAUSER VERLAG AG PI BASEL PA VIADUKSTRASSE 40-44, PO BOX 133, CH-4010 BASEL, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD APR PY 2004 VL 61 IS 9 BP 1095 EP 1105 DI 10.1007/s00018-004-4014-2 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 815QK UT WOS:000221056600008 PM 15112056 ER PT J AU Le, YY Zhou, Y Iribarren, P Wang, JM AF Le, Yingying Zhou, Ye Iribarren, Pablo Wang, Ji Ming TI Chemokines and Chemokine Receptors: Their Manifold Roles in Homeostasis and Disease SO CELLULAR & MOLECULAR IMMUNOLOGY LA English DT Review DE chemokine; receptor; development; leukocyte homing; angiogenesis; metastasis AB Chemokines are a superfamily of small proteins that bind to G protein-coupled receptors on target cells and were originally discovered as mediators of directional migration of immune cells to sites of inflammation and injury. In recent years, it has become clear that the function of chemokines extends well beyond the role in leukocyte chemotaxis. They participate in organ development, angiogenesis/angiostasis, leukocyte trafficking and homing, tumorigenesis and metastasis, as well as in immune responses to microbial infection. Therefore, chemokines and their receptors are important targets for modulation of host responses in pathophysiological conditions and for therapeutic intervention of human diseases. C1 [Le, Yingying; Zhou, Ye; Iribarren, Pablo; Wang, Ji Ming] NCI, Mol Immunoregulat Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Le, YY (reprint author), NCI, Mol Immunoregulat Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM ley@ncifcrf.gov; wangji@ncifcrf.gov FU Federal funds from the National Cancer Institute, National Institutes of Health [N01-C0-12400]; U.S. Government FX The authors thank Dr. Joost J. Oppenheim for reviewing the manuscript; Wanghua Gong and Nancy M. Dunlop for technical support. The secretarial assistance by C. Fogle and C. Nolan is gratefully acknowledged. This project has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. N01-C0-12400.; The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The publisher or recipient acknowledges right of the U.S. Government to retain a nonexclusive, royalty-free license in and to any copyright covering the article. NR 104 TC 157 Z9 165 U1 2 U2 8 PU CHIN SOCIETY IMMUNOLOGY PI BEING PA 5 DONGDAN SANTIAO, DONGCHEN DISTRICT, BEING, 100005, PEOPLES R CHINA SN 1672-7681 EI 2042-0226 J9 CELL MOL IMMUNOL JI Cell. Mol. Immunol. PD APR PY 2004 VL 1 IS 2 BP 95 EP 104 PG 10 WC Immunology SC Immunology GA V31ZT UT WOS:000208922200003 PM 16212895 ER PT J AU Randazzo, PA Hirsch, DS AF Randazzo, PA Hirsch, DS TI Arf GAPs: multifunctional proteins that regulate membrane traffic and actin remodelling SO CELLULAR SIGNALLING LA English DT Review DE ADP ribosylation factor; GTPase activating proteins; enclosomes; Golgi apparatus; membrane traffic; actin; cytoskeleton; focal adhesions ID ADP-RIBOSYLATION-FACTOR; GTPASE-ACTIVATING PROTEIN; TRANS-GOLGI NETWORK; LUTEINIZING HORMONE/CHORIOGONADOTROPIN RECEPTOR; PAXILLIN KINASE LINKER; FOCAL ADHESION KINASE; OVARIAN FOLLICULAR MEMBRANES; ZINC-FINGER MOTIF; BINDING-PROTEIN; COATED VESICLES AB The ADP-fibosylation factor (Arf) Arf GTPase-activating proteins (GAPs) are a family of proteins that induce hydrolysis of GTP bound to Arf. A conserved domain containing a zinc finger motif mediates catalysis. The substrate, Arf GTP, affects membrane trafficking and actin remodelling. Consistent with activity as an Arf regulator, the Arf GAPs affect both of these pathways. However, the Arf GAPs are likely to have Arf-independent activities that contribute to their cellular functions. Structures of the Arf GAPs are diverse containing catalytic, protein-protein interaction and lipid interaction domains in addition to the Arf GAP domain. Some Arf GAPs have been identified and characterized on the basis of activities other than Arf GAP. Here, we describe the Arf GAP family, enzymology of some members of the Arf GAP family and known functions of the proteins. The results discussed illustrate roles for both Arf-dependent and -independent activities in the regulation of cellular architecture. (C) 2003 Elsevier Inc. All rights reserved. C1 NCI, Canc Res Ctr, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Randazzo, PA (reprint author), NCI, Canc Res Ctr, Cellular Oncol Lab, Bldg 37,Room 4118, Bethesda, MD 20892 USA. EM randazzo@helix.nih.gov NR 150 TC 136 Z9 140 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 J9 CELL SIGNAL JI Cell. Signal. PD APR PY 2004 VL 16 IS 4 BP 401 EP 413 DI 10.1016/j.eellsig.2003.09.012 PG 13 WC Cell Biology SC Cell Biology GA 765PX UT WOS:000188293600001 PM 14709330 ER PT J AU Floel, A Poeppel, D Buffalo, EA Braun, A Wu, CWH Seo, HJ Stefan, K Knecht, S Cohen, LG AF Floel, A Poeppel, D Buffalo, EA Braun, A Wu, CWH Seo, HJ Stefan, K Knecht, S Cohen, LG TI Prefrontal cortex asymmetry for memory encoding of words and abstract shapes SO CEREBRAL CORTEX LA English DT Article DE episodic memory; frontal cortex; nonverbal; transcranial magnetic stimulation; verbal ID TRANSCRANIAL MAGNETIC STIMULATION; MEDIAL TEMPORAL-LOBE; LONG-TERM-MEMORY; EPISODIC MEMORY; FRONTAL LOBES; RECOGNITION MEMORY; BRAIN ACTIVITY; LATERALIZATION; SPECIALIZATION; NEUROSCIENCE AB Previous work suggested a differential contribution of prefrontal cortex (PFC) to successful encoding depending on the stimulus material. Here, we tested the hypothesis that encoding of words preferentially involves the left PFC, while encoding of nonverbal items (abstract shapes) relies on the right PFC. We used an experimental design that evaluated encoding of both words and abstract shapes in the same healthy volunteers. A transient virtual lesion of the left or the right PFC was elicited with transcranial magnetic stimulation (TMS) while subjects memorized verbal and nonverbal items. We found that encoding of verbal material was disrupted by left PFC stimulation, whereas encoding of nonverbal material was disrupted by right PFC stimulation. These results demonstrate a functionally relevant lateralization of prefrontal contribution for verbal and nonverbal memory encoding. C1 NINDS, Cort Phys Sect, NIH, Bethesda, MD 20892 USA. Univ Munster, Dept Neurol, D-4400 Munster, Germany. Univ Maryland, Dept Linguist, College Pk, MD 20742 USA. Univ Maryland, Dept Biol, College Pk, MD 20742 USA. NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. NIDCD, Voice Speech & Language Branch, NIH, Bethesda, MD USA. RP Cohen, LG (reprint author), NINDS, Cort Phys Sect, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM cohenl@ninds.nih.gov RI Floel, Agnes/A-9426-2017; OI Knecht, Stefan/0000-0003-1056-9228 NR 48 TC 72 Z9 72 U1 2 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD APR PY 2004 VL 14 IS 4 BP 404 EP 409 DI 10.1093/cercor/bhh002 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 805AQ UT WOS:000220339600005 PM 15028644 ER PT J AU Hershkowitz, I Horowitz, D Lamb, ME Orbach, Y Sternberg, KJ AF Hershkowitz, I Horowitz, D Lamb, ME Orbach, Y Sternberg, KJ TI Interviewing youthful suspects in alleged sex crimes: a descriptive analysis SO CHILD ABUSE & NEGLECT LA English DT Article DE sexual abuse; forensic interviews; juvenile sexual offenders ID INVESTIGATIVE UTTERANCE TYPES; CHILD WITNESSES; ABUSE VICTIMS; FORENSIC INTERVIEWS/; QUESTION TYPE; CONTRADICTIONS; RESPONSES AB Objective: To introduce and evaluate a structured interview protocol designed for investigative interviews of youthful alleged perpetrators of child sexual abuse. Method: Seventy-two alleged perpetrators ranging from 9 to 14 years of age (M = 12 years) were interviewed by I of 13 experienced youth investigators, employed by the Israeli Ministry of Labour and Social Affairs, about incidents that had been reported by alleged victims. All interviews were conducted as part of the investigators' regular work and followed the structured interview guide appended to this article. Results: Interviewers questioned older and younger children similarly, but addressed fewer invitations, directive questions, and option-posing prompts to suspects who denied the allegations than to those who partially or fully admitted them. The total number of details provided by the suspects did not vary depending on their age or whether or not they fully or partially admitted the allegations. In both cases, more information was elicited using invitations rather than suggestive or option-posing prompts. Conclusion: Contrary to expectations, suspects who at least partially admitted their involvement provided considerable amounts of information and were very responsive to free recall prompts, although interviewers used more risky (potentially en-or-inducing) prompts when interviewing suspects rather than alleged victims. Published by Elsevier Ltd. C1 NICHHD, Sect Social & Emot Dev, Bethesda, MD 20892 USA. NICHHD, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Minist Labour & Social Affairs, Dept Youth Invest, Jerusalem, Israel. Univ Haifa, Sch Social Work, Haifa, Israel. RP Lamb, ME (reprint author), NICHHD, Sect Social & Emot Dev, Rockledges 1 Ctr,Suite 8047,6705 Rockledge Dr, Bethesda, MD 20892 USA. NR 36 TC 17 Z9 17 U1 1 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2134 J9 CHILD ABUSE NEGLECT JI Child Abuse Negl. PD APR PY 2004 VL 28 IS 4 BP 423 EP 438 DI 10.1016/j.chiabu.2003.09.021 PG 16 WC Family Studies; Psychology, Social; Social Work SC Family Studies; Psychology; Social Work GA 820DD UT WOS:000221366100006 PM 15120924 ER PT J AU Redman, AR Dickmann, LJ Kidd, RS Goldstein, JA Ritchie, DM Hon, YY AF Redman, AR Dickmann, LJ Kidd, RS Goldstein, JA Ritchie, DM Hon, YY TI CYP2C9 genetic polymorphisms and warfarin SO CLINICAL AND APPLIED THROMBOSIS-HEMOSTASIS LA English DT Article DE warfarin; cytochrome P-450 enzyme system; genotype ID HUMAN LIVER-MICROSOMES; CYTOCHROME P4502C9; ANTICOAGULATION THERAPY; DOSE REQUIREMENT; METABOLISM; ASSOCIATION; ENANTIOMERS; VARIANTS; IDENTIFICATION; PHENYTOIN AB The objective of this study was to report 2 cases of CYP2C9 genetic polymorphism and elevated warfarin S:R ratios in patients taking low doses of warfarin, and compare the observed characteristics with those in published reports. Two patients of different age groups and races were evaluated for CYP2C9 genotype and warfarin S:R ratios. The patients had been stabilized on weekly warfarin doses of 10.5 mg and 10 mg, respectively. Each patient was found to have at least I variant CYP2C9 allele. Elevated warfarin S:R ratios in both patients provided evidence for impaired metabolism of S-warfarin. This report of a CYP2C9*3 heterozygous individual taking a low dose of warfarin is consistent with previous reports in the literature. This summary of a CYP2C9*6 homozygous individual taking a low dose of warfarin is the first such published report. CYP2C9 genotyping in these patients provided a likely explanation for their continued low warfarin dosage requirements. Awareness of a patient's CYP2C9 genotype may provide an explanation for low warfarin dosage requirements in stable patients and may help in determining the optimal dose in patients being initiated on warfarin. C1 Mercer Univ, So Sch Pharm, Dept Clin & Adm Sci, Atlanta, GA 30341 USA. Univ Washington, Dept Med Chem, Seattle, WA 98195 USA. Shenandoah Univ, Bernard J Dunn Sch Pharm, Dept Biopharmaceut Sci, Winchester, VA USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. Atlanta Vet Affairs Med Ctr, Anticoagulat Clin, Atlanta, GA USA. RP Redman, AR (reprint author), Mercer Univ, So Sch Pharm, Dept Clin & Adm Sci, 3001 Mercer Univ Dr, Atlanta, GA 30341 USA. EM Redman_ar@mercer.edu RI Goldstein, Joyce/A-6681-2012 NR 25 TC 12 Z9 12 U1 0 U2 0 PU WESTMINSTER PUBL INC PI GLEN HEAD PA 708 GLEN COVE AVE, GLEN HEAD, NY 11545 USA SN 1076-0296 J9 CLIN APPL THROMB-HEM JI Clin. Appl. Thromb.-Hemost. PD APR PY 2004 VL 10 IS 2 BP 149 EP 154 DI 10.1177/107602960401000205 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 812ZL UT WOS:000220877300005 PM 15094935 ER PT J AU Srivastava, M Bubendorf, L Raffeld, M Bucher, C Torhorst, J Sauter, G Olsen, C Kallioniemi, OP Eidelman, O Pollard, HB AF Srivastava, M Bubendorf, L Raffeld, M Bucher, C Torhorst, J Sauter, G Olsen, C Kallioniemi, OP Eidelman, O Pollard, HB TI Prognostic impact of ANX7-GTPase in metastatic and HER2-negative breast cancer patients SO CLINICAL CANCER RESEARCH LA English DT Article ID TISSUE MICROARRAYS; PROSTATE-CANCER; GENE; ANX7 AB Purpose: ANX7-GTPase located on chromosome 10q21 is significantly altered and associated with hormone-refractory metastatic prostate cancers. Therefore, we investigated whether levels of ANX7 correlate with breast cancer progression and survival Experimental Design: A diagnostic tumor tissue microarray containing 525 human breast tissue specimens at different stages of the disease was assayed for ANX7 using immunocytochemical methods with ANX7 monoclonal antibody. A separate prognostic tumor tissue microarray containing 553 human breast tissue specimens annotated with clinicopathological parameters was assayed for ANX7, HER2, estrogen receptor, progesterone receptor, and p53 protein. Results: We report here for the first time that the expression of ANX7-GTPase is significantly enhanced and associated with the presence of metastatic disease (P < 0.0001) in the 525 human breast tissue specimens analyzed. Furthermore, using a separate 553 case retrospective prognostic tumor tissue microarray, we found that increased ANX7 expression is also significantly associated with poor overall patient survival (P < 0.014). This is particularly true when restricted to patients in whom the BRE clinical grade is 2 (P < 0.001) or for whom there is a lack of HER2 expression (P < 0.002). Finally, Cox regression analysis shows that as the expression of ANX7 rises, the probability of survival decreases by more than 10-fold for those patients with HER2-negative tumors. These latter patients represented 66% of the population affected with breast cancer in this study. Conclusions: High levels of ANX7 in tumor correlate strongly with poor survival of HER2-negative patients and the most aggressive forms of breast cancer. This is the first study to demonstrate that ANX7 antibody has the potential for development into an in vivo diagnostic and therapeutic tool. This simple and reliable immunohistochemical assay may therefore become an important biomarker for metastatic breast cancer diagnosis and management of HER2-negative breast tumor patients. C1 Uniformed Serv Univ Hlth Sci, Sch Med, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. Univ Basel, Inst Pathol, Basel, Switzerland. NCI, Pathol Lab, Hematopathol Sect, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Sch Med, Inst Mol Med, Bethesda, MD 20814 USA. NHGRI, Mol Genet Sect, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Srivastava, M (reprint author), Uniformed Serv Univ Hlth Sci, Sch Med, Dept Anat Physiol & Genet, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM msrivastava@usuhs.mil RI bucher, christoph/A-2520-2008; Kallioniemi, Olli/H-5111-2011; Bubendorfl, Lukas/H-5880-2011; Kallioniemi, Olli/H-4738-2012 OI Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332 NR 16 TC 24 Z9 40 U1 0 U2 0 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 APR 1 PY 2004 VL 10 IS 7 BP 2344 EP 2350 DI 10.1158/1078-0432.CCR-03-0278 PG 7 WC Oncology SC Oncology GA 810JX UT WOS:000220701700019 PM 15073110 ER PT J AU Harden, SV Thomas, DC Benoit, N Minhas, K Westra, WH Califano, JA Koch, W Sidransky, D AF Harden, SV Thomas, DC Benoit, N Minhas, K Westra, WH Califano, JA Koch, W Sidransky, D TI Real-time gap ligase chain reaction: A rapid semiquantitative assay for detecting p53 mutation at low levels in surgical margins and lymph nodes from resected lung and head and neck tumors SO CLINICAL CANCER RESEARCH LA English DT Article ID MINIMAL RESIDUAL CANCER; MOLECULAR ASSESSMENT; GENE-MUTATIONS; DNA; LIGATION; IDENTIFICATION; DISEASE; TISSUE; CELLS AB Purpose: We have developed a real-time semiquantitative gap ligase chain reaction for detecting p53 point mutations at low level in a background of excess of wild-type DNA. Experimental Design: This method was validated by direct comparison to a previously validated but cumbersome phage plaque hybridization assay. Forty-one surgical margins and lymph nodes from 10 cases of head and neck squamous cell carcinoma and lung carcinoma were tested for p53 mutant clones. Results: Both methods detected p53 mutants in margins from 8 of the 10 cases, whereas standard pathology detected cancer cells in only 3 cases. Positive margins included tissue samples with a tumor/normal DNA ratio of up to 1:1000. Conclusions: This novel molecular approach can be performed in <5 h facilitating intraoperative use for realtime surgical resection. C1 Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. RP Sidransky, D (reprint author), Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, 818 Ross Res Bldg,720 Rutland Ave, Baltimore, MD 21205 USA. EM dsidrans@jhmi.edu FU NIDCR NIH HHS [5R01 DE13152, R01 DE12588-04] NR 24 TC 18 Z9 19 U1 4 U2 7 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 APR 1 PY 2004 VL 10 IS 7 BP 2379 EP 2385 DI 10.1158/1078-0432.CCR-03-0405 PG 7 WC Oncology SC Oncology GA 810JX UT WOS:000220701700023 PM 15073114 ER PT J AU Yanagawa, N Tamura, G Honda, T Endoh, M Nishizuka, S Motoyama, T AF Yanagawa, N Tamura, G Honda, T Endoh, M Nishizuka, S Motoyama, T TI Demethylation of the Synuclein gamma gene CpG island in primary gastric cancers and gastric cancer cell lines SO CLINICAL CANCER RESEARCH LA English DT Article ID DNA METHYLATION; HYPOMETHYLATION; BREAST; IDENTIFICATION; EXPRESSION; CARCINOGENESIS; POLYMORPHISM; CARCINOMA AB Purpose: Whereas synuclein gamma (SNCG) gene expression is usually highly tissue-specific and restricted to the nervous system, SNCG is expressed in advanced-stage breast and ovarian cancers. When overexpressed, SNCG stimulates cancer cell proliferation and metastasis. It is thought that the molecular mechanism of CpG island demethylation may underlie aberrant SNCG expression. To determine whether aberrant SNCG expression and demethylation play a role in gastric carcinogenesis, we examined the expression and methylation status of SNCG in primary gastric cancers, gastric cancer cell lines, and non-neoplastic gastric mucosal tissues. Experimental Design: Ten gastric cancer cell lines, 105 primary gastric cancers, and 10 non-neoplastic gastric mucosal tissues were examined. SNCG expression and methylation status were examined by reverse transcription-PCR and bisulfite-single-strand conformational polymorphism followed by direct sequencing, respectively. The relationship between SNCG methylation status and various clinicopathological factors of the primary gastric cancers was then analyzed. Results: SNCG mRNA expression was observed in 5 of 10 cell lines. Analysis of cell lines positive for SNCG expression revealed that most of the SNCG CpGs were demethylated. SNCG mRNA was not expressed in the 10 non-neoplastic gastric mucosal tissues, although several CpGs were demethylated. Of the 105 primary gastric cancers, 40 (38.1%) showed apparent SNCG demethylation, similar to the result obtained using cell lines. SNCG demethylation was more frequent in primary gastric cancers positive for lymph node metastasis (51%; 26 of 51) than in cancers without lymph node involvement (26%; 14 of 54; P < 0.05), and also more common in stage II-IV (48%; 27 of 56) than in stage I (27%; 13 of 49) cancers (P < 0.05). Conclusions: Aberrant SNCG gene expression can occur via CpG island demethylation, and tends to occur during the more progressive stages of gastric carcinogenesis. C1 Yamagata Univ, Sch Med, Dept Pathol, Yamagata 9909585, Japan. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Tamura, G (reprint author), Yamagata Univ, Sch Med, Dept Pathol, 2-2-2 Iida Nishi, Yamagata 9909585, Japan. EM gtamura@med.id.yamagata-u.ac.jp NR 25 TC 41 Z9 48 U1 0 U2 0 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 APR 1 PY 2004 VL 10 IS 7 BP 2447 EP 2451 DI 10.1158/1078-0432.CCR-03-0107 PG 5 WC Oncology SC Oncology GA 810JX UT WOS:000220701700032 PM 15073123 ER PT J AU Neville, K Parise, RA Thompson, P Aleksic, A Egorin, MJ Balis, FM McGuffey, L McCully, C Berg, SL Blaney, SM AF Neville, K Parise, RA Thompson, P Aleksic, A Egorin, MJ Balis, FM McGuffey, L McCully, C Berg, SL Blaney, SM TI Plasma and cerebrospinal fluid pharmacokinetics of imatinib after administration to nonhuman primates SO CLINICAL CANCER RESEARCH LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; ABL TYROSINE KINASE; ACUTE LYMPHOBLASTIC-LEUKEMIA; PHILADELPHIA-CHROMOSOME; BCR-ABL; ALPHA-1-ACID GLYCOPROTEIN; CYTOGENETIC RESPONSES; MESYLATE; INHIBITOR AB Purpose: Imatinib mesylate (Gleevec, Glivec, STI571, imatinib) is a potent tyrosine kinase inhibitor approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. The role of imatinib in the treatment of malignant gliomas and other solid tumors is being evaluated. We used a nonhuman primate model that is highly predictive of the cerebrospinal fluid penetration of drugs in humans to study the pharmacokinetics of imatinib in plasma and cerebrospinal fluid (CSF) after i.v. and p.o. administration. Experimental Design: Imatinib, 15 mg/kg i.v. over 30 min (n = 3) or 30 mg/kg p.o. (n = 3), was administered to nonhuman primates. Imatinib was measured in serial samples of plasma and CSF using high-pressure liquid chromatography with UV absorbance or mass spectroscopic detection. Pharmacokinetic parameters were estimated using model-independent methods. Results: Peak plasma imatinib concentrations ranged from 6.4 to 9.5 muM after i.v. dosing and 0.8 to 2.8 muM after p.o. dosing. The mean +/- SD area under the plasma concentration versus time curve was 2480 +/- 1340 muM(.)min and 1191 +/- 146 muM(.)min after i.v. and p.o. dosing, respectively. The terminal half-life was 529 +/- 167, min after i.v. dosing and 266 +/- 88 min after p.o. dosing. After i.v. dosing the steady state volume of distribution was 5.9 +/- 2.8 liter/kg, and the total body clearance was 12 +/- 5 ml/min/kg. The mean peak CSF concentration was 0.25 +/- 0.07 muM after i.v. dosing and 0.07 +/- 0.04 muM after p.o. dosing. The mean CSF:plasma area under the plasma concentration versus time curve ratio for all of the animals was 5% +/- 2%. Conclusions: There is limited penetration of imatinib into the CSF of nonhuman primates after i.v. and p.o. administration. C1 Texas Childrens Canc Ctr, Houston, TX 77030 USA. Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. Univ Pittsburgh, Inst Canc, Program Mol Therapeut & Drug Discovery, Pittsburgh, PA USA. Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA. Univ Pittsburgh, Sch Med, Dept Pharmacol, Pittsburgh, PA 15261 USA. Natl Canc Inst, Pediat Oncol Branch, NIH, Bethesda, MD USA. RP Blaney, SM (reprint author), Texas Childrens Canc Ctr, 6621 Fannin St,CC1410 00, Houston, TX 77030 USA. EM sblaney@txccc.org FU NCI NIH HHS [2P30 CA 47904]; NICHD NIH HHS [U01 HD 37242-03S, U01 HD37242] NR 29 TC 46 Z9 49 U1 0 U2 0 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 APR 1 PY 2004 VL 10 IS 7 BP 2525 EP 2529 DI 10.1158/1078-0432.CCR-03-0155 PG 5 WC Oncology SC Oncology GA 810JX UT WOS:000220701700041 PM 15073132 ER PT J AU Ouyang, XM Yam, D Hejtmancik, JF Jacobson, SG Li, AR Du, LL Angeli, S Kaiser, M Balkany, T Liu, XZ AF Ouyang, XM Yam, D Hejtmancik, JF Jacobson, SG Li, AR Du, LL Angeli, S Kaiser, M Balkany, T Liu, XZ TI Mutational spectrum in Usher syndrome type II SO CLINICAL GENETICS LA English DT Article DE USH2; USH2A; Usher syndrome; Usherin ID RECESSIVE DEAFNESS; GENOMIC STRUCTURE; GENE; PREVALENCE; PROTEIN; USH2A; IDENTIFICATION; HARMONIN; MEMBER; CDH23 AB Usher syndrome type II is an autosomal recessive disorder characterized by moderate to severe hearing impairment and progressive visual loss due to retinitis pigmentosa (RP). We carried out a mutation screening of the USH2A gene in 88 probands with Usher syndrome type II to determine the frequency of USH2A mutations as a cause for USH2. Six mutations, including 2299delG, 921-922insCAGC, R334W, N346H, R626X, and N357T were identified, with 2299delG mutation being the most frequent (16.5% of alleles), accounting for 77.5% of the pathologic alleles. Thirty-five percent (31/88) of the probands had a USH2A mutation. Nine of them carried two pathogenic mutations: six cases were homozygotes and three were compound heterozygotes. Twenty-two probands (25%) were found to carry only single USH2A mutations. One new missense mutation (N357T) occuring within the laminin N-terminal (type VI) domain of usherin was identified. Eight polymorphisms were found, five of which are novel. Our data support the view that the 2299delG is the most common mutation in USH2A. C1 Univ Miami, Dept Otolaryngol, Miami, FL 33136 USA. NEI, NIH, Bethesda, MD 20892 USA. Univ Penn, Scheie Eye Inst, Philadelphia, PA 19104 USA. RP Univ Miami, Dept Otolaryngol, D-48,1666 NW 12th Ave, Miami, FL 33136 USA. EM xliu@med.miami.edu FU NEI NIH HHS [EY-13385]; NIDCD NIH HHS [DC05575] NR 32 TC 17 Z9 18 U1 0 U2 2 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9163 EI 1399-0004 J9 CLIN GENET JI Clin. Genet. PD APR PY 2004 VL 65 IS 4 BP 288 EP 293 DI 10.1046/j.1399-0004.2004.00216.x PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 802QF UT WOS:000220177300008 PM 15025721 ER PT J AU Whybra, C Kampmann, C Krummenauer, F Ries, M Mengel, E Miebach, E Baehner, F Kim, K Bajbouj, M Schwarting, A Gal, A Beck, M AF Whybra, C Kampmann, C Krummenauer, F Ries, M Mengel, E Miebach, E Baehner, F Kim, K Bajbouj, M Schwarting, A Gal, A Beck, M TI The Mainz Severity Score Index: a new instrument for quantifying the Anderson-Fabry disease phenotype, and the response of patients to enzyme replacement therapy SO CLINICAL GENETICS LA English DT Article DE Anderson-Fabry disease; enzyme replacement therapy; Mainz Severity Score Index; alpha-galactosidase A ID CLINICAL MANIFESTATIONS; FEATURES; IMPACT; COHORT AB Anderson-Fabry disease (AFD) is an X-linked disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. The availability of enzyme replacement therapy (ERT) for this debilitating condition has led to the need for a convenient and sensitive instrument to monitor clinical effects in an individual patient. This study aimed to develop a scoring system - the Mainz Severity Score Index (MSSI) - to measure the severity of AFD and to monitor the clinical course of the disease in response to ERT. Thirty-nine patients (24 males and 15 females) with AFD were assessed using the MSSI immediately before and 1 year after commencing agalsidase alfa ERT. Control data were obtained from 23 patients in whom AFD was excluded. The MSSI of patients with AFD was significantly higher than that of patients with other severe debilitating diseases. The MSSI indicated that, although more men than women had symptoms classified as severe, overall, the median total severity scores were not significantly different between male and female patients. One year of ERT with agalsidase alfa led, in all patients, to a significant (p < 0.001) reduction in MSSI score (by a median of nine points). This study has shown that the MSSI score may be a useful, specific measure for objectively assessing the severity of AFD and for monitoring ERT-related treatment effects. C1 Univ Mainz, Childrens Hosp, D-55131 Mainz, Germany. Univ Mainz, Dept Med Biometry Epidemiol & Informat, D-6500 Mainz, Germany. NINDS, Dev & Metab Neurol Branch, Bethesda, MD USA. Univ Mainz, Dept Nephrol, D-6500 Mainz, Germany. Univ Hamburg, Inst Human Genet, D-2000 Hamburg, Germany. RP Beck, M (reprint author), Univ Mainz, Childrens Hosp, Langenbeckstr 1, D-55131 Mainz, Germany. EM beck@kinder.klinik.uni-mainz.de OI Ries, Markus/0000-0002-5054-5741 NR 12 TC 129 Z9 133 U1 0 U2 2 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD APR PY 2004 VL 65 IS 4 BP 299 EP 307 DI 10.1111/j.1399-0004.2004.00219.x PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 802QF UT WOS:000220177300010 PM 15025723 ER PT J AU Easton, AJ Domachowske, JB Rosenberg, HF AF Easton, AJ Domachowske, JB Rosenberg, HF TI Animal pneumoviruses: Molecular genetics and pathogenesis SO CLINICAL MICROBIOLOGY REVIEWS LA English DT Review ID RESPIRATORY SYNCYTIAL-VIRUS; TURKEY RHINOTRACHEITIS VIRUS; REPLICATION IN-VITRO; EXPERIMENTALLY INFECTED CALVES; ATTACHMENT G-PROTEIN; AMINO-ACID-SEQUENCE; MACROPHAGE-INFLAMMATORY PROTEIN-1-ALPHA; MONOCLONAL-ANTIBODY PALIVIZUMAB; TRANSCRIPTION ELONGATION-FACTOR; HUMAN METAPNEUMOVIRUS INFECTION AB Pneumoviruses are single-stranded, negative-sense, nonsegmented RNA viruses of the family Paramyxoviridae, subfamily Pneumovirinae, and include pathogens that infect humans (respiratory syncytial virus and human metapneumovirus), domestic mammals (bovine, ovine, and caprine respiratory syncytial viruses), rodents (pneumonia virus of mice), and birds (avian metapneumovirus). Among the topics considered in this review are recent studies focused on the roles of the individual virus-encoded components in promoting virus replication as well as in altering and evading innate antiviral host defenses. Advances in the molecular technology of pneumoviruses and the emergence of recombinant pneumoviruses that are leading to improved virus-based vaccine formulations are also discussed. Since pneumovirus infection in natural hosts is associated with a profound inflammatory response that persists despite adequate antiviral therapy, we also review the recent experimental treatment strategies that have focused on combined antiviral, anti-inflammatory, and immunomodulatory approaches. C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. Statae Univ New York Upstate Med Univ, Syracuse, NY USA. RP Rosenberg, HF (reprint author), NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike,Bldg 10,Room 11N104, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov NR 389 TC 100 Z9 101 U1 1 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0893-8512 J9 CLIN MICROBIOL REV JI Clin. Microbiol. Rev. PD APR PY 2004 VL 17 IS 2 BP 390 EP + DI 10.1128/CMR.17.2.390-412.2004 PG 24 WC Microbiology SC Microbiology GA 814JX UT WOS:000220972100008 PM 15084507 ER PT J AU Kitago, T Mazzocchio, R Liuzzi, G Cohen, LG AF Kitago, T Mazzocchio, R Liuzzi, G Cohen, LG TI Modulation of H-reflex excitability by tetanic stimulation SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE H-reflex; somatosensory evoked potential; transcranial magnetic stimulation; locomotor; plasticity ID SPINAL-CORD; MOTOR SYSTEMS; PLASTICITY; POTENTIATION AB Objective: This study investigated a strategy to elicit reversible facilitation of the soleus monosynaptic H-reflex in humans using a modified tetanic stimulation technique. Methods: Interventional tetanic stimulation (ITS) was applied to the tibial nerve in the popliteal fossa, and soleus H-reflexes were recorded before and after stimulation in 15 healthy volunteers. Results: ITS resulted in significantly increased soleus H-reflex amplitudes that outlasted the stimulation period by approximately 16 min. The effect of ITS on soleus motor evoked potentials to transcranial magnetic stimulation and on somatosensory evoked potentials to tibial nerve stimulation was also investigated; no significant changes were found. Conclusions: ITS produced a reversible increase in H-reflexes in the absence of changes in motor evoked potential or somatosensory evoked potential that outlasted the intervention period for up to 16 min. Significance: This technique may be used in future studies to investigate whether the induced increased H-reflex excitability influences locomotion. (C) 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. C1 NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. Univ Siena, Dipartimento Sci Neurol & Comportamento, Sez Neurofisiol Clin, I-53100 Siena, Italy. RP Cohen, LG (reprint author), NINDS, Human Cort Physiol Sect, NIH, Bldg 10,Room 5N226,10 Ctr Dr MSC 1430, Bethesda, MD 20892 USA. EM cohenl@ninds.nih.gov RI Mazzocchio, Riccardo/H-4223-2012 OI Mazzocchio, Riccardo/0000-0002-0628-2868 NR 21 TC 20 Z9 21 U1 1 U2 4 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1388-2457 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD APR PY 2004 VL 115 IS 4 BP 858 EP 861 DI 10.1016/j.clinph.2003.11.029 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 806DO UT WOS:000220414800017 PM 15003766 ER PT J AU Mulligan, R Phelan, JA Brunelle, J Redford, M Pogoda, JM Nelson, E Seirawan, H Greenspan, JS Navazesh, M Greenspan, D Alves, MEAF AF Mulligan, R Phelan, JA Brunelle, J Redford, M Pogoda, JM Nelson, E Seirawan, H Greenspan, JS Navazesh, M Greenspan, D Alves, MEAF TI Baseline characteristics of participants in the oral health component of the Women's Interagency HIV Study SO COMMUNITY DENTISTRY AND ORAL EPIDEMIOLOGY LA English DT Article DE caries; CD4 count; demographics; dental; HIV; periodontal disease; WIHS; women ID SALIVARY-GLAND HYPOFUNCTION; DIAGNOSTIC-CRITERIA; MILITARY PERSONNEL; MUCOSAL LESIONS; VIRAL LOAD; INFECTION; MANIFESTATIONS; CANDIDIASIS; PREVALENCE; DISEASE AB Objectives: This study described baseline sociodemographic and oral health characteristics of a subset of HIV sero-positive and sero-negative women who participated in the oral health component of the Women's Interagency HIV Study (WIHS). Methods: In 1995-96, 584 HIV sero-positive and 151 sero-negative women from five WIHS core sites were enrolled in the oral study. Data on oral mucosa, salivary glands, dentition and periodontium, along with demographics, socioeconomics, and behavioral characteristics, were used to characterize this population. Results: Mean (SD) age was 37 (8) years for HIV sero-positive and 36 (8) years for sero-negative women; 27% of sero-positive women had CD4 counts less than or equal to200 and 34% had viral loads >50000 copies/ml. Sero-positive and sero-negative women were similar demographically, as well as on plaque index, gingival bleeding, linear gingival banding, and numbers of DMF teeth and surfaces, but sero-positive women had more abnormal gingival papilla (P=0.004) and fewer teeth (P=0.01). Among sero-positive women, those with <200 CD4 counts had more DMF teeth (P=0.007), and the number of DMF surfaces increased with decreasing CD4 counts (P=0.04). Sero-positive women who fit the Center for Disease Control (CDC) AIDS criteria were also more likely to have more DMF teeth (P=0.004), DMF surfaces (P=0.003), and decayed and/or filled (DF) root surfaces (P=0.0002) compared to sero-positive women without AIDS. Conclusions: Dental and periodontal variables showed little difference between HIV sero-positive and sero-negative women. Among sero-positive women, there were significant differences in coronal and root caries by AIDS diagnostic criteria, but no periodontal indicators by either AIDS diagnostic criteria or CD4 status, were observed. C1 Univ So Calif, Sch Dent, Los Angeles, CA 90089 USA. NYU, Coll Dent, New York, NY USA. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. NEI, NIH, Bethesda, MD 20892 USA. Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Illinois, Coll Dent, Chicago, IL USA. RP Mulligan, R (reprint author), Univ So Calif, Sch Dent, 925 W 34th St,Room 4338, Los Angeles, CA 90089 USA. EM mulligan@usc.edu FU NICHD NIH HHS [5U01HD32632] NR 41 TC 16 Z9 18 U1 0 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0301-5661 J9 COMMUNITY DENT ORAL JI Community Dentist. Oral Epidemiol. PD APR PY 2004 VL 32 IS 2 BP 86 EP 98 DI 10.1111/j.0301-5661.2004.00128.x PG 13 WC Dentistry, Oral Surgery & Medicine; Public, Environmental & Occupational Health SC Dentistry, Oral Surgery & Medicine; Public, Environmental & Occupational Health GA 808SO UT WOS:000220589000002 PM 15061857 ER PT J AU Yeganova, L Smith, L Wilbur, WJ AF Yeganova, L Smith, L Wilbur, WJ TI Identification of related gene/protein names based on an HMM of name variations SO COMPUTATIONAL BIOLOGY AND CHEMISTRY LA English DT Article DE automatic term recognition; gene name variation; hidden Markov model; information extraction ID HIDDEN MARKOV-MODELS; BIOMEDICAL LITERATURE; GENE ONTOLOGY; PROTEIN NAMES; SEQUENCE; SEARCH; TERMS; TEXT; TOOL AB Gene and protein names follow few, if any, true naming conventions and are subject to great variation in different occurrences of the same name. This gives rise to two important problems in natural language processing. First, can one locate the names of genes or proteins in free text, and second, can one determine when two names denote the same gene or protein? The first of these problems is a special case of the problem of named entity recognition, while the second is a special case of the problem of automatic term recognition (ATR), We study the second problem, that of gene or protein name variation. Here we describe a system which, given a query gene or protein name, identifies related gene or protein names in a large list. The system is based on a dynamic programming algorithm for sequence alignment in which the mutation matrix is allowed to vary under the control of a fully trainable hidden Markov model. (C) 2003 Published by Elsevier Ltd. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, NIH, Bethesda, MD 20894 USA. RP Yeganova, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, NIH, Bldg 38A,8600 Rockville Pike, Bethesda, MD 20894 USA. EM yegaiiova@ncbi.nlm.nih.gov NR 46 TC 12 Z9 13 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1476-9271 J9 COMPUT BIOL CHEM JI Comput. Biol. Chem. PD APR PY 2004 VL 28 IS 2 BP 97 EP 107 DI 10.1016/j.compbiolchem.2003.12.003 PG 11 WC Biology; Computer Science, Interdisciplinary Applications SC Life Sciences & Biomedicine - Other Topics; Computer Science GA 822XO UT WOS:000221574300001 PM 15130538 ER PT J AU Maxwell, SK Nuckols, JR Ward, MH Hoffer, RM AF Maxwell, SK Nuckols, JR Ward, MH Hoffer, RM TI An automated approach to mapping corn from Landsat imagery SO COMPUTERS AND ELECTRONICS IN AGRICULTURE LA English DT Article DE satellite remote sensing; geospatial technology; crop mapping; corn ID AREA ESTIMATION; MSS DATA; CLASSIFICATION; IDENTIFICATION; CROPS AB Most land cover maps generated from Landsat imagery involve classification of a wide variety of land cover types, whereas some studies may only need spatial information on a single cover type. For example, we required a map of corn in order to estimate exposure to agricultural chemicals for an environmental epidemiology study. Traditional classification techniques, which require the collection and processing of costly ground reference data, were not feasible for our application because of the large number of images to be analyzed. We present a new method that has the potential to automate the classification of corn from Landsat satellite imagery, resulting in a more timely product for applications covering large geographical regions. Our approach uses readily available agricultural area estimates to enable automation of the classification process resulting in a map identifying land cover as 'highly likely corn,' 'likely corn' or 'unlikely corn.' To demonstrate the feasibility of this approach, we produced a map consisting of the three corn likelihood classes using a Landsat image in south central Nebraska. Overall classification accuracy of the map was 92.2% when compared to ground reference data. (C) 2003 Elsevier B.V. All tights reserved. C1 US Geol Survey, Earth Resources Observ Syst Data Ctr, Sci Applicat Int Corp, Sioux Falls, SD 57198 USA. Colorado State Univ, Dept Forest Rangeland & Watershed Stewardship, Ft Collins, CO 80521 USA. NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. Colorado State Univ, Dept Environm & Radiol Hlth Sci, Ft Collins, CO 80523 USA. RP Maxwell, SK (reprint author), US Geol Survey, Earth Resources Observ Syst Data Ctr, Sci Applicat Int Corp, Sioux Falls, SD 57198 USA. EM maxwell@usgs.gov NR 21 TC 13 Z9 19 U1 1 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0168-1699 J9 COMPUT ELECTRON AGR JI Comput. Electron. Agric. PD APR PY 2004 VL 43 IS 1 BP 43 EP 54 DI 10.1016/j.compag.2003.09.001 PG 12 WC Agriculture, Multidisciplinary; Computer Science, Interdisciplinary Applications SC Agriculture; Computer Science GA 806PF UT WOS:000220445100003 ER PT J AU Goodman, PJ Tangen, CM Crowley, JJ Carlin, SM Ryan, A Coltman, CA Ford, LG Thompson, IM AF Goodman, PJ Tangen, CM Crowley, JJ Carlin, SM Ryan, A Coltman, CA Ford, LG Thompson, IM TI Implementation of the prostate cancer prevention trial (PCPT) SO CONTROLLED CLINICAL TRIALS LA English DT Article DE study organization; study management; chemoprevention; prostate cancer; finasteride ID ANTIGEN; 5-ALPHA-REDUCTASE; MEN; FINASTERIDE; HYPERPLASIA; INHIBITION AB The Prostate Cancer Prevention Trial is a randomized double blind chemoprevention trial of 18,882 men. It is designed to test the difference in the histologically proven prostate cancer prevalence between a group of participants given finasteride and another given placebo for 7 years. We present an overview of the study design, details of the administrative structure of the study and a description of the successful implementation of the accrual phase. (C) 2004 Elsevier Inc. All rights reserved. C1 SW Oncol Grp, Operat Off, San Antonio, TX 78245 USA. SW Oncol Grp, Ctr Stat, Seattle, WA 98109 USA. Natl Canc Inst, Clin Res, Bethesda, MD USA. San Antonio Canc Inst, San Antonio, TX USA. Univ Texas, Hlth Sci Ctr, Div Urol, San Antonio, TX USA. RP Goodman, PJ (reprint author), SW Oncol Grp, Operat Off, SWOG-9217,14980 Omicron Dr, San Antonio, TX 78245 USA. EM pgoodman@fhcrc.org FU NCI NIH HHS [CA38926, 5U10-CA37429] NR 17 TC 22 Z9 22 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD APR PY 2004 VL 25 IS 2 BP 203 EP 222 DI 10.1016/j.cct.2003.11.007 PG 20 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 809MA UT WOS:000220639600005 PM 15020037 ER PT J AU Patterson, AJ Zhu, WZ Chow, A Agrawal, R Kosek, J Xiao, RP Kobilka, B AF Patterson, AJ Zhu, WZ Chow, A Agrawal, R Kosek, J Xiao, RP Kobilka, B TI Protecting the myocardium: A role for the beta 2 adrenergic receptor in the heart SO CRITICAL CARE MEDICINE LA English DT Article DE adrenoceptor; knockout; myocardium; heart failure; apoptosis ID TACHYCARDIA-INDUCED CARDIOMYOPATHY; BETA-ADRENERGIC DRUGS; PDZ-BINDING MOTIF; CARDIAC MYOCYTES; TARGETED DISRUPTION; PRESENT STATE; APOPTOSIS; CONSEQUENCES; KINASE; MICE AB Objective: The sympathetic nervous system enhances cardiac muscle function by activating 0 adrenergic receptors (betaARs). Recent studies suggest that chronic PAR stimulation is detrimental, however, and that it may play a role in the clinical deterioration of patients with congestive heart failure. To examine the impact of chronic beta1AR and beta2AR subtype stimulation individually, we studied the cardiovascular effects of catecholamine infusions in PAR subtype knockout mice (beta1K0, beta2K0). Design: Prospective, randomized, experimental study. Setting: Animal research laboratory. Subjects: beta1K0 and beta2K0 mice and wild-type controls. Interventions. The animals were subjected to 2 wks of continuous infusion of the PAR agonist isoproterenol. Analyses of cardiac function and structure were performed during and 3 days after completion of the infusions. Functional studies included graded exercise treadmill testing, in vivo assessments of left ventricular function using Mikro-Tip catheter transducers, right ventricular pressure measurements, and analyses of organ weight to body weight ratios. Structural studies included heart weight measurements, assessments of myocyte ultrastructure using electron microscopy, and in situ terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick-end labeling staining to quantitate myocyte apoptosis. Measurements and Main Results: We found that isoproterenol-treated beta2K0 mice experienced greater mortality rates (p = .001, chi-square test using Fisher's exact method) and increased myocyte apoptosis at 3- and 7-day time points (p = .04 and p = .0007, respectively, two-way analysis of variance). Conclusion. The results of this study suggest that in vivo beta2AR activation is antiapoptotic and contributes to myocardial protection. C1 Stanford Univ, Med Ctr, Dept Anesthesia, Stanford, CA 94305 USA. Stanford Univ, Med Ctr, Dept Med, Stanford, CA 94305 USA. Stanford Univ, Med Ctr, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA. Vet Adm Med Ctr, Dept Pathol, Palo Alto, CA 94304 USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Patterson, AJ (reprint author), Stanford Univ, Med Ctr, Dept Anesthesia, Stanford, CA 94305 USA. EM ajpanes@leland.stanford.edu NR 34 TC 58 Z9 65 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD APR PY 2004 VL 32 IS 4 BP 1041 EP 1048 DI 10.1097/01.CCM.0000120049.43113.90 PG 8 WC Critical Care Medicine SC General & Internal Medicine GA 812XR UT WOS:000220872700021 PM 15071399 ER PT J AU Hamer, DH AF Hamer, DH TI Can HIV be cured? Mechanisms of HIV persistence and strategies to combat it SO CURRENT HIV RESEARCH LA English DT Review DE HIV-1; latency; viral reservoir; immunotoxin ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; CD4(+) T-CELLS; EXOTOXIN HYBRID PROTEIN; LONG TERMINAL REPEAT; NF-KAPPA-B; STRUCTURED TREATMENT INTERRUPTIONS; RESIDUAL VIRAL REPLICATION; HUMAN-FACTORS YY1; IN-VIVO AB Stable remission is the ultimate goal of HIV therapy. A review Of recent Studies oil the ability of HIV to persist despite highly active antiretroviral therapy (HAART) and immune stimulation Suggests that achieving this goal will require four developments in basic and clinical science. First, more effective antiretroviral therapies, targeted at proteins other than reverse transcriptase and protease, in order to eliminate the cryptic replication that continues despite best available HAART. Second, agents that activate latent HIV gene expression in quiescent CD4 memory T cells, thereby exposing this viral reservoir to therapeutic intervention by a "shock and kill" strategy. Third, molecules such as immunotoxins that specifically recognize HIV-encoded membrane proteins and thereby potentiate the destruction of infected cells. Fourth, and still most distant, novel approaches such as genetically engineered cytotoxic T lymphocytes or anti-HIV microbes to suppress rekindling of infection by residual virus sequestered ill anatomical and cellular reservoirs. Although each of these steps will be difficult to achieve, the many benefits of a cure for HIV make this a worthwhile pursuit. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Hamer, DH (reprint author), NCI, Biochem Lab, NIH, 9000 Rockville Pike,Bldg 37,Rm 60002, Bethesda, MD 20892 USA. EM DeanH@helix.nih.gov NR 183 TC 51 Z9 54 U1 0 U2 4 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 1570-162X J9 CURR HIV RES JI Curr. HIV Res. PD APR PY 2004 VL 2 IS 2 BP 99 EP 111 DI 10.2174/1570162043484915 PG 13 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 813VQ UT WOS:000220935000001 PM 15078175 ER PT J AU Pacher, P Kecskemeti, V AF Pacher, P Kecskemeti, V TI Trends in the development of new antidepressants. Is there a light at the end of the tunnel? SO CURRENT MEDICINAL CHEMISTRY LA English DT Review ID CORTICOTROPIN-RELEASING-FACTOR; SEROTONIN REUPTAKE INHIBITORS; MELANIN-CONCENTRATING-HORMONE; MAJOR DEPRESSIVE DISORDER; PLACEBO-CONTROLLED TRIAL; TREATMENT-REFRACTORY DEPRESSION; RECEPTOR ANTAGONISTIC ACTIVITY; IMPAIRED STRESS-RESPONSE; ANXIETY-RELATED BEHAVIOR; NEUROPEPTIDE-Y NPY AB Since the introduction of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) in mid-1950's, treatment of depression has been dominated by monoamine hypotheses. The well-established clinical efficacy of TCAs and MAOIs is due, at least in part, to the enhancement of noradrenergic or scrotonergic mechanisms, or to both. Unfortunately, their very broad mechanisms of action also include many unwanted effects related to their potent activity on cholinergic, adrenergic and histaminergic receptors. The introduction of selective serotonin reuptake inhibitors (SSRls) over twenty years ago had been the next major step in the evolution of antidepressants to develop drugs as effective as the TCAs but of higher safety and tolerability profile. During the past two decades SSRIs (fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram) gained incredible popularity and have become the most widely prescribed medication in the psychiatric practice. The evolution of antidepressants continued resulting in introduction of selective and reversible monoamine oxidase inhibitors (eg. moclobemid), selective noradrenaline (eg. reboxetine), dual noradrenaline and serotonin reuptake inhibitors (milnacipram, venlafaxin, duloxetin) and drugs with distinct neurochemical profiles such as mirtazapine, nefazadone and tianeptine. Different novel serotonin receptor ligands have also been intensively investigated. In spite of the remarkable structural diversity, most currently introduced antidepressants are 'monoamine based'. Furthermore, these newer agents are neither more efficacious nor rapid acting than their predecessors and approximately 30% of the population do not respond to current therapies. By the turn of the new millennium, we are all witnessing a result of innovative developmental strategies based on the better understanding of pathophysiology of depressive disorder. Several truly novel concepts have emerged suggesting that the modulation of neuropeptide (substance P, corticotrophin-releasing factor, neuropeptide Y, vasopressin V-lb, melanin-concentrating hormone-1), N-methyl-D-aspartate, nicotinic acetylcholine, dopaminergic, glucocorticoid, delta-opioid, cannabinoid and cytokine receptors, gamma-amino butyric acid (GABA) and intracellular messenger systems, transcription, neuroprotective and neurogenic factors, may provide an entirely new set of potential therapeutic targets, giving hope that further major advances might be anticipated in the treatment of depressive disorder soon. The goal of this review is to give a brief overview of the major advances from monoamine-based treatment strategies, and particularly focus on the new emerging approaches in the treatment of depression. C1 NIAAA, Lab Physiol Stuidies, NIH, Rockville, MD 20852 USA. Semmelweis Univ, Dept Pharmacol & Pharmacotherapy, Budapest, Hungary. RP Pacher, P (reprint author), NIAAA, Lab Physiol Stuidies, NIH, Pk Bldg,Rm 442,12420 Parklawn Dr,MSC 8115, Rockville, MD 20852 USA. EM ppacher@lycos.com RI Pacher, Pal/B-6378-2008 OI Pacher, Pal/0000-0001-7036-8108 FU Intramural NIH HHS [Z99 AA999999] NR 222 TC 97 Z9 105 U1 4 U2 18 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 0929-8673 J9 CURR MED CHEM JI Curr. Med. Chem. PD APR PY 2004 VL 11 IS 7 BP 925 EP 943 DI 10.2174/0929867043455594 PG 19 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 809KH UT WOS:000220635100010 PM 15078174 ER PT J AU Berg, JM Lippard, SJ AF Berg, JM Lippard, SJ TI Bioinorganic chemistry - Editorial overview SO CURRENT OPINION IN CHEMICAL BIOLOGY LA English DT Editorial Material C1 Natl Inst Gen Med Sci, Bethesda, MD 20892 USA. MIT, Dept Chem, Cambridge, MA 02139 USA. RP Berg, JM (reprint author), Natl Inst Gen Med Sci, 45 Ctr Dr, Bethesda, MD 20892 USA. EM bergj@mail.nih.gov; lippard@lippard.mit.edu OI Berg, Jeremy/0000-0003-3022-0963 NR 6 TC 2 Z9 3 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1367-5931 J9 CURR OPIN CHEM BIOL JI Curr. Opin. Chem. Biol. PD APR PY 2004 VL 8 IS 2 BP 160 EP 161 DI 10.1016/j.cbpa.2004.02.014 PG 2 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 815XN UT WOS:000221075100009 ER PT J AU Plosky, BS Woodgate, R AF Plosky, BS Woodgate, R TI Switching from high-fidelity replicases to low-fidelity lesion-bypass polymerases SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Article ID UBIQUITIN-CONJUGATING-ENZYME; DNA-DAMAGE CHECKPOINT; THYMINE DIMER BYPASS; SACCHAROMYCES-CEREVISIAE; ESCHERICHIA-COLI; XERODERMA-PIGMENTOSUM; POSTREPLICATION REPAIR; INDUCED MUTAGENESIS; CRYSTAL-STRUCTURE; ERROR-PRONE AB Replication of damaged DNA often requires a DNA polymerase in addition to the cell's normal replicase. Recent research has begun to shed light on the switch from a high-fidelity replicative polymerase to a low-fidelity translesion polymerase that occurs at a stalled replication fork. A picture is emerging in which eukaryotic replicative clamps are posttranslationally modified by ubiquitination, SUMOylation or phosphorylation. It is believed that such modifications help to regulate the access of translesion polymerases to the nascent primer terminus. C1 NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. RP Plosky, BS (reprint author), NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. EM woodgate@nih.gov NR 52 TC 88 Z9 88 U1 0 U2 4 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD APR PY 2004 VL 14 IS 2 BP 113 EP 119 DI 10.1016/j.gde.2004.02.002 PG 7 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 812II UT WOS:000220832800003 PM 15196456 ER PT J AU Hakim, FT Flomerfelt, FA Boyiadzis, M Gress, RE AF Hakim, FT Flomerfelt, FA Boyiadzis, M Gress, RE TI Aging, immunity and cancer SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID CD8(+) T-CELLS; BONE-MARROW-TRANSPLANTATION; LEUKEMIA INHIBITORY FACTOR; AGE-RELATED-CHANGES; THYMIC ATROPHY; INTENSIVE CHEMOTHERAPY; ELDERLY HUMANS; NK CELLS; B-CELLS; RECONSTITUTION AB Immunosenescence, the progressive decline in immune function that develops with age, results from cumulative alterations in critical B- and T-cell subpopulations. Decreases in circulating memory B cells and in germinal center formation are evident in the elderly, possibly due to diminished follicular dendritic-cell function. T-cell dysfunction is associated with reduced thymic generation of naive T cells, virus-induced expansion of terminal effectors and increased levels of memory cells producing type I and II cytokines. The diversity of the T-cell receptor repertoire is diminished by the first two changes, and elevated type I cytokines might contribute to the pro-inflammatory cytokine milieu present in the elderly. C1 NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. RP Hakim, FT (reprint author), NCI, Expt Transplantat & Immunol Branch, 10 Ctr Dr, Bethesda, MD 20892 USA. EM gressr@exchange.nih.gov NR 58 TC 74 Z9 84 U1 0 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD APR PY 2004 VL 16 IS 2 BP 151 EP 156 DI 10.1016/j.coi.2004.01.009 PG 6 WC Immunology SC Immunology GA 807JX UT WOS:000220498900005 PM 15023406 ER PT J AU Terabe, M Berzofsky, JA AF Terabe, M Berzofsky, JA TI Immunoregulatory T cells in tumor immunity SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID IMMUNOLOGICAL SELF-TOLERANCE; CD1D-RESTRICTED NKT CELLS; COLONY-STIMULATING FACTOR; NATURAL-KILLER NK; REGULATORY CELLS; DENDRITIC CELLS; CANCER-PATIENTS; IN-VIVO; ALPHA-GALACTOSYLCERAMIDE; STAT6-DEFICIENT MICE AB One mechanism of cancer immune evasion is the suppression of anti-tumor immunity by immunoregulatory T cells. Recent studies of these cells, especially CD4(+)CD25(+) T cells and NKT cells, have revealed molecular and cellular mechanisms of immunosuppression. Mouse studies have shown that either removing immunoregulatory T cells or blocking an immunoregulatory pathway induced by such cells unmasks natural tumor immunosurveillance and improves responses to cancer vaccines. Studies of the corresponding T-cell populations in human cancer patients support a similar role for immunoregulatory T cells in immunosuppression, implying that blocking immunoregulatory T-cell activity might improve the efficacy of tumor vaccines or the immunotherapy of cancer. C1 NCI, Vaccine Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Terabe, M (reprint author), NCI, Vaccine Branch, Ctr Canc Res, 10 Ctr Dr, Bethesda, MD 20892 USA. EM terabe@mail.nih.gov NR 74 TC 184 Z9 212 U1 0 U2 14 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD APR PY 2004 VL 16 IS 2 BP 157 EP 162 DI 10.1016/j.coi.2004.01.010 PG 6 WC Immunology SC Immunology GA 807JX UT WOS:000220498900006 PM 15023407 ER PT J AU Chowdhury, D Sen, RJ AF Chowdhury, D Sen, RJ TI Mechanisms for feedback inhibition of the immunoglobulin heavy chain locus SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID B-CELL DEVELOPMENT; ALLELIC EXCLUSION; ANTIGEN RECEPTOR; TRANSGENIC MICE; V(D)J RECOMBINATION; DEFICIENT MICE; GENE SEGMENTS; IG-BETA; SURFACE EXPRESSION; PRO-B AB The production of immunoglobulin heavy chain (IgH) protein in pro-B cells provides feedback to terminate further V-H gene recombination. This phenomenon is referred to as allelic exclusion. The chromatin structure of the V-H genes regulates their recombination potential, hence alterations in chromatin are a key factor in allelic exclusion. In pro-B cells, IL-7/lL-7R signaling induces histone hyperacetylation and nuclease accessibility of the largest family Of V-H genes (J558) and potentially activates these genes for recombination. Loss of these signals in the later stages of B-cell development reverts the V(H)J558 gene segments to a less accessible state, making them recombinationally refractive. This provides a molecular mechanism for allelic exclusion of these genes. Similar transient signals may be responsible for enforcing allelic exclusion in other V-H gene families. D-proximal V-H genes, however, appear to be less susceptible to feedback inhibition. C1 Ctr Blood Res, Boston, MA 02115 USA. NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Chowdhury, D (reprint author), Ctr Blood Res, 800 Huntington Ave, Boston, MA 02115 USA. EM senranja@grc.nia.nih.gov NR 51 TC 13 Z9 13 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD APR PY 2004 VL 16 IS 2 BP 235 EP 240 DI 10.1016/j.coi.2004.02.003 PG 6 WC Immunology SC Immunology GA 807JX UT WOS:000220498900017 PM 15023418 ER PT J AU Storz, G Opdyke, JA Zhang, AX AF Storz, G Opdyke, JA Zhang, AX TI Controlling mRNA stability and translation with small, noncoding RNAs SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID BINDING-PROTEIN HFQ; SM-LIKE PROTEINS; ESCHERICHIA-COLI; REGULATORY RNA; DSRA RNA; COMPARATIVE GENOMICS; RPOS TRANSLATION; GENE-EXPRESSION; IRON-METABOLISM; ANTISENSE RNA AB Recent studies have lead to the identification of more than 50 small regulatory RNAs in Escherichia coli. Only a subset of these RNAs has been characterized. However, it is clear that many of the RNAs, such as the MicF, OxyS, DsrA, Spot42 and RyhB RNAs, act by basepairing to activate or repress translation or to destabilize mRNAs. Basepairing between these regulatory RNAs and their target mRNAs requires the Sm-like Hfq protein which most likely functions as an RNA chaperone to increase RNA unfolding or local target RNA concentration. Here we summarize the physiological roles of the basepairing RNAs, examine their prevalence in bacteria and discuss unresolved questions regarding their mechanisms of action. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Storz, G (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. EM storz@helix.nih.gov OI Storz, Gisela/0000-0001-6698-1241 NR 45 TC 221 Z9 234 U1 1 U2 18 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD APR PY 2004 VL 7 IS 2 BP 140 EP 144 DI 10.1016/j.mib.2004.02.015 PG 5 WC Microbiology SC Microbiology GA 815TY UT WOS:000221065800008 PM 15063850 ER PT J AU Davis, JL Gilger, BC Robinson, MR AF Davis, JL Gilger, BC Robinson, MR TI Novel approaches to ocular drug delivery SO CURRENT OPINION IN MOLECULAR THERAPEUTICS LA English DT Article ID EXPERIMENTAL PROLIFERATIVE VITREORETINOPATHY; INTRAVITREAL TRIAMCINOLONE ACETONIDE; BIODEGRADABLE POLYMERIC DEVICE; CYSTOID MACULAR EDEMA; SUSTAINED INTRAOCULAR DELIVERY; RELEASE GANCICLOVIR IMPLANT; RANDOMIZED CLINICAL-TRIAL; RETINAL VEIN OCCLUSION; IN-VIVO EVALUATION; CHOROIDAL NEOVASCULARIZATION AB Recent advances in surgical techniques, therapeutic approaches and materials sciences have produced revolutionary new therapies for ocular diseases. The development of prodrug formulations and permeability enhancers, sustained-release drug delivery devices, novel injectable medications and new and improved vectors, both viral and non-viral, for delivery of genes to all segments of the eye has greatly increased the chances of success in treating eye diseases. This review will discuss the most recent advances in drug delivery systems for the treatment of ocular diseases. C1 N Carolina State Univ, Clin Pharmacol & Comparat Ophthalmol Res Labs, Coll Vet Med, Raleigh, NC 27606 USA. NEI, NIH, Bethesda, MD 20892 USA. RP Davis, JL (reprint author), N Carolina State Univ, Clin Pharmacol & Comparat Ophthalmol Res Labs, Coll Vet Med, 4700 Hillsborough St, Raleigh, NC 27606 USA. EM jennifer_davis@ncsu.edu NR 83 TC 41 Z9 42 U1 0 U2 11 PU CURRENT DRUGS LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1P 6LB, ENGLAND SN 1464-8431 J9 CURR OPIN MOL THER JI Curr. Opin. Mol. Ther. PD APR PY 2004 VL 6 IS 2 BP 195 EP 205 PG 11 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 838UA UT WOS:000222737600012 PM 15195932 ER PT J AU De Gabrieli, J Murray, EA AF De Gabrieli, J Murray, EA TI Cognitive neuroscience - Editorial overview SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Editorial Material ID MEMORY C1 Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. NIMH, Sect Neurobiol Learning & Memory, Neuropsychol Lab, Bethesda, MD 20892 USA. RP De Gabrieli, J (reprint author), Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. EM gabrieli@psych.stanford.edu NR 7 TC 0 Z9 0 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 EI 1873-6882 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD APR PY 2004 VL 14 IS 2 BP 135 EP 138 DI 10.1016/j.conb.2004.03.018 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 821AD UT WOS:000221430600001 ER PT J AU Hampton, RR Schwartz, BL AF Hampton, RR Schwartz, BL TI Episodic memory in nonhumans: what, and where, is when? SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Review ID JAYS APHELOCOMA-COERULESCENS; MENTAL TIME-TRAVEL; SCRUB-JAYS; HIPPOCAMPUS; ANIMALS; PIGEONS; MONKEYS; RATS; SEQUENCES; REMEMBER AB Episodic memory is defined as the recollection of specific events in one's past, accompanied by the experience of having been there personally. This definition presents high hurdles to the investigation of episodic memory in nonhumans. Recent studies operationalize episodic memory as memory for when and where an event occurred, for the order in which events occurred, or for an animal's own behavior. None of these approaches has yet generalized across species, and each fails to capture features of human episodic memory. Nonetheless, the study of episodic memory in nonhumans seems less daunting than it did five years ago. To demonstrate a correspondence between human episodic memory and nonhuman memory, progress is needed in three areas. Putative episodic memories in nonhumans should be shown to be; first, represented in long-term memory, rather than short-term or working memory; second, explicit, or accessible to introspection; and third, distinct from semantic memory, or general knowledge about the world. C1 NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. Florida Int Univ, Dept Psychol, Miami, FL 33199 USA. RP Hampton, RR (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 49,Room 1B-80, Bethesda, MD 20892 USA. EM hamptonr@mail.nih.gov NR 48 TC 51 Z9 52 U1 1 U2 13 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD APR PY 2004 VL 14 IS 2 BP 192 EP 197 DI 10.1016/j.conb.2004.03.006 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 821AD UT WOS:000221430600009 PM 15082324 ER PT J AU Mattay, VS Goldberg, TE AF Mattay, VS Goldberg, TE TI Imaging genetic influences in human brain function SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Review ID SEROTONIN TRANSPORTER GENE; PREFRONTAL CORTEX NEURONS; ANXIETY-RELATED TRAITS; ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E; DOPAMINE MODULATION; ACTIVATION PATTERNS; WORKING-MEMORY; IN-VITRO; POLYMORPHISM AB The association between genes and brain function using functional brain imaging techniques is an emerging and promising area of research that will help to better characterize the influence of genes on cognition and behavior as well as the link between genetic susceptibility and neuropsychiatric disorders. Neurophysiological imaging provides information regarding the effect of genes on brain function at the level of information processing, and neurochemical imaging provides information on the intrinsic mechanisms on how these genes affect the brain response. In this review, we highlight recent studies that have begun to explore the influence of genetic mutations on brain function with these techniques. The results, even from these few studies, illustrate the potential of these techniques to provide a more sensitive assay than behavioral measures used alone. The results also show that neuroimaging techniques can elucidate the influence of genes on brain function in relatively small sample populations, sometimes even in the absence of significant differences in behavioral measures. C1 NIMH, Clin Brain Disorders Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Goldberg, TE (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Dept Hlth & Human Serv, Bldg 10,Ctr Dr,Room 4S-235, Bethesda, MD 20892 USA. EM goldbert@intra.nimh.nih.gov NR 53 TC 33 Z9 33 U1 2 U2 5 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD APR PY 2004 VL 14 IS 2 BP 239 EP 247 DI 10.1016/j.conb.2004.03.014 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 821AD UT WOS:000221430600016 PM 15082331 ER PT J AU Winslow, JT Insel, TR AF Winslow, JT Insel, TR TI Neuroendocrine basis of social recognition SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Review ID OLFACTORY-BULB NOREPINEPHRINE; PITUITARY-ADRENAL AXIS; MALE-RATS; NEUROHYPOPHYSEAL PEPTIDES; COGNITIVE NEUROSCIENCE; VASOPRESSIN RECEPTOR; ARGININE-VASOPRESSIN; CHEMICAL CUES; OXYTOCIN; MEMORY AB Studies conducted in the past two years have yielded several new insights about neuroendocrine regulation of social recognition. The social recognition deficits seen in oxytocin knockout mice have now been demonstrated in both males and females, as well as in female estrogen receptor knockout mice. The male vasopressin V1A receptor knockout mouse (but not V1B) has a profound social recognition deficit. Preliminary evidence suggests that female V1B receptor knockout mice could also have social memory deficits. Several lines of evidence have emerged that indicate that neuropeptide regulation is significantly modulated by gonadal and corticosteroid activation. C1 NIMH, Natl Inst Hlth Anim Ctr, Bethesda, MD 20892 USA. RP Insel, TR (reprint author), NIMH, Natl Inst Hlth Anim Ctr, 6001 Execut Blvd,Room 8235,Mail Stop Code 9669, Bethesda, MD 20892 USA. EM insel@mail.nih.gov NR 56 TC 94 Z9 94 U1 3 U2 14 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD APR PY 2004 VL 14 IS 2 BP 248 EP 253 DI 10.1016/j.conb.2004.03.009 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 821AD UT WOS:000221430600017 PM 15082332 ER PT J AU Schiffmann, R van der Knaap, MS AF Schiffmann, R van der Knaap, MS TI The latest on leukodystrophies SO CURRENT OPINION IN NEUROLOGY LA English DT Article DE adrenoleukodystrophy; eukaryocytic initiation factor; H-ABC; LBSL; leukodystrophy; proteolipid protein ID VANISHING WHITE-MATTER; X-LINKED ADRENOLEUKODYSTROPHY; PELIZAEUS-MERZBACHER-DISEASE; INITIATION-FACTOR EIF2B; CHILDHOOD ATAXIA; LEUKOENCEPHALOPATHY; PROTEIN; HYPOMYELINATION; MUTATIONS; INVOLVEMENT AB Purpose of review Important advances in our understanding of genetic disorders of the white matter have been made and are discussed here. Recent findings It has recently been discovered that mutations in the genes encoding the five subunits of eukaryocytic initiation factor 2B (eIF2B) are the cause of vanishing white-matter disease/ childhood ataxia with central hypomyelination syndrome. The extension of the clinical features of the eIF2B-related disorders to encompass both infant- and adult-onset disorders is discussed. New clinico-imaging syndromes such as hypomyelination with atrophy of the basal ganglia and cerebellum and leukoencephalopathy with brain-stem and spinal cord involvement and elevated white-matter lactate are described. Recent findings include evidence that mitochondrial fat-oxidation abnormalities may be important in the pathogenesis of adrenoleukodystrophy, and that a mutant myelin protein can cause maldistribution of other myelin proteins, causing dysmyelination, axonal damage, or both. Summary This review focuses on advances in the understanding of the role of eIF2B as a cause of a common leukodystrophy syndrome. eIF2B-related disorders have a clinical spectrum ranging from a severe, rapidly progressive congenital or early infantile encephalopathy to a slowly progressive cognitive and motor deterioration often associated with premature ovarian failure. Two newly recognized leukodystrophy syndromes are described: hypomyelination with atrophy of the basal ganglia and cerebellum, and leukoencephalopathy with brain-stem and spinal cord involvement and elevated white-matter lactate. An update is also given for adrenoleukodystrophy and myelin-protein-related disorders. This update demonstrates that an increasing number of genetic defects are being identified that may cause primary white-matter disorders. C1 Free Univ Amsterdam, Med Ctr, Dept Child Neurol, NL-1007 MB Amsterdam, Netherlands. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD USA. RP van der Knaap, MS (reprint author), Free Univ Amsterdam, Med Ctr, Dept Child Neurol, POB 7057, NL-1007 MB Amsterdam, Netherlands. EM ms.vanderknaap@vumc.nl NR 29 TC 60 Z9 63 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1350-7540 J9 CURR OPIN NEUROL JI Curr. Opin. Neurol. PD APR PY 2004 VL 17 IS 2 BP 187 EP 192 DI 10.1097/01.wco.0000124710.26506.23 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 810BO UT WOS:000220680000016 PM 15021247 ER PT J AU Buchete, NV Straub, JE Thirumalai, D AF Buchete, NV Straub, JE Thirumalai, D TI Development of novel statistical potentials for protein fold recognition SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Article ID RESIDUE FORCE-FIELD; SHORT-RANGE INTERACTIONS; GAS REFERENCE STATE; STRUCTURE PREDICTION; GLOBULAR-PROTEINS; ENERGY FUNCTIONS; MEAN FORCE; STRUCTURE SIMULATIONS; STRUCTURE SELECTION; SCORING FUNCTIONS AB The need to perform large-scale studies of protein fold recognition, structure prediction and protein-protein interactions has led to novel developments of residue-level minimal models of proteins. A minimum requirement for useful protein force-fields is that they be successful in the recognition of native conformations. The balance between the level of detail in describing the specific interactions within proteins and the accuracy obtained using minimal protein models is the focus of many current protein studies. Recent results suggest that the introduction of explicit orientation dependence in a coarse-grained, residue-level model improves the ability of inter-residue potentials to recognize the native state. New statistical and optimization computational algorithms can be used to obtain accurate residue-dependent potentials for use in protein fold recognition and, more importantly, structure prediction. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Boston Univ, Dept Chem, Boston, MA 02215 USA. Univ Maryland, Inst Phys Sci & Technol, College Pk, MD 20742 USA. RP Buchete, NV (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM straub@bu.edu; thirum@glue.umd.edu RI Buchete, Nicolae-Viorel/C-6200-2015 OI Buchete, Nicolae-Viorel/0000-0001-9861-1157 FU NINDS NIH HHS [R01 NS41356-01] NR 73 TC 76 Z9 79 U1 0 U2 7 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD APR PY 2004 VL 14 IS 2 BP 225 EP 232 DI 10.1016/j.sbi.2004.03.002 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 819UG UT WOS:000221340700015 PM 15093838 ER PT J AU Saint-Germain, N Lee, YH Zhang, YH Sargent, TD Saint-Jeannet, JP AF Saint-Germain, N Lee, YH Zhang, YH Sargent, TD Saint-Jeannet, JP TI Specification of the otic placode depends on Sox9 function in Xenopus SO DEVELOPMENT LA English DT Article DE Sox9; Tbx2; Pax8; Dlx3; otic placode; inner ear; Wnt; Fgf; Xenopus ID INNER-EAR DEVELOPMENT; SRY-RELATED GENE; NEURAL CREST DEVELOPMENT; AUTOSOMAL SEX REVERSAL; CAMPOMELIC DYSPLASIA; EMBRYONIC-DEVELOPMENT; INDUCTIVE PROCESSES; SONIC HEDGEHOG; HOMEOBOX GENE; CELL LINEAGES AB The vertebrate inner ear develops from a thickening of the embryonic ectoderm, adjacent to the hindbrain, known as the otic placode. All components of the inner ear derive from the embryonic otic placode. Sox proteins form a large class of transcriptional regulators implicated in the control of a variety of developmental processes. One member of this family, Sox9, is expressed in the developing inner ear, but little is known about the early function of Sox9 in this tissue. We report the functional analysis of Sox9 during development of Xenopus inner ear. Sox9 otic expression is initiated shortly after gastrulation in the sensory layer of the ectoderm, in a bilateral patch of cells immediately adjacent to the cranial neural crest. In the otic placode, Sox9 colocalizes with Pax8 one of the earliest gene expressed in response to otic placode inducing signals. Depletion of Sox9 protein in whole embryos using morpholino antisense oligonucleotides causes a dramatic loss of the early otic placode markers Pax8 and Tbx2. Later in embryogenesis, Sox9 morpholino-injected embryos lack a morphologically recognizable otic vesicle and fail to express late otic markers (Tbx2, Bmp4, Otx2 and Wnt3a) that normally exhibit regionalized expression pattern throughout the otocyst. Using a hormone inducible inhibitory mutant of Sox9, we demonstrate that Sox9 function is required for otic placode specification but not for its subsequent patterning. We propose that Sox9 is one of the key regulators of inner ear specification in Xenopus. C1 Univ Penn, Sch Vet Med, Dept Anim Biol, Philadelphia, PA 19104 USA. NICHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. RP Saint-Jeannet, JP (reprint author), Univ Penn, Sch Vet Med, Dept Anim Biol, 3800 Spruce St, Philadelphia, PA 19104 USA. EM saintj@vet.upenn.edu NR 70 TC 48 Z9 50 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD APR PY 2004 VL 131 IS 8 BP 1755 EP 1763 DI 10.1242/dev.01066 PG 9 WC Developmental Biology SC Developmental Biology GA 817CP UT WOS:000221155900008 PM 15084460 ER PT J AU Yuhki, M Yamada, M Kawano, M Iwasato, T Itohara, S Yoshida, H Ogawa, M Mishina, Y AF Yuhki, M Yamada, M Kawano, M Iwasato, T Itohara, S Yoshida, H Ogawa, M Mishina, Y TI BMPR1A signaling is necessary for hair follicle cycling and hair shaft differentiation in mice SO DEVELOPMENT LA English DT Article DE bone morphogenetic protein; type 1 receptor; hair follicle cycling; mouse ID BONE MORPHOGENETIC PROTEINS; SONIC-HEDGEHOG; BETA-CATENIN; BUD DEVELOPMENT; GROWTH; SKIN; RECEPTOR; EXPRESSION; INDUCTION; NOGGIN AB Interactions between ectodermal and mesenchymal extracellular signaling pathways regulate hair follicle (HF) morphogenesis and hair cycling. Bone morphogenetic proteins (BMPs) are known to be important in hair follicle development by affecting the local cell fate modulation. To study the role of BNIP signaling in the HF, we disrupted Bmpr1a, which encodes the BMP receptor type IA (BMPR1A) in an HF cell-specific manner, using the Cre/loxP system. We found that the differentiation of inner root sheath, but not outer root sheath, was severely impaired in mutant mice. The number of HFs was reduced in the dermis and subcutaneous tissue, and cycling epithelial cells were reduced in mutant mice HFs. Our results strongly suggest that BMPR1A signaling is essential for inner root sheath differentiation and is indispensable for HF renewal in adult skin. C1 RIKEN, Brain Sci Inst, Lab Cell Culture Dev, Saitama 3510198, Japan. RIKEN, Brain Sci Inst, Mol Neuropathol Grp, Saitama 3510198, Japan. RIKEN, Brain Sci Inst, Lab Behav Genet, Saitama 3510198, Japan. Nara Inst Sci & Technol, Div Gene Funct Anim, Nara 6300192, Japan. RIKEN, Res Ctr Allergy & Immunol, Immune Syst Dev Grp, Kanagawa 2300045, Japan. NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Yamada, M (reprint author), RIKEN, Brain Sci Inst, Lab Cell Culture Dev, Saitama 3510198, Japan. EM masahisa@brain.riken.go.jp RI Itohara, Shigeyoshi/I-8769-2012 OI Itohara, Shigeyoshi/0000-0002-2410-9989 NR 40 TC 57 Z9 59 U1 0 U2 5 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD APR PY 2004 VL 131 IS 8 BP 1825 EP 1833 DI 10.1242/dev.01079 PG 9 WC Developmental Biology SC Developmental Biology GA 817CP UT WOS:000221155900014 PM 15084466 ER PT J AU Kemp, CA Kopish, KR Zipperlen, P Ahringer, J O'Connell, KF AF Kemp, CA Kopish, KR Zipperlen, P Ahringer, J O'Connell, KF TI Centrosome maturation and duplication in C. elegans require the coiled-coil protein SPD-2 SO DEVELOPMENTAL CELL LA English DT Article ID TUBULIN RING COMPLEX; POLO-LIKE KINASE; CAENORHABDITIS-ELEGANS; GAMMA-TUBULIN; CELL-CYCLE; MICROTUBULE ORGANIZATION; MAMMALIAN-CELLS; ANIMAL-CELLS; AURORA-A; SPINDLE AB Centrosomes are major determinants of mitotic spindle structure, but the mechanisms regulating their behavior remain poorly understood. The spd-2 gene of C. elegans is required for centrosome assembly or "maturation." Here we show that spd-2 encodes a coiled-coil protein that localizes within pericentriolar material (PCM) and in the immediate vicinity of centrioles. During maturation, SPD-2 gradually accumulates at the centrosome in a manner that is partially dependent on Aurora-A kinase and cytoplasmic dynein. Interestingly, SPD-2 interacts genetically with dynein heavy chain and SPD-5, another coiled-coil protein required for centrosome maturation. SPD-2 and SPD-5 are codependent for localization to the PCM, but SPD2 localizes to centrioles independently of SPD-5. Surprisingly, we also find that SPD-2 is required for centrosome duplication and genetically interacts with ZYG-1, a kinase required for duplication. Thus, we have identified SPD-2 as a factor critical for the two basic functions of the centrosome-microtubule organization and duplication. C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. Promega Corp, Madison, WI 53711 USA. Univ Cambridge, Wellcome Trust Canc Res UK Inst, Cambridge CB2 1QR, England. RP O'Connell, KF (reprint author), NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM kevino@intra.niddk.nih.gov FU Wellcome Trust [054523] NR 50 TC 145 Z9 159 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD APR PY 2004 VL 6 IS 4 BP 511 EP 523 DI 10.1016/S1534-5807(04)00066-8 PG 13 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 834XA UT WOS:000222443000010 PM 15068791 ER PT J AU Kikuchi, Y Verkade, H Reiter, JF Kim, CH Chitnis, AB Kuroiwa, A Stainier, DYR AF Kikuchi, Y Verkade, H Reiter, JF Kim, CH Chitnis, AB Kuroiwa, A Stainier, DYR TI Notch signalling can regulate endoderm formation in zebrafish SO DEVELOPMENTAL DYNAMICS LA English DT Article DE notch; endoderm; sox17; foxA2; zebrafish ID PRIMARY NEUROGENESIS; ACTS DOWNSTREAM; IN-VIVO; GENE; PROTEIN; HOMOLOG; DELTA; SPECIFICATION; EXPRESSION; CASANOVA AB Early in vertebrate development, the processes of gastrulation lead to the formation of the three germ layers: ectoderm, mesoderm, and endoderm. The mechanisms leading to the segregation of the endoderm and mesoderm are not well understood. In mid-blastula stage zebrafish embryos, single marginal cells can give rise to both endoderm and mesoderm (reviewed by Warga and Stainier [2002] The guts of endoderm formation. In: Solnica-Krezel L, editor. Pattern formation in zebrafish. Berlin: Springer-Veriag. p 28-47). By the late blastula stage, however, single marginal cells generally give rise to either endoderm or mesoderm. To investigate this segregation of the blastoderm into cells with either endodermal or mesodermal fates, we analyzed the role of Notch signaling in this process. We show that deltaC, deltaD, and notch1 are expressed in the marginal domain of blastula stage embryos and that this expression is dependent on Nodal signaling. Activation of Notch signaling from an early stage leads to a reduction of endodermal cells, as assessed by sox17 and foxA2 expression. We further find that this reduction in endoderm formation by the activation of Notch signaling is preceded by a reduction in the expression of bonnie and clyde (bon) and faust/gata5, two genes necessary for endoderm formation (Reiter et al. [1999] Genes Dev 13:2983-2995; Reiter et al. [2001] Development 128:125-135; Kikuchi et al. [2001] Genes Dev 14:1279-1289). However, activation of Notch signaling in bon mutant embryos leads to a further reduction in endodermal cells, also arguing for a bon-independent role for Notch signaling in endoderm formation. Altogether, these results suggest that Notch signaling plays a role in the formation of the endoderm, possibly in its segregation from the mesoderm. Developmental Dynamics 229. 756-762, 2004. (C) 2004 Wiley-Liss, Inc. C1 Nagoya Univ, Grad Sch Sci, Div Biol Sci, Chikusa Ku, Nagoya, Aichi 4648602, Japan. Univ Calif San Francisco, Dept Biochem & Biophys, Programs Dev Biol Genet & Human Genet, San Francisco, CA 94143 USA. NICHD, NIH, Genet Mol Lab, Bethesda, MD USA. RP Kikuchi, Y (reprint author), Nagoya Univ, Grad Sch Sci, Div Biol Sci, Chikusa Ku, Nagoya, Aichi 4648602, Japan. EM yutaka@cc.nagoya-u.ac.jp RI Verkade, Heather/J-2401-2013 FU NIDDK NIH HHS [R01 DK058181] NR 40 TC 34 Z9 34 U1 2 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD APR PY 2004 VL 229 IS 4 BP 756 EP 762 DI 10.1002/dvdy.10483 PG 7 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 807KC UT WOS:000220499400005 PM 15042699 ER PT J AU McKenzie, E Krupin, A Kelley, MW AF McKenzie, E Krupin, A Kelley, MW TI Cellular growth and rearrangement during the development of the mammalian organ of corti SO DEVELOPMENTAL DYNAMICS LA English DT Article DE hair cell; convergent extension; cochlea; p27(kip1) ID INNER-EAR DEVELOPMENT; HAIR-CELLS; XENOPUS-LAEVIS; POSTNATAL-DEVELOPMENT; CONVERGENT EXTENSION; PROTRUSIVE ACTIVITY; RAT COCHLEA; E-CADHERIN; MOUSE; EXPRESSION AB The sensory epithelium of the mammalian cochlea, the organ of Corti, is comprised of ordered rows of cells, including inner and outer hair cells. Recent results suggest that physical changes in the overall size and shape of the cochlear duct, including possible convergence and extension, could play a role in the development of this pattern. To examine this hypothesis, changes in cell size and distribution were determined for different regions of the cochlea duct during embryonic development. In addition, changes in the spatial distribution of sensory precursor cells were determined kip(1) at different developmental time points based on expression of p27(kip1). Unique changes in luminal surface area, cell density, and number of cell contacts were observed for each region of the duct. Moreover, the spatial distribution of p27(kip1)-positive cells changed from short and broad early in development, to long and narrow. These results are consistent with the hypothesis that convergence and extension plays a role in cellular patterning within the organ of Corti. Published 2004 Wiley-Liss, Inc.dagger. C1 Natl Inst Deafness & Other Commun Disorders, Sect Dev Neurosci, NIH, Rockville, MD USA. RP Kelley, MW (reprint author), 5 Res Court, Rockville, MD 20850 USA. EM kelleymt@nidcd.nih.gov NR 43 TC 45 Z9 47 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD APR PY 2004 VL 229 IS 4 BP 802 EP 812 DI 10.1002/dvdy.10500 PG 11 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 807KC UT WOS:000220499400010 PM 15042704 ER PT J AU Holvoet, P Kritchevsky, SB Tracy, RP Mertens, A Rubin, SM Butler, J Goodpaster, B Harris, TB AF Holvoet, P Kritchevsky, SB Tracy, RP Mertens, A Rubin, SM Butler, J Goodpaster, B Harris, TB TI The metabolic syndrome, circulating oxidized LDL, and risk of myocardial infarction in well-functioning elderly people in the health, aging, and body composition cohort SO DIABETES LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; CORONARY-ARTERY-DISEASE; C-REACTIVE PROTEIN; ISCHEMIC-HEART-DISEASE; MINIATURE PIGS; IN-VIVO; CHOLESTEROL; OXIDATION; ATHEROSCLEROSIS; GLUCOSE AB The object of this study was to establish the association between the metabolic syndrome and oxidized LDL (oxLDL) and to determine the risk for coronary heart disease (CHD) in relation to the metabolic syndrome and levels of oxLDL. OxLDL was measured in plasma from 3,033 elderly participants in the Health, Aging, and Body Composition study. The metabolic syndrome was defined according to criteria established in the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. We observed that the metabolic syndrome was associated with higher levels of oxLDL due to a higher fraction of oxLDL, not to higher levels of LDL cholesterol. Individuals with the metabolic syndrome had twice the odds of having high oxLDL (>1.90 mg/dl) compared with those not having the metabolic syndrome, after adjusting for age, sex, ethnicity, smoking status, and LDL cholesterol. Among those participants who had the metabolic syndrome at study entry, incidence rates of future CHD events were 1.6-fold higher, after adjusting for age, sex, ethnicity, and smoking status. OxLDL was not an independent predictor of total CHD risk. However, those with high oxLDL showed a greater disposition to myocardial infarction (relative risk 2.25, 95% confidence interval 1.22-4.15). We concluded that the metabolic syndrome, a risk factor for CHD, is associated with higher levels of circulating oxLDL that are associated with a greater disposition to atherothrombotic coronary disease. C1 Katholieke Univ Leuven, Ctr Expt Surg & Anesthesiol, B-3000 Louvain, Belgium. Wake Forest Univ, J Paul Sticht Ctr Aging, Winston Salem, NC 27109 USA. Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. Univ Vermont, Dept Biochem, Burlington, VT 05405 USA. Univ Calif San Francisco, Prevent Sci Grp, San Francisco, CA 94143 USA. Vanderbilt Univ, Nashville, TN USA. Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. NIA, Lab Epidemiol Demog & Biomet, NIH, Bethesda, MD 20892 USA. RP Holvoet, P (reprint author), Katholieke Univ Leuven, Ctr Expt Surg & Anesthesiol, Herestr 49, B-3000 Louvain, Belgium. EM paul.holvoet@med.kuleuven.ac.be FU NIA NIH HHS [N01-AG-6-210, N01-AG-6-2103, N01-AG-6-2106] NR 43 TC 182 Z9 190 U1 1 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD APR PY 2004 VL 53 IS 4 BP 1068 EP 1073 DI 10.2337/diabetes.53.4.1068 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 809AE UT WOS:000220608800023 PM 15047623 ER PT J AU Silander, K Mohlke, KL Scott, LJ Peck, EC Hollstein, P Skol, AD Jackson, AU Deloukas, P Hunt, S Stavrides, G Chines, PS Erdos, MR Narisu, N Conneely, KN Li, C Fingerlin, TE Dhanjal, SK Valle, TT Bergman, RN Tuomilehto, J Watanabe, RM Boehnke, M Collins, FS AF Silander, K Mohlke, KL Scott, LJ Peck, EC Hollstein, P Skol, AD Jackson, AU Deloukas, P Hunt, S Stavrides, G Chines, PS Erdos, MR Narisu, N Conneely, KN Li, C Fingerlin, TE Dhanjal, SK Valle, TT Bergman, RN Tuomilehto, J Watanabe, RM Boehnke, M Collins, FS TI Genetic variation near the hepatocyte nuclear factor-4 alpha gene predicts susceptibility to type 2 diabetes SO DIABETES LA English DT Article ID AUTOSOMAL GENOME SCAN; FACTOR 4-ALPHA; LINKAGE DISEQUILIBRIUM; CHROMOSOME 20Q; TRANSCRIPTION FACTORS; WIDE SEARCH; SIB PAIRS; MELLITUS; PROMOTER; NIDDM AB The Finland-United States Investigation Of NIDDM Genetics (FUSION) study aims to identify genetic variants that predispose to type 2 diabetes by studying affected sibling pair families from Finland. Chromosome 20 showed our strongest initial evidence for linkage. It currently has a maximum logarithm of odds (LOD) score of 2.48 at 70 cM in a set of 495 families. In this study, we searched for diabetes susceptibility variant(s) at 20q13 by genotyping single nucleotide polymorphism (SNP) markers in case and control DNA pools. Of 291 SNPs successfully typed in a 7.5-Mb interval, the strongest association confirmed by individual genotyping was with SNP rs2144908, located 1.3 kb downstream of the primary beta-cell promoter P2 of hepatocyte nuclear factor-4alpha (HNF4A). This SNP showed association with diabetes disease status (odds ratio [OR] 1.33, 95% CI 1.06-1.65, P = 0.011) and with several diabetes-related traits. Most of the evidence for linkage at 20q13 could be attributed to the families carrying the risk allele. We subsequently found nine additional associated SNPs spanning a 64-kb region, including the P2 and P1 promoters and exons 1-3. Our results and the independent observation of association of SNPs near the P2 promoter with diabetes in a separate study population of Ashkenazi Jewish origin suggests that variant(s) located near or within HNF4A increases susceptibility to type 2 diabetes. C1 Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. Wellcome Trust Res Labs, Sanger Inst, Hinxton, England. Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. Natl Publ Hlth Inst, Diabet & Genet Epidemiol Unit, Dept Epidemiol & Hlth Promot, Helsinki, Finland. Natl Publ Hlth Inst, Dept Biochem, Helsinki, Finland. Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA USA. Univ Helsinki, Dept Publ Hlth, Helsinki, Finland. RP Boehnke, M (reprint author), Univ Michigan, Sch Publ Hlth, Dept Biostat, 1420 Washington Hts, Ann Arbor, MI 48109 USA. EM boehnke@umich.edu RI Li, Chun/B-8388-2012; Deloukas, Panos/B-2922-2013 OI Deloukas, Panos/0000-0001-9251-070X FU NHGRI NIH HHS [HG00040, HG00376]; NIDDK NIH HHS [DK27619, DK29867, DK62370, R01 DK029867] NR 50 TC 183 Z9 190 U1 0 U2 6 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD APR PY 2004 VL 53 IS 4 BP 1141 EP 1149 DI 10.2337/diabetes.53.4.1141 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 809AE UT WOS:000220608800033 PM 15047633 ER PT J AU Kino, T Pavlakis, GN AF Kino, T Pavlakis, GN TI Partner molecules of accessory protein Vpr of the human immunodeficiency virus type 1 SO DNA AND CELL BIOLOGY LA English DT Article ID CELL-CYCLE ARREST; YEAST SCHIZOSACCHAROMYCES-POMBE; HIV-1 PREINTEGRATION COMPLEX; DNA-REPAIR PROTEIN; N-TERMINAL DOMAIN; REGULATORY PROTEIN; NUCLEAR-LOCALIZATION; VIRION INCORPORATION; GLUCOCORTICOID-RECEPTOR; BIOLOGICAL FUNCTIONS AB Vpr (Viral protein-R) of the Human Immunodeficiency Virus type-1 is a 14-kDa virion-associated protein, conserved in HIV-1, -2 and the Simian Immunodeficiency Virus (SIV). Vpr is incorporated into the virion, travels to the nucleus, and has multiple activities including promoter activation, cell cycle arrest at the G2/M transition and apoptosis induction. Through these activities, Vpr is thought to influence not only viral replication but also numerous host cell functions. These functions may be categorized in three groups depending on the domains of Vpr that support them: (1) functions mediated by the amino terminal portion of Vpr, like virion packaging; (2) functions mediated by the carboxyl terminal portion such as cell cycle arrest; and (3) functions that depend on central alpha-helical structures such as transcriptional activation, apoptosis and subcellular shuttling. Association of these activities to specific regions of the Vpr molecule appears to correlate to the host/viral molecules that interact with corresponding portion of Vpr. They include Gag, host transcription factors/coactivators such as SP1, the glucocorticoid receptor, p300/CREB-binding protein and TFIIB, apoptotic adenine nucleotide translocator, cyclophilin A and 14-3-3 proteins. The properties of Vpr molecule has made it difficult to assess its function and determine the true cellular interactors. Further studies on Vpr function are needed to fully assess the function of this important early regulatory molecule of HIV and other lentiviruses. C1 NCI Frederick, Ctr Canc Res, Human Retrovirus Sect, Ft Detrick, MD 21702 USA. NICHHD, NIH, Pediat & Reprod Endocrinol Branch, Bethesda, MD USA. RP Pavlakis, GN (reprint author), NCI Frederick, Ctr Canc Res, Human Retrovirus Sect, Bldg 535,Rm 210, Ft Detrick, MD 21702 USA. EM pavlakis@ncifcrf.gov NR 112 TC 39 Z9 42 U1 0 U2 2 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1044-5498 J9 DNA CELL BIOL JI DNA Cell Biol. PD APR PY 2004 VL 23 IS 4 BP 193 EP 205 DI 10.1089/104454904773819789 PG 13 WC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity GA 818QN UT WOS:000221259700003 PM 15142377 ER PT J AU Dunn, PM Kim, HS Jacobson, KA Burnstock, G AF Dunn, PM Kim, HS Jacobson, KA Burnstock, G TI Northern ring conformation of methanocarba-adenosine 5 '-triphosphate required for activation of P2X receptors SO DRUG DEVELOPMENT RESEARCH LA English DT Article DE ATP; P2X receptors; structure activity relationship ID RECOMBINANT P2X(3); SENSORY NEURONS; P2Y(1); TARGETS; POTENCY AB Replacement of the ribose moiety of adenosine 5'-triphosphate (ATP) with a carbocyclic ring constrained in either the Northern (N) or Southern (S) conformation produces agonists with widely differing activities at P2Y receptors (Kim et al. [2002] J Med Chem 45:208-218). We have used whole cell patch clamp recording to investigate the agonist activity of these two methanocarba analogs of ATP at four different P2X receptors (P2X(1), P2X(2), P2X(3), and P2X(2/3)). On dorsal root ganglion neurons, (N) methanocarba-ATP ((1'S,2'R,3'S,4'R,5'S)-4-(6-amino-9H-purin-9-yl)-1-[triphosphoryloxymethyl]bicyclo[3.1.0]hexane-2,3-diol; MRS 2340) activated rapidly-desensitizing (P2X(3)) and slowly-desensitizing (P2X(2/3)) receptors with a similar potency to ATP. In contrast, (S) methanocarba-ATP ((+/-)-5-(6-amino-9H-purin-9-yl)-1-[triphosphoryloxymethyl] bicycle [3.1.0]hexane-2,3-diol MRS 2312) was devoid of agonist activity. On nodose ganglion neurones, that express mainly P2X(2/3) receptors, ATP evoked a slowly desensitizing inward current with an EC(50) value of 26 muM. MRS 2340 was an effective agonist, but less potent than ATP, while MRS 2312 at concentrations up to 100 muM produced a barely detectable response. On mammalian cell lines expressing recombinant hP2X(1) and hP2X(2) receptors, MRS 2340 evoked inward currents similar in amplitude to those produced by the same concentration of ATP or alpha,beta-mATP. In contrast, MRS 2312 failed to give a detectable response. Although the conformation of the ribose affects agonist activity at P2Y receptors, there is a strong requirement for the (N) conformation for the activation of these P2X receptors. Furthermore, the region of the agonist binding site that accommodates the ribose moiety appears to be highly conserved among different P2X receptors. C1 UCL Royal Free & Univ Coll Med Sch, Auton Neurosci Inst, London NW3 2PF, England. Wonkwang Univ, Coll Pharm, Chonbuk, South Korea. Wonkwang Univ, Med Resources Res Ctr, Chonbuk, South Korea. NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Dunn, PM (reprint author), UCL Royal Free & Univ Coll Med Sch, Auton Neurosci Inst, Rowland Hill St, London NW3 2PF, England. EM p.dunn@ucl.ac.uk RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z99 DK999999, Z01 DK031116-20] NR 15 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0272-4391 J9 DRUG DEVELOP RES JI Drug Dev. Res. PD APR PY 2004 VL 61 IS 4 BP 227 EP 232 DI 10.1002/ddr.10381 PG 6 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 860ED UT WOS:000224321900005 PM 22833693 ER PT J AU Nikolic, D van Breemen, RB AF Nikolic, D van Breemen, RB TI New metabolic pathways for flavanones catalyzed by rat liver microsomes SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID TANDEM MASS-SPECTROMETRY; HOPS HUMULUS-LUPULUS; POTENT PHYTOESTROGEN; DIETARY FLAVONOIDS; CYTOCHROME-P450; IDENTIFICATION; OXIDATION; QUERCETIN; AGLYCONES AB Flavonoids represent a diverse group of natural pigments widely distributed in the plant kingdom and are an important component of human diet due to their high content in fruits and vegetables. Since many flavonoids have been shown to be potent inhibitors, substrates, and even inducers of various cytochrome P450 isoforms, there is considerable interest in studying interactions of this class of molecules with the cytochrome P450 enzyme system. In this study, the metabolism of several simple flavanones by rat liver microsomes was investigated and compared. In addition to the expected aromatic hydroxylation products, several novel metabolic pathways were observed including C-ring desaturation to form the corresponding flavones, oxidation of the B-ring to generate an unusual quinol oxidation product, B-ring cleavage with the formation of chromone derivatives, and reduction of carbonyl group to form flavan-4-ol derivatives. The metabolites were characterized and identified primarily by using liquid chromatography-tandem mass spectrometry with comparison to authentic standards. Formation of flavones from dietary flavanones might have biological significance since flavones often exhibit pharmacological activities that are different from those of flavanones. However, little is known about the pharmacological activities of the other types of flavonone metabolites. C1 Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, NIH,Ctr Bot Dietary Supplements Res, Chicago, IL 60612 USA. RP van Breemen, RB (reprint author), Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, NIH,Ctr Bot Dietary Supplements Res, 833 S Wood St, Chicago, IL 60612 USA. EM breemen@uic.edu FU NCCIH NIH HHS [P50AT00155] NR 31 TC 34 Z9 36 U1 0 U2 8 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD APR 1 PY 2004 VL 32 IS 4 BP 387 EP 397 DI 10.1124/dmd.32.4.387 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 805XS UT WOS:000220399600005 PM 15039291 ER PT J AU Heidbreder, CA Andreoli, M Marcon, C Thanos, PK Ashby, CR Gardner, EL AF Heidbreder, CA Andreoli, M Marcon, C Thanos, PK Ashby, CR Gardner, EL TI Role of dopamine D-3 receptors in the addictive properties of ethanol SO DRUGS OF TODAY LA English DT Review ID TRIDIMENSIONAL PERSONALITY QUESTIONNAIRE; HUMAN COCAINE FATALITIES; VENTRAL TEGMENTAL AREA; RAT NUCLEUS-ACCUMBENS; D3 RECEPTOR; ALCOHOL-DEPENDENCE; MESSENGER-RNA; HUMAN BRAIN; SELECTIVE ANTAGONISM; WITHDRAWAL SYNDROME AB After the cloning of the dopamine D-1 and D-2 receptors (1-3), several additional dopamine receptors were identified. These new subtypes included the D-3 and D-4 receptors, which are similar to D-2, and the D-5 receptor, which is similar to D-1 (4-6). Although most studies have focused on the role of dopamine D-1 and D-2 receptors in mediating the addictive liability of drugs, the lack of selective pharmacological tools has significantly hampered this particular field of research. In contrast, recent studies using selective competitive antagonists have shown that the dopamine D-3 receptor is involved in drug-seeking behavior. The present review is intended to highlight a new, promising area in alcohol research that focuses on the role of the dopamine D-3 receptor in the addictive properties of ethanol. (C) 2004 Prous Science. All rights reserved. C1 GlaxoSmithKline Pharmaceut, Ctr Excellence Drug Discovery Psychiat, Dept Biol, I-37135 Verona, Italy. Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. St Johns Univ, Coll Pharm & Allied Hlth Profess, Dept Pharmaceut Sci, Jamaica, NY 11439 USA. Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD 21224 USA. RP Heidbreder, CA (reprint author), GlaxoSmithKline Pharmaceut, Ctr Excellence Drug Discovery Psychiat, Dept Biol, Via A Fleming 4, I-37135 Verona, Italy. EM Christian_A_Heidbreder@gsk.com NR 93 TC 31 Z9 31 U1 2 U2 3 PU PROUS SCIENCE, SA PI BARCELONA PA PO BOX 540, PROVENZA 388, 08025 BARCELONA, SPAIN SN 0025-7656 J9 DRUGS TODAY JI Drugs Today PD APR PY 2004 VL 40 IS 4 BP 355 EP 365 DI 10.1358/dot.2004.40.4.820081 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 827TF UT WOS:000221923000004 PM 15190388 ER PT J AU Buzas, Z Antal, J Gilligan, JJ Backlund, PS Yergey, AL Chrambach, A AF Buzas, Z Antal, J Gilligan, JJ Backlund, PS Yergey, AL Chrambach, A TI An electroelution apparatus for sequential transfer of sodium dodecyl sulfate-proteins into agarose and mass spectrometric identification of Li-Na-dodecyl sulfate-proteins from solubilized agarose SO ELECTROPHORESIS LA English DT Article DE agarose solubilization; gel band transfer apparatus; matrix-assisted laser desorption; ionization-mass spectrometry; sequential electroelution ID POLYACRYLAMIDE-GEL-ELECTROPHORESIS; LASER-DESORPTION IONIZATION; FLIGHT; TIME; SAMPLES AB Separated protein bands are sequentially electrophoresed into low melting agarose plugs distributed in an apparatus of original design along the surface of a plastic drum. The rotation of the drum is synchronized to migration of electrophoretic bands to receive each band individually. Agarose plugs are dissolved enzymatically for transfer into the mass spectrometer. One muL of the agarose solution containing 1 pmol of each of three lithium and natrium salts of dodecyl sulfate (Li-Na-DS)-proteins were applied to matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) without any prepurification. It yields a signal indistinguishable from that obtained in the absence of agarose. C1 NICHHD, Sect Metab Anal, NIH, Bethesda, MD 20892 USA. NICHHD, Mass Spectrometry Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. Agr Biotechnol Ctr, H-2101 Godollo, Hungary. Eotvos Lorand Univ, Budapest, Hungary. RP Chrambach, A (reprint author), NICHHD, Sect Metab Anal, NIH, Bldg 10,Rm 9D50, Bethesda, MD 20892 USA. EM acc@helix.nih.gov NR 12 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD APR PY 2004 VL 25 IS 7-8 BP 966 EP 969 DI 10.1002/elps.200305797 PG 4 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 817HN UT WOS:000221168700003 PM 15095434 ER PT J AU Buzas, Z Chrambach, A AF Buzas, Z Chrambach, A TI Moving boundaries in sodium dodecyl sulfate-polyacrylamide gel electrophoresis SO ELECTROPHORESIS LA English DT Article DE extended stack; moving boundary; steady state ID MULTIPHASIC ZONE ELECTROPHORESIS; DISC ELECTROPHORESIS; BUFFER SYSTEMS; GRADIENT; PROTEINS AB In sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SIDS-PAGE), moving boundaries I-IV (Table 1) form. They migrate isotachophoretically at displacement rates that increase in the order of I to II to III. Moving boundaries IV and V comprising Pyronin-SDS as a leading constituent are retarded at high gel concentrations in comparison with the isotachophoretically migrating species. Since analytes depending on their net mobilities stack within any of those moving boundaries, previous R-f values and Ferguson plots may have to be revised. C1 NICHHD, Macromol Anal Sect, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. Agr Biotechnol Ctr, H-2101 Godollo, Hungary. RP Chrambach, A (reprint author), NICHHD, Macromol Anal Sect, Lab Cellular & Mol Biophys, NIH, Bldg 10,Rm 9D50, Bethesda, MD 20892 USA. EM acc@helix.nih.gov NR 13 TC 3 Z9 3 U1 1 U2 3 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD APR PY 2004 VL 25 IS 7-8 BP 970 EP 972 DI 10.1002/elps.200305798 PG 3 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 817HN UT WOS:000221168700004 PM 15095435 ER PT J AU Wheeler, D Chrambach, A Ashburn, P Jovin, TM AF Wheeler, D Chrambach, A Ashburn, P Jovin, TM TI Discontinuous buffer systems operative at pH 2.5-11.0, 0 degrees C and 25 degrees C, available on the Internet SO ELECTROPHORESIS LA English DT Article DE buffer systems; discontinuous buffer systems; Internet ID MULTIPHASIC ZONE ELECTROPHORESIS AB This communication is an announcement of the availability on the Internet of a computer output of discontinuous buffer systems operative at pH 2.5-11.0, 0degreesC and 25degreesC, generated by the theory and program of T M. Jovin. The output and instructions for its use can be accessed under http://www.buffers.nichd.nih.gov. C1 NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. NICHHD, Macromol Anal Sect, Lab Cellular & Mol Biophys, Bethesda, MD 20892 USA. Max Planck Inst Biophys Chem, Dept Mol Biol, D-37077 Gottingen, Germany. RP Chrambach, A (reprint author), NIH, Ctr Informat Technol, Bldg 10,Rm 9D50, Bethesda, MD 20892 USA. EM acc@helix.nih.gov NR 4 TC 3 Z9 3 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD APR PY 2004 VL 25 IS 7-8 BP 973 EP 974 DI 10.1002/elps.200305799 PG 2 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 817HN UT WOS:000221168700005 PM 15095436 ER PT J AU Haluzik, M Gavrilova, O Leroith, D AF Haluzik, M Gavrilova, O Leroith, D TI Peroxisome proliferator-activated receptor-alpha deficiency does not alter insulin sensitivity in mice maintained on regular or high-fat diet: Hyperinsulinemic-euglycemic clamp studies SO ENDOCRINOLOGY LA English DT Article ID GLUCOSE-PRODUCTION; HEPATIC STEATOSIS; DIABETES-MELLITUS; LIPOATROPHIC MICE; ACID CYCLE; NULL MICE; RESISTANCE; MUSCLE; REVERSES; OBESITY AB Chronic peroxisome proliferator-activated receptor (PPAR)-alpha activation improves glucose metabolism in rodent models of insulin resistance and diabetes; however, PPAR-alpha deficiency was also reported to protect against high-fat diet (HFD)induced insulin resistance. The aim of this study was to clarify the role of PPAR-alpha in the development of insulin resistance using PPAR-alpha knockout (KO) mice and wild-type controls (WT). Both WT and PPAR-alpha KO mice on HFD gained significantly more weight relative to chow-fed groups and displayed an increase in insulin levels and a decrease in adiponectin levels. Hyperinsulinemic-euglycemic clamp performed in the nonfasting state demonstrated that HFD caused a marked reduction in whole body, muscle, and white and brown adipose tissue glucose uptake in both WT and PPAR-alpha KO mice relative to chow-fed groups. Suppression of endogenous glucose production during the clamp was markedly blunted in both WT and PPAR-alpha KO HFD-fed mice, indicating liver insulin resistance. The magnitude of HFD-induced changes in the clamp parameters of insulin sensitivity was comparable in PPAR-alpha KO and WT mice. In conclusion, these data show that PPAR-alpha deficiency does not alter insulin sensitivity in mice fed normal chow diet and does not protect against HFD-induced insulin resistance as measured by hyperinsulinemic-euglycemic clamp in nonfasted state. C1 Charles Univ, Fac Med 1, Dept Med 3, Prague 12808 2, Czech Republic. NIDDKD, Mouse Metab Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Haluzik, M (reprint author), Charles Univ, Fac Med 1, Dept Med 3, Nemocnice 1, Prague 12808 2, Czech Republic. EM mhalu@lf1.cuni.cz NR 34 TC 27 Z9 28 U1 0 U2 1 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD APR 1 PY 2004 VL 145 IS 4 BP 1662 EP 1667 DI 10.1210/en.2003-1015 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 803DT UT WOS:000220212500024 PM 14670996 ER PT J AU Srinivasan, S Bunch, DO Feng, Y Rodriguiz, RM Li, M Ravenell, RL Luo, GX Arimura, A Fricker, LD Eddy, EM Wetsel, WC AF Srinivasan, S Bunch, DO Feng, Y Rodriguiz, RM Li, M Ravenell, RL Luo, GX Arimura, A Fricker, LD Eddy, EM Wetsel, WC TI Deficits in reproduction and pro-gonadotropin-releasing hormone processing in male Cpe(fat) mice SO ENDOCRINOLOGY LA English DT Article ID CARBOXYPEPTIDASE-E MUTATION; OBESE FAT/FAT MICE; METALLOCARBOXYPEPTIDASE D; PROHORMONE CONVERTASES; PYROGLUTAMYL-PEPTIDES; TISSUE DISTRIBUTION; FAT MUTATION; RAT; EXPRESSION; PROPROTEIN AB Cpe(fat/fat) mice are obese, diabetic, and infertile. These animals have a point mutation in carboxypeptidase E (CPE), an exopeptidase that removes C-terminal basic amino acids from peptide intermediates. The mutation renders the enzyme unstable, and it is rapidly degraded. Although the infertility of Cpe(fat/fat) mice has not been systematically investigated, it is thought to be due to a deficit in GnRH processing. We have evaluated this hypothesis and found hypothalamic GnRH levels to be reduced by 65-78% and concentrations of pro-GnRH and C-terminal-extended intermediates to be high. Basal serum gonadotropin contents are similar among wild-type, heterozygous, and homozygous mice. Testis morphology and function are abnormal in older obese Cpe(fat/fat) mice. Matings between homozygous mutants yield a 5% pregnancy rate. By comparison, when 50-d-old Cpe(fat/fat) males are paired with heterozygous females, rates increase to 43%, and they rapidly decrease to negligible levels by 120 d. As fertility declines without accompanying changes in the hypothalamic-pituitary-gonadal axis and before obesity is evident, reproduction is more complex than originally thought. This suspicion is confirmed in 90-d-old Cpe(fat/fat) males, who readily interact with females, but rarely mount and fail to show intromission or ejaculation behaviors. Together, these findings show that CPE is a key enzyme for pro-GnRH processing in vivo; however, the reproductive deficits in Cpe(fat/fat) males appear to be due primarily to abnormal sexual behavior. C1 Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Med Endocrinol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Cell Biol & Mouse Behav, Durham, NC 27710 USA. Duke Univ, Med Ctr, Nauroendocrine Anal Core Facil, Durham, NC 27710 USA. Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA. NIEHS, Gamete Biol Sect, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. Tulane Univ, Hebert Ctr, US Japan Biomed Res Labs, Belle Chasse, LA 70037 USA. RP Wetsel, WC (reprint author), Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Box 3497,028 CARL Bldg, Durham, NC 27710 USA. EM wetse001@mc.duke.edu OI Srinivasan, Sudha/0000-0003-0777-4044 FU NICHD NIH HHS [HD-36015] NR 50 TC 22 Z9 22 U1 0 U2 2 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD APR 1 PY 2004 VL 145 IS 4 BP 2023 EP 2034 DI 10.1210/en.2003-1442 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 803DT UT WOS:000220212500064 PM 14715715 ER PT J AU Hoppin, JA Ulmer, R London, SJ AF Hoppin, JA Ulmer, R London, SJ TI Phthalate exposure and pulmonary function SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE monobutyl phthalate; pulmonary function; urine samples ID RESPIRATORY SYMPTOMS; YOUNG-CHILDREN; LUNG-FUNCTION; METABOLITES; HEALTH; DUST; POPULATION; SAMPLES; ASTHMA; HOME AB Exposure to phthalates is widespread because of their use in plastics, cosmetics, and other consumer products. Phthalate exposure has been associated with adverse respiratory outcomes in children. With urinary phthalate measures, we assessed the association between phthalate exposure and four pulmonary function parameters [forced vital capacity (FVC), forced expiratory volume at 1 sec (FEV1), peak expiratory flow (PEF), and maximum mid-expiratory flow] among the 240 adult Third National Health and Nutrition Examination Survey (NHANES III) participants with urinary phthalate data. Linear regression models controlled for race, age, age squared, standing height, body mass index, cumulative smoking, and current smoking. Monobutyl phthalate (MBP) was significantly associated with decrements in three measures of pulmonary function (FVC, FEV1, PEF) in males but not in females. For a change from the 25th to the 75th percentile in MBP level among men, FEV1 decreased 112 mL (SE = 51, p = 0.03). Monoethyl phthalate (MEP) was associated with lower FVC and FEV1 values in men. Monoethythexyl phthalate (MEHP), the metabolite of the plasticizer commonly used in medical tubing, was not adversely associated with any of the pulmonary function parameters evaluated. Our results suggest that MBP and MEP, but not MEHP, may influence pulmonary function among adult males. C1 NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. WESTAT Corp, Res Triangle Pk, NC USA. RP Hoppin, JA (reprint author), NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, MD A3-05,POB 12233, Res Triangle Pk, NC 27709 USA. EM hoppin1@niehs.nih.gov OI London, Stephanie/0000-0003-4911-5290 FU NIEHS NIH HHS [Y1-ES-8062-02] NR 23 TC 64 Z9 69 U1 1 U2 18 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2004 VL 112 IS 5 BP 571 EP 574 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 811KI UT WOS:000220770400044 PM 15064163 ER PT J AU Flower, KB Hoppin, JA Lynch, CF Blair, A Knott, C Shore, DL Sandler, DP AF Flower, KB Hoppin, JA Lynch, CF Blair, A Knott, C Shore, DL Sandler, DP TI Cancer risk and parental pesticide application in children of agricultural health study participants SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE agricultural workers; cancer; children; occupational exposure; pesticides ID NON-HODGKINS-LYMPHOMA; CHILDHOOD-CANCER; OCCUPATIONAL EXPOSURES; MALIGNANT-LYMPHOMAS; CRITICAL WINDOWS; LEUKEMIA; ENVIRONMENT; ETIOLOGY; WORK; IOWA AB Parental exposure to pesticides may contribute to childhood cancer risk. Through the Agricultural Health Study, a prospective study of pesticide applicators in Iowa and North Carolina, we examined childhood cancer risk and associations with parental pesticide application. Identifying information for 17,357 children of Iowa pesticide applicators was provided by parents via questionnaires (1993-1997) and matched against the Iowa Cancer Registry. Fifty incident childhood cancers were identified (1975-1998). Risk of A childhood cancers combined was increased [standardized incidence ratio (SIR) = 1.36; 95% confidence interval (CI), 1.03-1.79]. Risk of all lymphomas combined was also increased (SIR = 2.18; 95% CI, 1.13-4.19), as was risk of Hodgkin's lymphoma (SIR = 2.56; 95% CI, 1.06-6.14). We used logistic regression to explore associations between self-reported parental pesticide application practices and childhood cancer risk. No association was detected between frequency of parental pesticide application and childhood cancer risk. An increased risk of cancer was detected among children whose fathers did not use chemically resistant gloves [odds ratio (OR) = 1.98; 95% CI, 1.05-3.76] compared with children whose fathers used gloves. Of 16 specific pesticides used by fathers prenatally, ORs were increased for aldrin (OR = 2.66), dichlorvos (OR = 2.06), and ethyl dipropylthiocarbamate (OR = 1.91). However, these results were based on small numbers and not supported by prior biologic evidence. Identification of excess lymphoma risk suggests that farm exposures including pesticides may play a role in the etiology of childhood lymphoma. C1 Univ N Carolina, Sch Publ Hlth, Robert Wood Johnson Clin Scolars Program, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Publ Hlth, Div Community Pediat, Dept Pediat, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Publ Hlth, Dept Maternal & Child Hlth, Chapel Hill, NC 27599 USA. Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. Univ Iowa, Dept Epidemiol, Iowa City, IA USA. NCI, Occupat & Environm Epidemiol Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. Battelle Mem Inst, Durham, NC USA. WESTAT Corp, Durham, NC USA. RP Flower, KB (reprint author), Univ N Carolina, Sch Publ Hlth, Robert Wood Johnson Clin Scolars Program, CB 7105, Chapel Hill, NC 27599 USA. EM kori_flower@med.unc.edu OI Sandler, Dale/0000-0002-6776-0018 FU NIEHS NIH HHS [P30 ES 05605] NR 46 TC 68 Z9 71 U1 0 U2 5 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2004 VL 112 IS 5 BP 631 EP 635 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 811KI UT WOS:000220770400054 PM 15064173 ER PT J AU Quandt, SA Doran, AM Rao, P Hoppin, JA Snively, BM Arcury, TA AF Quandt, SA Doran, AM Rao, P Hoppin, JA Snively, BM Arcury, TA TI Reporting pesticide assessment results to farmworker families: Development, implementation, and evaluation of a risk communication strategy SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article; Proceedings Paper CT East Coast Migrant Stream Forum CY OCT 26, 2002 CL Savannah, GA DE agriculture; children; community; environmental justice; exposure; health communication; house dust; Latino/a ID HEALTH; EXPOSURE; METABOLITES; MECONIUM AB The collection of environmental samples presents a responsibility to return information to the affected participants. Explaining complex and often ambiguous scientific information to a lay audience is a challenge. As shown by environmental justice research, this audience frequently has limited formal education, increasing the challenge for researchers to explain the data collected, the risk indicated by the findings, and action the affected community should take. In this study we describe the development and implementation of a risk communication strategy for environmental pesticide samples collected in the homes of Latino/a migrant and seasonal farmworkers in a community-based participatory research project. The communication strategy was developed with community input and was based on face-to-face meetings with members of participating households. Using visual displays of data effectively conveyed information about individual household contamination and placed it in the context of community findings. The lack of national reference data and definitive standards for action necessitated a simplified risk message. We review the strengths and weaknesses of such an approach and suggest areas for future research in risk communication to communities affected by environmental health risks. C1 Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27157 USA. Wake Forest Univ, Sch Med, Dept Family & Community Med, Winston Salem, NC 27157 USA. NIH, Inst Enmvironm Hlth Sci, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. RP Quandt, SA (reprint author), Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Piedmont Plaza 2,Suite 512, Winston Salem, NC 27157 USA. EM squandt@wfubmc.edu FU NIEHS NIH HHS [R01 ES 08739] NR 23 TC 31 Z9 32 U1 0 U2 12 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2004 VL 112 IS 5 BP 636 EP 642 DI 10.1289/ehp.6754 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 811KI UT WOS:000220770400055 PM 15064174 ER PT J AU Ryu, J Lee, MS Na, JG Chung, K Song, BJ Park, K AF Ryu, J Lee, MS Na, JG Chung, K Song, BJ Park, K TI Molecular cloning of cytochrome P4501A cDNA of medaka (Oryzias latipes) and messenger ribonucleic acid regulation by environmental pollutants SO ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY LA English DT Article DE medaka; cytochrome P4501A; cloning; reverse transciption-polymerase chain reation; environmental pollutants ID FISH FUNDULUS-HETEROCLITUS; DAB LIMANDA-LIMANDA; RAINBOW-TROUT; BETA-NAPHTHOFLAVONE; DIETARY BENZOPYRENE; INDUCTION; CYP1A; EXPRESSION; METABOLISM; EXPOSURE AB The sequence of cytochrome P4501A (CYP1A) cDNA of medaka (Oryzias latipes) was determined, and its messenger ribonucleic acid (mRNA) regulation by beta-naphthoflavone (betaNF) was evaluated. The determined cDNA sequence contained 2,349 base pairs (bp), and the open reading frame contained a total of 1,563 bp encoding 521 predicted amino acids. The induction of CYP1A mRNA in medaka was evaluated using reverse transcription-polymerase chain reaction. The concentration-dependent induction of CYP1A mRNA in the liver was observed after exposure to betaNF at nominal concentrations of 20, 100, and 500 mug/ L for 2 d. Time-dependent changes of CYP1A mRNA levels were also observed in the liver, gill, gut, and caudal fin tissues of medaka exposed to 100 mug/L of betaNF for 7 d. Our results showed that the degree of CYP1A mRNA induction in the gill, gut, and caudal fin after exposure to betaNF was relatively higher than that in the liver, possibly because of low basal levels of CYP1A mRNA in the gill, gut, and caudal fin of nonexposed fish. The induction of medaka CYP1A mRNA was also observed after exposure to an environmental sample, landfill leachate. The CYP1A mRNA inductions in the gill, gut, and caudal fin were also higher than that in the liver as shown in the betaNF-treated groups. These results show that CYP1A mRNA determination in the gill, gut, and caudal fin, which are in direct contact with the polluted water, may become a useful method for monitoring CYP1A-inducible chemicals. C1 Dongduk Womens Univ, Coll Pharm, Seoul 136714, South Korea. NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. Sungkyunkwan Univ, Coll Pharm, Suwon 440746, Gyeonggido, South Korea. Natl Inst Environm Res, Environm Risk Res Dept, Inchon 404170, South Korea. RP Park, K (reprint author), Dongduk Womens Univ, Coll Pharm, 23-1 Wolgok Dong, Seoul 136714, South Korea. EM kspark@dongduk.ac.kr NR 38 TC 9 Z9 12 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0730-7268 J9 ENVIRON TOXICOL CHEM JI Environ. Toxicol. Chem. PD APR PY 2004 VL 23 IS 4 BP 1004 EP 1011 DI 10.1897/03-27 PG 8 WC Environmental Sciences; Toxicology SC Environmental Sciences & Ecology; Toxicology GA 807EE UT WOS:000220484000025 PM 15095898 ER PT J AU Garcia-Rivera, J Chang, YC Kwon-Chung, KJ Casadevall, A AF Garcia-Rivera, J Chang, YC Kwon-Chung, KJ Casadevall, A TI Cryptococcus neoformans CAP59 (or cap59p) is involved in the extracellular trafficking of capsular glucuronoxylomannan SO EUKARYOTIC CELL LA English DT Article ID MONOCLONAL-ANTIBODY; VIRULENCE; POLYSACCHARIDE; GENE; SPECIFICITY; MUTANTS; UREASE AB Several genes are essential for Cryptococcus neoformans capsule synthesis, but their functions are unknown. We examined the localization of glucuronoxylomannan (GXM) in strain B-3501 and in cap59 mutants B-4131 and C536. Wild-type strain B-3501 showed a visible capsule by India ink staining and immunofluorescence with anticapsular monoclonal antibodies (MAbs) 12A1 and 18B7. B-4131, a mutant containing a missense mutation in CAP59, showed no capsule by India ink staining but revealed the presence of capsular polysaccharide on the cell surface by immunofluorescence. The cap59 gene deletion mutant (C536), however, did not show a capsule by either India ink staining or immunofluorescence. Analysis of cell lysates for GXM by enzyme-linked immunosorbent assay revealed GXM in C536 samples. Furthermore, the epitopes recognized by MAbs 12A1, 2D10, 13F1, and 18B7 were each detected in the cytoplasm of all strains by immunogold electron microscopy, although there were differences in location consistent with differences in epitope synthesis and/or transport. In addition, the cells of B-3501 and B-4131, but not those of the cap59 deletant, assimilated raffinose or urea. Hence, the missense mutation of CAP59 in B-4131 partially hampered the trafficking of GXM but allowed the secretion of enzymes involved in hydrolysis of raffinose or urea. Furthermore, the cell diameter and volume for strain C536 are higher than those for strain B-3501 or B-4131 and may suggest the accumulation of cellular material in the cytoplasm. Our results suggest that CAP59 is involved in capsule synthesis by participating in the process of GXM (polysaccharide) export. C1 Yeshiva Univ Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Casadevall, A (reprint author), Yeshiva Univ Albert Einstein Coll Med, Dept Med, 1300 Morris Pk Ave,610 Belfer, Bronx, NY 10461 USA. EM casadeva@aecom.yu.edu FU NHLBI NIH HHS [HL59842, R01 HL059842]; NIAID NIH HHS [AI13342, AI33774, R01 AI033774]; NIGMS NIH HHS [GM64100, F31 GM064100] NR 29 TC 71 Z9 74 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1535-9778 J9 EUKARYOT CELL JI Eukaryot. Cell PD APR PY 2004 VL 3 IS 2 BP 385 EP 392 DI 10.1128/EC.3.2.385-392.2004 PG 8 WC Microbiology; Mycology SC Microbiology; Mycology GA 813ZP UT WOS:000220945300014 PM 15075268 ER PT J AU Westmoreland, TJ Marks, JR Olson, JA Thompson, EM Resnick, MA Bennett, CB AF Westmoreland, TJ Marks, JR Olson, JA Thompson, EM Resnick, MA Bennett, CB TI Cell cycle progression in G(1) and S phases is CCR4 dependent following ionizing radiation or replication stress in Saccharomyces cerevisiae SO EUKARYOTIC CELL LA English DT Article ID DOUBLE-STRAND BREAKS; PUTATIVE RNA HELICASE; DNA-DAMAGING AGENTS; BUDDING YEAST; PROTEIN-KINASE; POLYMERASE-II; SYSTEMATIC IDENTIFICATION; TRANSCRIPTIONAL RESPONSE; MOLECULAR ANALYSIS; GENETIC-CONTROL AB To identify new nonessential genes that affect genome integrity, we completed a screening for diploid mutant Saccharomyces cerevisiae strains that are sensitive to ionizing radiation (IR) and found 62 new genes that confer resistance. Along with those previously reported (Bennett et al., Nat. Genet. 29:426-434, 2001), these genes bring to 169 the total number of new IR resistance genes identified. Through the use of existing genetic and proteomic databases, many of these genes were found to interact in a damage response network with the transcription factor Ccr4, a core component of the CCR4-NOT and RNA polymerase-associated factor 1 (PAF1)-CDC73 transcription complexes. Deletions of individual members of these two complexes render cells sensitive to the lethal effects of IR as diploids, but not as haploids, indicating that the diploid G(1) cell population is radiosensitive. Consistent with a role in G(1), diploid ccr4Delta cells irradiated in G(1) show enhanced lethality compared to cells exposed as a synchronous G(2) Population. In addition, a prolonged RAD9-dependent G(1) arrest occurred following IR of ccr4Delta cells and CCR4 is a member of the RAD9 epistasis group, thus confirming a role for CCR4 in checkpoint control. Moreover, ccr4Delta cells that transit S phase in the presence of the replication inhibitor hydroxyurea (HU) undergo prolonged cell cycle arrest at G(2) followed by cellular lysis. This S-phase replication defect is separate from that seen for rad52 mutants, since rad52Delta ccr4Delta cells show increased sensitivity to HU compared to rad52Delta or ccr4Delta mutants alone. These results indicate that cell cycle transition through G(1) and S phases is CCR4 dependent following radiation or replication stress. C1 Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Bennett, CB (reprint author), Duke Univ, Med Ctr, Dept Surg, Rm 379 MSRB,Box 3873,Res Dr, Durham, NC 27710 USA. EM benne048@mc.duke.edu NR 73 TC 37 Z9 38 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1535-9778 J9 EUKARYOT CELL JI Eukaryot. Cell PD APR PY 2004 VL 3 IS 2 BP 430 EP 446 DI 10.1128/EC.3.2.430-446.2004 PG 17 WC Microbiology; Mycology SC Microbiology; Mycology GA 813ZP UT WOS:000220945300019 PM 15075273 ER PT J AU Mahalingam, B Wang, YF Boross, PI Tozser, J Louis, JM Harrison, RW Weber, IT AF Mahalingam, B Wang, YF Boross, PI Tozser, J Louis, JM Harrison, RW Weber, IT TI Crystal structures of HIV protease V82A and L90M mutants reveal changes in the indinavir-binding site SO EUROPEAN JOURNAL OF BIOCHEMISTRY LA English DT Article DE aspartic protease; crystal structure; drug resistance; HIV-1 ID VIRUS TYPE-1 PROTEASE; DRUG-RESISTANT MUTANTS; IN-VIVO; CROSS-RESISTANCE; INHIBITORS; RESOLUTION; REFINEMENT; SAQUINAVIR; MECHANISMS; SEQUENCES AB The crystal structures of the wild-type HIV-1 protease (PR) and the two resistant variants, PRV82A and PRL90M, have been determined in complex with the antiviral drug, indinavir, to gain insight into the molecular basis of drug resistance. V82A and L90M correspond to an active site mutation and nonactive site mutation, respectively. The inhibition (K-i) of PRV82A and PRL90M was 3.3- and 0.16-fold, respectively, relative to the value for PR. They showed only a modest decrease, of 10-15%, in their k(cat)/K-m values relative to PR. The crystal structures were refined to resolutions of 1.25-1.4 Angstrom to reveal critical features associated with inhibitor resistance. PRV82A showed local changes in residues 81-82 at the site of the mutation, while PRL90M showed local changes near Met90 and an additional interaction with indinavir. These structural differences concur with the kinetic data. C1 Georgia State Univ, Dept Biol, Atlanta, GA 30302 USA. Univ Debrecen, Dept Biochem & Mol Biol, Debrecen, Hungary. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Georgia State Univ, Dept Comp Sci, Atlanta, GA 30303 USA. Georgia State Univ, Dept Chem, Atlanta, GA 30303 USA. RP Weber, IT (reprint author), Georgia State Univ, Dept Biol, POB 4010, Atlanta, GA 30302 USA. EM iweber@gsu.edu RI Tozser, Jozsef/A-7840-2008; OI Tozser, Jozsef/0000-0003-0274-0056; Tozser, Jozsef/0000-0001-5076-8729 FU FIC NIH HHS [TW 01001]; NIGMS NIH HHS [GM 62920, R01 GM062920] NR 31 TC 51 Z9 52 U1 1 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0014-2956 J9 EUR J BIOCHEM JI Eur. J. Biochem. PD APR PY 2004 VL 271 IS 8 BP 1516 EP 1524 DI 10.1111/j.1432-1033.2004.04060.x PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 809GV UT WOS:000220626100011 PM 15066177 ER PT J AU Jung, ID Lee, J Lee, KB Park, CG Kim, YK Seo, DW Park, D Lee, HW Han, JW Lee, HY AF Jung, ID Lee, J Lee, KB Park, CG Kim, YK Seo, DW Park, D Lee, HW Han, JW Lee, HY TI Activation of p21-activated kinase 1 is required for lysophosphatidic acid-induced focal adhesion kinase phosphorylation and cell motility in human melanoma A2058 cells SO EUROPEAN JOURNAL OF BIOCHEMISTRY LA English DT Article DE focal adhesion kinase; lysophosphatidic acid; motility stimulation; p21-activated kinase 1 ID PROTEIN-COUPLED RECEPTOR; GROWTH-FACTOR RECEPTOR; PAXILLIN TYROSINE PHOSPHORYLATION; STRESS FIBER FORMATION; GTP-BINDING PROTEIN; RHO-FAMILY GTPASES; G-BETA-GAMMA; PHOSPHATIDYLINOSITOL 3-KINASE; ENDOTHELIAL-CELLS; EDG FAMILY AB Lysophosphatidic acid (LPA), one of the naturally occurring phospholipids, stimulates cell motility through the activation of Rho family members, but the signaling mechanisms remain to be elucidated. In the present study, we investigated the roles of p21-activated kinase 1 (PAK1) on LPA-induced focal adhesion kinase (FAK) phosphorylation and cell motility. Treatment of human melanoma cells A2058 with LPA increased phosphorylation and activation of PAK1, which was blocked by treatment with pertussis toxin and by inhibition of phosphoinositide 3-kinase (PI3K) with an inhibitor LY294002 or by overexpression of catalytically inactive mutant of PI3Kgamma, indicating that LPA-induced PAK1 activation was mediated via a Gi protein and the PI3Kgamma signaling pathway. In addition, we demonstrated that Rac1/Cdc42 signals acted as upstream effector molecules of LPA-induced PAK activation. However, Rho-associated kinase, MAP kinase kinase 1/2 or phospholipase C might not be involved in LPA-induced PAK1 activation or cell motility stimulation. Furthermore, PAK1 was necessary for FAK phosphorylation by LPA, which might cause cell migration, as transfection of the kinase deficient mutant of PAK1 or PAK auto-inhibitory domain significantly abrogated LPA-induced FAK phosphorylation. Taken together, these findings strongly indicated that PAK1 activation was necessary for LPA-induced cell motility and FAK phosphorylation that might be mediated by sequential activation of Gi protein, PI3Kgamma and Rac1/Cdc42. C1 Konyang Univ, Coll Med, Dept Pharmacol, Nonsan 320711, South Korea. Kwandong Univ, Coll Med, Gangneung, South Korea. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Seoul Natl Univ, Sch Biol Sci, Seoul 151, South Korea. Sungkyunkwan Univ, Coll Pharm, Suwon, South Korea. RP Lee, HY (reprint author), Konyang Univ, Coll Med, Dept Pharmacol, Nonsan 320711, South Korea. EM hoi@konyang.ac.kr OI Seo, Dong-Wan/0000-0003-4971-834X NR 59 TC 26 Z9 28 U1 1 U2 4 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0014-2956 J9 EUR J BIOCHEM JI Eur. J. Biochem. PD APR PY 2004 VL 271 IS 8 BP 1557 EP 1565 DI 10.1111/j.1432-1033.2004.04066.x PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 809GV UT WOS:000220626100015 PM 15066181 ER PT J AU Sausville, EA Newell, DR AF Sausville, EA Newell, DR TI Preclinical models in cancer drug discovery and development - Introduction SO EUROPEAN JOURNAL OF CANCER LA English DT Editorial Material C1 NCI, DCTD, Dev Therapeut Program, Rockville, MD 20852 USA. Univ Newcastle, No Inst Canc Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. RP Sausville, EA (reprint author), NCI, DCTD, Dev Therapeut Program, EPN 8018,6130 Execut Blvd, Rockville, MD 20852 USA. NR 0 TC 7 Z9 8 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD APR PY 2004 VL 40 IS 6 BP 783 EP 784 DI 10.1016/j.ejca.2004.01.010 PG 2 WC Oncology SC Oncology GA 815IC UT WOS:000221035000001 ER PT J AU Holbeck, SL AF Holbeck, SL TI Update on NCI in vitro drug screen utilities SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE neoplasms; antineoplastic agents; computational biology; molecular biology; proteomics; genomics; pharmacogenetics; human genome project; genetic research; (therapies, investigational); Saccharomyces cerevisiae ID TUMOR-CELL-LINES; NATIONAL-CANCER-INSTITUTE; SMALL-MOLECULE INHIBITORS; GENE-EXPRESSION PATTERNS; TOPOISOMERASE-II; TUBULIN POLYMERIZATION; BIOLOGICAL EVALUATION; ENZYME EXPRESSION; ANTITUMOR AGENTS; PROTEIN AB Development of new anti-cancer drugs is a costly and risky proposition. The Developmental Therapeutics Program (DTP) of the National Cancer Institutes of the United States (U.S.) facilitates the drug development process by providing access to preclinical screening services. Since the early 1990's, DTP has screened tens of thousands of compounds against a panel of 60 human tumour cell lines representing nine tissue sites. At the same time, DTP began to accumulate information on the expression of molecular entities in the same 60 cell line panel. Many of these data are freely available to the public at http://dtp.nci.nih.gov. More recently. additional. more focused screens have entered the picture, with data also available through the web site. These include screening of roughly 100 000 compounds against a panel of yeast mutants, and screening of the NCI Diversity Set in assays designed to detect effects on Molecular Targets of interest. Published by Elsevier Ltd. C1 NCI, Dev Therapeut Program, Informat Technol Branch, Bethesda, MD 20892 USA. RP Holbeck, SL (reprint author), NCI, Dev Therapeut Program, Informat Technol Branch, 6130 Execut Blvd Room 8014, Bethesda, MD 20892 USA. EM holbecks@mail.nih.gov NR 57 TC 83 Z9 84 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD APR PY 2004 VL 40 IS 6 BP 785 EP 793 DI 10.1016/j.ejca.2003.11.022 PG 9 WC Oncology SC Oncology GA 815IC UT WOS:000221035000002 PM 15120034 ER PT J AU Decker, S Hollingshead, M Bonomi, CA Carter, JP Sausville, EA AF Decker, S Hollingshead, M Bonomi, CA Carter, JP Sausville, EA TI The hollow fibre model in cancer drug screening: the NCI experience SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE hollow fibre; drug discovery; drug screening; in vivo models ID TUMOR-CELL-LINES AB The in vivo hollow fibre model was developed by the National Cancer Institute (NCI) in the United States of America (USA) at a time when the number of potential anti-cancer drugs arising from in vitro screening efforts exceeded the available capacity for testing in traditional xenograft models. Updated analysis of the predictive value of the hollow fibre model continues to indicate that the greater the response in the hollow fibre assay, the more likely it is that activity will be seen in subsequent xenograft models. The original 12 cell line hollow fibre panel has been Supplemented with histology-specific panels, and we begin here to analyse their utility in predicting activity in subsequent in vivo models. The key goal of using the hollow fibre model as a way to decrease the cost, both financial and in the number of animals used, to evaluate initial evidence of a compound's capacity to act across physiological barriers continues to be reinforced With our enlarging experience. (C) 2004 Elsevier Ltd. All rights reserved. C1 NCI, Div Canc Treatment & Diagnosis, Dev Therapeut Program, Rockville, MD 20852 USA. SAIC, Frederick, MD 21701 USA. RP Sausville, EA (reprint author), NCI, Div Canc Treatment & Diagnosis, Dev Therapeut Program, 6130 Execut Blvd,Room 8018, Rockville, MD 20852 USA. EM sausville@nih.gov RI Ain, Kenneth/A-5179-2012 OI Ain, Kenneth/0000-0002-2668-934X NR 9 TC 37 Z9 41 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD APR PY 2004 VL 40 IS 6 BP 821 EP 826 DI 10.1016/j.ejca.2003.11.029 PG 6 WC Oncology SC Oncology GA 815IC UT WOS:000221035000005 PM 15120037 ER PT J AU Hansen, K Khanna, C AF Hansen, K Khanna, C TI Spontaneous and genetically engineered animal models: use in preclinical cancer drug development SO EUROPEAN JOURNAL OF CANCER LA English DT Review DE cancers; GEM; mouse; transgenic; canine comparative; spontaneous ID TRANSGENIC MOUSE MODEL; ENCAPSULATED MURAMYL TRIPEPTIDE; TRANSITIONAL-CELL CARCINOMA; COLONY-STIMULATING FACTOR; POLYETHYLENE-GLYCOL CONJUGATE; PROTEIN TRANSFERASE INHIBITOR; ACUTE PROMYELOCYTIC LEUKEMIA; TYROSINE KINASE INHIBITOR; SOFT-TISSUE SARCOMAS; SV40 T-ANTIGEN AB The preclinical development of anticancer drugs has been based primarily on the transplantation of murine or human cancers into mice. Alternatives to these transplantation models are animals that naturally develop cancers with features relevant to the human disease. The first group of these models arises in mice that are genetically engineered to develop cancer. The second group includes pet dogs and cats that naturally develop cancer. This review will discuss the use and integration of these spontaneous cancer models into a comprehensive and comparative approach to preclinical drug development. Examples of their successful use and an outline of their relative strengths and weaknesses will be provided. (C) 2004 Elsevier Ltd. All rights reserved. C1 NCI, Canc Res Ctr, Comparat Oncol Program, NIH, Rockville, MD USA. RP Khanna, C (reprint author), NCI, Canc Res Ctr, Comparat Oncol Program, NIH, Rockville, MD USA. EM khannac@mail.nih.gov NR 148 TC 125 Z9 131 U1 1 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD APR PY 2004 VL 40 IS 6 BP 858 EP 880 DI 10.1016/j.ejca.2003.11.031 PG 23 WC Oncology SC Oncology GA 815IC UT WOS:000221035000010 PM 15120042 ER PT J AU Hollingshead, MG Bonomi, CA Borgel, SD Carter, JP Shoemaker, R Melillo, G Sausville, EA AF Hollingshead, MG Bonomi, CA Borgel, SD Carter, JP Shoemaker, R Melillo, G Sausville, EA TI A potential role for imaging technology in anticancer efficacy evaluations SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE in vivo imaging; bioluminescence; luciferase; cancer efficacy studies ID IN-VIVO; GENE-EXPRESSION; MAMMALIAN-CELLS; BIOLUMINESCENT REPORTER; DRUG DEVELOPMENT; PROSTATE-CANCER; LUCIFERASE GENE; REAL-TIME; MICE; TUMORS AB The introduction of imaging methods suitable for rodents offers opportunities for new anticancer efficacy models. Traditional models do not provide the level of sensitivity afforded by these precise and quantitative techniques. Bioluminescent endpoints, now feasible because of sensitive charge-coupled device cameras, can be non-invasively detected in live animals. Currently, the most common luminescence endpoint is firefly luciferase, which, in the presence of O-2 and ATP, catalyses the cleavage of the substrate luciferin and results in the emission of a photon of light. In vivo implantation of tumour cells transfected with the luciferase gene allows sequential monitoring of tumour growth within the viscera by measuring these photon signals. Furthermore, tumour cell lines containing the luciferase gene transcribed from an inducible promoter offer opportunities to study molecular-target modulation without the need for ex vivo evaluations of serial tumour samples. In conjunction with this, transgenic juice bearing a luciferase reporter mechanism can be used to monitor the tumour microenvironment as well as to signal when transforming events occur. This technology has the potential to reshape the efficacy evaluations and drug-testing algorithms of the future. Published by Elsevier Ltd. C1 NCI, Dev Therapeut Program, Div Canc Diagnosis & Treatment, Bethesda, MD 20892 USA. SAIC Frederick Inc, Ft Detrick, MD 21702 USA. RP Hollingshead, MG (reprint author), NCI, Dev Therapeut Program, Div Canc Diagnosis & Treatment, Bethesda, MD 20892 USA. EM hollingm@mail.nih.gov NR 44 TC 29 Z9 31 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD APR PY 2004 VL 40 IS 6 BP 890 EP 898 DI 10.1016/j.ejca.2003.12.018 PG 9 WC Oncology SC Oncology GA 815IC UT WOS:000221035000012 PM 15120044 ER PT J AU Tomaszewski, JE AF Tomaszewski, JE TI Multi-species toxicology approaches for oncology drugs: the US perspective SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE antineoplastic agents; drug evaluation; preclinical; toxicology; pharmacology; models; animals ID CHRONIC MYELOID-LEUKEMIA; EARLY CLINICAL-TRIALS; ABL TYROSINE KINASE; PHASE-I TRIAL; REGULATORY CONSIDERATIONS; PRECLINICAL TOXICOLOGY; ANTICANCER DRUGS; HOLLOW FIBERS; INHIBITOR; TOXICITY AB The Toxicology and Pharmacology Branch (T&PB) of the National Cancer Institute (NCI) performs pharmacological and toxicological evaluations of new oncology agents according to an agent-directed paradigm in which all studies are tailored to each agent. The United States Food and Drug Administration (US FDA) requires that preclinical toxicology studies be conducted in two species. a rodent and a non-rodent for all small molecules, and T&PB has successfully used this formula. While pharmacokinetic (PK) studies are considered optional, T&PB routinely develops new methods for plasma/tissue drug analysis and employs this methodology throughout development to determine kinetics in various species and toxicokinetics in the toxicity studies. In the current era of molecular target-based development, the T&PB also develops or employs methodology to evaluate effects of the new chemical entity on appropriate biomarkers in tumour and normal tissues. In this comprehensive programme, T&PB is able to correlate safety and toxicity with both plasma drug levels and biomarker modulation in two species for a seamless entry into phase I. Published by Elsevier Ltd. C1 NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diagnosis, Rockville, MD 20852 USA. RP Tomaszewski, JE (reprint author), NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diagnosis, Execut Plaza N,Room 8034,6130 Execut Blvd, Rockville, MD 20852 USA. EM tomasze@mail.nih.gov NR 40 TC 16 Z9 18 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD APR PY 2004 VL 40 IS 6 BP 907 EP 913 DI 10.1016/j.ejca.2003.11.024 PG 7 WC Oncology SC Oncology GA 815IC UT WOS:000221035000014 PM 15120046 ER PT J AU Hirvonen, T Tornwall, ME Pietinen, P Korhonen, P Albanes, D Virtamo, J AF Hirvonen, T Tornwall, ME Pietinen, P Korhonen, P Albanes, D Virtamo, J TI Flavonol and flavone intake and the risk of intermittent claudication in male smokers SO EUROPEAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE antioxidants; cohort studies; flavonoids; intermittent claudication ID CORONARY-HEART-DISEASE; POTENTIALLY ANTICARCINOGENIC FLAVONOIDS; PERIPHERAL ARTERIAL-DISEASE; MIDDLE-AGED MEN; BETA-CAROTENE; VITAMIN-E; QUERCETIN; DIET; SUPPLEMENTATION; QUESTIONNAIRE AB The objective of this study was to investigate the association between flavonol and flavone intake and the risk of intermittent claudication in male smokers. The study population consisted of participants of the Finnish alpha-Tocopherol, beta-Carotene Cancer Prevention (ATBC) Study, who were free of intermittent claudication at study entry. These 25,041 male smokers were 50 - 69 years old at baseline. Participants completed a validated dietary questionnaire at baseline. The occurrence of intermittent claudication was assessed by annual administration of the Rose questionnaire. During the median follow-up of 4.1 years, 2412 new cases of intermittent claudication were observed. Dietary intake of flavonols and flavones was inversely associated with the risk of intermittent claudication when adjusted for cardiovascular risk factors (relative risk, RR in the highest vs. lowest quintile of intake 0.86, 95% confidence interval, CI: 0.75 - 0.98, p for trend 0.007). However, after further adjustment for intakes of vitamins C and E and total carotenoids, the association was attenuated (RR: 0.93, 95% CI: 0.81 - 1.08, p for trend 0.12). The risk of intermittent claudication was lower among men in the highest quintile of vegetable consumption (RR: 0.78, 95% CI: 0.69 - 0.89, p for trend 0.0001) and among wine drinkers (RR: 0.63, 95% CI: 0.41 - 0.98). Adjustment for flavonol and flavone intake only marginally changed these associations. In conclusion, flavonol and flavone intake was not independently associated with the risk of intermittent claudication. C1 Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, SF-00300 Helsinki, Finland. NCI, Div Clin Sci, Bethesda, MD 20892 USA. RP Hirvonen, T (reprint author), Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Mannerheimintie 166, SF-00300 Helsinki, Finland. EM tero.hirvonen@ktl.fi RI Albanes, Demetrius/B-9749-2015 FU NCI NIH HHS [N01-SC-45165] NR 36 TC 5 Z9 5 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0393-2990 J9 EUR J EPIDEMIOL JI Eur. J. Epidemiol. PD APR PY 2004 VL 19 IS 4 BP 305 EP 311 DI 10.1023/B:EJEP.0000024699.81170.07 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 813SV UT WOS:000220927700004 PM 15180100 ER PT J AU Mayne, M Moffatt, T Kong, H McLaren, PJ Fowke, KR Becker, KG Namaka, M Schenck, A Bardoni, B Bernstein, CN Melanson, M AF Mayne, M Moffatt, T Kong, H McLaren, PJ Fowke, KR Becker, KG Namaka, M Schenck, A Bardoni, B Bernstein, CN Melanson, M TI CYFIP2 is highly abundant in CD4(+) cells from multiple sclerosis patients and is involved in T cell adhesion SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE human; T lymphocytes; multiple sclerosis; adhesion molecules and signal transduction ID GENE-EXPRESSION; CEREBROSPINAL-FLUID; MICROARRAY ANALYSIS; LESIONS; LYMPHOCYTES; PROTEIN; RAC1; ENCEPHALOMYELITIS; PATHOGENESIS; ACTIVATION AB DNA microarray profiling of CD4(+) and CD8(+) cells from non-treated relapsing and remitting multiple sclerosis (MS) patients determined that the cytoplasmic binding partner of fragile X protein (CYFIP2, also called PIR121) was increased significantly compared to healthy controls. Western analysis confirmed that CYFIP2 protein was increased approximately fourfold in CD4(+) cells from MS compared to inflammatory bowel disorder (IBD) patients or healthy controls. Because CYFIP2 acts as part of a tetrameric complex that regulates WAVE1 activation we hypothesized that high levels of CYFIP2 facilitate T cell adhesion, which is elevated in MS patients. Several findings indicated that increased levels of CYFIP2 facilitated adhesion. First, adenoviral-mediated overexpression of CYFIP2 in Jurkat cells increased fibronectin-mediated adhesion. Secondly, CYFIP2 knock-down experiments using anti-sense oligodeoxynucleotides reduced fibronectin-mediated binding in Jurkat and CD4(+) cells. Thirdly, inhibition of Rac-1, a physical partner with CYFIP2 and regulator of WAVE1 activity, reduced fibronectin-mediated adhesion in Jurkat and CD4(+) cells. Finally, inhibition of Rac-1 or reduction of CYFIP2 protein decreased fibronectin-mediated adhesion in CD4(+) cells from MS patients to levels similar to controls. These studies suggest that overabundance of CYFIP2 protein facilitates increased adhesion properties of T cells from MS patients. C1 Natl Res Council Canada, Inst Nutrisci & Hlth, Classroom Ctr 106C, Charlottetown, PE C1A 4P3, Canada. Univ Manitoba, St Boniface Hosp Res Ctr, Dept Pharmacol & Therapeut, Div Neurosci, Winnipeg, MB, Canada. Univ Manitoba, Dept Med Microbiol & Infect Dis, Winnipeg, MB, Canada. NIA, DNA Array Unit, Baltimore, MD 21224 USA. Univ Manitoba, Fac Pharm, Winnipeg, MB R3T 2N2, Canada. ULP, Dept Mol Pathol, IGBMC, CNRS,INSERM, Strasbourg, France. Univ Manitoba, Inflammatory Bowel Dis Clin & Res Ctr, Winnipeg, MB, Canada. Univ Manitoba, Dept Internal Med, Hlth Sci Ctr, Multiple Sclerosis Clin, Winnipeg, MB, Canada. RP Mayne, M (reprint author), Natl Res Council Canada, Inst Nutrisci & Hlth, Classroom Ctr 106C, 550 Univ Ave, Charlottetown, PE C1A 4P3, Canada. EM michael.mayne@nrc.gc.ca RI Bardoni, Barbara/F-9918-2013; Schenck, Annette/E-4514-2012 OI Becker, Kevin/0000-0002-6794-6656; Fowke, Keith/0000-0001-8227-6649; Schenck, Annette/0000-0002-6918-3314 NR 41 TC 22 Z9 23 U1 0 U2 4 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD APR PY 2004 VL 34 IS 4 BP 1217 EP 1227 DI 10.1002/eji.200324726 PG 11 WC Immunology SC Immunology GA 812JA UT WOS:000220834600033 PM 15048733 ER PT J AU Raffa, D Edler, MC Daidone, G Maggio, B Merickech, M Plescia, S Schillaci, D Bai, RL Hamel, E AF Raffa, D Edler, MC Daidone, G Maggio, B Merickech, M Plescia, S Schillaci, D Bai, RL Hamel, E TI Synthesis, cytotoxicity, and inhibitory effects on tubulin polymerization of a new 3-heterocyclo substituted 2-styrylquinazolinones SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE 2-styrylquinazolinones; antimitotic agents; cytotoxic activity; microtubules ID BIOLOGICAL EVALUATION; AGENTS; DERIVATIVES; COLCHICINE AB In order to study the influence of 3-substitution on the cytotoxic activity of 2-styrylquinazolinones, new 6-chloro-2-styryl-3-(heteroaryl)-4(3H)-quinazolinones were synthesized by refluxing equimolar amounts of 6-chloro-2-methyl-3-(heteroaryl)-4(3H)-quinazolinones and benzaldehyde in glacial acetic acid. At 1 mug ml(-1) concentration, almost all 2-styrylquinazolinones showed some cytotoxic activity against the L1210 and K562 leukemia cell lines. However, only 6-chloro-2-styryl-3-(pyrimidin-2yl)-4(3H)-quinazolinone inhibited the growth of these cells by over 50%. This last compound was also the only member of the series that inhibited tubulin polymerization, with air IC50 value of 5.8 versus 3.2 muM for colchicine. It was also examined for effects on the growth of human MCF7 breast carcinoma cells and Burkitt lymphoma CA46 cells, which had IC50 values of 0.34 and 1.0 muM, respectively. At 10 muM 6-chloro-2-styryl-3-(pyrimidin-2yl)-4(3H)-quinazolinone induced G2/M arrest (66%) in Burkitt cells, with a mitotic index of 20%. At 3.4 muM, it caused disruption of the cellular microtubule system of the MCF7 cells. Both these cellular effects are consistent with its mechanism of action resulting from its inhibitory effect on tubulin assembly. (C) 2004 Elsevier SAS. All rights reserved. C1 Univ Palermo, Dipartimento Chim & Tecnol Farmaceut, I-90123 Palermo, Italy. NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. RP Daidone, G (reprint author), Univ Palermo, Dipartimento Chim & Tecnol Farmaceut, Via Archirafi 32, I-90123 Palermo, Italy. EM gdaidone@unipa.it OI Daidone, Giuseppe/0000-0002-9529-8449; Raffa, Demetrio/0000-0002-1073-7706 NR 25 TC 37 Z9 37 U1 0 U2 1 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD APR PY 2004 VL 39 IS 4 BP 299 EP 304 DI 10.1016/j.ejmech.2003.12.009 PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 817ZJ UT WOS:000221215100001 PM 15072839 ER PT J AU Schoenbaum, G Saddoris, MP Ramus, SJ Shaham, Y Setlow, B AF Schoenbaum, G Saddoris, MP Ramus, SJ Shaham, Y Setlow, B TI Cocaine-experienced rats exhibit learning deficits in a task sensitive to orbitofrontal cortex lesions SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE addiction; discrimination; learning; motivation; olfactory; reversal ID VENTROMEDIAL PREFRONTAL CORTEX; NUCLEUS-ACCUMBENS; BEHAVIORAL SENSITIZATION; DECISION-MAKING; BASOLATERAL AMYGDALA; DENDRITIC SPINES; DRUG-ABUSE; AMPHETAMINE; ADDICTION; STIMULUS AB Addictive drugs, such as cocaine, cause long-lasting neural changes in prefrontal cortex. It has been hypothesized that these changes affect the behavioural control mediated by orbitofrontal cortex. To test this hypothesis, rats were given injections of cocaine (30 mg/kg/d, i.p.) or vehicle for 14 days and then trained after a 2-week withdrawal period in an odor discrimination task sensitive to the effects of orbitofrontal cortex lesions. We found that cocaine-treated rats, who demonstrated long-lasting sensitization to the locomotor activating effects of cocaine, failed to show normal changes in response latency during discrimination learning and were also slower than controls to acquire serial reversals. These behavioural impairments are identical to the effects of orbitofrontal cortex lesions in this task and show that cocaine exposure in rats can cause long-lasting effects on orbitofrontal-dependent functions. Notably, these effects were not correlated with increases in locomotor activity linked to cocaine-induced psychomotor sensitization observed before or after training, suggesting that the brain changes underlying the behavioural effects in the discrimination task are different from those mediating psychomotor sensitization. C1 Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. Johns Hopkins Univ, Dept Psychol & Brain Sci, Baltimore, MD 21218 USA. Bowdoin Coll, Dept Psychol, Brunswick, ME 04011 USA. Bowdoin Coll, Dept Neurosci, Brunswick, ME 04011 USA. NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD USA. Texas A&M Univ, Dept Psychol, College Stn, TX 77843 USA. RP Schoenbaum, G (reprint author), Univ Maryland, Sch Med, Dept Anat & Neurobiol, 685 W Baltimore St,HSF-1 Rm 280K, Baltimore, MD 21201 USA. EM schoenbg@schoenbaumlab.org RI shaham, yavin/G-1306-2014 FU NIDA NIH HHS [R01-DA015718]; NIMH NIH HHS [F32-MH21699, R01-MH53667, R01-MH60179] NR 44 TC 115 Z9 118 U1 1 U2 4 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD APR PY 2004 VL 19 IS 7 BP 1997 EP 2002 DI 10.1111/j.1460.9568.2004.03274.x PG 6 WC Neurosciences SC Neurosciences & Neurology GA 810XK UT WOS:000220736800035 PM 15078575 ER PT J AU Petralia, RS Sans, N Wang, YX Vissel, B Chang, K Noben-Trauth, K Heinemann, SF Wenthold, RJ AF Petralia, RS Sans, N Wang, YX Vissel, B Chang, K Noben-Trauth, K Heinemann, SF Wenthold, RJ TI Loss of GLUR2 alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor subunit differentially affects remaining synaptic glutamate receptors in cerebellum and cochlear nuclei SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE auditory; delta glutamate receptor; EAAT4; GluR4; mGluR1; mouse ID LONG-TERM DEPRESSION; AMPA RECEPTORS; PURKINJE-CELLS; NMDA RECEPTORS; MESSENGER-RNAS; RAT-BRAIN; HIPPOCAMPAL SYNAPSES; DELTA-2 SUBUNITS; FIBER SYNAPSES; ANTIBODY SHOWS AB The alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) type of ionotropic glutamate receptor is the major mediator of fast neurotransmission in the brain and spinal cord. Most AMPA receptors are impermeable to calcium because they contain the GluR2 subunit. However, some AMPA receptors lack GluR2 and pass calcium which can mediate synaptic plasticity and, in excess, neurotoxicity. Previously, we showed a decrease in the density of synaptic AMPA receptors in the hippocampus of mice lacking GluR2. In this study, using these GluR2-lacking mice, we examined other areas of the brain that differ in the amount of GluR2 normally present. Like hippocampal spines, cerebellar Purkinje spines normally express AMPA receptors with high GluR2 and showed a decrease in synaptic AMPA receptors in mutant mice. In contrast, neurons that normally express AMPA receptors with little or no GluR2, such as in the anteroventral cochlear nucleus, showed no decrease in AMPA receptors and even showed an increase in one AMPA receptor subunit. These two different patterns may relate to preadaptations to prevent calcium neurotoxicity; such mechanisms might be absent in Purkinje and hippocampal spines so that these neurons must decrease their total expression of synaptic AMPA receptors (calcium permeable in mutant mice) to prevent calcium neurotoxicity. In addition, we found that another glutamate receptor, GluRdelta2, which is abundant only in parallel fibre synapses on Purkinje cells and in the dorsal cochlear nucleus, is up-regulated at these synapses in mutant mice; this probably reflects some change in GluRdelta2 targeting to these synapses. C1 NIH, Neurochem Lab, NIDCD, Bethesda, MD 20892 USA. Salk Inst Biol Studies, La Jolla, CA USA. St Vincents Hosp, Garvan Inst Med Res, Darlinghurst, NSW 2010, Australia. NIDCD, Neurogenet Sect, Mol Biol Lab, NIH, Bethesda, MD USA. RP Petralia, RS (reprint author), NIH, Neurochem Lab, NIDCD, 50-4142,50 South Dr MSC 8027, Bethesda, MD 20892 USA. EM petralia@nidcd.nih.gov NR 66 TC 13 Z9 15 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD APR PY 2004 VL 19 IS 8 BP 2017 EP 2029 DI 10.1111/j.1460-9568.2004.03324.x PG 13 WC Neurosciences SC Neurosciences & Neurology GA 817SQ UT WOS:000221197600002 PM 15090029 ER PT J AU Peeters, M Romieu, P Maurice, T Su, TP Maloteaux, JM Hermans, E AF Peeters, M Romieu, P Maurice, T Su, TP Maloteaux, JM Hermans, E TI Involvement of the sigma(1) receptor in the modulation of dopaminergic transmission by amantadine SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE [S-35]GTP gamma S binding; BD1047; calcium signalling; PRE-084; rat ID SIGMA-RECEPTOR LIGANDS; CENTRAL-NERVOUS-SYSTEM; BINDING-SITES; RAT STRIATUM; NEUROPHARMACOLOGICAL PROFILE; EXTRACELLULAR CONCENTRATION; NEUROPROTECTIVE PROPERTIES; NMDA RECEPTORS; NG108-15 CELLS; IN-VIVO AB Pharmacological effects of amantadine on dopaminergic transmission are proposed to result from an uncompetitive antagonism at glutamate N-methyl-D-aspartate (NMDA) receptors. However, our previous studies examining amantadine-mediated dopamine receptor regulation in the rat striatum revealed a discrepancy from a direct interference with glutamate transmission. Preliminary in vitro binding data from the literature suggested the interaction of amantadine with the sigma, receptor. Therefore, we have now further characterized the pharmacological properties of amantadine and memantine at this receptor and investigated its involvement in the modulation of striatal dopaminergic transmission. Our binding studies using [H-3]-(+)SKF-10,047 indicated that amantadine and memantine behave as ligands of the sigma(1) receptor in rat forebrain homogenates (K-i values of 7.44 +/- 0.82 and 2.60 +/- 0.62 muM, respectively). In NG108-15 neuroblastoma cells, both drugs (amantadine (100 muM) and memantine (10 muM)) potentiated the bradykinin-induced mobilization of intracellular Ca2+, mimicking the effect of the sigma(1) receptor agonist PRE-084 (1 muM). Finally, we previously showed that in striatal membranes from amantadine-treated rats, the functional coupling of dopamine receptors with G-proteins was enhanced. Similarly, PRE-084 dose-dependently increased the [S-35]GTPgammaS binding induced by dopamine (E-max 28 and 26% of basal, 0.3 and 1 mg/kg PRE-084, respectively). By contrast, BD1047, which is without effect on its own, antagonized the effects of amantadine and PRE-084. Together, these data demonstrate that aminoadamantanes behave as sigma, receptor agonists, and confirm an involvement of this receptor in modulating dopamine receptors exerted by therapeutically relevant concentrations of amantadine. C1 Univ Catholique Louvain, Lab Pharmacol Expt, B-1200 Brussels, Belgium. Univ Montpellier 2, CNRS, UMR 5102, Montpellier, France. NIDA, IRP, NIH, DHHS, Baltimore, MD USA. RP Hermans, E (reprint author), Univ Catholique Louvain, Lab Pharmacol Expt, 54-10,Ave Hippocrate 54, B-1200 Brussels, Belgium. EM emmanuel.hermans@farl.ucl.ac.be RI Hermans, Emmanuel/A-1654-2015 NR 53 TC 51 Z9 53 U1 1 U2 4 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD APR PY 2004 VL 19 IS 8 BP 2212 EP 2220 DI 10.1111/j.1460-9568.2004.03297.x PG 9 WC Neurosciences SC Neurosciences & Neurology GA 817SQ UT WOS:000221197600020 PM 15090047 ER PT J AU Nguyen, VT Chernyavsky, AI Arredondo, J Bercovich, D Orr-Urtreger, A Vetter, DE Wess, J Beaudet, AL Kitajima, Y Grando, SA AF Nguyen, VT Chernyavsky, AI Arredondo, J Bercovich, D Orr-Urtreger, A Vetter, DE Wess, J Beaudet, AL Kitajima, Y Grando, SA TI Synergistic control of keratinocyte adhesion through muscarinic and nicotinic acetylcholine receptor subtypes SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE keratinocytes; intercellular adhesions; nicotinic cholinergic receptors alpha 3 and alpha 9 muscarinic cholinergic receptors M-3; E-cadherin; gamma-and beta-catenins ID PROTEIN-KINASE-C; CELL-CELL ADHESION; E-CADHERIN; TYROSINE PHOSPHORYLATION; BETA-CATENIN; EPITHELIAL-CELLS; GENE-EXPRESSION; PEMPHIGUS-VULGARIS; IN-VITRO; PHARMACOLOGICAL-PROPERTIES AB The biological mechanisms involved in initiating, coordinating, and ultimately terminating cell-cell adhesion in the stratified epithelium are not well understood at present. This study was designed to elucidate the roles of the muscarinic M-3, the nicotinic alpha3, and the mixed muscarinic-nicotinic alpha9 acetylcholine receptors in physiologic control of keratinocyte adhesion. Both muscarinic and nicotinic antagonists caused keratinocyte detachment and reversibly increased the permeability of keratinocyte monolayers, indicative of the involvement of both muscarinic and nicotinic pathways in the cholinergic control of keratinocyte adhesion. Since phosphorylation of adhesion proteins plays an important role in rapid assembly and disassembly of intercellular junctions, we measured muscarinic and nicotinic effects on phosphorylation of keratinocyte adhesion molecules. The phosphorylation levels of E-cadherin, beta-catenin, and gamma-catenin increased following pharmacological blockage of muscarinic receptors. Long-term blocking of alpha3, alpha9, and M-3 receptor signaling pathways with antisense oligonucleotides resulted in cell-cell detachment and changes in the expression levels of E-cadherin, beta-catenin, and gamma-catenin in cultured human keratinocytes. Simultaneous inhibition of several receptor subtypes with a mixture of antisense oligonucleotides produced intensified abnormalities with cell adhesion. Moreover, altered cell-cell adhesion was found in the stratified epithelium of alpha3, alpha9, and M-3 receptor knockout mice. Keratinocytes from these mice exhibited abnormal expression of adhesion molecules at both the protein and the mRNA levels. Thus, our data indicate that the alpha3, alpha9, and M-3 acetylcholine receptors play key roles in regulating in a synergistic mode keratinocyte adhesion, most probably by modulating cadherin and catenin levels and activities. These findings may aid in the development of novel methods useful for the treatment of skin adhesion diseases and tumor metastasis. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Calif Davis, Dept Dermatol, Sacramento, CA 95817 USA. Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. Migal Galilee Technol Ctr, Dept Mol Genet, IL-11016 Kiryat Shmona, Israel. Tel Aviv Sourasky Med Ctr, Inst Genet, IL-64239 Tel Aviv, Israel. Tel Aviv Univ, IL-64239 Tel Aviv, Israel. Tufts Univ, Sch Med, Dept Neurosci, Boston, MA 02111 USA. NIDDK, Bioorgan Chem Lab, Mol Signaling Sect, NIH, Bethesda, MD 20892 USA. Gifu Univ, Dept Dermatol, Gifu 5008705, Japan. RP Grando, SA (reprint author), Univ Calif Davis, Dept Dermatol, 4860 Y St,Suite 3400, Sacramento, CA 95817 USA. EM sagrando@ucdavis.edu FU NIDCR NIH HHS [DE14173]; NIGMS NIH HHS [GM62136] NR 98 TC 43 Z9 45 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 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD APR 1 PY 2004 VL 294 IS 2 BP 534 EP 549 DI 10.1016/j.yexer.2003.12.010 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 804HN UT WOS:000220289900019 PM 15023540 ER PT J AU Song, L Tuan, RS AF Song, L Tuan, RS TI Transdifferentiation potential of human mesenchymal stem cells derived from bone marrow SO FASEB JOURNAL LA English DT Article DE plasticity; osteogenesis; adipogenesis; chondrogenesis ID PROGENITOR CELLS; DNA METHYLATION; TRABECULAR BONE; DIFFERENTIATION; HETEROGENEITY; PLURIPOTENCY; REGENERATION; EXPRESSION; PHENOTYPE; FUSION AB Transdifferentiation is a process whereby one cell type committed to and progressing along a specific developmental lineage switches into another cell type of a different lineage through genetic reprogramming. Even though this process has been well studied and established in amphibian systems, it is unclear if mammalian cells possess the same potential. Recent in vivo transplantation studies showed that adult mesenchymal stem cells (MSCs) were able to differentiate into mesoderm-derived cell types as well as cells with neuroectodermal and endodermal characteristics, suggesting that transdifferentiation occurs in mammalian systems. However, there are concerns over these findings because of the possibility of progenitor cell contamination and cell fusion. In this study, we have developed an in vitro differentiation strategy to assess if human MSCs that have differentiated into a given mesenchyme cell lineage can transdifferentiate into other cell types in response to inductive extracellular cues. Our results showed that fully differentiated cells from hMSCs were capable of dedifferentiation and transdifferentiation into cells of another developmental lineage at single cell levels. C1 NIAMSD, Cartilage & Orthopaed Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage & Orthopaed Branch, NIH, US Dept HHS, 50 South Dr,Room 1503, Bethesda, MD 20892 USA. EM tuanr@mail.nih.gov NR 31 TC 210 Z9 227 U1 1 U2 8 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2004 VL 18 IS 6 BP 980 EP + DI 10.1096/fj.03-1100fje PG 15 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 816KM UT WOS:000221108800007 PM 15084518 ER PT J AU Kageyama, Y Koshiji, M To, KKW Tian, YM Ratcliffe, PJ Huang, LE AF Kageyama, Y Koshiji, M To, KKW Tian, YM Ratcliffe, PJ Huang, LE TI Leu-574 of human HIF-1a is a molecular determinant of prolyl hydroxylation SO FASEB JOURNAL LA English DT Article DE hypoxia; prolyl-4-hydroxylases; transcription factor ID HYPOXIA-INDUCIBLE FACTOR; TUMOR-SUPPRESSOR PROTEIN; UBIQUITIN-PROTEASOME PATHWAY; ARNT TRANSCRIPTION FACTOR; STRUCTURAL BASIS; FACTOR 1-ALPHA; GENE-EXPRESSION; ALPHA-SUBUNIT; HIF-1-ALPHA; VHL AB Hypoxia-inducible factor (HIF)-1alpha, a master regulator of oxygen homeostasis, regulates genes crucial for cell growth and survival. In normoxia, HIF-1alpha is constantly degraded via the ubiquitin-proteasome pathway. The von Hippel-Lindau (VHL) E3 ubiquitin ligase binds HIF-1alpha through specific recognition of hydroxylated Pro-402 or Pro-564, both of which are modified by the oxygen-dependent HIF prolyl hydroxylases (PHDs/HPHs). Despite the identification of a conserved Leu-X-X-Leu-Ala-Pro motif, the molecular requirement of HIF-1alpha for PHDs/HPHs binding remains elusive. Recently, we demonstrated that Leu-574 of human HIF-1alpha-10 residues downstream of Pro-564-is essential for VHL recognition. We show here that the role of Leu-574 is to recruit PHD2/HPH2 for Pro-564 hydroxylation. An antibody specific for hydroxylated Pro-564 has been used to determine the hydroxylation status; mutation or deletion of Leu-574 results in a significant decrease in the ratio of the hydroxylated HIF-1alpha to the total amount. The nine-residue spacing between Pro-564 and Leu-574 is not obligatory for prolyl hydroxylation. Furthermore, mutation of Leu-574 disrupts the binding of PHD2/HPH2, a key prolyl hydroxylase for oxygen-dependent proteolysis of HIF-1alpha. Hence, our findings indicate that Leu-574 is essential for recruiting PHD2/HPH2, thereby providing a molecular basis for modulating HIF-1alpha activity. C1 NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. Henry wellcome Bldg Genom Med, Oxford OX3 7BN, England. RP Huang, LE (reprint author), NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. EM huange@mail.nih.gov RI To, Kenneth /M-4500-2013 OI To, Kenneth /0000-0003-2755-0283 NR 43 TC 43 Z9 44 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2004 VL 18 IS 6 BP 1028 EP + DI 10.1096/fj.03-1233fje PG 18 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 816KM UT WOS:000221108800003 PM 15084514 ER PT J AU Wright, GL Hanlon, P Amin, K Steenbergen, C Murphy, E Arcasoy, MO AF Wright, GL Hanlon, P Amin, K Steenbergen, C Murphy, E Arcasoy, MO TI Erythropoietin receptor expression in adult rat cardiomyocytes is associated with an acute cardioprotective effect for recombinant erythropoietin during ischemia-reperfusion injury SO FASEB JOURNAL LA English DT Article DE ATP; myocardium; signal transduction ID ENDOTHELIAL-CELLS; IN-VIVO; PROTECTS; APOPTOSIS; NEURONS; GENE; RECOVERY; HYPOXIA; HEARTS; DAMAGE AB Erythropoietin (EPO), the principal hematopoietic cytokine that regulates mammalian erythropoiesis, exhibits diverse cellular effects in non-hematopoietic tissues. The physiologic functions of EPO are mediated by its specific cell-surface receptor EPOR. In this study, we demonstrate EPOR expression in adult rat cardiac myocytes and examine the direct effects of EPO on the heart to investigate whether recombinant EPO may exert an acute cardioprotective effect during ischemia-reperfusion injury. To determine whether EPO is cardioprotective, isolated rat hearts were perfused for 10 min in the Langendorff-mode with Krebs-Henseleit buffer in the absence or presence of brief recombinant EPO treatment while left-ventricular-developed pressure (LVDP) was measured continuously to assess contractile function. The hearts were then subjected to 20 min of normothermic global ischemia followed by 25 min of reperfusion. The post-ischemic recovery of LVDP in the untreated control hearts was 26 +/- 5% of their baseline LVDP, whereas hearts pretreated with EPO exhibited significantly improved post-ischemic recovery to 57 +/- 7%. We used P-31 nuclear magnetic resonance (NMR) spectroscopy to determine whether modulation of intracellular pH and/or high-energy phosphate levels during ischemia contributed to EPO-mediated cardioprotection. These experiments revealed that the rapid cardioprotective effect of EPO during ischemia-reperfusion injury was associated with preservation of ATP levels in the ischemic myocardium. C1 Duke Univ, Sch Med, Dept Med, Div Hematol, Durham, NC 27710 USA. NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. SRI Int, Biosci Div, Menlo Pk, CA 94025 USA. Duke Univ, Sch Med, Dept Pathol, Durham, NC 27706 USA. RP Arcasoy, MO (reprint author), Duke Univ, Sch Med, Dept Med, Div Hematol, DUMC Box 3912, Durham, NC 27710 USA. EM arcas001@mc.duke.edu FU NHLBI NIH HHS [R01-HL-39752, R01 HL039752]; NIDDK NIH HHS [R21-DK-65065] NR 43 TC 165 Z9 174 U1 0 U2 7 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2004 VL 18 IS 6 BP 1031 EP + DI 10.1096/fj.03-1289fje PG 19 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 816KM UT WOS:000221108800016 PM 15059965 ER PT J AU Brinton, LA Kjaer, SK Thomsen, BL Sharif, HF Graubard, BI Olsen, JH Bock, JE AF Brinton, LA Kjaer, SK Thomsen, BL Sharif, HF Graubard, BI Olsen, JH Bock, JE TI Childhood tumor risk after treatment with ovulation-stimulating drugs SO FERTILITY AND STERILITY LA English DT Article DE childhood cancer; risk; infertility; clomiphene citrate ID IN-VITRO FERTILIZATION; CHILDREN BORN; NEUROECTODERMAL TUMORS; HORMONAL TREATMENT; CANCER; NEUROBLASTOMA; CLOMIPHENE; PREGNANCY; INDUCTION; LYMPHOMA AB Objective: To assess childhood cancer risk among children conceived following the use of ovulation-stimulating drugs. Design: Record linkage study. Setting: Infertility patients and their offspring as identified through medical records. Patient(s): Cohort of 30,364 Danish women evaluated for infertility beginning in the early 1960s. Main Outcome Measure(s): Standardized incidence ratios (SIRs) compared cancer incidence in the children to the Danish Population. Case-cohort techniques calculated rate ratios (RRs) according to prior maternal drug exposures. Result(s): A total of 51 cancers were identified among the study children, resulting in an SIR of 1.14 (95% confidence interval [CI] 0.8-1.5). Usage of any fertility drug was associated with an RR of 0.82 (95% CI 0.4-1.6) and clomiphene citrate with an RR of 0.77 (95% CI 0.4-1.6). Tumors occur-ring early in life and nonhematopoietic malignancies (including neuroblastomas) were not associated with drug usage. Nonsignificant elevations in the risk of cancers occurring later in life, especially childhood hematopoietic malignancies (RR for use of any ovulation-stimulating drugs of 2.30, 95% CI 0.8-6.6), may have been related to underlying reasons for medication usage. Conclusion(s): Although the findings of this Study are reassuring, additional adequately powered studies should continue monitoring the effects of ovulation-stimulating drugs on specific tumors, including hematopoietic malignancies. (Fertil Steril(R) 2004:81:1083-91. (C) 2004 by American Society for Reproductive Medicine.). C1 NCI, Div Canc Epidemiol, Bethesda, MD 20892 USA. Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. RP Brinton, LA (reprint author), NCI, Div Canc Epidemiol, 6120 Execut Blvd,Room 7068, Bethesda, MD 20892 USA. EM brinton@nih.gov RI Brinton, Louise/G-7486-2015; OI Brinton, Louise/0000-0003-3853-8562; Olsen, Jorgen Helge/0000-0001-9633-5662; Kjaer, Susanne/0000-0002-8347-1398 NR 25 TC 27 Z9 30 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD APR PY 2004 VL 81 IS 4 BP 1083 EP 1091 DI 10.1016/j.fertnstert.2003.08.042 PG 9 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 811LR UT WOS:000220773900027 PM 15066468 ER PT J AU Barnhart, KT Bader, T Huang, XG Frederick, MM Timbers, KA Zhang, JJ AF Barnhart, KT Bader, T Huang, XG Frederick, MM Timbers, KA Zhang, JJ TI Hormone pattern after misoprostol administration for a nonviable first-trimester gestation SO FERTILITY AND STERILITY LA English DT Article DE miscarriage; misoprostol; medical management; hCG; progesterone ID HUMAN CHORIONIC-GONADOTROPIN; SINGLE SERUM PROGESTERONE; ECTOPIC PREGNANCY; RANDOMIZED TRIAL; MISSED ABORTION; MANAGEMENT; MISCARRIAGE; EVACUATION; DIAGNOSIS AB Objective: To evaluate serial hormone concentrations in subjects treated with vaginally administered misoprostol for early pregnancy failure. Design: As part of a randomized clinical trial, serum was collected on treatment days 1, 3, 8, and 15. Setting: Multicenter clinical trial. Patient(s): Women with a nonviable first-trimester pregnancy. Intervention(s): Serum concentrations of human chorionic gonadotropin (hCG), progesterone, and sex hormone binding globulin (SHBG) were evaluated. Main Outcome Measure(s): A logistic regression model was constructed to assess the associations of percent and complete expulsion of the gestational sac and/or successful management. Result(s): The percent change from the day of treatment until the first follow-up visit was predictive for complete expulsion for progesterone (P) (P < .005) and hCG (P < .005), but not for SHBG. The actual value was not significantly associated with complete expulsion or Successful management. A decrease (day 1-3) of 79% for both hCG and P was associated with a 90% probability of complete passage of the gestational sac. A 90% probability of successful management was noted if P decreased by 78% on day 3 or 59% on day 7, or hCG decreased by 74% on day 3 or 78% on day 7 compared with pretreatment values. Conclusion(s): Percent change, but not absolute change, in serial hormone values are strongly associated with both the complete expulsion of the gestational sac with one dose of misoprostol and ultimate success. (Fertil Steril(R) 2004;81:1099-105. (C) 2004 by American Society for Reproductive Medicine.). C1 Univ Penn, Med Ctr, Div Reprod Endocrinol & Infertil, Philadelphia, PA 19104 USA. Clin Trials & Surveys Corp, Baltimore, MD USA. NICHD, Rockville, MD USA. RP Barnhart, KT (reprint author), Univ Penn, Med Ctr, Div Reprod Endocrinol & Infertil, 3701 Market St,Suite 810, Philadelphia, PA 19104 USA. EM kbarnhart@mail.obgyn.upenn.edu RI Perez , Claudio Alejandro/F-8310-2010 OI Perez , Claudio Alejandro/0000-0001-9688-184X FU NICHD NIH HHS [N01-HD-1-3321, N01-HD-1-3322, N01-HD-1-3323, N01-HD-1-3324, N01-HD-1-3325] NR 22 TC 7 Z9 7 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD APR PY 2004 VL 81 IS 4 BP 1099 EP 1105 DI 10.1016/j.fertnstert.2003.08.041 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 811LR UT WOS:000220773900029 PM 15066470 ER PT J AU Browne, SE Roberts, LJ Dennery, PA Doctrow, SR Beal, MF Barlow, C Levine, RL AF Browne, SE Roberts, LJ Dennery, PA Doctrow, SR Beal, MF Barlow, C Levine, RL TI Treatment with a catalytic antioxidant corrects the neurobehavioral defect in ataxia-telangiectasia mice SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE ataxia-telangiectasia; oxidative stress; antioxidant; superoxide dismutase; catalase; salen-manganese antioxidant; thymoma; free radicals ID WERNER-SYNDROME PROTEIN; OXIDATIVE STRESS; SUPEROXIDE-DISMUTASE; HEME OXYGENASE; DEFICIENT MICE; DNA HELICASE; IN-VIVO; ATM; DAMAGE; CELLS AB Ataxia-telangiectasia is caused by mutations in the ATM gene, the protein product of which is essential for effective response to double-stranded DNA breaks. Loss of ATM function explains most aspects of the disease, but not the cerebellar neurodegeneration characteristic of the disease. Mice lacking ATM provide an excellent model of the human disorder. In addition to deficient response to DNA damage, these mice exhibit oxidative stress, which we hypothesized is the cause of cerebellar dysfunction. We show that treatment with a catalytic antioxidant corrects the neurobehavioral deficit in these mice. (C) 2004 Elsevier Inc. All rights reserved. C1 Cornell Univ, Weill Med Coll, Dept Neurol & Neurosci, New York, NY USA. Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. Eukar Inc, Bedford, MA USA. Salk Inst Biol Studies, Genet Lab, La Jolla, CA 92037 USA. NHLBI, Biochem Lab, Bethesda, MD 20892 USA. RP Levine, RL (reprint author), NIH, Bldg 50,Room 2351, Bethesda, MD 20892 USA. EM rlevine@nih.gov RI Levine, Rodney/D-9885-2011; OI Dennery, Phyllis/0000-0001-5745-1855 FU NIGMS NIH HHS [GM42056] NR 25 TC 57 Z9 57 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD APR 1 PY 2004 VL 36 IS 7 BP 938 EP 942 DI 10.1016/j.freeradbiomed.2004.01.003 PG 5 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 807AX UT WOS:000220475500012 PM 15019978 ER PT J AU Shiffman, ML Di Bisceglie, AM Lindsay, KL Morishima, C Wright, EC Everson, GT Lok, AS Morgan, TR Bonkovsky, HL Lee, WM Dienstag, JL Ghany, MG Goodman, ZD Everhart, JE AF Shiffman, ML Di Bisceglie, AM Lindsay, KL Morishima, C Wright, EC Everson, GT Lok, AS Morgan, TR Bonkovsky, HL Lee, WM Dienstag, JL Ghany, MG Goodman, ZD Everhart, JE CA HALT-C Trial Grp TI Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment SO GASTROENTEROLOGY LA English DT Article ID INITIAL TREATMENT; PLUS RIBAVIRIN; INTERFERON THERAPY; COMBINATION; TRIAL; CIRRHOSIS; VIRUS AB Background & Aims: The most effective therapy currently available for treatment of chronic hepatitis C virus (HCV) is the combination of peginterferon and ribavirin. This study evaluated the effectiveness of this treatment in patients who were nonresponders to previous interferon-based therapy. Methods: The first 604 patients enrolled in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial were evaluated. All were HCV RNA positive, previous nonresponders to interferon, with or without ribavirin, and had bridging fibrosis or cirrhosis on liver biopsy (Ishak fibrosis stage 3-6). Patients were retreated with peginterferon alfa-2a 180 mug/wk plus ribavirin 1000-1200 mg/day. Those with no detectable HCV RNA in serum at week 20 continued treatment for a total of 48 weeks and were then followed for an additional 24 weeks. Results: Thirty-five percent of patients had no detectable HCV RNA in serum at treatment week 20, and 18% achieved sustained virologic response (SVR). Factors associated with an SVR included previous treatment with interferon monotherapy, infection with genotypes 2 or 3, a lower AST:ALT ratio, and absence of cirrhosis. Reducing the dose of ribavirin from greater than or equal to80% to less than or equal to60% of the starting dose during the first 20 weeks of treatment was associated with a decline in SVR from 21% to 11% (P less than or equal to 0.05). In contrast, reducing the dose of peginterferon or reducing ribavirin after week 20, when HCV RNA was already undetectable, did not significantly affect SVR. Conclusions: Selected nonresponders to previous interferon-based therapy can achieve SVR following retreatment with peginterferon alfa-2a and ribavirin. C1 Virginia Commonwealth Univ, Hepatol Sect, Hlth Syst, Richmond, VA 23298 USA. St Louis Univ, Sch Med, Div Gastroenterol, St Louis, MO 63103 USA. Univ So Calif, Div Gastrointestinal & Liver Dis, Los Angeles, CA USA. Univ Washington, Dept Pediat & Lab Med, Seattle, WA 98195 USA. New England Res Inst, Watertown, MA 02172 USA. Univ Colorado, Sect Hepatol, Div Gastroenterol & Hepatol, Denver, CO 80202 USA. Univ Michigan, Med Ctr, Div Gastroenterol, Ann Arbor, MI USA. Univ Calif Irvine, Div Gastroenterol, Irvine, CA USA. Univ Connecticut, Ctr Hlth, Liver Biliary Pancreat Ctr, Farmington, CT 06030 USA. Univ Connecticut, Ctr Hlth, Gen Clin Res Ctr, Farmington, CT 06030 USA. Univ Texas, Div Digest & Liver Dis, SW Med Ctr, Dallas, TX 75230 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Massachusetts Gen Hosp, Gastrointestinal Unit, Med Serv, Boston, MA 02114 USA. NIDDKD, Liver Dis Sect, Div Digest Dis & Nutr, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. Armed Forces Inst Pathol, Div Hepat Pathol, Washington, DC 20306 USA. Armed Forces Inst Pathol, Vet Adm Special Reference Lab Pathol, Washington, DC 20306 USA. NIDDKD, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. RP Shiffman, ML (reprint author), Virginia Commonwealth Univ, Hepatol Sect, Hlth Syst, Box 980341, Richmond, VA 23298 USA. EM mshiffma@hsc.vcu.edu RI Lok, Anna /B-8292-2009; OI Yang, Shuman/0000-0002-9638-0890 FU NCRR NIH HHS [M01RR-00042, M01RR-00043, M01RR-00051, M01RR-00065, M01RR-00633, M01RR-00827, M01RR-01066, M01RR-06192]; NIDDK NIH HHS [N01-DK-9-2324, N01-DK-9-2318, N01-DK-9-2319, N01-DK-9-2320, N01-DK-9-2321, N01-DK-9-2322, N01-DK-9-2323, N01-DK-9-2325, N01-DK-9-2326, N01-DK-9-2327, N01-DK-9-2328] NR 21 TC 326 Z9 340 U1 0 U2 3 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD APR PY 2004 VL 126 IS 4 BP 1015 EP 1023 DI 10.1053/j.gastro.2004.01.014 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 810ER UT WOS:000220688100014 PM 15057741 ER PT J AU Leon, F Roy, G AF Leon, F Roy, G TI On the complexity of human CD3(-) intraepithelial lymphocytes SO GASTROENTEROLOGY LA English DT Letter ID CELIAC-DISEASE; GAMMA-DELTA; INTESTINE; SUBSETS C1 NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. Hosp Ramon y Cajal, Serv Inmunol, E-28034 Madrid, Spain. RP Leon, F (reprint author), NIAID, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 9 TC 5 Z9 5 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD APR PY 2004 VL 126 IS 4 BP 1217 EP 1218 DI 10.1053/j.gastro.2004.02.039 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 810ER UT WOS:000220688100039 PM 15057770 ER PT J AU Wang, J Voutetakis, A Zheng, C Baum, BJ AF Wang, J Voutetakis, A Zheng, C Baum, BJ TI Rapamycin control of exocrine protein levels in saliva after adenoviral vector-mediated gene transfer SO GENE THERAPY LA English DT Article DE salivary glands; saliva; adenoviral vectors; rapamycin; gene therapeutics; gene regulation; human growth hormone ID RAT SUBMANDIBULAR GLANDS; IN-VIVO; GROWTH-HORMONE; REGULATED EXPRESSION; RESISTANT-BACTERIA; ORAL MUCOSITIS; SECRETION; DELIVERY; SYSTEM; STREPTOCOCCI AB Transgene-encoded therapeutic secretory proteins can be efficiently secreted from salivary glands into saliva or the bloodstream after adenoviral (Ad)-mediated gene transfer. Since transgene expression from conventional vectors is typically unregulated, we evaluated the rapamycin-based dimerizer regulation system for control of transgene expression in, and consequent exocrine protein secreted from, rat salivary glands. We used human growth hormone (hGH) as a surrogate exocrine secretory protein. Two Ad vectors, Ad C4ZF3, encoding activation and DNA binding domain fusion polypeptides, and Ad Z12-I-GH-2, encoding hGH, were constructed and shown useful in vitro. Thereafter, both vectors were delivered into submandibular glands by retroductal infusion. After 24 h, rapamycin (0, 1, 3 or 10 mg/kg) was administered, and 20 h later hGH levels in saliva were determined. Salivary hGH levels were rapamycin concentration dependent. At a rapamycin dose of 10 mg/kg, total salivary hGH was 693 +/- 197 ng and the hGH concentration in saliva was 4.6 +/- 1.3 mug/ml. Over a 16-day experimental period, three separate administrations of rapamycin (3 mg/kg) induced distinct elevations of salivary hGH (similar to100-200 ng total hGH) that were entirely rapamycin dependent. This study demonstrates for the first time pharmacological control of transgenic exocrine protein production and presence in saliva after salivary gland gene transfer, and the potential for its application to the management of oral, oropharyngeal and upper gastrointestinal tract disorders. C1 NIDCR, GTTB, NIH, DHHS, Bethesda, MD 20892 USA. RP Baum, BJ (reprint author), NIDCR, GTTB, NIH, DHHS, Bldg 10,Rm 1N113,MSC-1190, Bethesda, MD 20892 USA. NR 39 TC 16 Z9 16 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD APR PY 2004 VL 11 IS 8 BP 729 EP 733 DI 10.1038/sj.gt.3302225 PG 5 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 808GV UT WOS:000220558500010 PM 14737095 ER PT J AU Lin, YW Perkins, JJ Zhang, ZH Aplan, PD AF Lin, YW Perkins, JJ Zhang, ZH Aplan, PD TI Distinct mechanisms lead to HPRT gene mutations in leukemic cells SO GENES CHROMOSOMES & CANCER LA English DT Article ID HUMAN HYPOXANTHINE PHOSPHORIBOSYLTRANSFERASE; COMPARATIVE GENOMIC HYBRIDIZATION; MICROSATELLITE MUTATOR PHENOTYPE; ACUTE LYMPHOBLASTIC-LEUKEMIA; IN-SITU HYBRIDIZATION; TUMOR-CELLS; MUTANT FREQUENCIES; PERIPHERAL-BLOOD; LYMPHOCYTE-T; LINE AB Leukemias are considered malignant clonal disorders arising from the accumulation of mutations in hematopoietic cells; the majority of these mutations are thought to be acquired somatically. Measurement of mutation frequency (Mf) at the hypoxanthine phosphoribosyltransferase (HPRT) locus has been developed as a method for estimating genomic instability. We investigated the Mf in 16 leukemic cell lines to determine whether these cell lines showed evidence of genomic instability. Although some leukemic cell lines had markedly elevated Mfs, the Mfs at the HPRT locus in leukemic cell lines were not always higher than those of B-lymphoblastoid cell lines and T lymphocytes from normal individuals. We were able to identify the HPRT mutation for 159 of 160 individual HPRT mutants. The HPRT mutations were characterized at a molecular level and classified as either gross chromosomal rearrangements (GCRs) or point mutations, such as single-nucleotide substitutions, insertions, or deletions. With rare exceptions, individual leukemic cell lines showed either point mutations or GCR, but not both. Of note, all the cell lines that primarily showed point mutations are known to be defective in mismatch repair machinery. (C) 2004 Wiley-Liss, Inc. C1 NCI, Ctr Canc Res, Genet Branch, NIH, Bethesda, MD 20889 USA. Kyoto Univ, Grad Sch Med, Dept Pediat, Kyoto, Japan. RP Aplan, PD (reprint author), NCI, Ctr Canc Res, Genet Branch, NIH, Navy 8,Room 5101,8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM aplanp@mail.nih.gov RI Aplan, Peter/K-9064-2016 NR 56 TC 6 Z9 6 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD APR PY 2004 VL 39 IS 4 BP 311 EP 323 DI 10.1002/gcc.20005 PG 13 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 800WH UT WOS:000220057900005 PM 14978792 ER PT J AU Brzostowski, JA Parent, CA Kimmel, AR AF Brzostowski, JA Parent, CA Kimmel, AR TI A G alpha-dependent pathway that antagonizes multiple chemoattractant responses that regulate directional cell movement SO GENES & DEVELOPMENT LA English DT Article DE cAMP; cGMP; PI(3,4,5)P(3); actin; myosin; Dictyostelium ID RECEPTOR-MEDIATED ACTIVATION; HETEROTRIMERIC G-PROTEIN; DICTYOSTELIUM-DISCOIDEUM; ADENYLYL-CYCLASE; LIVING CELLS; PHOSPHATIDYLINOSITOL 3-KINASE; SIGNALING PATHWAYS; LEADING-EDGE; CHEMOTAXIS; PHOSPHORYLATION AB Chemotactic cells, including neutrophils and Dictyostelium discoideum, orient and move directionally in very shallow chemical gradients. As cells polarize, distinct structural and signaling components become spatially constrained to the leading edge or rear of the cell. It has been suggested that complex feedback loops that function downstream of receptor signaling integrate activating and inhibiting pathways to establish cell polarity within such gradients. Much effort has focused on defining activating pathways, whereas inhibitory networks have remained largely unexplored. We have identified a novel signaling function in Dictyostelium involving a Galpha subunit (Galpha9) that antagonizes broad chemotactic response. Mechanistically, Galpha9 functions rapidly following receptor stimulation to negatively regulate PI3K/PTEN, adenylyl cyclase, and guanylyl cyclase pathways. The coordinated activation of these pathways is required to establish the asymmetric mobilization of actin and myosin that typifies polarity and ultimately directs chemotaxis. Most dramatically, cells lacking Galpha9 have extended PI(3,4,5)P(3), cAMP, and cGMP responses and are hyperpolarized. In contrast, cells expressing constitutively activated Galpha9 exhibit a reciprocal phenotype. Their second message pathways are attenuated, and they have lost the ability to suppress lateral pseudopod formation. Potentially, functionally similar Galpha-mediated inhibitory signaling may exist in other eukaryotic cells to regulate chemoattractant response. C1 NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kimmel, AR (reprint author), NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. EM ark1@helix.nih.gov NR 48 TC 30 Z9 33 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD APR 1 PY 2004 VL 18 IS 7 BP 805 EP 815 DI 10.1101/gad.1173404 PG 11 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 813RB UT WOS:000220923100008 PM 15059962 ER PT J AU Kanei-Ishii, C Ninomiya-Tsuji, J Tanikawa, J Nomura, T Ishitani, T Kishida, S Kokura, K Kurahashi, T Ichikawa-Iwata, E Kim, Y Matsumoto, K Ishii, S AF Kanei-Ishii, C Ninomiya-Tsuji, J Tanikawa, J Nomura, T Ishitani, T Kishida, S Kokura, K Kurahashi, T Ichikawa-Iwata, E Kim, Y Matsumoto, K Ishii, S TI Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via TAK1, HIPK2, and NLK SO GENES & DEVELOPMENT LA English DT Article DE Myb; HIPK2; NLK; TAK1; phosphorylation; degradation ID HISTONE DEACETYLASE COMPLEX; KINASE KINASE KINASE; DNA-BINDING ACTIVITY; I-KAPPA-B; TRANSCRIPTIONAL ACTIVATION; BETA-CATENIN; V-MYB; MAP KINASE; FUNCTIONAL INTERACTION; ONCOGENIC ACTIVATION AB The c-myb proto-oncogene product (c-Myb) regulates both the proliferation and apoptosis of hematopoietic cells by inducing the transcription of a group of target genes. However, the biologically relevant molecular mechanisms that regulate c-Myb activity remain unclear. Here we report that c-Myb protein is phosphorylated and degraded by Wnt-1 signal via the pathway involving TAK1 (TGF-beta-activated kinase), HIPK2 (homeodomain-interacting protein kinase 2), and NLK (Nemo-like kinase). Wnt-1 signal causes the nuclear entry of TAK1, which then activates HIPK2 and the mitogen-activated protein (MAP) kinase-like kinase NLK. NLK binds directly to c-Myb together with HIPK2, which results in the phosphorylation of c-Myb at multiple sites, followed by its ubiquitination and proteasome-dependent degradation. Furthermore, overexpression of NLK in M1 cells abrogates the ability of c-Myb to maintain the undifferentiated state of these cells. The down-regulation of Myb by Wnt-1 signal may play an important role in a variety of developmental steps. C1 RIKEN, Tsukuba Inst, Mol Genet Lab, Tsukuba, Ibaraki 3050074, Japan. Univ Tsukuba, Grad Sch Comprehens Human Sci, Tsukuba, Ibaraki 3058577, Japan. Nagoya Univ, Grad Sch Sci, Dept Mol Biol, Chikusa Ku, Nagoya, Aichi 4648602, Japan. Japan Sci & Technol Corp, CREST, Chikusa Ku, Nagoya, Aichi 4648602, Japan. NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. RP Ishii, S (reprint author), RIKEN, Tsukuba Inst, Mol Genet Lab, Tsukuba, Ibaraki 3050074, Japan. EM sishii@rte.riken.jp RI Ishitani, Tohru/E-9781-2014; KISHIDA, Satoshi/I-7265-2014; Ishii, Shunsuke/A-5271-2016 NR 62 TC 124 Z9 133 U1 1 U2 10 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD APR 1 PY 2004 VL 18 IS 7 BP 816 EP 829 DI 10.1101/gad.1170604 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 813RB UT WOS:000220923100009 PM 15082531 ER PT J AU Nyholt, DR Gillespie, NG Heath, AC Merikangas, KR Duffy, DL Martin, NG AF Nyholt, DR Gillespie, NG Heath, AC Merikangas, KR Duffy, DL Martin, NG TI Latent class and genetic analysis does not support migraine with aura and migraine without aura as separate entities SO GENETIC EPIDEMIOLOGY LA English DT Article DE headache continuum; etiology; twins; heritability ID FAMILIAL HEMIPLEGIC MIGRAINE; ORAL-CONTRACEPTIVES; GENERAL-POPULATION; DIAGNOSTIC-CRITERIA; DOUBLE-BLIND; HEADACHE; TWIN; PREVALENCE; QUESTIONNAIRE; HETEROGENEITY AB Latent class and genetic analyses were used to identify subgroups of migraine sufferers in a community sample of 6,265 Australian twins (55% female) aged 25-36 who had completed an interview based on International Headache Society UHS) criteria. Consistent with prevalence rates from other population-based studies, 703 (20%) female and 250 (9%) male twins satisfied the IHS criteria for migraine without aura (MO), and of these, 432 (13%) female and 166 (6%) male twins satisfied the criteria for migraine with aura (MA) as indicated by visual symptoms. Latent class analysis (LCA) of IHS symptoms identified three major symptomatic classes, representing 1) a mild form of recurrent nonmigrainous headache, 2) a moderately severe form of migraine, typically without visual aura symptoms (although 40% of individuals in this class were positive for aura), and 3) a severe form of migraine typically with visual aura symptoms (although 24% of individuals were negative for aura). Using the LCA classification, many more individuals were considered affected to some degree than when using IHS criteria (35% vs. 13%). Furthermore, genetic model fitting indicated a greater genetic contribution to migraine using the LCA classification (heritability, h(2) =0.40; 95% CI, 0.29-0.46) compared with the IHS classification (h(2)=0.36; 95% CI, 0.22-0.42). Exploratory latent class modeling, fitting up to 10 classes, did not identify classes corresponding to either the IHS MO or MA classification. Our data indicate the existence of a continuum of severity, with MA more severe but not etiologically distinct from MO. In searching for predisposing genes, we should therefore expect to find some genes that may underlie all major recurrent headache subtypes, with modifying genetic or environmental factors that may lead to differential expression of the liability for migraine. (C) 2004 Wiley-Liss, Inc. C1 Queensland Inst Med Res, Brisbane, Qld 4029, Australia. Washington Univ, Sch Med, Dept Psychiat, St Louis, MO USA. NIMH, Sect Dev Genet Epidemiol, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Nyholt, DR (reprint author), Queensland Inst Med Res, PO Royal Brisbane Hosp, Brisbane, Qld 4029, Australia. EM daleN@qimr.edu.au RI Nyholt, Dale/C-8384-2013; Gillespie, Nathan/D-6029-2013; Duffy, David/B-7392-2013 OI Martin, Nicholas/0000-0003-4069-8020; Duffy, David/0000-0001-7227-632X FU NIAAA NIH HHS [AA10249, AA07728, AA11998] NR 54 TC 72 Z9 72 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD APR PY 2004 VL 26 IS 3 BP 231 EP 244 DI 10.1002/gepi.10311 PG 14 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 807QM UT WOS:000220516000005 PM 15022209 ER PT J AU Lewis, LK Storici, F Van Komen, S Calero, S Sung, P Resnick, MA AF Lewis, LK Storici, F Van Komen, S Calero, S Sung, P Resnick, MA TI Role of the nuclease activity of Saccharomyces cerevisiae Mre11 in repair of DNA double-strand breaks in mitotic cells SO GENETICS LA English DT Article ID TELOMERE MAINTENANCE; CROSSING-OVER; MRE11-RAD50-XRS2 COMPLEX; ENDONUCLEASE CLEAVAGE; DAMAGE RESPONSE; PROTEIN COMPLEX; GENETIC-CONTROL; YEAST; RECOMBINATION; MUTANTS AB The Rad50:Mre11:Xrs2 (RMX) complex functions in repair of DNA double-strand breaks (DSBs) by recombination and nonhomologous end-joining (NHEJ) and is also required for telomere stability. The Mre11 subunit exhibits nuclease activities in vitro, but the role of these activities in repair in mitotic cells has not been established. In this study we have performed a comparative study of three mutants (mre11-D16A, -D56N, and -H125N) previously shown to have reduced nuclease activities in vitro, In ends-ill and ends-out chromosome recombination assays using defined plasmid and oligonucleotide DNA substrates, mre11-D16A cells were as deficient as mre11 null strains, but defects were small in mre11-D56N and -H125N mutants. mre11-D16A cells, but not the other mutants, also displayed strong sensitivity to ionizing radiation, with residual resistance largely dependent on the presence of the partially redundant nuclease Exo1. mre11-D16A mutants were also most sensitive to the S-phase-dependent clastogens hydroxyurea and methyl methanesulfonate but, as previously observed for D56N and H125N mutants, were not defective in NHEJ. Importantly, the affinity of purified Mre11-D16A protein for Rad50 and Xrs2 Was indistinguishable from wild type and the mutant protein formed complexes with equivalent stoichiometry. Although the role of the nuclease activity has been questioned in previous studies, the comparative data presented here suggest that the nuclease function of Mre11 is required for RMX-mediated recombinational repair and telomere stabilization in mitotic cells. C1 Texas State Univ, Dept Chem & Biochem, San Marcos, TX 78666 USA. NIEHS, Genet Mol Lab, NIH, Res Triangle Pk, NC 27709 USA. Yale Univ, Sch Med, New Haven, CT 06520 USA. RP Lewis, LK (reprint author), Texas State Univ, Dept Chem & Biochem, San Marcos, TX 78666 USA. EM ll18@txstate.edu FU NIEHS NIH HHS [ES07061] NR 56 TC 58 Z9 60 U1 0 U2 3 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD APR PY 2004 VL 166 IS 4 BP 1701 EP 1713 DI 10.1534/genetics.166.4.1701 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 820HH UT WOS:000221377700010 PM 15126391 ER PT J AU Blanchette, M Kent, WJ Riemer, C Elnitski, L Smit, AFA Roskin, KM Baertsch, R Rosenbloom, K Clawson, H Green, ED Haussler, D Miller, W AF Blanchette, M Kent, WJ Riemer, C Elnitski, L Smit, AFA Roskin, KM Baertsch, R Rosenbloom, K Clawson, H Green, ED Haussler, D Miller, W TI Aligning multiple genomic sequences with the threaded blockset aligner SO GENOME RESEARCH LA English DT Article ID DNA-SEQUENCES; ALIGNMENT; SERVER; TOOLS AB We define a "threaded blockset," which is a novel generalization of the classic notion of a multiple alignment. A new computer program called TBA (for "threaded blockset aligner") builds a threaded blockset under the assumption that all matching segments occur in the same order and orientation in the given sequences; inversions and duplications are not addressed. TBA is designed to be appropriate for aligning many, but by no means all, megabase-sized regions of multiple mammalian genomes. The output of TBA can be projected onto any genome chosen as a reference, thus guaranteeing that different projections present consistent predictions of which genomic positions are orthologous. This capability is illustrated using a new visualization tool to view TBA-generated alignments of vertebrate Hox clusters from both the mammalian and fish perspectives. Experimental evaluation of alignment quality, using a program that simulates evolutionary change in genomic sequences, indicates that TBA is more accurate than earlier programs. To perform the dynamic-programming alignment step, TBA runs a stand-alone program called MULTIZ, which can be used to align highly rearranged or incompletely sequenced genomes. We describe our use of MULTIZ to produce the whole-genome multiple alignments at the Santa Cruz Genome Browser. C1 Penn State Univ, Ctr Comparat Genom & Bioinformat, University Pk, PA 16802 USA. Univ Calif Santa Cruz, Howard Hughes Med Inst, Santa Cruz, CA 95064 USA. Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. Inst Syst Biol, Seattle, WA 98103 USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. RP Penn State Univ, Ctr Comparat Genom & Bioinformat, University Pk, PA 16802 USA. EM webb@bx.psu.edu FU NHGRI NIH HHS [1P41HG02371, HG-02238, HG02325, P41 HG002371, R01 HG002238, F32 HG002325] NR 26 TC 678 Z9 702 U1 1 U2 23 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD APR PY 2004 VL 14 IS 4 BP 708 EP 715 DI 10.1101/gr.1933104 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 809IH UT WOS:000220629900025 PM 15060014 ER PT J AU Ambasudhan, R Wang, XF Jablonski, MM Thompson, DA Lagali, PS Wong, PW Sieving, PA Ayyagari, R AF Ambasudhan, R Wang, XF Jablonski, MM Thompson, DA Lagali, PS Wong, PW Sieving, PA Ayyagari, R TI Atrophic macular degeneration mutations in ELOVL4 result in the intracellular misrouting of the protein SO GENOMICS LA English DT Article ID TRANS-GOLGI NETWORK; DOMINANT RETINITIS-PIGMENTOSA; POLYUNSATURATED FATTY-ACIDS; ENDOPLASMIC-RETICULUM; BREFELDIN-A; SUBCELLULAR-LOCALIZATION; DOCOSAHEXAENOIC ACID; QUALITY-CONTROL; DYSTROPHY; GENE AB Elongation of very long chain fatty acids 4 (ELOVL4) is a novel member of the ELO family of genes that are involved in fatty acid metabolism. ELOVL4 encodes a putative transmembrane protein of 314 amino acids that carries a possible endoplasmic reticulum (ER) retention/retrieval signal (KXKXX) at the C-terminus. Two distinct mutations, a 5-bp deletion and a complex mutation from the same region in exon 6 of this gene. have been reported so far and are associated with autosomal dominant atrophic macular degeneration (adMD/STGD3). Both of these deletions could result in C-terminal truncation and loss of the ER retention signal in the mutant protein. We expressed the wildtype and mutant proteins in COS-7 and CHO cells to study the intracellular distribution of ELOVL4 and to identify possible implications of the above mutations in its localization. Immunofluorescence analysis of these proteins along with organelle marker antibodies revealed predominant ER localization for wild-type ELOVL4. Targeted deletion of the dilysine motif at the C-terminus of the protein resulted in the loss of ER localization. Immunoelectron microscopy and immunofluorescence analysis revealed a similar ER localization pattern for the protein in human photoreceptors. These data indicate that ELOVL4 is an ER-resident protein, which supports its suggested function in fatty acid elongation. We also demonstrate that the localization of both mutant proteins was dramatically changed from an ER to a Golgi distribution. Our observations suggest that the consequences of defective protein trafficking could underlie the molecular mechanism associated with degeneration of the macula in the patients with adMD/STGD3. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Michigan, Kellogg Eye Ctr, Ann Arbor, MI 48105 USA. Univ Texas, Hlth Sci Ctr, Retinal Degenerat Res Ctr, Memphis, TN 38163 USA. Univ Alberta, Edmonton, AB T6G 2E9, Canada. NEI, NIH, Bethesda, MD 20892 USA. RP Ayyagari, R (reprint author), Univ Michigan, Kellogg Eye Ctr, Room 325,1000 Wall St, Ann Arbor, MI 48105 USA. EM ayyagari@umich.edu FU NEI NIH HHS [EY13198, EY13080, EY07060, EY07003] NR 56 TC 44 Z9 46 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD APR PY 2004 VL 83 IS 4 BP 615 EP 625 DI 10.1016/j.ygeno.2003.10.004 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 806TY UT WOS:000220457400009 PM 15028284 ER PT J AU Mandal, MNA Ambasudhan, R Wong, PW Gage, MJ Sieving, PA Ayyagari, R AF Mandal, MNA Ambasudhan, R Wong, PW Gage, MJ Sieving, PA Ayyagari, R TI Characterization of mouse orthologue of ELOVL4: genomic organization and spatial and temporal expression SO GENOMICS LA English DT Article DE ELOVL4; macular degeneration; adMD; STGD3; gene expression; photoreceptor; retina; development; mouse ID POLYUNSATURATED FATTY-ACIDS; STRATUM-CORNEUM CERAMIDES; HUMAN LENS MEMBRANES; ROD OUTER SEGMENTS; MACULAR DYSTROPHY; VERTEBRATE RETINA; GENE-EXPRESSION; BRAIN; METABOLISM; DEHYDROGENASE AB Mutations in ELOVL4 are associated with dominant macular degeneration (adMD/STGD3). This gene is highly expressed in the retina and is conserved through evolution. Here we report the genomic organization of the mouse orthologue of ELOVL4 and its temporal and spatial expression. A significant amount of ELOVL4 mRNA expression is detected in the adult retina, brain, skin, testis, and lens. During development, expression is first noted at embryonic day 7 (E7). A significant level of the mRNA is observed both in brain and in eyes at postnatal day 1 (P 1), after which levels decrease in the brain and increase in the retina until they stabilize at P30. ELOVL4 protein is evident in the ocular tissues by E10.5 and becomes restricted predominantly to the photoreceptor layer in the mature retina. These observations suggest that ELOVL4 may play an important role in embryonic development and in maintaining normal physiology of retina and brain at later stages of development. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Michigan, Dept Ophthalmol & Visual Sci, Kellogg Eye Ctr, Ann Arbor, MI 48105 USA. Univ Alberta, Dept Biol Sci, Edmonton, AB T6G 2E9, Canada. NEI, NIH, Bethesda, MD 20892 USA. RP Ayyagari, R (reprint author), Univ Michigan, Dept Ophthalmol & Visual Sci, Kellogg Eye Ctr, 1000 Wall St,Room 325, Ann Arbor, MI 48105 USA. EM ayyagari@umich.edu OI Gage, Philip/0000-0001-5536-6702 FU NEI NIH HHS [EY07003, R01 EY014126, EY13198, EY07060] NR 34 TC 52 Z9 53 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD APR PY 2004 VL 83 IS 4 BP 626 EP 635 DI 10.1016/i.ygeno.2003.09.020 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 806TY UT WOS:000220457400010 PM 15028285 ER PT J AU Modi, WS AF Modi, WS TI CCL3L1 and CCL4L1 chemokine genes are located in a segmental duplication at chromosome 17ql2 SO GENOMICS LA English DT Article ID NON-ALLELIC VARIANT; LD78-BETA; IDENTIFICATION; MIP-1-ALPHA; MIP-1-BETA; EXPRESSION; LAG-1 AB Sixteen CC chemokine genes localize to a 2.06-Mb interval at 17q11.2-ql2 on genomic contig NT_010799.13. Four of these genes comprise two closely related paralogous pairs: CCL3-CCL3L1 and CCL4-CCL4L1. Members within each pair share 95% sequence identity at both the genomic and the amino acid levels. One BAC clone (AC131056.5) on the contig with substantial internal sequence duplication contains two complete copies of CCL3L1 and CCL4L1 and one truncated copy of CCL3L1, while a partially overlapping clone (AC003976.1) contains one copy each of CCL3 and CCL4. Dot-matrix comparison of the regions of AC131056.5 with those of AC003976.1 containing the four genes reveals 90% sequence similarity over 37 kb. These observations support the idea that the multiple copies of CCL3L1 and CCL4L1 present in a single diploid genome are the result of segmental duplication. (C) 2003 Elsevier Inc. All rights reserved. C1 NCI, SAIC Frederick, Basic Res Program, Ft Detrick, MD 21702 USA. RP Modi, WS (reprint author), NCI, SAIC Frederick, Basic Res Program, Ft Detrick, MD 21702 USA. EM modi@ncifcrf.gov FU NCI NIH HHS [N01-CO-124000] NR 13 TC 27 Z9 31 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD APR PY 2004 VL 83 IS 4 BP 735 EP 738 DI 10.1016/j.ygeno.2003.09.019 PG 4 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 806TY UT WOS:000220457400020 PM 15028295 ER PT J AU Ess, KC Uhlmann, EJ Li, W Li, HZ Declue, JE Crino, PB Gutmann, DH AF Ess, KC Uhlmann, EJ Li, W Li, HZ Declue, JE Crino, PB Gutmann, DH TI Expression profiling in tuberous sclerosis complex (TSC) knockout mouse astrocytes to characterize human TSC brain pathology SO GLIA LA English DT Article DE tuber; hamartoma; hamartin; tuberin ID GIANT-CELL ASTROCYTOMA; BINDING PROTEIN; GENE-PRODUCTS; GLIAL-CELLS; HAMARTIN; NEURONS; MICE; IDENTIFICATION; TUMORIGENESIS; INHIBITORS AB Individuals with tuberous sclerosis complex (TSC) exhibit a variety of neurologic abnormalities, including mental retardation, epilepsy, and autism. Examination of human TSC brains demonstrate dysplastic astrocytes and neurons, areas of abnormal neuronal migration (tubers), and hamartomatous growths, termed subependymal nodules, which can progress to subependymal giant cell astrocytomas (SEGA). Previous studies have suggested that these neuropathologic features may result from abnormal neuroglial cell differentiation. In an effort to provide support for this hypothesis and to identify specific markers of aberrant neuroglial cell differentiation in TSC, we employed gene expression profiling on Tsc1 conditional knockout (Tsc1(GFAP) CKO) mouse astrocytes. We identified several transcripts implicated in central nervous system development that are differentially expressed in Tsc1(-/-) astrocytes compared to wild-type astrocytes. We validated the differential expression of select transcripts on the protein level both in primary cultures of Tsc1(-/-) astrocytes and in Tsc1(GFAP) CKO mouse brains. Moreover, we show that these markers are also differentially expressed within cortical tubers, but not in adjacent normal tissue from TSC patient brains. This study provides supportive evidence for a developmental defect in neuroglial cell differentiation relevant to the genesis of TSC nervous system pathology and underscores the utility of mouse modeling for understanding the molecular pathogenesis of human disease. (C) 2004 Wiley-Liss, Inc. C1 Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. Univ Penn, Dept Neurol, PENN Epilepsy Ctr, Philadelphia, PA 19104 USA. NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Gutmann, DH (reprint author), Washington Univ, Sch Med, Dept Neurol, Box 8111,660 S Euclid Ave, St Louis, MO 63110 USA. EM gutmannd@neuro.wustl.edu FU NINDS NIH HHS [5T32-NS07205-21, NS045021] NR 48 TC 28 Z9 28 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 0894-1491 J9 GLIA JI Glia PD APR 1 PY 2004 VL 46 IS 1 BP 28 EP 40 DI 10.1002/glia.10324 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 804NE UT WOS:000220304600004 PM 14999811 ER PT J AU Hold, GL Smith, MG Chow, WH Rabkin, CS El-Omar, EM AF Hold, GL Smith, MG Chow, WH Rabkin, CS El-Omar, EM TI A functional toll like receptor 4 polymorphism increases risk of gastric cancer SO GUT LA English DT Meeting Abstract CT Annual Meeting of the British-Society-of-Gastroenterology CY MAR 21-24, 2004 CL Glasgow, Scotland SP British Soc Gastroenterol C1 Univ Aberdeen, Inst Med Sci, Dept Med & Therapeut, Aberdeen, Scotland. NCI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 J9 GUT JI Gut PD APR PY 2004 VL 53 SU 3 MA 089 BP A23 EP A23 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 808QV UT WOS:000220584500089 ER PT J AU Nezhat, F Wadler, S Muggia, F Mandeli, J Goldberg, G Rahaman, J Runowicz, C Murgo, AJ Gardner, GJ AF Nezhat, F Wadler, S Muggia, F Mandeli, J Goldberg, G Rahaman, J Runowicz, C Murgo, AJ Gardner, GJ TI Phase II trial of the combination of bryostatin-1 and cisplatin in advanced or recurrent carcinoma of the cervix: a New York Gynecologic Oncology Group study SO GYNECOLOGIC ONCOLOGY LA English DT Article DE bryostatin (NSC 339555); cisplatin; cervical cancer ID PROTEIN-KINASE-C; SQUAMOUS-CELL CARCINOMA; RANDOMIZED TRIAL; IN-VIVO; CHEMOTHERAPY; CANCER; INHIBITOR; UCN-01 AB Objective. Bryostatin-1 is a macrocyclic lactone that has been shown to regulate protein kinase C (PKC) activity and thereby potentially inhibit tumor invasion, angiogenesis, cell adhesion, and multidrug resistance. In preclinical experiments, bryostatin-1 induces tumor growth inhibition and enhances cytotoxicity when combined with other agents including cisplatin in cervical cancer cells. It was therefore anticipated that combination bryostatin-1-cisplatin therapy would be effective in patients with cervical cancer. The current study was conducted to evaluate this therapeutic approach in patients with recurrent or advanced-stage cervical carcinoma. Methods. An IRB-approved New York Gynecologic Oncology Group (NYGOG) trial was activated for patients with a histological diagnosis of metastatic cervical cancer or in patients with recurrent disease not eligible for surgery or radiation. Enrolled patients received bryostatin-1 (50-65 mug/m(2)) as a 1-h infusion followed by cisplatin (50 mg/m(2)). The combined treatment was administered every 21 days. Results. Fourteen patients were enrolled. The majority of patients had squamous cell carcinoma. Ten out of fourteen patients had recurrent disease. Fifty percent of the patients received bryostatin at 50 mug/m(2) and 50% received bryostatin at 65 mug/m(2). Seventy-one percent completed two cycles of treatment. The most common grade II-III toxicities were myalgia, anemia, and nausea or vomiting. One patient developed a hypersensitivity reaction and one developed grade III nephrotoxicity. Seventy-one percent (10/14) of patients were evaluated for tumor response. Eight out of ten (80%) of patients had progressive disease and 2/10 (20%) had stable disease. There were no treatment responses. Conclusion. Despite promising preclinical data, this clinical trial indicates that the combination of cisplatin and bryostatin-1 at the doses and schedule used is not effective in patients with advanced-stage or recurrent cervical cancer. There is even the possibility of therapeutic antagonism. The development of a serum assay for bryostatin-1 and additional mechanistic studies would be useful for future bryostatin clinical trials. (C) 2004 Elsevier Inc. All rights reserved. C1 CUNY Mt Sinai Sch Med, New York, NY 10029 USA. NYU, Sch Med, New York, NY 10016 USA. Cornell Univ, Weill Med Coll, New York, NY 10021 USA. Yeshiva Univ Albert Einstein Coll Med, Bronx, NY 10461 USA. NCI, CTEP, NIH, Bethesda, MD 20892 USA. RP Nezhat, F (reprint author), Mt Sinai Med Ctr, Dept Obstet & Gynecol, 1176 5th Ave,Box 1173, New York, NY 10029 USA. EM farr.nezhat@mssm.edu OI Muggia, Franco/0000-0003-0703-9146 FU NCI NIH HHS [N01-CM-07003] NR 30 TC 24 Z9 28 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 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD APR PY 2004 VL 93 IS 1 BP 144 EP 148 DI 10.1016/j.ygyno.2003.12.021 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 812PG UT WOS:000220850800023 PM 15047228 ER PT J AU Feldman, ED Hughes, MS Stratton, P Schrump, DS Alexander, HR AF Feldman, ED Hughes, MS Stratton, P Schrump, DS Alexander, HR TI Pseudo-Meigs' syndrome secondary to isolated colorectal metastasis to ovary: a case report and review of the literature SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Meigs' syndrome; colorectal cancer; gastric adenocarcinoma ID CANCER; TUMORS AB Introduction: Pseudo-Meigs' syndrome is a syndrome that includes hydrothorax and/or ascites secondary to ovarian neoplasms other than benign primary tumors. Gastrointestinal malignancies, including colorectal or gastric adenocarcinoma, are rare etiologies for this syndrome. Case Report: In this report, we present the case of a 49-year-old woman with metastatic colon cancer who acutely developed a massive pleural effusion and ascites coincident with a rapidly enlarging adnexal mass and a rising CA-125 level. Discussion: Seven cases of pseudo-Meigs' syndrome secondary to gastrointestinal primaries have been reported to date. This case highlights the difficulty in discerning the diagnosis of pseudo-Meigs' syndrome from that of disseminated colorectal cancer or a new primary ovarian neoplasm and the importance in making the distinction to initiate appropriate therapy. (C) 2004 Elsevier Inc. All rights reserved. C1 NCI, Surg Metab Sect, Surg Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Pediat & Reprod Endocrine Branch, Bethesda, MD 20892 USA. RP Alexander, HR (reprint author), NCI, Surg Metab Sect, Surg Branch, NIH, Bldg 10,Room 2B07, Bethesda, MD 20892 USA. EM Richard_Alexander@nih.gov NR 8 TC 12 Z9 14 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD APR PY 2004 VL 93 IS 1 BP 248 EP 251 DI 10.1016/j.ygyno.2003.12.025 PG 4 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 812PG UT WOS:000220850800040 PM 15047245 ER PT J AU Kirkpatrick, B Fleming, LE Squicciarini, D Backer, LC Clark, R Abraham, W Benson, J Cheng, YS Johnson, D Pierce, R Zaias, J Bossart, GD Baden, DG AF Kirkpatrick, B Fleming, LE Squicciarini, D Backer, LC Clark, R Abraham, W Benson, J Cheng, YS Johnson, D Pierce, R Zaias, J Bossart, GD Baden, DG TI Literature review of Florida red tide: implications for human health effects SO HARMFUL ALGAE LA English DT Review DE Florida red tide; red tide; neurotoxic shellfish poisoning; NSP; brevetoxins; harmful algal bloom; HAB; karenia brevis; shellfish poisoning; respiratory irritation; marine toxin diseases ID NEUROTOXIC SHELLFISH TOXINS; FORMERLY GYMNODINIUM-BREVE; SENSITIVE SODIUM-CHANNELS; RAT-BRAIN SYNAPTOSOMES; MARINE ALGAL TOXINS; PTYCHODISCUS-BREVIS; NEW-ZEALAND; DINOFLAGELLATE TOXINS; CRASSOSTREA-GIGAS; MOUSE BIOASSAY AB Florida red tides are a natural phenomenon caused by dense aggregations of single cell or several species Of unicellular organisms. Patches of discolored water, dead or dying fish, and respiratory irritants in the air often characterize these algal blooms. In humans, two distinct clinical entities, depending on the route of exposure, are associated with exposure to the Florida red tide toxins (particularly the brevetoxins). With the ingestion of brevetoxin-contaminated shellfish, neurotoxic shellfish poisoning (NSP) presents as a milder gastroenteritis with neurologic symptoms compared with other marine toxin diseases such as paralytic shellfish poisoning (PSP) or ciguatera fish poisoning. With the inhalation of the aerosolized red tide toxins (especially the brevetoxins) from the sea spray, respiratory irritation and possibly other health effects are reported in both humans and other mammals [Nat. Toxins Drugs (1995) 141; Fleming, L.E., Baden, D.G., 1988. Neurotoxic shellfish poisoning: public health and human health effects. White Paper for the Proceedings of the Texas Conference on Neurotoxic Shellfish Poisoning. In: Proceedings of the Texas NSP Conference, Corpus Christi, TX, pp. 27-34; Travel Med, 2 (10) (1998b) 1: Travel Med. 3 (10) (1999a) 1; Toxins Pathol. 26 (2) (1998) 276; J. Allergy Clin. Imunol. 69 (1982) 418; Arch. Intern. Med. 149 (1989) 1735; Toxicon 24 (1986) 955; Florida Med. J. 60 (11) (1773) 27; J. Nat. Toxins 4 (1995) 181; J. Nat. Toxins 4 (1995) 18 1: Sci. Ani. 271 (4) (1994) 62]. This paper reviews the literature on the known and possible human health effects of exposure to the Florida red tides and their toxins. The review includes discussion of the red tide organisms and their toxins, as well as the effects of these toxins on both wild and laboratory animals as they relate to possible human health effects and exposures. (C) 2004 Elsevier B.V. All rights reserved. C1 Mote Marine Lab, Sarasota, FL 34236 USA. Univ Miami, NIEHS, Marine & Freshwater Biomed Sci Ctr, Miami, FL 33149 USA. Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA. Florida Dept Hlth, Tallahassee, FL 32399 USA. Lovelace Resp Inst, Albuquerque, NM 87108 USA. Univ N Carolina, Ctr Marine Sci, Wilmington, NC 28409 USA. RP Kirkpatrick, B (reprint author), Mote Marine Lab, 1600 Ken Thompson Pkwy, Sarasota, FL 34236 USA. EM bkirkpat@mote.org FU NIEHS NIH HHS [P01 ES010594, P01 ES010594-04] NR 147 TC 180 Z9 185 U1 12 U2 75 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-9883 J9 HARMFUL ALGAE JI Harmful Algae PD APR PY 2004 VL 3 IS 2 BP 99 EP 115 DI 10.1016/j.hal.2003.08.005 PG 17 WC Marine & Freshwater Biology SC Marine & Freshwater Biology GA 813RY UT WOS:000220925400001 PM 20411030 ER PT J AU Tong, BC Dhir, K Ha, PK Westra, WH Alter, BP Sidransky, D Koch, WM Califano, JA AF Tong, BC Dhir, K Ha, PK Westra, WH Alter, BP Sidransky, D Koch, WM Califano, JA TI Use of single nucleotide polymorphism arrays to identify a novel region of loss on chromosome 6Q in squamous cell carcinomas of the oral cavity SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Article DE single nucleotide polymorphism; squamous cell carcinoma; chromosome 6q; oral cavity ID HUMAN-PAPILLOMAVIRUS INFECTION; FANCONIS ANEMIA; NECK CANCERS; RISK FACTOR; HEAD; DELETION; LARYNX AB Background. A subset of patients with oral cavity squamous cell carcinoma (SCC), often of young age yet lacking a history of carcinogen exposure, has been identified, with no clear etiology for tumor development. Methods. To identify somatic genetic alterations unique to this patient population, we performed a high throughput single nucleotide polymorphism (SNP) analysis, quantitative PCR of the E6 and E7 regions of human papillomavirus (HPV) 16, sequencing of the IVSF-4+ locus of the FANC-C gene, and microsatellite analysis for 18 nonsmoking patients, age 23 to 57 years (median age, 39 years). We compared these results with oral SCC from 17 patients 47 to 81 (median, 64) years of age with significant tobacco exposure (>40 pack-years) to identify unique genetic alterations for each group. Results. SNP analysis demonstrated variable rates of allelic imbalance (AI) and no significant difference in terms of Al patterns between the two groups. However, we found an elevated rate of Al in chromosomal arms 6q (47% 17 of 36]) by performing microsatellite analysis of both groups. Only one tumor demonstrated the presence of HPV 16, and none of the tumors demonstrated mutations in the IVSF-4+ region of FANC-C. Conclusions. Despite variable marker density, SNP array analysis is an emerging technique for genome-wide assessment and is a useful tool for discovery of novel sites of allelic loss in oral SCC, including a novel region of allelic loss on chromosome 6q. (C) 2004 Wiley Periodicals, Inc. C1 Johns Hopkins Med Sch, Dept Otolaryngol Head & Neck Surg, Head & Neck Canc Res Div, Baltimore, MD 21205 USA. Johns Hopkins Univ Hosp, Dept Surg, Baltimore, MD 21287 USA. Johns Hopkins Univ Hosp, Dept Pathol, Baltimore, MD 21287 USA. NCI, Clin Genet Branch, NIH, Bethesda, MD 20892 USA. RP Califano, JA (reprint author), Johns Hopkins Med Sch, Dept Otolaryngol Head & Neck Surg, Head & Neck Canc Res Div, 818 Ross Res Bldg,720 Rutland Ave, Baltimore, MD 21205 USA. EM jcalifa@jhmi.edu FU NIDCR NIH HHS [1R01 DE13152-01] NR 16 TC 11 Z9 11 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1043-3074 J9 HEAD NECK-J SCI SPEC JI Head Neck-J. Sci. Spec. Head Neck PD APR PY 2004 VL 26 IS 4 BP 345 EP 352 DI 10.1002/hed.10391 PG 8 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 808EW UT WOS:000220553400006 PM 15054738 ER PT J AU Gao, B Hong, F Radaeva, S AF Gao, B Hong, F Radaeva, S TI Host factors and failure of interferon-alpha treatment in hepatitis C virus SO HEPATOLOGY LA English DT Review ID TUMOR-NECROSIS-FACTOR; PRIMARY HUMAN HEPATOCYTES; ALCOHOLIC LIVER-DISEASE; RECEPTOR MESSENGER-RNA; ANTIVIRAL TREATMENT; SUSTAINED RESPONSE; GAMMA-INTERFERON; VIRAL CLEARANCE; GENE-EXPRESSION; INTRAHEPATIC EXPRESSION AB Failure of interferon-alpha (IFN-alpha) treatment in patients with chronic hepatitis C virus (HCV) infection is a challenging obstacle for clinical and experimental hepatology. Both viral and host factors have been implicated in reducing responsiveness to IFN-alpha therapy. The role of viral factors has been studied extensively and has been summarized in several review articles; however, much less attention has been paid to host factors. In this paper, we review evidence of host factor involvement in IFN-alpha treatment failure. We discuss possible underlying mechanisms responsible for these effects. Potential therapeutic strategies to enhance the effectiveness of IFN-alpha therapy for HCV are also proposed. C1 NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. RP Gao, B (reprint author), NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Pk Bldg,Rm 120,12420 Parklawn Dr,MSC 8115, Bethesda, MD 20892 USA. EM bgao@mail.nih.gov NR 110 TC 114 Z9 120 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD APR PY 2004 VL 39 IS 4 BP 880 EP 890 DI 10.1002/hep.20139 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 807ZL UT WOS:000220539300001 PM 15057887 ER PT J AU Drenth, JPH Tahvanainen, E Morsche, RHMT Tahvanainen, P Kaariainen, H Hockerstedt, K van de Kamp, JM Breuning, MH Jansen, JBMJ AF Drenth, JPH Tahvanainen, E Morsche, RHMT Tahvanainen, P Kaariainen, H Hockerstedt, K van de Kamp, JM Breuning, MH Jansen, JBMJ TI Abnormal hepatocystin caused by truncating PRKCSH mutations leads to autosomal dominant polycystic liver disease SO HEPATOLOGY LA English DT Article ID PROTEIN-KINASE-C; KIDNEY-DISEASE; LOD SCORES; IDENTIFICATION; LINKAGE; CYSTS AB Mutations in protein kinase C substrate 80K-H (PRKCSH), encoding for the protein hepatocystin, cause autosomal dominant polycystic liver disease (PCLD), which is clinically characterized by the presence of multiple liver cysts. PCLD has been documented in families from Europe (Netherlands, Belgium, Finland) as well as from the United States. In this article, we report results from extensive mutational analysis of the PRKCSH gene in a group of 14 PCLD families and 65 singleton cases of Dutch and Finnish descent with multiple simple liver cysts. We identified PRKCSH mutations in 12 families and in 3 sporadic cases. In 8 of 10 Finnish families we detected the 1437+2delTG splice-site mutation. In Dutch families, we found 2 other mutations that affect correct splicing of PRKCSH: 292+1 G>C (2 families) and 1338-2 A>G (1 family). In another Dutch family, we detected a novel deletion (374-375delAG) in exon 6, predicting an abnormal shortened protein. Investigation of the carrier haplotypes identified a common founder chromosome in unrelated individuals in each of the 3 identified splice-site mutations. In 2 Finnish families with dominantly inherited PCLD, and in 62 of 65 sporadic cases with multiple simple liver cysts, we failed to demonstrate any PRKCSH mutation. This corroborates the notion that autosomal dominant PCLD is genetically heterogeneous. In conclusion, we propose that, on the basis of our results, genetic screening for PRKCSH gene mutations should be limited to patients either with a positive family history for PCLD or who have severe polycystic liver disease. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. Univ Med Ctr St Radboud, Dept Med, Div Gastroenterol & Hepatol, Nijmegen, Netherlands. Univ Helsinki, Dept Med Genet, Helsinki, Finland. Natl Publ Hlth Inst, Dept Human Mol Genet, Helsinki, Finland. Univ Turku, Dept Med Genet, Turku, Finland. Turku Univ, Cent Hosp, Dept Pediat, Turku, Finland. Univ Helsinki Hosp, Transplantat & Liver Surg Unit, Helsinki, Finland. Leiden Univ, Med Ctr, Dept Human & Clin Genet, Leiden, Netherlands. RP Drenth, JPH (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bldg 18T,Rm 101, Bethesda, MD 20892 USA. EM JoostPHDrenth@CS.com RI Drenth, J.P.H./H-8025-2014; te Morsche, Rene/P-9143-2015 NR 18 TC 25 Z9 26 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD APR PY 2004 VL 39 IS 4 BP 924 EP 931 DI 10.1002/hep.20141 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 807ZL UT WOS:000220539300008 PM 15057895 ER PT J AU Strader, DB Wright, T Thomas, DL Seeff, LB AF Strader, DB Wright, T Thomas, DL Seeff, LB TI Diagnosis, management, and treatment of hepatitis C SO HEPATOLOGY LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; INTERFERON-ALPHA-2B PLUS RIBAVIRIN; NORMAL AMINOTRANSFERASE LEVELS; LIVER-TRANSPLANT RECIPIENTS; INJECTION-DRUG USERS; CHRONIC VIRAL-HEPATITIS; HIV-INFECTED PATIENTS; STAGE RENAL-DISEASE; NON-B HEPATITIS; HEMODIALYSIS-PATIENTS C1 Univ Vermont, Coll Med, Fletcher Allen Hlth Care, Burlington, VT USA. Univ Calif San Francisco, Sch Med, San Francisco, CA USA. Vet Affairs Med Ctr, San Francisco, CA 94121 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. NIDDKD, Bethesda, MD 20892 USA. Vet Affairs Med Ctr, Washington, DC 20422 USA. RP Seeff, LB (reprint author), Amer Assoc Study Liver Dis, 1729 King St,Suite 200, Alexandria, VA 22314 USA. EM seeffl@extra.niddk.nih.gov NR 213 TC 1191 Z9 1273 U1 13 U2 39 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD APR PY 2004 VL 39 IS 4 BP 1147 EP 1171 DI 10.1002/hep.20119 PG 25 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 807ZL UT WOS:000220539300031 PM 15057920 ER PT J AU Arbab, AS Jordan, EK Wilson, LB Yocum, GT Lewis, BK Frank, JA AF Arbab, AS Jordan, EK Wilson, LB Yocum, GT Lewis, BK Frank, JA TI In vivo trafficking and targeted delivery of magnetically labeled stem cells SO HUMAN GENE THERAPY LA English DT Article ID TRANSFECTION AGENTS; MULTIPLE-SCLEROSIS; PROGENITOR CELLS; TRANSPLANTATION; RESONANCE; STROKE; MICROSPHERES; MYOCARDIUM; MIGRATION; CARCINOMA AB Targeted delivery of intravenously administered genetically altered cells or stem cells is still in an early stage of investigation. We developed a method of delivering iron oxide (ferumoxide)-labeled mesenchymal stem cells (MSCs) to a targeted area in an animal model by applying an external magnet. Rats with or without an external magnet placed over the liver were injected intravenously with ferumoxide-labeled MSCs and magnetic resonance imaging (MRI) signal intensity (SI) changes, iron concentration, and concentration of MSCs in the liver were monitored at different time points. SI decreased in the liver after injection of MSCs and returned gradually to that of control rat livers at approximately day 29. SI decreases were greater in rats with external magnets. Higher iron concentration and increased labeled cell numbers were detected in rat livers with external magnets. The external magnets influenced the movement of labeled MSCs such that the cells were retained in the region of interest. These results potentially open a new area of investigation for delivering stem cells or genetically altered cells. C1 NIH, Expt Neuroimaging Sect, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. RP Arbab, AS (reprint author), NIH, Expt Neuroimaging Sect, Lab Diagnost Radiol Res, Bldg 10,Room B1N256, Bethesda, MD 20892 USA. EM saali@cc.nih.gov NR 37 TC 111 Z9 121 U1 3 U2 15 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD APR PY 2004 VL 15 IS 4 BP 351 EP 360 DI 10.1089/104303404322959506 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 823JD UT WOS:000221606300002 PM 15053860 ER PT J AU Lizee, G Gonzales, MI Topalian, SL AF Lizee, G Gonzales, MI Topalian, SL TI Lentivirus vector-mediated expression of tumor-associated epitopes by human antigen presenting cells SO HUMAN GENE THERAPY LA English DT Article ID MHC CLASS-I; TRANSDUCED DENDRITIC CELLS; CYTOTOXIC T-CELLS; GENE DELIVERY; EFFICIENT TRANSDUCTION; CANCER-IMMUNOTHERAPY; MELANOMA PATIENTS; B-LYMPHOCYTES; VACCINATION; RECOGNITION AB Directing the human immune system to recognize and eliminate tumor cells is the ultimate goal of cancer immunotherapy. Vaccinating patients with autologous antigen presenting cells (APC) expressing tumor-associated antigens (TAA) represents a promising approach for activating tumor-reactive T cells in vivo. In addition, APC expressing TAA provide a means of generating tumor-specific T cells in vitro, for therapeutic and diagnostic applications. Lentiviral vectors are attractive vehicles for introducing TAA-encoding genes into APC. In this study, lentiviral vectors expressing the reporter gene GFP or the melanoma-associated antigen tyrosinase were used to transduce three different kinds of human APC: monocyte-derived dendritic cells ( DC), CD40L-activated B lymphocytes, and Epstein Barr virus (EBV)-transformed B lymphocytes. Using optimized transduction conditions for each cell type, tyrosinase was expressed at levels sufficient to stimulate antigen-specific major histocompatibility complex (MHC) class I-restricted T cells from melanoma patients. While transduced EBV-B cells demonstrated the highest level of transgene expression, optimal T-cell recognition was achieved with transduced DC. Substituting the CAG promoter for PGK in lentiviral constructs enhanced transgene expression in DC and EBV-B cells, amplifying T cell recognition. Lentiviruses inducing sustained transgene expression with relatively low cellular toxicity and background viral gene expression may be ideal vectors for immunotherapeutic applications. C1 NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Topalian, SL (reprint author), NCI, Surg Branch, Ctr Canc Res, NIH, 10-2B47, Bethesda, MD 20892 USA. EM Suzanne_Topalian@nih.gov NR 33 TC 44 Z9 47 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD APR PY 2004 VL 15 IS 4 BP 393 EP 404 DI 10.1089/104303404322959542 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 823JD UT WOS:000221606300006 PM 15053864 ER PT J AU Petrucelli, L Dickson, D Kehoe, K Taylor, J Snyder, H Grover, A De Lucia, M McGowan, E Lewis, J Prihar, G Kim, J Dillmann, WH Browne, SE Hall, A Voellmy, R Tsuboi, Y Dawson, TM Wolozin, B Hardy, J Hutton, M AF Petrucelli, L Dickson, D Kehoe, K Taylor, J Snyder, H Grover, A De Lucia, M McGowan, E Lewis, J Prihar, G Kim, J Dillmann, WH Browne, SE Hall, A Voellmy, R Tsuboi, Y Dawson, TM Wolozin, B Hardy, J Hutton, M TI CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation SO HUMAN MOLECULAR GENETICS LA English DT Article ID PROGRESSIVE SUPRANUCLEAR PALSY; PAIRED HELICAL FILAMENTS; HEAT-SHOCK PROTEINS; NEUROFIBRILLARY TANGLES; ALZHEIMERS-DISEASE; CORTICOBASAL DEGENERATION; CHAPERONE SUPPRESSION; PARKINSONS-DISEASE; LIGASE ACTIVITY; STRESS AB Molecular chaperones, ubiquitin ligases and proteasome impairment have been implicated in several neurodegenerative diseases, including Alzheimer's and Parkinson's disease, which are characterized by accumulation of abnormal protein aggregates (e.g. tau and alpha-synuclein respectively). Here we report that CHIP, an ubiquitin ligase that interacts directly with Hsp70/90, induces ubiquitination of the microtubule associated protein, tau. CHIP also increases tau aggregation. Consistent with this observation, diverse of tau lesions in human postmortem tissue were found to be immunopositive for CHIP. Conversely, induction of Hsp70 through treatment with either geldanamycin or heat shock factor 1 leads to a decrease in tau steady-state levels and a selective reduction in detergent insoluble tau. Furthermore, 30-month-old mice overexpressing inducible Hsp70 show a significant reduction in tau levels. Together these data demonstrate that the Hsp70/CHIP chaperone system plays an important role in the regulation of tau turnover and the selective elimination of abnormal tau species. Hsp70/CHIP may therefore play an important role in the pathogenesis of tauopathies and also represents a potential therapeutic target. C1 Mayo Clin, Jacksonville, FL 32224 USA. Loyola Univ, Sch Med, Dept Pharmacol, Maywood, IL 60153 USA. Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. Cornell Univ, Weill Med Coll, New York, NY 10021 USA. Univ Miami, Sch Med, Miami, FL 33136 USA. Fukuoka Univ, Dept Internal Med, Fukuoka, Japan. Johns Hopkins Univ, Sch Med, Inst Cell Engn, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. NIH, Dept Neurogenet, Bethesda, MD 20892 USA. RP Hutton, M (reprint author), Dept Neurosci, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. EM hutton.michael@mayo.edu RI Kim, Jungsu/A-1372-2009; Hardy, John/C-2451-2009; Kim, Jungsu/F-2457-2012; OI Kim, Jungsu/0000-0002-6931-8581; Hall, Alexis/0000-0002-0305-400X; Dickson, Dennis W/0000-0001-7189-7917 FU NINDS NIH HHS [R01-NS41816-01] NR 38 TC 365 Z9 387 U1 7 U2 32 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 APR 1 PY 2004 VL 13 IS 7 BP 703 EP 714 DI 10.1093/hmg/ddh083 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 802RF UT WOS:000220179900004 PM 14962978 ER PT J AU Singleton, A Myers, A Hardy, J AF Singleton, A Myers, A Hardy, J TI The law of mass action applied to neurodegenerative disease: a hypothesis concerning the etiology and pathogenesis of complex diseases SO HUMAN MOLECULAR GENETICS LA English DT Review ID CREUTZFELDT-JAKOB-DISEASE; ALPHA-SYNUCLEIN GENE; PROGRESSIVE SUPRANUCLEAR PALSY; ONSET ALZHEIMERS-DISEASE; PRECURSOR PROTEIN LOCUS; PARKINSONS-DISEASE; ALLELIC VARIATION; FUNCTIONAL-ANALYSIS; TAU; DEMENTIA AB Loci underlying autosomal dominant forms of most neurodegenerative disease have been identified: prion mutations cause Gerstmann Straussler syndrome and hereditary Creuzfeldt-Jakob disease, tau mutations cause autosomal dominant frontal temporal dementia, and alpha-synuclein mutations cause autosomal dominant Parkinson's disease. In all these cases, the pathogenic mutation is in the protein that is deposited in the diseased tissue and in these cases the whole protein is deposited. In Alzheimer's disease, mutations in APP or presenilin 1 or 2 cause autosomal dominant disease and these are the substrate and proteases, respectively, which are responsible for the production of the deposited peptide, Abeta. Thus, in all cases, the mutations lead to the disease by a mechanism that involves the deposition process. We briefly review this remarkably predictable biology, but also point out that it seems sporadic forms of all these diseases are predisposed to by genetic variability at the same loci, strongly suggesting that the quantity of the normal protein produced influences risk for the sporadic forms of the disease. The evidence for this assertion is strongest in Parkinson's disease (PD), where genetic variability in alpha-synuclein expression affects risk of developing disease, although the oldest evidence for the notion that increased expression of normal sequence protein can lead to disease comes from the observation of Alzheimer's disease in trisomy 21 cases. From these observations, we make predictions concerning the etiology and pathogenesis of neurodegenerative diseases in general. C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Hardy, J (reprint author), NIA, Neurogenet Lab, NIH, Bldg 10,Room 6C103,MSC1589, Bethesda, MD 20892 USA. EM hardyj@mail.nih.gov RI Myers, Amanda/B-1796-2010; Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009 OI Myers, Amanda/0000-0002-3100-9396; NR 36 TC 69 Z9 71 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD APR PY 2004 VL 13 SI 1 BP R123 EP R126 DI 10.1093/hmg/ddh093 PG 4 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 811TF UT WOS:000220793500012 PM 14976159 ER PT J AU Winkler, C An, P O'Brien, SJ AF Winkler, C An, P O'Brien, SJ TI Patterns of ethnic diversity among the genes that influence AIDS SO HUMAN MOLECULAR GENETICS LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-1 DISEASE PROGRESSION; CHEMOKINE-RECEPTOR GENE; AMINO-ACID CHANGES; CYTOTOXIC T-CELLS; LINKAGE DISEQUILIBRIUM; NATURAL-SELECTION; AFRICAN-AMERICANS; INFECTIOUS-DISEASES; BALANCING SELECTION AB Although HIV-1/AIDS emerged late in the last century, more than 42 million individuals have been infected and 25 million have died worldwide, making AIDS, like malaria, a strong selective force for disease-associated genetic factors. Many of the genes that mediate immune response or that are co-opted by HIV-1 for completion of its lifecycle show differences in allele frequencies, as a result of drift, migration or selection. Here we show that the majority of AIDS candidate genes and AIDS restriction genes show significant differences in allele frequencies, possibly the result of historic selective pressures. These genes are undergoing present day natural selection in populations with high AIDS prevalence. C1 NCI, Lab Genom Divers, Frederick, MD 21702 USA. NCI, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP O'Brien, SJ (reprint author), NCI, Lab Genom Divers, Bldg 560,Room 21-105, Frederick, MD 21702 USA. EM obrien@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 108 TC 26 Z9 28 U1 0 U2 6 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 APR PY 2004 VL 13 SI 1 BP R9 EP R19 DI 10.1093/hmg/ddh075 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 811TF UT WOS:000220793500002 PM 14764621 ER PT J AU Bigelow, JL Dunson, DB Stanford, JB Ecochard, R Gnoth, C Colombo, B AF Bigelow, JL Dunson, DB Stanford, JB Ecochard, R Gnoth, C Colombo, B TI Mucus observations in the fertile window: a better predictor of conception than timing of intercourse SO HUMAN REPRODUCTION LA English DT Article DE Bayesian analysis; cervical mucus; day-specific pregnancy probabilities; menstrual cycle; ovulation ID HUMAN CERVICAL-MUCUS; MENSTRUAL-CYCLE; TWODAY ALGORITHM; PREGNANCY; OVULATION; SPERM; PROBABILITIES AB BACKGROUND: Intercourse results in a pregnancy essentially only if it occurs during the 6-day fertile interval ending on the day of ovulation. The strong association between timing of intercourse within this interval and the probability of conception typically is attributed to limited sperm and egg life times. METHODS: A total of 782 women recruited from natural family planning centres in Europe contributed prospective data on 7288 menstrual cycles. Daily records of intercourse, basal body temperature and vaginal discharge of cervical mucus were collected. Probabilities of conception were estimated according to the timing of intercourse relative to ovulation and a 1-4 score of mucus quality. RESULTS: There was a strong increasing trend in the day-specific probabilities of pregnancy with increases in the mucus score. Adjusting for the mucus score, the day-specific probabilities had limited variability across the fertile interval. CONCLUSIONS: Changes in mucus quality across the fertile interval predict the observed pattern in the day-specific probabilities of conception. To maximize the likelihood of conception, intercourse should occur on days with optimal mucus quality, as observed in vaginal discharge, regardless of the exact timing relative to ovulation. C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. Univ Utah, Dept Family & Prevent Med, Salt Lake City, UT 84112 USA. Ctr Hosp Univ, Serv Biostat, Lyon, France. Kliniken Duesseldorf gGmbH, Frauenklin Benrath, Dept Gynecol Endocrinol & Reprod Med, Dusseldorf, Germany. Univ Padua, Dept Stat, Padua, Italy. RP Dunson, DB (reprint author), NIEHS, Biostat Branch, POB 12233, Res Triangle Pk, NC 27709 USA. EM dunson1@niehs.nih.gov NR 30 TC 69 Z9 69 U1 1 U2 13 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD APR PY 2004 VL 19 IS 4 BP 889 EP 892 DI 10.1093/humrep/deh173 PG 4 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 807FG UT WOS:000220486800020 PM 14990542 ER PT J AU Hoagland, KM Flasch, AK Dahly-Vernon, AJ dos Santos, EA Knepper, MA Roman, RJ AF Hoagland, KM Flasch, AK Dahly-Vernon, AJ dos Santos, EA Knepper, MA Roman, RJ TI Elevated BSC-1 and ROMK expression in Dahl salt-sensitive rat kidneys SO HYPERTENSION LA English DT Article DE rats, Dahl; Na+,K+-transporting ATPase; sodium; hypertension ID THICK ASCENDING LIMB; PRESSURE-NATRIURESIS; ARACHIDONIC-ACID; CHLORIDE REABSORPTION; SS/JR RATS; S RATS; HYPERTENSION; METABOLITES; 20-HETE; LOOP AB This study compared the expression of enzymes and transport and channel proteins involved in the regulation of sodium reabsorption in the kidney of Dahl salt-sensitive (DS) and salt-resistant Brown-Norway (BN) and consomic rats (SS.BN13), in which chromosome 13 from the BN rat has been introgressed into the DS genetic background. The expression of the Na+/K+/2Cl(-) (BSC-1) cotransporter, Na+/H+ exchanger (NHE3), and Na+-K+-ATPase proteins were similar in the renal cortex of DS, BN, and SS.BN13 rats fed either a low-salt (0.1% NaCl) or a high-salt (8% NaCl) diet. The expression of the BSC-1 and the renal outer medullary K+ channel (ROMK) were higher, whereas the expression of the cytochrome P4504A proteins responsible for the formation of 20-hydroxyeicosatetraenoic (20-HETE) was lower in the outer medulla of the kidney of DS than in BN or SS.BN13 rats fed either a low-salt or a high-salt diet. In addition, the renal formation and excretion of 20-HETE was lower in DS than in BN and SS.BN13 rats. These results suggest that overexpression of ROMK and BSC-1 in the thick ascending limb combined with a deficiency in renal formation of 20-HETE may predispose Dahl S rats fed a high-salt diet to Na+ retention and hypertension. C1 Med Coll Wisconsin, Dept Physiol, Milwaukee, WI 53226 USA. NHLBI, Kidney & Electrolyte Metab Lab, Bethesda, MD 20892 USA. RP Roman, RJ (reprint author), Med Coll Wisconsin, Dept Physiol, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM rroman@mcw.edu FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999]; NHLBI NIH HHS [Z01-HL-01282-KE, HL-36279, HL-29587, HL10364-03] NR 34 TC 39 Z9 39 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD APR PY 2004 VL 43 IS 4 BP 860 EP 865 DI 10.1161/01.HYP.0000120123.44945.47 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 806RF UT WOS:000220450300032 PM 14967839 ER PT J AU Chobanian, AV Roccella, EJ AF Chobanian, AV Roccella, EJ TI Mortality from stroke and ischemic heart disease increases exponentially with blood pressure - Response SO HYPERTENSION LA English DT Letter C1 Boston Univ, Sch Med, Boston, MA 02118 USA. NHLBI, Bethesda, MD 20892 USA. RP Chobanian, AV (reprint author), Boston Univ, Sch Med, Boston, MA 02118 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD APR PY 2004 VL 43 IS 4 BP E28 EP E28 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 806RF UT WOS:000220450300057 ER PT J AU Chobanian, AV Roccella, EJ AF Chobanian, AV Roccella, EJ TI Orthostatic hypotension in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: Which version is right? Response SO HYPERTENSION LA English DT Letter C1 Boston Univ, Sch Med, Boston, MA 02118 USA. NHLBI, Bethesda, MD 20892 USA. RP Chobanian, AV (reprint author), Boston Univ, Sch Med, Boston, MA 02118 USA. NR 3 TC 0 Z9 0 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD APR PY 2004 VL 43 IS 4 BP E27 EP E27 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 806RF UT WOS:000220450300055 ER PT J AU Yewdell, JW Princiotta, MF AF Yewdell, JW Princiotta, MF TI Proteasomes get by with lots of help from their friends SO IMMUNITY LA English DT Editorial Material ID MHC CLASS-I; ANTIGEN PRESENTATION; GENERATION; MOLECULES; PEPTIDES; DEGRADATION AB Proteasomes can't do it all. It was previously known that aminopeptidases frequently degrade proteasome-generated peptides. Now it appears that another protease, tripeptidyl peptidase 11 (TPP 11), plays a critical role in cleaving proteasomal produced peptides into shorter peptides that can then be degraded by aminopeptidases. C1 NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RI yewdell, jyewdell@nih.gov/A-1702-2012 NR 11 TC 9 Z9 9 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD APR PY 2004 VL 20 IS 4 BP 362 EP 363 DI 10.1016/S1074-7613(04)00086-X PG 2 WC Immunology SC Immunology GA 821EK UT WOS:000221442800002 PM 15084265 ER PT J AU Jarrett, CO Sebbane, F Adamovicz, JJ Andrews, GP Hinnebusch, BJ AF Jarrett, CO Sebbane, F Adamovicz, JJ Andrews, GP Hinnebusch, BJ TI Flea-borne transmission model to evaluate vaccine efficacy against naturally acquired bubonic plague SO INFECTION AND IMMUNITY LA English DT Article ID YERSINIA-PESTIS; TRANSFERABLE PLASMID; VECTOR; INFECTIVITY; RESISTANCE; MODULATION; DISEASES; SURVIVAL; PROTEIN; GENES AB A flea-to-mouse transmission model was developed for use in testing new candidate vaccines for the ability to protect against flea-borne plague. The model was used to evaluate a recombinant fusion protein vaccine consisting of the Yersinia pestis F1 and V antigens. After one to three challenges with Y pestis-infected fleas, 14 of 15 unvaccinated control mice developed plague, with an average septicemia level of 9.2 X 10(8) Y. pestis CFU/ml. None of 15 vaccinated mice developed the disease after similar challenges, and serological testing indicated that transmitted bacteria were eliminated by the immune system before extensive replication and systemic infection could occur. The transmission and development of disease in control mice correlated with the number of bites by blocked fleas hut not with the total number of fleabites. The model provides a means to directly assess the efficacy of new vaccines to prevent naturally acquired bubonic plague and to study events at the vector-host interface that lead to dissemination and disease. C1 NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. USA, Med Res Inst Infect Dis, Div Bacteriol, Ft Detrick, MD 21702 USA. RP Hinnebusch, BJ (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM jhinnebusch@niaid.nih.gov RI Sebbane, Florent/D-4213-2009 NR 33 TC 23 Z9 24 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD APR PY 2004 VL 72 IS 4 BP 2052 EP 2056 DI 10.1128/IAI.72.4.2052-2056.2004 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 807DG UT WOS:000220481600024 PM 15039326 ER PT J AU McCutchan, TF Grim, KC Li, J Weiss, W Rathore, D Sullivan, M Graczyk, TK Kumar, S Cranfield, MR AF McCutchan, TF Grim, KC Li, J Weiss, W Rathore, D Sullivan, M Graczyk, TK Kumar, S Cranfield, MR TI Measuring the effects of an ever-changing environment on malaria control SO INFECTION AND IMMUNITY LA English DT Article ID PENGUINS SPHENISCUS-DEMERSUS; COLONY-STIMULATING FACTOR; PLASMODIUM-FALCIPARUM; AVIAN MALARIA; CIRCUMSPOROZOITE PROTEIN; INTERFERON-GAMMA; DNA VACCINES; T-CELL; IMMUNIZATION; PROTECTION AB The effectiveness of malaria control measures depends not only on the potency of the control measures themselves but also upon the influence of variables associated with the environment. Environmental variables have the capacity either to enhance or to impair the desired outcome. An optimal outcome in the field, which is ultimately the real goal of vaccine research, will result from prior knowledge of both the potency of the control measures and the role of environmental variables. Here we describe both the potential effectiveness of control measures and the problems associated with testing in an area of endemicity. We placed canaries with different immunologic backgrounds (e.g., naive to malaria infection, vaccinated naive, and immune) directly into an area where avian malaria, Plasmodium relictum, is endemic. In our study setting, canaries that are naive to malaria infection routinely suffer approximately 50% mortality during their first period of exposure to the disease. In comparison, birds vaccinated and boosted with a DNA vaccine plasmid encoding the circumsporozoite protein of P. relictum exhibited a moderate degree of protection against natural infection (P < 0.01). In the second year we followed the fate of all surviving birds with no further manipulation. The vaccinated birds from the first year were no longer statistically distinguishable for protection against malaria from cages of naive birds. During this period, 36% of vaccinated birds died of malaria. We postulate that the vaccine-induced protective immune responses prevented the acquisition of natural immunity similar to that concurrently acquired by birds in a neighboring cage. These results indicate that dominant environmental parameters associated with malaria deaths can be addressed before their application to a less malleable human system. C1 NIAID, Parasit Dis Lab, Sect Growth & Dev, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Review & Res, Div Emerging Transfus Transmitted Dis, Bethesda, MD 20014 USA. USN, Med Res Ctr, Malaria Program, Silver Spring, MD 20903 USA. Johns Hopkins Univ, Johns Hopkins Sch Med, Baltimore, MD USA. Baltimore Zoo, Dept Med, Baltimore, MD USA. St Clares Hosp, Dept Pathol, Denville, NJ USA. RP McCutchan, TF (reprint author), NIAID, Parasit Dis Lab, Sect Growth & Dev, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM tmccutchan@niaid.nih.gov NR 31 TC 5 Z9 5 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD APR PY 2004 VL 72 IS 4 BP 2248 EP 2253 DI 10.1128/IAI.72.4.2248-2253.2004 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 807DG UT WOS:000220481600047 PM 15039349 ER PT J AU Scanga, CA Bafica, A Feng, CG Cheever, AW Hieny, S Sher, A AF Scanga, CA Bafica, A Feng, CG Cheever, AW Hieny, S Sher, A TI MyD88-deficient mice display a profound loss in resistance to Mycobacterium tuberculosis associated with partially impaired Th1 cytokine and nitric oxide synthase 2 expression SO INFECTION AND IMMUNITY LA English DT Article ID TOLL-LIKE RECEPTORS; INTERFERON-GAMMA; HOST-DEFENSE; CUTTING EDGE; MACROPHAGE RESPONSES; KNOCKOUT MICE; NO ROLE; INFECTION; MYD88; INTERLEUKIN-1 AB Mycobacterium tuberculosis possesses agonists for several Toll-like receptors (TLRs), yet mice with single TLR deletions are resistant to acute tuberculosis. MyD88(-/-) mice were used to examine whether TLRs play any role in protection against aerogenic M. tuberculosis H37Rv infection. MyD88(-/-) mice failed to control mycobacterial replication and rapidly succumbed. Moreover, expressions of interleukin 12, tumor necrosis factor alpha, gamma interferon, and nitric oxide synthase 2 were markedly decreased in the knockout animals. These results argue that resistance to M. tuberculosis must depend on MyD88-dependent signals mediated by an as-yet-undetermined TLR or a combination of TLRs. C1 NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Biomed Res Inst, Rockville, MD 20852 USA. RP Scanga, CA (reprint author), Bldg 50,Room 6148,50 S Dr, Bethesda, MD 20892 USA. EM cscanga@niaid.nih.gov NR 30 TC 127 Z9 129 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD APR PY 2004 VL 72 IS 4 BP 2400 EP 2404 DI 10.1128/IAI.72.4.2400-2404.2004 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 807DG UT WOS:000220481600066 PM 15039368 ER PT J AU Langley, J Brenner, R AF Langley, J Brenner, R TI What is an injury? SO INJURY PREVENTION LA English DT Editorial Material ID HOSPITAL DISCHARGE DATA C1 Univ Otago, Dunedin Sch Med, Dept Prevent & Social Med, Injury Prevent Res Unit, Dunedin, New Zealand. NICHHD, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Langley, J (reprint author), Univ Otago, Dunedin Sch Med, Dept Prevent & Social Med, Injury Prevent Res Unit, Dunedin, New Zealand. EM john.langley@ipru.otago.ac.nz NR 10 TC 25 Z9 26 U1 4 U2 14 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1353-8047 J9 INJURY PREV JI Inj. Prev. PD APR PY 2004 VL 10 IS 2 BP 69 EP 71 DI 10.1136/ip.2003.003715 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 820AX UT WOS:000221359900004 PM 15066967 ER PT J AU Dellinger, RP Carlet, JM Masur, H Gerlach, H Calandra, T Cohen, J Gea-Banacloche, J Keh, D Marshall, JC Parker, MM Ramsay, G Zimmerman, JL Vincent, JL Levy, MM AF Dellinger, RP Carlet, JM Masur, H Gerlach, H Calandra, T Cohen, J Gea-Banacloche, J Keh, D Marshall, JC Parker, MM Ramsay, G Zimmerman, JL Vincent, JL Levy, MM TI Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock SO INTENSIVE CARE MEDICINE LA English DT Editorial Material DE sepsis; severe sepsis; septic shock; sepsis syndrome; infection; guidelines; evidence-based medicine; Surviving Sepsis Campaign ID RESPIRATORY-DISTRESS-SYNDROME; CRITICALLY-ILL PATIENTS; INTENSIVE-CARE-UNIT; ACUTE LUNG INJURY; CONTROLLED CLINICAL-TRIAL; MEAN AIRWAY PRESSURE; PROLONGED NEUROMUSCULAR BLOCKADE; MECHANICALLY VENTILATED PATIENTS; RECOMBINANT-HUMAN-ERYTHROPOIETIN; RANDOMIZED CONTROLLED TRIAL AB Objective. To develop management guidelines for severe sepsis and septic shock that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and improve outcome in severe sepsis. Design. The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee. The modified Delphi methodology used for grading recommendations built upon a 2001 publication sponsored by the International Sepsis Forum. We undertook a systematic review of the literature graded along 5 levels to create recommendation grades from A-E, with A being the highest grade. Pediatric considerations were provided to contrast adult and pediatric management. Participants. Participants included 44 critical care and infectious disease experts representing 11 international organizations. Results. A total of 46 recommendations plus pediatric management considerations. Conclusions. Evidence-based recommendations can be made regarding many aspects of the acute management of sepsis and septic shock that will hopefully translate into improved outcomes for the critically ill patient. The impact of these guidelines will be formally tested and guidelines updated annually, and even more rapidly when some important new knowledge becomes available. C1 Cooper Univ Hosp, Sect Crit Care Med, Camden, NJ 08103 USA. Fdn Hop St Joseph, Serv Reanimat Polyvalente, Paris, France. NIH, Bethesda, MD 20892 USA. Vivantes Klinikum Neukoelln, Dept Anesthesiol & Crit Care Med, Berlin, Germany. CHU Vaudois, Dept Med Interne, Lab Malad Invect, CH-1011 Lausanne, Switzerland. Brighton & Sussex Med Sch, Falmer, England. Charite, Clin Anesthesiol & Surg Intens Care Med, Berlin, Germany. NCI, Infect Dis Sect, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. Toronto Gen Hosp, Toronto, ON, Canada. SUNY Stony Brook, Stony Brook, NY 11794 USA. Univ Hosp, Maastricht, Netherlands. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Erasme Univ Hosp, Dept Intens Care, B-1070 Brussels, Belgium. Brown Univ, Sch Med, Providence, RI 02912 USA. Cooper Hlth Syst, Camden, NJ 08103 USA. RP Dellinger, RP (reprint author), Cooper Univ Hosp, Sect Crit Care Med, 1 Cooper Plaza,393 Dorrance, Camden, NJ 08103 USA. RI Calandra, Thierry/D-9017-2015 OI Calandra, Thierry/0000-0003-3051-1285 NR 135 TC 447 Z9 520 U1 1 U2 12 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0342-4642 J9 INTENS CARE MED JI Intensive Care Med. PD APR PY 2004 VL 30 IS 4 BP 536 EP 555 DI 10.1007/s00134-004-2210-z PG 20 WC Critical Care Medicine SC General & Internal Medicine GA 808IM UT WOS:000220562800004 PM 14997291 ER PT J AU Flanders, KC AF Flanders, KC TI Smad3 as a mediator of the fibrotic response SO INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY LA English DT Review DE fibrosis; halofuginone; Smad3; Smad7; TGF-beta; wound healing ID GROWTH-FACTOR-BETA; COLLAGEN GENE-TRANSCRIPTION; HEPATIC STELLATE CELLS; MICE LACKING SMAD3; ACTIVATOR INHIBITOR-1 EXPRESSION; LENS EPITHELIAL-CELLS; HUMAN MESANGIAL CELLS; TGF-BETA; TRANSFORMING GROWTH-FACTOR-BETA-1; SIGNAL-TRANSDUCTION AB Transforming growth factor-beta (TGF-beta) plays a central role in fibrosis, contributing to the influx and activation of inflammatory cells, the epithelial to mesenchymal transdifferentiation (EMT) of cells and the influx of fibroblasts and their subsequent elaboration of extracellular matrix. TGF-beta signals through transmembrane receptor serine/threonine kinases to activate novel signalling intermediates called Smad proteins, which modulate the transcription of target genes. The use of mice with a targeted deletion of Smad3, one of the two homologous proteins which signals from TGF-beta/activin, shows that most of the pro-fibrotic activities of TGF-beta are mediated by Smad3. Smad3 null inflammatory cells and fibroblasts do not respond to the chemotactic effects of TGF-beta and do not autoinduce TGF-beta. The loss of Smad3 also interferes with TGF-beta-mediated induction of EMT and genes for collagens, plasminogen activator inhibitor-1 and the tissue inhibitor of metalloprotease-1. Smad3 null mice are resistant to radiation-induced cutaneous fibrosis, bleomycin-induced pulmonary fibrosis, carbon tetrachloride-induced hepatic fibrosis as well as glomerular fibrosis induced by induction of type 1 diabetes with streptozotocin. In fibrotic conditions that are induced by EMT, such as proliferative vitreoretinopathy, ocular capsule injury and glomerulosclerosis resulting from unilateral ureteral obstruction, Smad3 null mice also show an abrogated fibrotic response. Animal models of scleroderma, cystic fibrosis and cirrhosis implicate involvement of Smad3 in the observed fibrosis. Additionally, inhibition of Smad3 by overexpression of the inhibitory Smad7 protein or by treatment with the small molecule, halofuginone, dramatically reduces responses in animal models of kidney, lung, liver and radiation-induced fibrosis. Small moleucule inhibitors of Smad3 may have tremendous clinical potential in the treatment of pathological fibrotic diseases. C1 NCI, LCRC, NIH, Bethesda, MD 20892 USA. RP Flanders, KC (reprint author), NCI, LCRC, NIH, Bldg 41,Rm C-629,41 Lib Dr MSC 5055, Bethesda, MD 20892 USA. EM flanderk@dce41.nci.nih.gov NR 105 TC 352 Z9 397 U1 6 U2 35 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0959-9673 J9 INT J EXP PATHOL JI Int. J. Exp. Pathol. PD APR PY 2004 VL 85 IS 2 BP 47 EP 64 DI 10.1111/j.0959-9673.2004.00377.x PG 18 WC Pathology SC Pathology GA 822IX UT WOS:000221533800001 PM 15154911 ER PT J AU FitzGerald, DJ Kreitman, R Wilson, W Squires, D Pastan, I AF FitzGerald, DJ Kreitman, R Wilson, W Squires, D Pastan, I TI Recombinant immunotoxins for treating cancer SO INTERNATIONAL JOURNAL OF MEDICAL MICROBIOLOGY LA English DT Article; Proceedings Paper CT 11th European Workshop Conference on Bacterial Protein Toxins CY JUN 28-JUL 02, 2003 CL Celakovice, CZECH REPUBLIC SP Federat European Microbiol Soc, Acad Sci Czech Republic, Inst Microbiol, Chiron S r l DE immunotoxin; recombinant; cancer; Pseudomonas exotoxin ID SINGLE-CHAIN IMMUNOTOXINS; COLONY-STIMULATING FACTOR; DISULFIDE-STABILIZED FV; ACUTE MYELOID-LEUKEMIA; PHASE-I TRIAL; PSEUDOMONAS EXOTOXIN; CYTOTOXIC ACTIVITY; MALIGNANT-CELLS; FUSION PROTEINS; CARCINOMA-CELLS AB Recombinant immunotoxins are antibody-toxin chimeric molecules that kill cancer cells via binding to a surface antigen, internalization and delivery of the toxin moiety to the cell cytosol. In the cytosol, toxins catalytically inhibit a critical cell function and cause cell death. The antibody portion of the chimera targets antigens that are expressed preferentially on the surface of cancer cells. Truncated versions of either diphtheria toxin (DT) or Pseudomonas exotoxin (PE) can be used to construct fusions with cDNAs encoding antibody fragments or cell-binding ligands. Recombinant immunotoxins are routinely produced in E. coli and purified using standard chromatographic: methods. Before they can be evaluated for anticancer activity in humans, recombinant immunotoxins undergo extensive preclinical testing. Immunotoxins must demonstrate cell-killing activity in tissue culture, antitumor activity in an animal model and have favorable pharmacokinetic and toxicity profiles. Candidate molecules with favorable characteristics are then evaluated in clinical trials. Here we report on the initial evaluation of BL22, a recombinant immunotoxin targeted to CD22 expressed on the surface of B-cell malignancies. C1 NCI, Mol Biol Lab, CCR, Bethesda, MD 20892 USA. NCI, Med Branch, CCR, Bethesda, MD 20892 USA. RP FitzGerald, DJ (reprint author), NCI, Mol Biol Lab, CCR, 37 Covent Dr,Bldg 375124, Bethesda, MD 20892 USA. EM djpf@helix.nih.gov NR 28 TC 52 Z9 58 U1 0 U2 2 PU URBAN & FISCHER VERLAG PI JENA PA BRANCH OFFICE JENA, P O BOX 100537, D-07705 JENA, GERMANY SN 1438-4221 J9 INT J MED MICROBIOL JI Int. J. Med. Microbiol. PD APR PY 2004 VL 293 IS 7-8 BP 577 EP 582 DI 10.1078/1438-4221-00302 PG 6 WC Microbiology; Virology SC Microbiology; Virology GA 821PV UT WOS:000221475300018 PM 15149034 ER PT J AU Pasha, MK Selvakumar, P Ashakumary, L Qureshi, M Guziec, FS Dimmock, JR Felsted, RL Glover, CJ Sharma, RK AF Pasha, MK Selvakumar, P Ashakumary, L Qureshi, M Guziec, FS Dimmock, JR Felsted, RL Glover, CJ Sharma, RK TI Lipidic inhibitors of human N-myristoyltransferase SO INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE LA English DT Article DE human N-myristoyltransferase; inhibitors; myristic acid analogs; myristoyl-CoA analogs ID MYRISTOYL-COA; BOVINE BRAIN; BIOCHEMICAL-CHARACTERIZATION; SACCHAROMYCES-CEREVISIAE; MOLECULAR-CLONING; MULTIPLE FORMS; CANCER-CELLS; PROTEIN; TRANSFERASE; PURIFICATION AB This study was undertaken in order to identify compounds which inhibit the activity of human myristoyl-CoA:protein N-myristoyltransferase (hNMT). In particular, the structural features of such molecules which contribute to enzyme inhibition were investigated. Two groups of compounds, namely myristic acid and analogs 1-13 and derivatives of myristoyl-CoA 14-19 were evaluated. All compounds were examined using cAMP-dependent protein kinase derived peptide substrate. The IC50 values were <1 muM, between 1 and 100 muM or >100 muM in eight, four and seven compounds, respectively. Of the six myristoyl-CoA analogs, five had IC50 values in the 0.06-0.59 muM range. These molecules were examined using three additional substrates viz pp60(src), MARCKS and M2 gene segment of reovirus type 3 which led to results similar to those obtained with the cAMP-dependent protein kinase substrate. On the other hand, evaluation of myristic acid and four related compounds revealed some differences in hNMT-inhibiting properties among the substrates. From the results obtained, the possible manner whereby potent inhibitors interact with the enzyme was formulated thus enabling the design of further analogs as candidate inhibitors of hNMT. C1 Univ Saskatchewan, Hlth Res Div, Dept Pathol, Coll Med, Saskatoon, SK S7N 4H4, Canada. Univ Saskatchewan, Canc Res Unit, Hlth Res Div, Saskatoon, SK S7N 4H4, Canada. Univ Saskatchewan, Coll Pharm & Nutr, Saskatoon, SK S7N 4H4, Canada. SW Univ, Dept Chem, Georgetown, TX USA. NCI, Frederick Canc Res & Dev Ctr, Screening Technol Branch,Dev Therapeut Program, Div Canc Treatment & Diagnosis, Frederick, MD 21701 USA. RP Sharma, RK (reprint author), Univ Saskatchewan, Hlth Res Div, Dept Pathol, Coll Med, 20 Campus Dr, Saskatoon, SK S7N 4H4, Canada. EM rsharma@scf.sk.ca NR 40 TC 8 Z9 8 U1 1 U2 1 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1107-3756 J9 INT J MOL MED JI Int. J. Mol. Med. PD APR PY 2004 VL 13 IS 4 BP 557 EP 563 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 802PY UT WOS:000220176600010 PM 15010856 ER PT J AU Rosenthal, AD Jin, F Shu, XO Yang, G Elasy, TA Chow, WH Ji, BT Xu, HX Li, Q Gao, YT Zheng, W AF Rosenthal, AD Jin, F Shu, XO Yang, G Elasy, TA Chow, WH Ji, BT Xu, HX Li, Q Gao, YT Zheng, W TI Body fat distribution and risk of diabetes among Chinese women SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE diabetes; BMI ID IMPAIRED GLUCOSE-TOLERANCE; ISLAND POPULATIONS; ADIPOSE-TISSUE; WEIGHT-GAIN; MELLITUS; PREVALENCE; OBESITY; INSULIN; ADULTS; NIDDM AB OBJECTIVE: To assess the relationship between measures of central and overall obesity and risk of diabetes. DESIGN: Nested case - control study. SETTING: Shanghai, China. PARTICIPANTS: A total of 57 130 women were screened for diabetes at enrollment for the Shanghai Women's Health Study ( SWHS), a population- based cohort study of Chinese women aged 40 - 70 y. In this study, 345 women diagnosed with diabetes and 2760 age- matched controls ( eight controls per case), randomly selected from women who tested negative for urine glucose, were included. RESULTS: Risk of diabetes increased significantly with increasing levels of obesity, particularly with measures of central obesity. Compared to those in the lowest quartile, women in the highest quartile of body mass index ( BMI) ( greater than or equal to 26.57) and waist to hip ratio ( WHR) ( greater than or equal to 0.855) had a 2.57- fold ( 95% CI 1.75 - 3.77) and a 6.05- fold ( 95% CI 4.05 - 9.04) increased risk of diabetes, respectively. The risk of diabetes was elevated with increasing WHR at all levels of BMI, while the positive association between BMI and diabetes was observed primarily among women with a low WHR. However, test for multiplicative interaction was not statistically significant. CONCLUSIONS: Our data indicated that central obesity is a stronger risk factor for diabetes than overall obesity, suggesting that WHR may be a better indicator of risk of diabetes than BMI among Chinese women. C1 Vanderbilt Univ, Ctr Hlth Serv Res, Dept Med, Nashville, TN 37232 USA. Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. Vanderbilt Univ, Diabet Res & Treatment Ctr, Nashville, TN USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Shu, XO (reprint author), Vanderbilt Univ, Ctr Hlth Serv Res, Dept Med, 6009 Med Ctr E,1215 21st Ave S, Nashville, TN 37232 USA. EM Xiao-ou.Shu@Vanderbilt.edu FU NCI NIH HHS [R01CA70867, N02-CP-81040-50, N02-CP11010-66] NR 35 TC 37 Z9 38 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD APR PY 2004 VL 28 IS 4 BP 594 EP 599 DI 10.1038/sj.ijo.0802597 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 804ME UT WOS:000220302000019 PM 14770196 ER PT J AU Fellowes, VS Husebekk, A Gress, RE Vance, BA AF Fellowes, VS Husebekk, A Gress, RE Vance, BA TI Minimal residual disease detection in breast cancer: Improved sensitivity using cytokeratin 19 and epidermal growth factor receptor RT-PCR SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE breast cancer; RT-PCR; CK19; EGF-R; beta 2M; Ber-EP4; minimal disease ID POLYMERASE-CHAIN-REACTION; PERIPHERAL-BLOOD; ILLEGITIMATE TRANSCRIPTION; PROGNOSTIC-SIGNIFICANCE; TUMOR-CELLS; CARCINOMA; PRODUCTS; MARKER; ASSAY; GENE AB Breast cancer cells pose a difficult target for detection due to their lack of tumor specific markers. Small numbers of metastatic cells circulate through the blood and reach target organs, but current methods are presently not sensitive enough to allow for early detection. Our goal is to develop a method for specific and sensitive detection for breast cancer tumor cells by using cell enrichment coupled to RT-PCR with selective primer pairs. Fifty million normal donor mononuclear cells (NDMNC) were spiked with serial dilutions of a breast cancer cell line, positively selected for surface expression of the epithelial cell adhesion molecule (EPCAM) with anti-Ber-EP4 mAb. Total RNA was isolated and the cDNA was transcribed and measured by quantitative PCR for cytokeratin 19 (CK19), epidermal growth factor receptor (EGF-R), and B-2-microglobulin (beta2M) transcripts using specific hybridization probes with the LightCycler System. A sensitivity of 1 tumor cell in 5 million NDMNC was consistently achieved with a metastatic breast cancer cell line with target primer sets for CK19 and EGF-R. Less, but appreciable sensitivity was achieved by spiking NDMNC with other breast cancer cells. Detection of both gene targets ranged between 1 in 5,000 to 5 million cells. The method described, a cell enrichment procedure and RT-PCR using specific hybridization probes (spanning introns and hybridizing to areas that discriminate transcribed pseudogenes), results in increased sensitivity while decreasing false positives above those methods previously reported. This general approach may have wide applicability to increasing sensitivity of minimal residual disease detection in other cancers. C1 Univ Penn, Abramson Family Res Inst, Philadelphia, PA 19104 USA. Univ Penn, Ctr Canc, Philadelphia, PA 19104 USA. NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. Univ Hosp No Norway, Dept Immunol & Transfus Med, Tromso, Norway. RP Vance, BA (reprint author), Univ Penn, Abramson Family Res Inst, 546 BRB 2-3,421 Curie Blvd, Philadelphia, PA 19104 USA. EM vanceb@mail.med.upenn.edu NR 18 TC 4 Z9 4 U1 0 U2 0 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD APR PY 2004 VL 24 IS 4 BP 861 EP 867 PG 7 WC Oncology SC Oncology GA 806CS UT WOS:000220412600013 PM 15010823 ER PT J AU Camphausen, K Menard, C Sproull, M Goley, E Basu, S Coleman, CN AF Camphausen, K Menard, C Sproull, M Goley, E Basu, S Coleman, CN TI Isoprostane levels in the urine of patients with prostate cancer receiving radiotherapy are not elevated SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article; Proceedings Paper CT ICTR 2003 Meeting CY 2003 CL Lugano, SWITZERLAND SP ICTR DE free radicals; radiotherapy; prostate cancer; prostaglandin isoprostanes; urine ID CATALYZED LIPID-PEROXIDATION; OXIDATIVE INJURY; EXCRETION RATE; IN-VIVO; F-2-ISOPROSTANES; RADIOIMMUNOASSAY; F2-ALPHA; INDEX AB Purpose: Previous studies have demonstrated that urinary 8-iso-prostaglandin F (PGF)(2alpha) serves as a powerful biomarker of lipid peroxidation in diseases in which oxidative stress plays an important role in its pathophysiology. The goal of this study was to measure the urinary isoprostane levels in patients with prostate cancer treated with radiotherapy (RT) in an effort to determine whether isoprostane levels are elevated compared with in historical controls, whether the levels increase after RT, and whether such an increase would correlate positively with the degree of GU symptoms during treatment. Methods and Materials: Urine samples were obtained before and during RT from patients enrolled on a recently reported Phase III trial examining the therapeutic efficacy of ibuprofen in decreasing the acute urinary symptoms of RT. Radioimmunoassays were performed on urine samples for 8-iso-PGF(2alpha) or 15-keto-dihydro-PGF(2alpha). Results: Fifteen patients provided samples both before and during RT. The levels of 8-iso-PGF(2alpha) and 15-keto-dihydro-PGF(2alpha) in the urine samples obtained before prostate RT (0.27 and 0.41 nmol/mmol creatinine) did not differ appreciably from the values observed in a normal cohort (0.27 and 0.46 nmol/mmol creatinine) and did not change after RT (0.23 and 0.37 nmol/mmol creatinine). Conclusion: We were unable to detect an increase in either 8-iso-PGF(2alpha) or 15-keto-dihydro-PGF(2alpha) in the urine of patients with prostate cancer compared with in historical normal controls. We were also unable to measure an increase in either of the eicosanoids during RT to the prostate gland. (C) 2004 Elsevier Inc. C1 NCI, Radiat Oncol Branch, Radiat Oncol Sci Program, Ctr Canc Res, Bethesda, MD 20892 USA. Uppsala Univ, Fac Med, Unit Geriatr & Clin Nutr Res, Uppsala, Sweden. RP Camphausen, K (reprint author), NCI, Radiat Oncol Branch, Radiat Oncol Sci Program, Ctr Canc Res, 10 Ctr Dr,Bldg 10,Rm B3B69, Bethesda, MD 20892 USA. EM camphauk@mail.nih.gov NR 13 TC 10 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD APR 1 PY 2004 VL 58 IS 5 BP 1536 EP 1539 DI 10.1016/j.ijrobp.2003.09.011 PG 4 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 807XA UT WOS:000220533000029 PM 15050334 ER PT J AU Torres-Cabala, C Panizo-Santos, A Krutzsch, HC Barazi, H Namba, M Sakaguchi, M Roberts, DD Merino, MJ AF Torres-Cabala, C Panizo-Santos, A Krutzsch, HC Barazi, H Namba, M Sakaguchi, M Roberts, DD Merino, MJ TI Differential expression of S100C in thyroid lesions SO INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE S100C; calgizzarin; galectin-3; thyroid; immunohistochemistry; proteomics ID CALCIUM-BINDING PROTEINS; NORMAL HUMAN FIBROBLASTS; SMOOTH-MUSCLE; GALECTIN-3; CARCINOMA; MARKER; LOCALIZATION; TISSUES; BENIGN; PROTEOMICS AB Identification of new potential markers that may help in the diagnosis of benign and malignant thyroid lesions is needed. By comparative 2-dimensional gel electrophoresis of microdissected cells from tumors and normal thyroid tissue, we identified a new protein, S100C, which is highly expressed in papillary carcinomas. In order to validate this finding, we investigated the immunohistochemical expression and the potential role in diagnosis of these markets in 94 specimens representing the spectrum of malignant and benign thyroid lesions. Normal thyroid tissue was evaluated in 57 specimens. Galectin-3, a marker reported as specific for malignant lesions, was also evaluated in the same lesions. S100C protein was expressed in the nuclei of normal tissue, hyperplastic nodules, and follicular adenomas and carcinomas. Papillary carcinomas showed a strong, but cytoplasmic, pattern of staining. Galectin-3 immunostaining was strongly positive in papillary carcinomas, and negative in benign lesions, confirming its value in differential diagnosis. These findings Suggest that immunohistochemical Staining of S100C could be helpful in the pathological study of thyroid lesions, especially in cases in which follicular variants of papillary carcinoma and follicular carcinoma are considered in the differential diagnosis. C1 NCI, Surg Pathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Biochem Pathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. Okayama Univ, Sch Med, Dept Cell Biol, Okayama, Japan. RP Merino, MJ (reprint author), NCI, Surg Pathol Sect, Pathol Lab, NIH, Bldg 10,Room 2N212,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Roberts, David/A-9699-2008; SAKAGUCHI, Masakiyo/B-2280-2011 OI Roberts, David/0000-0002-2481-2981; NR 39 TC 16 Z9 16 U1 0 U2 0 PU WESTMINSTER PUBL INC PI GLEN HEAD PA 708 GLEN COVE AVE, GLEN HEAD, NY 11545 USA SN 1066-8969 J9 INT J SURG PATHOL JI Int. J. Surg. Pathol. PD APR PY 2004 VL 12 IS 2 BP 107 EP 115 DI 10.1177/106689690401200203 PG 9 WC Pathology; Surgery SC Pathology; Surgery GA 816EK UT WOS:000221093000004 PM 15173915 ER PT J AU Gradstein, L Goldstein, HP Wizov, SS Reinecke, RD AF Gradstein, L Goldstein, HP Wizov, SS Reinecke, RD TI Extended slow phase in latent/manifest latent nystagmus SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID WAVE-FORM CHARACTERISTICS; CONGENITAL NYSTAGMUS; MANIFEST LATENT; FOVEATION STRATEGY; STRABISMUS; FIXATION AB PURPOSE. To investigate the slow phase in latent/manifest latent nystagmus (LMLN) by producing long eye-drift intervals devoid of fast phases (extended slow phases [ESPs]) and to relate ESP metrics to clinical findings. METHODS. Ten patients with LMLN had eye movements recorded while attending to paired visual and auditory cues presented to their left or right. Patients compared location of the visual target with that of the subsequently heard tone. The auditory cue and the comparison task directed attention away from vision and delayed the fast-phase onset to obtain ESPs. ESP metrics were analyzed with regard to patients' clinical characteristics. Five patients' data were further explored by isolating slow-phase components. RESULTS. All patients exhibited ESPs that resembled the usual slow phase but lasted two to three times longer. Five patients maintained alignment, whereas the other five made vergence movements. Greater eye velocity, excursion, and convergence during an ESP were associated with poor vision and large uncorrected esotropia. These metrics decreased when the viewing eye was in adduction, compared with primary position or abduction. Slow-phase components found in five patients consisted of a dominant decreasing-velocity or linear drift and a low-amplitude periodic oscillation. CONCLUSIONS. Shifting attention away from vision reliably delays the fast phase, revealing long intervals of slow phase, which can facilitate nystagmus investigation. ESP analysis in five patients with LMLN demonstrated two slow-phase components. ESP characteristics suggest that better ocular alignment is associated with improved stability in LMLN and provide metrics of eye drift that correlate with vision. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. Ben Gurion Univ Negev, Soroka Med Ctr, Dept Ophthalmol, IL-84105 Beer Sheva, Israel. Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA. Wills Eye Hosp & Res Inst, Foerderer Eye Movement Ctr Children, Philadelphia, PA USA. RP Gradstein, L (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 10,Room 10S229, Bethesda, MD 20892 USA. EM libe@nei.nih.gov NR 23 TC 2 Z9 2 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 IS 4 BP 1139 EP 1148 DI 10.1167/iovs.03-0324 PG 10 WC Ophthalmology SC Ophthalmology GA 806GK UT WOS:000220422200015 PM 15037580 ER PT J AU Ahmed, F Brown, KM Stephan, DA Morrison, JC Johnson, EC Tomarev, SI AF Ahmed, F Brown, KM Stephan, DA Morrison, JC Johnson, EC Tomarev, SI TI Microarray analysis of changes in mRNA levels in the rat retina after experimental elevation of intraocular pressure SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID OPTIC-NERVE HEAD; OPEN-ANGLE GLAUCOMA; DIFFERENTIAL GENE-EXPRESSION; NECROSIS-FACTOR-ALPHA; CLASS-I MHC; GANGLION-CELLS; TRABECULAR MESHWORK; COMPLEMENT ACTIVATION; TRANSCRIPTION FACTORS; EXTRACELLULAR-MATRIX AB PURPOSE. The goal of this study was to identify altered patterns of retinal mRNA expression after experimental elevation of intraocular pressure (IOP) in a rat glaucoma model. METHODS. Brown Norway rats (N = 16) received unilateral episcleral vein injection of hypertonic saline to elevate IOP. IOP was monitored daily by handheld tonometer, and retinas were collected 8 days and 5 weeks after surgery. Comparison of mRNA levels between experimental and fellow retinas was made using gene microarrays ( rat U34A rat arrays; Affymetrix, Santa Clara, CA). Semiquantitative RT-PCR was used to confirm selected results from array analysis and to compare with alterations after optic nerve transection. RESULTS. IOP elevation for 5 weeks resulted in reproducible changes in levels of 81 mRNAs. Of these, 74 increased, whereas only 7 decreased. The expression levels of 27 of these same messages were changed after 8 days of IOP elevation. In addition, four other genes demonstrated altered expression after the shorter period of elevated IOP exposure. Approximately half of the mRNAs with altered expression were associated with either neuroinflammatory responses or apoptosis. For 25 of the selected functionally relevant messages altered by array analysis, the alterations were confirmed by semiquantitative RT-PCR. The levels of 24 of 25 selected messages were also changed after optic nerve transection. CONCLUSIONS. The activation of glia and the complement system after IOP elevation, which is similar to that described in several neurodegenerative diseases and after optic nerve transection, suggests that this rat glaucoma model could be used to evaluate the neuroprotective potential of therapeutic agents that target these processes. C1 NEI, Sect mol Mech Glaucoma, Mol & Dev Biol Lab, NIH,DHHS, Bethesda, MD 20814 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. Translat Genom Res Inst, Neurogenom Div, Phoenix, AZ USA. Oregon Hlth Sci Univ, Casey Eye Inst, Kenneth C Swan Ocular Neurobiol Lab, Portland, OR 97201 USA. RP Tomarev, SI (reprint author), NEI, Sect mol Mech Glaucoma, Mol & Dev Biol Lab, NIH,DHHS, Bldg 7,Room 103, Bethesda, MD 20814 USA. EM tomarevs@nei.nih.gov NR 82 TC 134 Z9 139 U1 0 U2 4 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 IS 4 BP 1247 EP 1258 DI 10.1167/iovs.03-1123 PG 12 WC Ophthalmology SC Ophthalmology GA 806GK UT WOS:000220422200029 PM 15037594 ER PT J AU Aleman, TS Jacobson, SG Chico, JD Scott, ML Cheung, AY Windsor, EAM Furushima, M Redmond, TM Bennett, J Palczewski, K Cideciyan, AV AF Aleman, TS Jacobson, SG Chico, JD Scott, ML Cheung, AY Windsor, EAM Furushima, M Redmond, TM Bennett, J Palczewski, K Cideciyan, AV TI Impairment of the transient pupillary light reflex in Rpe65(-)/(-) mice and humans with Leber congenital amaurosis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID RETINAL GANGLION-CELLS; RETINITIS-PIGMENTOSA; MOUSE MODEL; CHILDHOOD BLINDNESS; SENSITIVITY; VISION; EYE; PHOTOTRANSDUCTION; THRESHOLD; RPE65 AB PURPOSE. To determine the impairment of the transient pupillary light reflex (TPLR) due to severe retinal dysfunction and degeneration in a murine model of Leber congenital amaurosis (LCA) and in patients with the disease. METHODS. Direct TPLR was elicited in anesthetized, dark-adapted Rpe65(-/-) and control mice with full-field light stimuli (0.1 second duration) of increasing intensities ( - 6.6 to + 2.3 log scot-cd . m(-2)). 9-cis-Retinal was administered orally to a subset of Rpe65(-/-) mice, and TPLR was recorded 48 hours after the treatment. TPLR was also measured in a group of patients with LCA. RESULTS. Baseline pupillary diameters in Rpe65(-/-) and control mice were similar. TPLR thresholds of Rpe65(-/-) mice were elevated by 5 log units compared with those of control animals. The waveform of the TPLR in Rpe65(-/-) mice was similar to that evoked by 4.8-log-unit dimmer stimuli in control mice. Treatment of Rpe65(-/-) mice with 9-cis-retinal lowered the TPLR threshold by 2.1 log units. Patients with LCA had baseline pupillary diameters similar to normal, but the TPLR was abnormal, with thresholds elevated by 3 to more than 6 log units. When adjusted to the elevation of TPLR threshold, pupillary constriction kinetics in most patients were similar to those in normal subjects. CONCLUSIONS. Pupillometry was used to quantify visual impairment and to probe transmission of retinal signals to higher nervous centers in a murine model of LCA and in patients with LCA. Mouse results were consistent with a dominant role of image-forming photoreceptors driving the early phase of the TPLR when elicited by short-duration stimuli. The objective and noninvasive nature of the TPLR measurement, and the observed post-treatment change toward normal in the animal model supports the notion that this may be a useful outcome measure in future therapeutic trials of LCA. C1 Univ Penn, Scheie Eye Inst, Dept Ophthalmol, Philadelphia, PA 19104 USA. NEI, Retinal Cell & Mol Biol Lab, Bethesda, MD 20892 USA. Univ Washington, Dept Ophthalmol, Seattle, WA 98195 USA. Univ Washington, Dept Chem, Seattle, WA 98195 USA. Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA. RP Cideciyan, AV (reprint author), Univ Penn, Scheie Eye Inst, Dept Ophthalmol, 51 N 39th St, Philadelphia, PA 19104 USA. EM cideciya@mail.med.upenn.edu RI Cideciyan, Artur/A-1075-2007; OI Cideciyan, Artur/0000-0002-2018-0905; Redmond, T. Michael/0000-0002-1813-5291 FU NEI NIH HHS [EY13203, EY13385, EY13729] NR 65 TC 65 Z9 68 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 IS 4 BP 1259 EP 1271 DI 10.1167/iovs.03-1230 PG 13 WC Ophthalmology SC Ophthalmology GA 806GK UT WOS:000220422200030 PM 15037595 ER PT J AU Acar, N Driessen, CA Cernuda, R Hudl, K Janssen, JJ Redmond, MT Seeliger, MW AF Acar, N Driessen, CA Cernuda, R Hudl, K Janssen, JJ Redmond, MT Seeliger, MW TI Phenotypic differences between two mouse models carrying defects in the retinoid cycle genes Rdh5 and Rpe65 SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 INRA, Lipid Nutr Unit, Dijon, 20892, France. Univ Eye Hosp, Retinal Electrodiagnost Res Grp, Tubingen, Germany. Univ Nijmegen, Dept Biochem, Nijmegen, Netherlands. Univ Nijmegen, Dept Ophthalmol, Nijmegen, Netherlands. Fac Med, Dept Morfol & Biol Celular, Oviedo, Spain. NEI, Retinal Cell & Mol Biol Lab, Bethesda, MD USA. RI Cernuda-Cernuda, Rafael/L-2011-2014 OI Cernuda-Cernuda, Rafael/0000-0002-0708-6500 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 1259 BP U525 EP U525 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338001222 ER PT J AU Agarwal, RK Silver, PB Su, SB Chan, CC Caspi, RR AF Agarwal, RK Silver, PB Su, SB Chan, CC Caspi, RR TI The benefits and pitfalls of protective DNA vaccination against experimental autoimmune uveitis (EAU) SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3443 BP U138 EP U138 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338200639 ER PT J AU Amaral, J Fariss, RN Campos, M Robison, WG Kim, H Lutz, R Becerra, SP AF Amaral, J Fariss, RN Campos, M Robison, WG Kim, H Lutz, R Becerra, SP TI Subconjuntival delivery of pigment epithelium-derived factor (PEDF) protein to the choroid and retina: Clinical implications SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, LRCMB, Bethesda, MD 20892 USA. NEI, Biol Imaging Core, Bethesda, MD 20892 USA. NIH, ORS, OD, DBEPS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 5056 BP U569 EP U569 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338202231 ER PT J AU Ansari, RR Datiles, MB Suh, KI Reed, GF AF Ansari, RR Datiles, MB Suh, KI Reed, GF TI Dynamic Light Scattering detects molecular lens changes associated with aging as well as with cataract formation in vivo SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NASA, Glenn Res Ctr, Cleveland, OH 44135 USA. NEI, NIH, Bethesda, MD 20892 USA. OAI, Cleveland, OH USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 349 BP U170 EP U170 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000324 ER PT J AU Armstrong, J Davis, MD Gangnon, RE Lee, LY Klein, R Klein, BE Milton, RC Ferris, FI Hubbard, LD AF Armstrong, J Davis, MD Gangnon, RE Lee, LY Klein, R Klein, BE Milton, RC Ferris, FI Hubbard, LD CA AREDS Study GRP TI Illustration ofthe AMD severity scale from the age-related eye diseases study SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Univ Wisconsin, Madison, WI USA. NEI, Bethesda, MD 20892 USA. EMMES Corp, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3052 BP U58 EP U58 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338200255 ER PT J AU Ayres, LM Lopez, P Caruso, RC AF Ayres, LM Lopez, P Caruso, RC TI Estimation of the scotopic electroretinographic intensity-response function using an abbreviated protocol SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 5144 BP U585 EP U585 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338202319 ER PT J AU Ayyagari, R Mandal, MNA Chen, L Burch, T Heckenlively, JR Sieving, PA AF Ayyagari, R Mandal, MNA Chen, L Burch, T Heckenlively, JR Sieving, PA TI Custom designed sequencing arrays to genotype patients with autosomal recessive retinitis pigmentosa (ARRP) SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Univ Michigan, Ann Arbor, MI 48109 USA. NEI, NIDCD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 2442 BP U940 EP U940 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338002377 ER PT J AU Bansal, A Csaky, KG Ponce, ML AF Bansal, A Csaky, KG Ponce, ML TI The origin of xenotransplanted putative endothelial progenitor cells in a modified chick chorioallantoic membrane (CAM) angiogenesis assay. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 1872 BP U734 EP U734 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338001832 ER PT J AU Belfort, R Belfort, RN Muccioli, C Silveira, C Rizzo, L Nussenblatt, V Nussenblatt, R AF Belfort, R Belfort, RN Muccioli, C Silveira, C Rizzo, L Nussenblatt, V Nussenblatt, R TI Toxoplasma gondii infection in pork meat samples from Erexim. Phase I: Characterization of the rate of contamination and identification of the organisms from tongue and diaphragm. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Univ Fed Sao Paulo, EPM, Sao Paulo, Brazil. Clin Silveira, Erechim, Brazil. Univ Sao Paulo, Dept Imunol, BR-05508 Sao Paulo, Brazil. NIH, Bethesda, MD 20892 USA. RI Rizzo, Luiz Vicente/B-4458-2009; Belfort Jr, Rubens/E-2252-2012; Muccioli, Cristina/C-3419-2013 OI Belfort Jr, Rubens/0000-0002-8422-3898; NR 0 TC 0 Z9 0 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 1674 BP U601 EP U601 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338001635 ER PT J AU Boesze-Battaglia, K Rachel, RA Copeland, NG Damek-Poprawa, M Jenkins, N AF Boesze-Battaglia, K Rachel, RA Copeland, NG Damek-Poprawa, M Jenkins, N TI Alterations in dsu expression results in abnormal photoreceptor morphology, implications for membrane fusion SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Univ Penn, Philadelphia, PA 19104 USA. NCI, SAIC, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3625 BP U181 EP U181 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338200818 ER PT J AU Bojanowski, CM Tuo, J Chew, EY Csaky, KG Chan, CC AF Bojanowski, CM Tuo, J Chew, EY Csaky, KG Chan, CC TI Analysis of the Hogg1 S326C, CSB-653OC/G, and E-selectin S149R single nucleotide polymorphisms in age-related macular degeneration SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3106 BP U67 EP U67 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338200311 ER PT J AU Bressler, S Bressler, NM Clemons, T Ferris, FL Milton, RC Klien, R Klien, B AF Bressler, S Bressler, NM Clemons, T Ferris, FL Milton, RC Klien, R Klien, B CA Age-Related Eye Dis Study Grp TI Ocular risk factors for developing neovascular AMD in the fellow eyes of patients with unilateral neovascular AMD SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Wilmer Eye Inst, Baltimore, MD USA. EMMES Corp, Rockville, MD USA. NEI, Bethesda, MD 20892 USA. Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI 53706 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 2360 BP U924 EP U924 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338002295 ER PT J AU Brooks, BP Kleta, R Caruso, R Stuart, C Stratakis, C AF Brooks, BP Kleta, R Caruso, R Stuart, C Stratakis, C TI Triple a Syndrome: Ophthalmic features and a novel mutation in the AAAS gene SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Bethesda, MD 20892 USA. NHGRI, NIH, Bethesda, MD 20892 USA. NICHHD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 2472 BP U945 EP U945 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338002406 ER PT J AU Bush, RA Lei, B Tao, W Raz, D Chan, CC Cox, TA Santos-Muffley, M Sieving, PA AF Bush, RA Lei, B Tao, W Raz, D Chan, CC Cox, TA Santos-Muffley, M Sieving, PA TI Encapsulated cell-based intraocular delivery of ciliary neurotrophic factor (CNTF) in normal rabbit: Dose dependent effects on ERG and retinal histology SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NIH, Bethesda, MD 20892 USA. Univ Michigan, Kellogg Eye Ctr, Ann Arbor, MI 48109 USA. Univ Missouri, Columbia, MO 65211 USA. Neurotech USA, Lincoln, RI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 856 BP U350 EP U350 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000830 ER PT J AU Campos, MM Fariss, RN Robison, WG AF Campos, MM Fariss, RN Robison, WG TI Novel techniques for imaging retinal vessels using whole retinas after long term fixation SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Biol Imaging Core, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 2416 BP U935 EP U935 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338002349 ER PT J AU Caruso, RC Quezado, Z Levin, SW Fischbeck, KH Gropman, AL Hofmann, S Patronas, N Wisniewski, K Zhang, Z Mukherjee, AB AF Caruso, RC Quezado, Z Levin, SW Fischbeck, KH Gropman, AL Hofmann, S Patronas, N Wisniewski, K Zhang, Z Mukherjee, AB TI Serial electrophysiological measurements of of visual function in infantile neuronal lipofuscinosis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. NIH, CC, Bethesda, MD USA. WRAMC, Washington, DC USA. NINDS, NIH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dallas, TX 75230 USA. NY State Basic Res Inst, Staten Isl, NY USA. RI Quezado, Zenaide/O-4860-2016 OI Quezado, Zenaide/0000-0001-9793-4368 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 5141 BP U584 EP U584 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338202312 ER PT J AU Chan, CC Tuo, J Bojanowski, CM Csaky, KG Green, WR AF Chan, CC Tuo, J Bojanowski, CM Csaky, KG Green, WR TI Detection of single nucleotide polymorphism and expression of CX3CR1 in human eyes with age-related macular degeneration SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Immunol Lab, Lab Genet Therapy, NIH, Bethesda, MD USA. Wilmer Eye Inst, Lab Eye Pathol, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 1827 BP U726 EP U726 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338001789 ER PT J AU Chaurasia, SS Provencio, I Jiang, G Hayes, WP Haque, R Natesan, A Zatz, M Rollag, MD Iuvone, PM AF Chaurasia, SS Provencio, I Jiang, G Hayes, WP Haque, R Natesan, A Zatz, M Rollag, MD Iuvone, PM TI Differential circadian regulation of melanopsin mRNA expression in the avian retina and pineal gland SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Emory Univ, Sch Med, Atlanta, GA 30322 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. Catholic Univ Amer, Washington, DC 20064 USA. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 4648 BP U489 EP U489 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201821 ER PT J AU Chen, J Vistica, BP Miyake, S Yamamura, T Chan, CC Wawrousek, EF Gery, I AF Chen, J Vistica, BP Miyake, S Yamamura, T Chan, CC Wawrousek, EF Gery, I TI The synthetic glycolipid "OCH", a stimulant of NKT cells, inhibits Th1 cell-mediated ocular inflammation, but enhances disease induced by Th2 cells. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. Natl Inst Neurosci, Dept Immunol, NCNP, Tokyo, Japan. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 BP U912 EP U912 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338002252 ER PT J AU Chen, S Fariss, RN Kutty, RK Nelson, R Wiggert, B AF Chen, S Fariss, RN Kutty, RK Nelson, R Wiggert, B TI Fenretinide induced neuronal differentiation of ARPE-19 cells: mediation by retinoid receptors and potential neuronal function. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Bethesda, MD 20892 USA. NINDS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 5350 BP U637 EP U637 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338202523 ER PT J AU Chen, S Diamond, JS AF Chen, S Diamond, JS TI NMDA receptors expand the dynamic range of ganglion cells in rat retina SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NINDS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 BP U408 EP U408 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201443 ER PT J AU Chew, EY Clemons, TE Klein, ML Klein, BEK Klein, R Friberg, T Bressler, S AF Chew, EY Clemons, TE Klein, ML Klein, BEK Klein, R Friberg, T Bressler, S CA AREDS Res Grp TI Cognitive function in the age-related eye disease study (AREDS) SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Bethesda, MD 20892 USA. EMMES Corp, Rockville, MD USA. Devers Eye Inst, Portland, OR USA. Univ Wisconsin, Madison, WI USA. Univ Pittsburgh, Inst Eye & Ear, Pittsburgh, PA 15213 USA. Wilmer Eye Inst, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3056 BP U58 EP U58 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338200257 ER PT J AU Chin, MS Hopper, LC Detrick, B Hooks, JJ AF Chin, MS Hopper, LC Detrick, B Hooks, JJ TI Identification of retinal autoantigens in Experimental Coronavirus Retinopathy (ECOR) SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Immunol Lab, NIH, Bethesda, MD USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 566 BP U210 EP U210 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000541 ER PT J AU Clemons, TE Klein, BEK Sperduto, RD AF Clemons, TE Klein, BEK Sperduto, RD CA AREDS Res Grp TI Risk factors for the progression of lens opacities in the age-related eye disease study (AREDS) SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 EMMES Corp, Rockville, MD USA. Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI USA. NEI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3751 BP U304 EP U304 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338200945 ER PT J AU Cox, CA John-Aryankalayil, M Jaworski, C Russell, P Gray, T Freedman, K Dushku, N Reid, TW Carper, D AF Cox, CA John-Aryankalayil, M Jaworski, C Russell, P Gray, T Freedman, K Dushku, N Reid, TW Carper, D TI The effect of doxycycline on the migration of pterygial epithelial cells grown in culture SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Sect Mol Therapeut, Bethesda, MD 20892 USA. Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. Kaiser Permanente Med Ctr, Sacramento, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 2939 BP U37 EP U37 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338200140 ER PT J AU Csaky, KG AF Csaky, KG CA C-PDT Study Group TI Phase II trial of celebrex in photodynamic therapy (C-PDT) for neovascular agerelated macular degeneration (AMD): Rationale and baseline characteristics SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, C PDT Study Grp, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 1186 BP U511 EP U511 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338001148 ER PT J AU Cusick, M Dahr, SS Srivastava, S Coleman, HR Thompson, D Chew, EY AF Cusick, M Dahr, SS Srivastava, S Coleman, HR Thompson, D Chew, EY TI Intravitreal anti-VEGF therapy for advanced ocular disease of von Hippel-Lindau disease SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. EMMES Corp, Potomac, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 1184 BP U511 EP U511 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338001147 ER PT J AU Cveki, A Chauhan, BK Yang, Y Stopka, T Cveklova, K Gao, CY AF Cveki, A Chauhan, BK Yang, Y Stopka, T Cveklova, K Gao, CY TI Synergistic and antagonistic interactions between transcription factors regulating crystallin gene expression SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Albert Einstein Coll Med, Bronx, NY 10467 USA. NEI, Lab Mol & Dev Biol, Bethesda, MD USA. RI Stopka, Tomas/D-5864-2017 OI Stopka, Tomas/0000-0001-7236-6894 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 4523 BP U461 EP U461 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201718 ER PT J AU Deai, T Fukuda, M Higaki, S Hayashi, K Shimomura, Y AF Deai, T Fukuda, M Higaki, S Hayashi, K Shimomura, Y TI Quantitation of HSV genome in recipient and eye-bank donor corneas. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Kinki Univ, Sch Med, Osaka 589, Japan. NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 1637 BP U594 EP U594 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338001600 ER PT J AU Ding, Y Jampel, H Quigley, H Marks, C Knezevich, F Congdon, N Friedman, D Vitale, S Zeimer, R AF Ding, Y Jampel, H Quigley, H Marks, C Knezevich, F Congdon, N Friedman, D Vitale, S Zeimer, R TI Baseline findings in the Glaucoma Imaging Longitudinal Study (GILS) SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Johns Hopkins Univ, Wilmer Eye Inst, Baltimore, MD 21218 USA. NEI, Div Epidemiol & Clin Res, Natl Inst Hlth, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 MA 4484 BP U453 EP U453 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201680 ER PT J AU Djalilian, AR Segre, JA AF Djalilian, AR Segre, JA TI Expression of gap junction proteins in the mouse corneal epithelium SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Bethesda, MD 20892 USA. NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3769 BP U307 EP U307 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338200964 ER PT J AU Dunaief, JL Hahn, P Rouault, T Harris, ZL AF Dunaief, JL Hahn, P Rouault, T Harris, ZL TI Retinal iron metabolism and its possible role in AMD pathogenesis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Univ Penn, FM Kirby Ctr Mol Ophthalmol, Philadelphia, PA 19104 USA. NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. Johns Hopkins Sch Med, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 2291 BP U906 EP U906 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338002234 ER PT J AU Duncan, T Wiggert, B AF Duncan, T Wiggert, B TI Phosphorylation of interphotoreceptor retinoid-binding protein: Characterization of phosphorylation sites SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 1254 BP U524 EP U524 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338001214 ER PT J AU Ehrlich, J Cogan, S Troyk, P Plante, T Bradley, D Bak, M Erickson, R McCreery, D Schmidt, E Towle, V AF Ehrlich, J Cogan, S Troyk, P Plante, T Bradley, D Bak, M Erickson, R McCreery, D Schmidt, E Towle, V TI Care and feeding of AIROF microelectrodes for visual prostheses SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 EIC Labs, Norwood, MA 02062 USA. IIT, Chicago, IL 60616 USA. Univ Chicago, Chicago, IL 60637 USA. NIH, Bethesda, MD 20892 USA. Huntington Med Res Inst, Pasadena, CA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 4208 BP U386 EP U386 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201404 ER PT J AU Espinosa, DG Caicedo, A Hernandez, EP Pereira, S Pina, Y Csaky, KG Cousins, SW AF Espinosa, DG Caicedo, A Hernandez, EP Pereira, S Pina, Y Csaky, KG Cousins, SW TI Aged bone marrow transfers age-related pathology into young recipients in experimental choroidal neovascularization (CNV). SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Univ Miami, Bascom Palmer Eye Inst, Miami, FL USA. NEI, NIH, Bethesda, MD USA. RI Caicedo, Alejandro/F-1202-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 1853 BP U730 EP U730 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338001811 ER PT J AU Fan, J Fariss, RN Quinlan, R Chepelinsky, AB AF Fan, J Fariss, RN Quinlan, R Chepelinsky, AB TI Gamma-E-crystallin Elo mutation disrupts the specific interaction between lens MIP/Aquaporin-0 and gamma-E-crystallin. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD USA. Univ Durham, Sch Biol & Biomed Sci, Durham, England. RI Quinlan, Roy/A-1348-2012 OI Quinlan, Roy/0000-0003-0644-4123 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3993 BP U348 EP U348 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201187 ER PT J AU Fan, J Rohrer, B Redmond, T Crouch, R AF Fan, J Rohrer, B Redmond, T Crouch, R TI Endogenous 9-cis retinal acts as the chromophore for visual pigment in the RPE65 knockout mouse SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 MUSC, Storm Eye Inst, Charleston, SC USA. NEI, Retinal Cell & Mol Biol Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3631 BP U182 EP U182 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338200826 ER PT J AU Feathers, K Redmond, TM Thompson, DA AF Feathers, K Redmond, TM Thompson, DA TI Apoptosis in the retina of the Rpe65 knockout mouse. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Univ Michigan, Kellogg Eye Ctr, Ann Arbor, MI 48109 USA. NEI, Retinal Cell & Mol Biol Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 5080 BP U573 EP U573 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338202251 ER PT J AU Fischette, MR Ma, X Chan, CC Adelstein, R AF Fischette, MR Ma, X Chan, CC Adelstein, R TI Abnormalities in the retinas of mice with a single amino acid mutation in nonmuscle myosin II-B SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NHLBI, Lab Mol Cardiol, Bethesda, MD USA. NEI, Lab Immunol, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3545 BP U165 EP U165 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338200739 ER PT J AU Garland, D Winn, K Neal, R Meyer, E Li, D Ma, W Sun, F Spector, A AF Garland, D Winn, K Neal, R Meyer, E Li, D Ma, W Sun, F Spector, A TI Mechanisms of epithelial cell adaptation to peroxide stress SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Bethesda, MD 20892 USA. Columbia Univ, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 1027 BP U384 EP U384 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338001002 ER PT J AU Golestaneh, N Fan, J Fariss, RN Lo, WK Chepelinsky, AB AF Golestaneh, N Fan, J Fariss, RN Lo, WK Chepelinsky, AB TI FGF-induced ERK and JNK signaling are required for MIP/Aquaporin 0 expression in rat lens explants SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. Morehouse Sch Med, Atlanta, GA 30310 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 2334 BP U919 EP U919 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338002277 ER PT J AU Gordiyenko, NV Lee, JW Farris, RN Alam, S Rodriguez, I AF Gordiyenko, NV Lee, JW Farris, RN Alam, S Rodriguez, I TI Subcellular localization of oxysterol binding proteins (OSBPs) in cultured human RPE cells SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, LRCMB, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 631 BP U310 EP U310 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000606 ER PT J AU Gradstein, L FitzGibbon, EJ Tsilou, E Kaiser-Kupfer, MI Huizing, M Gahl, WA AF Gradstein, L FitzGibbon, EJ Tsilou, E Kaiser-Kupfer, MI Huizing, M Gahl, WA TI Eye movements in Hermansky-Pudlak Syndrome SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Lsr, Bethesda, MD USA. NEI, Bethesda, MD 20892 USA. NHGRI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 2321 BP U916 EP U916 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338002264 ER PT J AU Grajewski, RS Silver, PB Agarwal, RK Su, SB Chan, CC Caspi, RR AF Grajewski, RS Silver, PB Agarwal, RK Su, SB Chan, CC Caspi, RR TI Thymus-derived CD4+CD25+ regulatory T cells set the threshold of susceptibility to Experimental Autoimmune Uveitis (EAU) SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Immunol Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 1007 BP U378 EP U378 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000979 ER PT J AU Grinchuk, OV Wu, X Zbinek, K Tomarev, SI AF Grinchuk, OV Wu, X Zbinek, K Tomarev, SI TI Pax-6 and Sox11 as possible regulators of the optimedin gene activity SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Lmdb, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 653 BP U314 EP U314 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000626 ER PT J AU Guo, Y Wyatt, K Wistow, G Mehrabyan, Z Bernstein, SL AF Guo, Y Wyatt, K Wistow, G Mehrabyan, Z Bernstein, SL TI Retbindin expression in human and monkey retina SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Univ Maryland, Baltimore, MD 21201 USA. NEI, Msf, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 662 BP U315 EP U315 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000636 ER PT J AU Gwiazda, JE Hyman, L Norton, T Hussein, M Marsh-Tootle, W Manny, R Wang, Y Everett, D AF Gwiazda, JE Hyman, L Norton, T Hussein, M Marsh-Tootle, W Manny, R Wang, Y Everett, D CA COMET Grp TI Baseline accommodation and related risk factors associated with myopia progression and their interaction with treatment in COMET children SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 New England Coll Optometry, Boston, MA USA. SUNY Stony Brook, Sch Med, Stony Brook, NY 11794 USA. Univ Alabama, Sch Optometry, Birmingham, AL 35294 USA. Univ Houston, Coll Optometry, Houston, TX USA. NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 2740 BP U995 EP U995 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338002674 ER PT J AU Hackett, J Chew, EY Crawford, MA Shen, D Chan, CC AF Hackett, J Chew, EY Crawford, MA Shen, D Chan, CC TI Immunohistochemistry and ultrastructure of angioma in von Hipple-Lindau disease SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 4683 BP U501 EP U501 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201856 ER PT J AU Haque, R Chong, NW Chaurasia, SS Klein, DC Iuvone, PM AF Haque, R Chong, NW Chaurasia, SS Klein, DC Iuvone, PM TI Retinal melatonin biosynthesis: Interactions of A/T-rich regions and CRE-like sequences contribute to cAMP-dependent regulation of the chicken AANAT promoter. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Emory Univ, Atlanta, GA 30322 USA. Univ Leicester, Leicester LE1 7RH, Leics, England. NICHHD, Dev Neurobiol Lab, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 659 BP U315 EP U315 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000632 ER PT J AU Hooper, LC Chin, MS Detrick, B Hooks, JJ AF Hooper, LC Chin, MS Detrick, B Hooks, JJ TI Alterations in TNF-alpha receptor signaling in experimental coronavirus retinopathy SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Immunol Lab, NIH, Bethesda, MD USA. Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 565 BP U210 EP U210 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000538 ER PT J AU Hyman, L Gwiazda, J Hussein, M Norton, TT Wang, Y Marsh-Tootle, W AF Hyman, L Gwiazda, J Hussein, M Norton, TT Wang, Y Marsh-Tootle, W TI Relationship of baseline age, gender and ethnicity with 3-year myopia progression and axial elongation in the correction of myopia evaluation trial (COMET) SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 SUNY Stony Brook, Ctr Med, Dept Prevent Med, Stony Brook, NY 11794 USA. New England Col Optometry, Boston, MA USA. SW Med Sch, Dallas, TX USA. Univ Alabama, Sch Optometry, Birmingham, AL 35294 USA. NEI, Div Collaborat Clin Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 2734 BP U994 EP U994 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338002668 ER PT J AU Jampel, HD Ding, Y Quigley, H Marks, C Knezevich, F Friedman, D Congdon, N Vitale, S Zeimer, R AF Jampel, HD Ding, Y Quigley, H Marks, C Knezevich, F Friedman, D Congdon, N Vitale, S Zeimer, R TI One-year changes in visual field, HRT, and RTA parameters in the Glaucoma Imaging Longitudinal Study (GILS) SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. NEI, Div Epidemiol & Clin Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 MA 5515 BP U668 EP U668 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338202690 ER PT J AU Khan, NW Kondo, M Jamison, JA Sieving, PA AF Khan, NW Kondo, M Jamison, JA Sieving, PA TI Impairment of depolarizing bipolar cell activity is necessary and sufficient to cause the CSNB1 phenotype. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Univ Michigan, Ophthalmol Kellogg Eye Ctr, Ann Arbor, MI 48109 USA. Nagoya Univ, Sch Med, Nagoya, Aichi 466, Japan. Alcon Labs Inc, Ft Worth, TX 76101 USA. NEI, NIDCD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 788 BP U338 EP U338 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000761 ER PT J AU Kim, H Robinson, MR Lizak, MJ Tansey, G Lutz, R Yuan, P Wang, NS Csaky, KG AF Kim, H Robinson, MR Lizak, MJ Tansey, G Lutz, R Yuan, P Wang, NS Csaky, KG TI Controlled drug release from an ocular implant: Real-time evaluation using magnetic resonance imaging SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Bethesda, MD 20892 USA. NINDS, MRI Res Facil, Bethesda, MD 20892 USA. ORS, Div Bioengn & Phys Sci, Bethesda, MD USA. CC, Dept Pharm, Bethesda, MD USA. Univ Maryland, Dept Chem Engn, College Pk, MD 20742 USA. RI Wang, Nam Sun/E-4253-2016 NR 0 TC 0 Z9 0 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 5043 BP U567 EP U567 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338202216 ER PT J AU Klein, ML Ferris, FL Gensler, G Davis, MD Armstrong, J Chew, EY Bressler, SB Gottlieb, J Friberg, T AF Klein, ML Ferris, FL Gensler, G Davis, MD Armstrong, J Chew, EY Bressler, SB Gottlieb, J Friberg, T CA AREDS Research Grp TI Clinical features and natural course of drusenoid pigment epithelial detachments in age-related macular degeneration SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Devers Eye Inst, Portland, OR USA. NEI, Bethesda, MD 20892 USA. EMMES Corp, Rockville, MD USA. Univ Wisconsin, Fundus Photograph Reading Ctr, Madison, WI USA. Wilmer Eye Inst, Baltimore, MD USA. Univ Pittsburgh, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3047 BP U57 EP U57 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338200252 ER PT J AU Knezevich, F Jampel, HD Ding, Y Quigley, H Marks, C Friedman, D Congdon, N Vitale, S Zeimer, R AF Knezevich, F Jampel, HD Ding, Y Quigley, H Marks, C Friedman, D Congdon, N Vitale, S Zeimer, R TI Normal human posterior pole retinal thickness measured with the Retinal Thickness Analyzer SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Johns Hopkins Univ, Wilmer Eye Inst, Baltimore, MD 21218 USA. NEI, Div Epidemiol & Clin Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 5251 BP U618 EP U618 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338202424 ER PT J AU Kozak, LR Castelo-Brancol, M Karmos, G Read, JCA AF Kozak, LR Castelo-Brancol, M Karmos, G Read, JCA TI A computational model of the motion aftereffect SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Univ Coimbra, IBILI Ctr Ophthalmol, Coimbra, Portugal. Hungarian Acad Sci, Inst Psychol, Budapest, Hungary. NEI, NIH, Bethesda, MD 20892 USA. RI Kozak, Lajos/B-4194-2011; Read, Jenny/A-7493-2013 OI Kozak, Lajos/0000-0003-0368-3663; Read, Jenny/0000-0002-9029-5185 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 4336 BP U431 EP U431 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201558 ER PT J AU Kurup, SK Ursea, R Tang, J Lim, WK Sen, HN Dahr, S Buggage, RR Nussenblatt, RB AF Kurup, SK Ursea, R Tang, J Lim, WK Sen, HN Dahr, S Buggage, RR Nussenblatt, RB TI Utility of a Gamma Interferon assay as an alternative to PPD TB skin testing in selected patients with intraocular inflammatory SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 1678 BP U601 EP U601 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338001637 ER PT J AU Kutty, RK Chen, S Samuel, W Duncan, T Bundek, AM Tsai, JY Fariss, RN Wiggert, B AF Kutty, RK Chen, S Samuel, W Duncan, T Bundek, AM Tsai, JY Fariss, RN Wiggert, B TI A pat7 nuclear localization signal targets the protein encoded by NORPEG gene into retinal pigment epithelial (RPE) cell nuclei SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Natl Inst Hlth, NEI, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 1302 BP U533 EP U533 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338001261 ER PT J AU Ledee, D Gery, J Zelenka, P AF Ledee, D Gery, J Zelenka, P TI Variants of CTACK (CCL27) are expressed in mouse eye SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 4716 BP U507 EP U507 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201887 ER PT J AU Lee, MT Ursea, R Hooper, L Nussenblatt, RN Hooks, JJ Detrick, B AF Lee, MT Ursea, R Hooper, L Nussenblatt, RN Hooks, JJ Detrick, B TI Elevated serum levels of the adhesion molecules E-selectin and sICAM-1 detected in patients with retinal vasculitis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Johns Hopkins Med Inst, Baltimore, MD 21205 USA. NEI, Immunol Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 2685 BP U986 EP U986 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338002617 ER PT J AU Lee, SS Garibaldi, DC Iliff, NT Chan, CC Kim, H Yuan, P Swords, G Csaky, KG Robinson, MR AF Lee, SS Garibaldi, DC Iliff, NT Chan, CC Kim, H Yuan, P Swords, G Csaky, KG Robinson, MR TI Corticosteroid-eluting lid spacers for eyelid retraction surgery SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Johns Hopkins Univ, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. NEI, NIH, Bethesda, MD 20892 USA. Porex Surg Inc, Surg Prod Grp, Newnan, GA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3955 BP U341 EP U341 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201147 ER PT J AU Li, A AF Li, A TI Bietti crystalline corneoretinal dystrophy is caused by mutations in the novel gene CYP4V2, a new member of the cytochrome P450 SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 4736 BP U511 EP U511 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201909 ER PT J AU Li, Z Kim, BJ Fariss, RN Shen, D Sankaranarayana, MP Egwuagu, C Yu, CR Nagineni, CN Chan, CC Nussenblatt, RB AF Li, Z Kim, BJ Fariss, RN Shen, D Sankaranarayana, MP Egwuagu, C Yu, CR Nagineni, CN Chan, CC Nussenblatt, RB TI Identification and characterization of GITRL (ligand for glucocorticoid induced TNF related receptor) in ocular tissues SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Immunol Lab, NIH, Bethesda, MD USA. NEI, Lab Mechanisms Ocular Dis, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 560 BP U209 EP U209 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000535 ER PT J AU Lim, W Ursea, R Pillai, M Chan, CC Buggage, R Silver, P Gery, I Nussenblatt, RB AF Lim, W Ursea, R Pillai, M Chan, CC Buggage, R Silver, P Gery, I Nussenblatt, RB TI Effects of interleukin 1 receptor antagonist on experimental autoimmune uveoretinitis in mice SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Immunol Lab, Bethesda, MD 20892 USA. Singapore Natl Eye Ctr, Singapore, Singapore. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 558 BP U209 EP U209 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000534 ER PT J AU Lopez, P Caruso, RC Valle, D Kaiser-Kupfer, M AF Lopez, P Caruso, RC Valle, D Kaiser-Kupfer, M TI Color discrimination in gyrate atrophy of the choroid and retina SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Ophthalm Genet Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Howard Hughes Med Inst, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 5157 BP U601 EP U601 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338202329 ER PT J AU Mahesh, SP Nussenblatt, RB Li, Z AF Mahesh, SP Nussenblatt, RB Li, Z TI Alpha tropomyosin as a self antigen in Behcet's disease SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 2699 BP U988 EP U988 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338002630 ER PT J AU Malyukova, IV Senatorov, VV Wawrousek, EF Swaminathan, S Sharan, SK Yang, H Avila, MA Civan, MM Tamarev, SI AF Malyukova, IV Senatorov, VV Wawrousek, EF Swaminathan, S Sharan, SK Yang, H Avila, MA Civan, MM Tamarev, SI TI Presence of mutant myocilin gene in mice doesn't lead to IOP elevation. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Bethesda, MD 20892 USA. NCI, NIH, Frederick, MD 21701 USA. Univ Penn, Dept Physiol, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 4372 BP U432 EP U432 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201566 ER PT J AU Mandal, MA Bush, RA Sieving, PA Ayyagari, R AF Mandal, MA Bush, RA Sieving, PA Ayyagari, R TI Early response of retina to damaging light - a microarray analysis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Univ Michigan, Kellogg Eye Ctr, Ann Arbor, MI 48109 USA. NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 684 BP U319 EP U319 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000658 ER PT J AU Mathers, PH Voronina, VA Wilson, C Kozlov, SV Lewandoski, M AF Mathers, PH Voronina, VA Wilson, C Kozlov, SV Lewandoski, M TI The Rx homeobox gene is required for both neural retina and lens placode induction SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 W Virginia Univ, Sch Med, Sensory Neurosci Res Ctr, Morgantown, WV 26506 USA. NCI, Canc & Dev Biol Lab, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 2249 BP U808 EP U808 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338002204 ER PT J AU Meallet, MA Jiao, X Rubin, BI Hejtmancik, JF Forster, RK AF Meallet, MA Jiao, X Rubin, BI Hejtmancik, JF Forster, RK TI Linkage analysis of Corneal Fleck Dystrophy (CFD) in a family with marked symptomatology maps to chromosome 2q35 SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Doheny Eye Inst, Los Angeles, CA 90033 USA. NEI, Bethesda, MD 20892 USA. Bascom Palmer Eye Inst, Miami, FL 33136 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 1522 BP U573 EP U573 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338001485 ER PT J AU Milton, RC Clemons, TE Sperduto, RD Klein, BEK AF Milton, RC Clemons, TE Sperduto, RD Klein, BEK CA AREDS Res Grp TI Centrum use and progression of age-related cataract in the Age-Related Eye Disease Study (AREDS) - A propensity score approach SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 EMMES Corp, Rockville, MD USA. NEI, Bethesda, MD 20892 USA. Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI 53706 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3416 BP U130 EP U130 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338200614 ER PT J AU Momma, Y Chin, MS Naginent, CN Hooks, JJ Detrick, B AF Momma, Y Chin, MS Naginent, CN Hooks, JJ Detrick, B TI Antiviral actions of interferons inhuman retinal pigment epithelial cells: a model system to evaluate the potency of interferons in resident retinal cells SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Tohoku Univ, Grad Sch Dent, Dept Lifelong Oral Sci, Sendai, Miyagi 980, Japan. NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 1642 BP U595 EP U595 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338001603 ER PT J AU Moroi, SE Maumenee, IH Karoukis, AJ Mandal, MNA Chen, L McLaren, NC Hitchcock, PF Sieving, PA Ayyagari, R AF Moroi, SE Maumenee, IH Karoukis, AJ Mandal, MNA Chen, L McLaren, NC Hitchcock, PF Sieving, PA Ayyagari, R TI A complex ocular phenotype of early-onset long anterior lens zonules and late onset autosomal dominant age-related macular degeneration due to a CTRP5 gene mutation SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Univ Michigan, Ann Arbor, MI 48109 USA. Johns Hopkins Sch Med, Wilmer Ophthalmol Inst, Baltimore, MD USA. NIDCD, NEI, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 4739 BP U511 EP U511 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201913 ER PT J AU Morozov, V Wawrousek, EE AF Morozov, V Wawrousek, EE TI Alpha-crystallin prevents cellular disintegration during the apoptosis-like program of lens fiber cell maturation. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Mol & Dev Biol Lab, NIH, DHHS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 1150 BP U503 EP U503 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338001117 ER PT J AU Muccioli, C Andrade, RE Farah, ME Peixoto, L Nussenblatt, RB Belfort, R AF Muccioli, C Andrade, RE Farah, ME Peixoto, L Nussenblatt, RB Belfort, R TI Intravitreal triamcinolone acetonide in the treatment of serous retinal detachment in Vogt-Koyanagi-Harada syndrome SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Univ Fed Sao Paulo, Sao Paulo, Brazil. NEI, Immunol Lab, NIH, Bethesda, MD USA. RI Belfort Jr, Rubens/E-2252-2012; Muccioli, Cristina/C-3419-2013 OI Belfort Jr, Rubens/0000-0002-8422-3898; NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 2677 BP U984 EP U984 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338002609 ER PT J AU Nagineni, CN Kutty, V Detrick, B Hooks, JJ AF Nagineni, CN Kutty, V Detrick, B Hooks, JJ TI Expression of transforming growth factor-beta 1 and beta 2 by human retinal pigment epithelial cells: Differential regulation by IFN-gamma SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21218 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 628 BP U310 EP U310 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000602 ER PT J AU Neal, RE Bettelheim, FA Garland, D Campbell-Winn, K Zigler, JS AF Neal, RE Bettelheim, FA Garland, D Campbell-Winn, K Zigler, JS TI The human vitreous proteome: Spatial analysis of protein expression SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 713 BP U324 EP U324 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000685 ER PT J AU Nelson, RF Connaughton, VP AF Nelson, RF Connaughton, VP TI Glutamate transporter drives the b-wave in zebrafish retina. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NINDS, Basic Neurosci Program, NIH, Bethesda, MD 20892 USA. American Univ, Dept Biol, Washington, DC 20016 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 815 BP U343 EP U343 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000791 ER PT J AU Nguyen, O Shah, SM Van Anden, E Sung, JU Vitale, S Campochiaro, PA AF Nguyen, O Shah, SM Van Anden, E Sung, JU Vitale, S Campochiaro, PA TI Supplemental oxygen improves diabetic macular edema: A pilot study SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Johns Hopkins Univ Hosp, Wilmer Ophthalmol Inst, Vitreoretinal Serv, Baltimore, MD 21287 USA. NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3461 BP U144 EP U144 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338200661 ER PT J AU Notari, L Seigel, GM Rogers, H Noguchi, CT Becerra, SP AF Notari, L Seigel, GM Rogers, H Noguchi, CT Becerra, SP TI PEDF and erythropoietin share protective properties on retinal neuronal precursor cell lines SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. SUNY Buffalo, Dept Ophthalmol Physiol & Biophys, Buffalo, NY 14260 USA. NIDDK, Biol Chem Lab, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 866 BP U352 EP U352 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000841 ER PT J AU Oh, DL Martin, JL Williams, AJ Pokorny, C Russell, P Birk, DE Rhee, DJ AF Oh, DL Martin, JL Williams, AJ Pokorny, C Russell, P Birk, DE Rhee, DJ TI Detection and quiantitation of mRNA of matrix metalloproteinase enzymes in cultured human trabecular meshwork and ciliary body treated with latanoprost. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Wills Eye Hosp & Res Inst, Lab Mol Ophthalmol, Philadelphia, PA USA. NEI, Lab Mechanisms Ocular Dis, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Dept Anat Pathol & Cell Biol, Philadelphia, PA 19107 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 4374 BP U433 EP U433 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201570 ER PT J AU Oharazawa, H Igarashi, T Kurai, T Matsui, H Shiwa, T Takahashi, H Ohara, K Shimada, T Oikawa, S AF Oharazawa, H Igarashi, T Kurai, T Matsui, H Shiwa, T Takahashi, H Ohara, K Shimada, T Oikawa, S TI Identification of gene expression profiling associated with angiogenesis in human retinal endothelial cells compared with different endothelial cells. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Gene Therapy Sect, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 1883 BP U735 EP U735 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338001843 ER PT J AU Ozyildirim, A Wistow, G Dickinson, D Laurie, GW AF Ozyildirim, A Wistow, G Dickinson, D Laurie, GW TI Development of the first public human and mouse lacrimal gland EST databases SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Univ Virginia, Charlottesville, VA USA. NEI, Sect Mol Struct & Funct, Bethesda, MD 20892 USA. Med Coll Georgia, Augusta, GA 30912 USA. RI Laurie, Gordon/A-5244-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3889 BP U329 EP U329 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201083 ER PT J AU Prescott, AR Sandilands, A James, J Kuszak, J Pekny, M Chepelinsky, A Wegener, A Zoltoski, R Maatta, A Quinlan, R AF Prescott, AR Sandilands, A James, J Kuszak, J Pekny, M Chepelinsky, A Wegener, A Zoltoski, R Maatta, A Quinlan, R TI Optical and anatomical analysis of dundee mice SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Univ Dundee, Sch Life Sci, Dundee, Scotland. Rush Med Coll, Rush Presbyterian St Lukes Med Ctr, Dept Ophthalmol, Chicago, IL USA. Rush Med Coll, Rush Presbyterian St Lukes Med Ctr, Dept Pathol, Chicago, IL USA. Univ Gothenburg, Dept Med Biochem, Gothenburg, Sweden. NEI, NIH, Bethesda, MD USA. Univ Bonn, D-5300 Bonn, Germany. Illinois Coll Optometry, Chicago, IL USA. Univ Durham, Sch Biol & Biomed Sci, Durham, England. RI Quinlan, Roy/A-1348-2012 OI Quinlan, Roy/0000-0003-0644-4123 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 4600 BP U477 EP U477 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201779 ER PT J AU Rabinowitz, YS Don, L Gao, J Buchoff, P AF Rabinowitz, YS Don, L Gao, J Buchoff, P TI Gene expression profile of keratocorms cornea for NEI Bank SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. Natl Eye Inst Hlth, Nei Bank, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 2883 BP U27 EP U27 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338200086 ER PT J AU Redmond, T Lu, Z Yu, SS Gentleman, S AF Redmond, T Lu, Z Yu, SS Gentleman, S TI Rpe65 interacts with multiple domains of caveolin1 SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 4591 BP U475 EP U475 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201771 ER PT J AU Reinoso, MA Caicedo, A Espinosa-Heidmann, DG Csaky, KH Cousins, SW AF Reinoso, MA Caicedo, A Espinosa-Heidmann, DG Csaky, KH Cousins, SW TI Blood-derived macrophages and bone marrow derived progenitor cells contribute to intrachoroidal vascular changes in experimental choroidal neovascularization (CNV). SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Univ Miami, Bascom Palmer Eye Inst, Miami, FL 33152 USA. NEI, NIH, Bethesda, MD 20892 USA. RI Caicedo, Alejandro/F-1202-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3386 BP U122 EP U122 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338200585 ER PT J AU Roberts, JE Rammal, M Smith, F Hamilton, MG Chignell, CF AF Roberts, JE Rammal, M Smith, F Hamilton, MG Chignell, CF TI Detection and prevention of ocular phototoxicity of ciprofloxacin, the prophylactic antidote for bioterrorism-related anthrax. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Fordham Univ, New York, NY 10023 USA. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 389 BP U178 EP U178 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000362 ER PT J AU Robinson, MR Kim, H Gravlin, L Tansey, G Grimes, G Potti, G Yuan, P Csaky, KG AF Robinson, MR Kim, H Gravlin, L Tansey, G Grimes, G Potti, G Yuan, P Csaky, KG TI Preclinical evaluation of a triamcinolone acetonide preservative free (TAC-PF) formulation for intravitreal injection SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Bethesda, MD 20892 USA. NIH, Clin Ctr Pharm, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 5058 BP U569 EP U569 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338202232 ER PT J AU Rodriguez, IR Gordiyenko, N Campos, M Lee, JW Farris, RN Sztein, J Alam, S AF Rodriguez, IR Gordiyenko, N Campos, M Lee, JW Farris, RN Sztein, J Alam, S TI RPE cell internalize LDL and oxLDL-cholesterol in large quantities in vitro and in vivo SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Bethesda, MD USA. RI Sztein, Jorge/B-7165-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 1842 BP U728 EP U728 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338001800 ER PT J AU Saika, S Ikeda, K Yamanaka, O Miyamoto, T Ohnishi, Y Ooshima, A Kao, WW Flanders, FC Roberts, AB AF Saika, S Ikeda, K Yamanaka, O Miyamoto, T Ohnishi, Y Ooshima, A Kao, WW Flanders, FC Roberts, AB TI Transient adenoviral gene transfer of Smad7 prevents formation of ulceration and scarring ofthe cornea following an alkali exposure in mice SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Wakayama Med Coll, Wakayama 640, Japan. Osaka City Univ, Wakayama, Japan. Univ Cincinnati, Med Ctr, Cincinnati, OH 45267 USA. NCI, Lerc, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 1165 BP U507 EP U507 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338001134 ER PT J AU Samuel, W Kutty, RK Chandraratna, RAS Wiggert, B AF Samuel, W Kutty, RK Chandraratna, RAS Wiggert, B TI Reactive oxygen species (ROS) mediates fenretinide-induced apoptosis in human retinal pigment epithelial (RPE) cells SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Bethesda, MD 20892 USA. Retinoid Res, Dept Chem, Irvine, CA USA. Retinoid Res, Dept Biol, Irvine, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3478 BP U148 EP U148 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338200674 ER PT J AU SanGiovanni, JP Chew, EY Ferris, FL Kurinij, N Sperduto, RD Lindblad, AS Seddon, J Klein, BEK Friberg, TR AF SanGiovanni, JP Chew, EY Ferris, FL Kurinij, N Sperduto, RD Lindblad, AS Seddon, J Klein, BEK Friberg, TR CA AREDS Res Grp TI Dietary carotenoids and risk for age-related macular degeneration in the Age-Related Eye Disease Study (AREDS) SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Div Epidemiol & Clin Res, Bethesda, MD 20892 USA. NEI, Div Extramural Res, Bethesda, MD 20892 USA. EMMES Corp, Rockville, MD USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI USA. Univ Pittsburgh, Pittsburgh, PA USA. RI SanGiovanni, John Paul/A-7605-2008 NR 0 TC 0 Z9 0 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 2242 BP U806 EP U806 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338002197 ER PT J AU Sarna, TJ Broniec, A Wielgus, A Roberts, J Land, EJ Truscott, TG Clarke, K Navaratnam, S Edge, R AF Sarna, TJ Broniec, A Wielgus, A Roberts, J Land, EJ Truscott, TG Clarke, K Navaratnam, S Edge, R TI Characterization of A2E free radicals SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Jagiellonian Univ, PL-31007 Krakow, Poland. NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. Fordham Univ, Bronx, NY 10458 USA. Univ Keele, Keele ST5 5BG, Staffs, England. Daresbury Lab, Free Rad Res Facil, Daresbury, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 748 BP U331 EP U331 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000722 ER PT J AU Sato, S Kawakami, Y Tsai, J Chen, Y Ma, J AF Sato, S Kawakami, Y Tsai, J Chen, Y Ma, J TI SMAA-GFP mice: A new tool to identify myofibroblasts in posterior capsular cataracts SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 OUHSC, Oklahoma City, OK USA. NIH, NEI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 356 BP U171 EP U171 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000328 ER PT J AU Schey, KL Han, J Ervin, LA Lindsey, KM Ball, LE Garland, DL Crouch, RK AF Schey, KL Han, J Ervin, LA Lindsey, KM Ball, LE Garland, DL Crouch, RK TI Modifications to lens membrane proteins during lens development and their potential functional consequences SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Med Univ S Carolina, Charleston, SC USA. NEI, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 4601 BP U478 EP U478 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201780 ER PT J AU Sen, HN Castillo, R Nussenblatt, RB Buggage, RR AF Sen, HN Castillo, R Nussenblatt, RB Buggage, RR TI Optical coherence tomography for the assessment of cystoid macular edema in patients with uveitis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Immunol Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 2705 BP U989 EP U989 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338002636 ER PT J AU Senatorov, V Malyukova, IV Fariss, RN Wawrousek, EF Swaminathan, S Sharan, SK Tomarev, SI AF Senatorov, V Malyukova, IV Fariss, RN Wawrousek, EF Swaminathan, S Sharan, SK Tomarev, SI TI Degeneration of ganglion cells in the peripheral retina of transgenic animals containingthe mutated mouse myocilin gene. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Bethesda, MD 20892 USA. NCI, NIH, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 4378 BP U433 EP U433 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201572 ER PT J AU Sepehrdad, R Shen, D Chan, CC AF Sepehrdad, R Shen, D Chan, CC TI Endotoxin-induced uveitis is diminished in interferon-gamma receptor deficient mice SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Bethesda, MD USA. New York Med Coll, Valhalla, NY 10595 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 574 BP U211 EP U211 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000548 ER PT J AU Sergeev, YV Hejtmancik, JF Wingfied, PT AF Sergeev, YV Hejtmancik, JF Wingfied, PT TI Energetics of beta-crystallins association SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NIAMS, Bethesda, MD USA. NEI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3974 BP U345 EP U345 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201166 ER PT J AU Shen, D Chan, CC Fischette, M Nussenblatt, RB Hochman, J AF Shen, D Chan, CC Fischette, M Nussenblatt, RB Hochman, J TI Murine model of primary intraocular lymphoma SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Hebrew Univ Jerusalem, Jerusalem, Israel. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 1226 BP U519 EP U519 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338001187 ER PT J AU Smaoui, N Li, S Belghith, N Chaabouni, M Rad, RM Maazoul, E Chaabouni, H Hejtmancik, JF AF Smaoui, N Li, S Belghith, N Chaabouni, M Rad, RM Maazoul, E Chaabouni, H Hejtmancik, JF TI Mutations in BBS8 gene causes Bardet-Biedl syndrome in two Tunisian families SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Bethesda, MD 20892 USA. EPS Charles Nicolle, Serv Malad Congenitales & Hereditaires, Tunis, Tunisia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 4759 BP U514 EP U514 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201932 ER PT J AU Smith, JA Cui, CY Schlessinger, D Chan, CC AF Smith, JA Cui, CY Schlessinger, D Chan, CC TI Ocular surface inflammation and meibomian gland aplasia in Tabby mice SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Bethesda, MD USA. NIA, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 130 BP U129 EP U129 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000105 ER PT J AU Song, Y Liu, Y Zhao, L Tanikawa, A Laties, AM Bush, RA Sieving, PA Wen, R AF Song, Y Liu, Y Zhao, L Tanikawa, A Laties, AM Bush, RA Sieving, PA Wen, R TI CNTF negatively regulates the phototransduction machinery in rod photoreceptors SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. NEI, NICHD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 4676 BP U497 EP U497 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201849 ER PT J AU Srivastava, S Martin, DF Mellow, S Parks, D Dastgheib, K AF Srivastava, S Martin, DF Mellow, S Parks, D Dastgheib, K TI Pathological findings in eyes with the ganciclovir implant SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Washington, DC USA. Emory Eye Ctr, Atlanta, GA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3948 BP U340 EP U340 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201143 ER PT J AU Stambolian, D Ibay, G Dana, D Reider, L Doan, B Holmes, T O'Neill, J Owens, R Ciner, E Bailey-Wilson, J AF Stambolian, D Ibay, G Dana, D Reider, L Doan, B Holmes, T O'Neill, J Owens, R Ciner, E Bailey-Wilson, J TI Genomic wide linkage of familial myopia and evidence for a locus on chromosome 22 SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. NHGRI, NIH, Baltimore, MD USA. Penn Coll Optometry, Philadelphia, PA 19141 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3723 BP U200 EP U200 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338200915 ER PT J AU Strunnikova, NV Hilmerz, S Flippin, J Cousins, S Csaky, K AF Strunnikova, NV Hilmerz, S Flippin, J Cousins, S Csaky, K TI Differences in gene expression profiles in dermal fibroblasts elicited by nonlethal injury from control and patients with age related macular degeneration (AMD). Phase I casecontrol study SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. Bascom Palmer Inst, Miami, FL USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 1826 BP U726 EP U726 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338001786 ER PT J AU Swamynathan, SK Piatigorsky, J AF Swamynathan, SK Piatigorsky, J TI An insulator-like sequence acts as a negative regulatory element in between the mouse Shsp/alpha B-crystallin enhancer and Mkbp/HspB2 promoter SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Mol & Dev Biol Lab, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 2250 BP U808 EP U808 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338002202 ER PT J AU Takada, Y Farris, R Tanikawa, A Zeng, Y Bush, RA Sieving, PA AF Takada, Y Farris, R Tanikawa, A Zeng, Y Bush, RA Sieving, PA TI Retinoschisin is expressed in a development wave through the retina following neuron birth and retinal layer formation SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIDCD, NIH, Bethesda, MD 20892 USA. NR 0 TC 3 Z9 3 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 2487 BP U948 EP U948 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338002420 ER PT J AU Takase, H Vistica, BP Chen, J Ham, DI Wawrousek, EF Durum, S Chan, CC Grey, I AF Takase, H Vistica, BP Chen, J Ham, DI Wawrousek, EF Durum, S Chan, CC Grey, I TI Localized T-lymphoid infiltration in eyes of transgenic mice expressing IL-7 selectively in their lens: a new model of ocular inflammation SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Bethesda, MD USA. NCI, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 562 BP U209 EP U209 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000536 ER PT J AU Tang, J Ursea, R Buggage, RR Kurup, S Caruso, RC AF Tang, J Ursea, R Buggage, RR Kurup, S Caruso, RC TI Multifocal electroretinogram findings and correlation with visual field testing in patients with birdshot retinochoroidopathy SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Ophthalm Genet & Visual Funct Branch, Bethesda, MD USA. NEI, Immunol Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 535 BP U205 EP U205 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000511 ER PT J AU Tanikawa, A Bush, RA Takada, Y Mears, AJ Swaroop, A Sieving, PA AF Tanikawa, A Bush, RA Takada, Y Mears, AJ Swaroop, A Sieving, PA TI Functional rods are required for photopic ERG amplitude increase during light adaptation: Study of Nrl-/- and Rho-/- mice. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NIH, Bethesda, MD 20892 USA. Univ Michigan, Kellogg Eye Ctr, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 811 BP U342 EP U342 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000786 ER PT J AU Therese, KL Therese, J Madhavan, HN AF Therese, KL Therese, J Madhavan, HN TI Development and application of a seminested polymerase chain reaction for detection of Mycobacterium fortuitum and Mycobacterium chelonae on sections of epitretinal membrane (ERM) of Eales disease. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Univ Fed Sao Paulo, EPM, Sao Paulo, Brazil. Clin Silveira, Erechim, Brazil. Univ Sao Paulo, Dept Imunol, Sao Paulo, Brazil. NIH, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 1676 BP U601 EP U601 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338001636 ER PT J AU Tomarev, SL Torrado, M Senatorov, VV Fariss, RN Trivedi, R AF Tomarev, SL Torrado, M Senatorov, VV Fariss, RN Trivedi, R TI A novel rat Pdlim2 protein interacts with actin-binding proteins in corneal epithelial cells SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Bethesda, MD 20892 USA. RI Torrado, Mario/A-4889-2010 OI Torrado, Mario/0000-0001-9762-7018 NR 0 TC 1 Z9 1 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3806 BP U314 EP U314 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201001 ER PT J AU Trese, MT Drenser, KA Prenner, J Sieving, P AF Trese, MT Drenser, KA Prenner, J Sieving, P TI A classification system for congenital X-linked retinoaschisis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Assoc Retinal Consultants, Royal Oak, MI USA. NEI, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 MA 3528 BP U162 EP U162 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338200726 ER PT J AU Tripathi, S Banzon, T Jalickee, S Miller, SS AF Tripathi, S Banzon, T Jalickee, S Miller, SS TI Resolution of osmotic (L-p(o)) and hydrostatic (L-p(h)) hydraulic conductivities of series barriers in bovine retinal pigment epitheliupm (BRPE) and Bruch's membrane-choroid complex. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Univ Calif Berkeley, Berkeley, CA 94720 USA. NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 1092 BP U402 EP U402 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338001066 ER PT J AU Troyk, PR Bradley, D Berg, J Bak, M Cogan, S Erickson, R Kufta, C McCreery, D Schmidt, E Towle, V AF Troyk, PR Bradley, D Berg, J Bak, M Cogan, S Erickson, R Kufta, C McCreery, D Schmidt, E Towle, V TI Comprehensive results of intracortical electrode stimulation in macaque VI SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 IIT, Pritzker Inst Biomed Sci & Eng, Chicago, IL 60616 USA. Univ Chicago, Chicago, IL 60637 USA. NIH, Bethesda, MD 20892 USA. EIC Labs, Norwood, MA 02062 USA. Huntington Med Res Inst, Pasadena, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 4224 BP U402 EP U402 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201418 ER PT J AU Tsilou, ET Caruso, R Rubin, B Iwata, F Gahl, W Kaiser-Kupfer, M AF Tsilou, ET Caruso, R Rubin, B Iwata, F Gahl, W Kaiser-Kupfer, M TI Posterior segment manifestations of infantile nephropathic cystinosis. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Ophth Genet & Visual Func Branch, Bethesda, MD 20892 USA. NHGRI, NIH, Sect Human Biochem Genet, Med Genet Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 2727 BP U993 EP U993 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338002659 ER PT J AU Ursea, R Nussenblatt, RB Sen, HN Buggage, RR AF Ursea, R Nussenblatt, RB Sen, HN Buggage, RR TI The role of humanized anti-IL-2 receptor antibody (HAT) therapy in incontrolled uveitis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 2637 BP U983 EP U983 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338002604 ER PT J AU Vasiliou, VK Merkouris, M Nees, DW Piatigorsky, J Petersen, DR Pappa, A AF Vasiliou, VK Merkouris, M Nees, DW Piatigorsky, J Petersen, DR Pappa, A TI ALDH3A1 protects cornea and lens against UVB-induced 4-HNE-protein adduct formation SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Univ Colorado, Hlth Sci Ctr, Sch Pharm, Denver, CO USA. NEI, Mol & Dev Biol Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3807 BP U314 EP U314 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338200999 ER PT J AU Vistica, BP Takase, H Chan, C Rittling, S Van Kaer, L Gery, I AF Vistica, BP Takase, H Chan, C Rittling, S Van Kaer, L Gery, I TI EAU does not always resemble other autoimmune diseases SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Immunol Lab, NIH, Bethesda, MD USA. Vanderbilt Univ, Nashville, TN USA. Rutgers State Univ, Piscataway, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 561 BP U209 EP U209 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000533 ER PT J AU Vitale, S Gump, A Cotch, MF Smith, JA AF Vitale, S Gump, A Cotch, MF Smith, JA TI Investigation of thyroid function and age-related macular degeneration in the NHANES III study SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Div Epidemiol & Clin Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 2246 BP U806 EP U806 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338002199 ER PT J AU Wallace, DJ Shen, D Buggage, RR Nussenblatt, RB Chan, CC AF Wallace, DJ Shen, D Buggage, RR Nussenblatt, RB Chan, CC TI Detection of bcl-2/IgH gene translocations in primary intraocular lymphoma SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Immunol Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 1071 BP U396 EP U396 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338001045 ER PT J AU Walter, MA Banerjee-Basu, S Berry, FB Baxevanis, A Saleem, RA AF Walter, MA Banerjee-Basu, S Berry, FB Baxevanis, A Saleem, RA TI Single amino acid probing of the function and molecular topology of the forkhead/winged-helix transcription factor FOXC1 SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Univ Alberta, Edmonton, AB T6G 2M7, Canada. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 691 BP U321 EP U321 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000665 ER PT J AU Wang, FE Jafari, A Shi, G Rendahl, KG Manning, WC Coyne, M Miller, SS AF Wang, FE Jafari, A Shi, G Rendahl, KG Manning, WC Coyne, M Miller, SS TI Changes in mRNA expression and protein level of angiogenic and anti-angiogenic factors in cultured human fetal retinal pigment epithelium (hfRPE) SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Bethesda, MD USA. Univ Calif Berkeley, Sch Optometry, Berkeley, CA 94720 USA. Chiron Corp, Gene Therapy Grp, Emeryville, CA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3711 BP U198 EP U198 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338200906 ER PT J AU Wang, X Garcia, CM Shui, YB Wistow, G Beebe, DC AF Wang, X Garcia, CM Shui, YB Wistow, G Beebe, DC TI Expression of crystalline in the mammalian lens epithelium SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Washington Univ, St Louis, MO USA. NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3961 BP U343 EP U343 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201155 ER PT J AU Watte, CM Nakamura, T Ortaldo, JR Stein-Streilein, J AF Watte, CM Nakamura, T Ortaldo, JR Stein-Streilein, J TI Role of Ly49 C/I, NK inhibitory molecule in ACAID SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Schepens Eye Res Inst, Boston, MA USA. NCI, Expt Immunol Lab, Canc Res Ctr, Frederick, MD USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pulm & Crit Care Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 587 BP U214 EP U214 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000560 ER PT J AU Webster, MK Blodi, BA Elledge, JA Csaky, KG AF Webster, MK Blodi, BA Elledge, JA Csaky, KG CA CPDTI Study Res Grp TI Comparison of OCT and fluorescein angiographic features of choroidal neovascularization due to age-related macular degeneration SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Univ Wisconsin, Madison, WI USA. NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3061 BP U59 EP U59 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338200265 ER PT J AU Wen, R Tanikawa, A Song, Y Zhao, L Liu, Y Laties, AM Bush, RA Sieving, PA AF Wen, R Tanikawa, A Song, Y Zhao, L Liu, Y Laties, AM Bush, RA Sieving, PA TI CNTF inhibition of the ERG a- and b-waves is reversible and correlates with down-regulation of rhodopsin and photo-transduction protein expression . SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. NEI, NIDCD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 785 BP U337 EP U337 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000759 ER PT J AU Wielgus, AR Chignell, CF Hu, D Roberts, JE AF Wielgus, AR Chignell, CF Hu, D Roberts, JE TI Comparison of the potential phototoxicity of A2E with its precursor trans-retinal in human retinal pigment epithelial cells SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. New York Eye & Ear Infirm, Tissue Culture Ctr, New York, NY 10003 USA. Fordham Univ, Dept Nat Sci, New York, NY 10023 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 1 MA 736 BP U329 EP U329 PG 1 WC Ophthalmology SC Ophthalmology GA 846TA UT WOS:000223338000710 ER PT J AU Wistow, G Dong, L Wyatt, K Kuszak, J Bernstein, S David, L Riviere, M AF Wistow, G Dong, L Wyatt, K Kuszak, J Bernstein, S David, L Riviere, M TI gamma S and gamma N-crystallin: Function and evolution in the gamma-crystallin family. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Bethesda, MD 20892 USA. Rush Univ, Sch Med, Chicago, IL 60612 USA. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3377 BP U120 EP U120 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338200577 ER PT J AU Yu, C Mahdi, R Mameza, M Vistica, B Chen, J Gery, I Egwuagu, CE AF Yu, C Mahdi, R Mameza, M Vistica, B Chen, J Gery, I Egwuagu, CE TI STAT1 and suppressors of cytokine signaling (SOCS) negatively regulate STAT6 signaling and growth of Th2 cells SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, Immunol Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3440 BP U138 EP U138 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338200640 ER PT J AU Zhao, X Russel, P AF Zhao, X Russel, P TI Proteomic and gene Microarray analyses of the effects of TGF beta on human trabecular meshwork cells SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 4377 BP U433 EP U433 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338201569 ER PT J AU Zhu, X Brown, B Rife, L Raskin, J Wang, XP Loh, YP Craft, CM AF Zhu, X Brown, B Rife, L Raskin, J Wang, XP Loh, YP Craft, CM TI Carboxypeptidase E knockout mice have abnormal retinal function SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol C1 USC, Keck Sch Med, Mary D Allen Lab Vis Res, Doheny Eye Inst, Los Angeles, CA USA. NICHD, Sect Cellular Neurobiol, Dev Neurobiol Lab, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2004 VL 45 SU 2 MA 3593 BP U175 EP U175 PG 1 WC Ophthalmology SC Ophthalmology GA 846TC UT WOS:000223338200786 ER PT J AU Anastos, K Shi, QH French, AL Levine, A Greenblatt, RM Williams, C DeHovitz, J Delapenha, R Hoover, DR AF Anastos, K Shi, QH French, AL Levine, A Greenblatt, RM Williams, C DeHovitz, J Delapenha, R Hoover, DR TI Total lymphocyte count, hemoglobin, and delayed-type hypersensitivity as predictors of death and AIDS illness in HIV-1-infected women receiving highly active antiretroviral therapy SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; highly active antiretroviral therapy; survival; disease progression; total lymphocyte count ID RESOURCE-LIMITED SETTINGS; HIV-INFECTED PATIENTS; CD4 CELL COUNT; DISEASE PROGRESSION; NUTRITIONAL-STATUS; INTERAGENCY HIV; VIRAL LOAD; ANERGY; ANEMIA; RELIABILITY AB Background: Total lymphocyte count (TLC) and hemoglobin level have been suggested as useful and inexpensive parameters to indicate need for HAART in settings in which CD4(+) cell counts are unavailable. If delayed-type hypersensitivity (DTH) response predicts clinical response in persons using highly active antiretroviral therapy (HAART), it may also prove useful in resource-poor settings. Objective: To examine whether TLC, hemoglobin, and DTH response observed prior to initiation of HAART predict post-HAART clinical response. Design: Prospective cohort study. Participants: 873 women in the Women's Interagency HIV Study. Measurements: TLC, hemoglobin, CD4(+) cell counts, and DTH testing using mumps, candida, and tetanus toxoid antigens, performed within 1 year prior to HAART initiation; death; self-report of initiation of HAART use and AIDS-defining illness (ADI). Results: Three different multivariate analyses were performed: 2 models that excluded CD4(+) cell count and assessed TLC at either <850 or <1250 cells/muL, and 1 model that excluded TLC and included CD4(+) <200 cells/muL. TLC <850, TLC <1250, CD4(+) <200 cells/muL, anergy to DTH testing, hemoglobin <10.6 g/dL, and a pre-HAART report of ADI were each consistently independently associated both with death and with incident ADI. Log likelihood chi(2) values suggested similar power among the 3 models in predicting both death and incident ADI. Conclusions: Pre-HAART TLC, hemoglobin level, anergy to DTH testing, and clinical disease each independently predicted morbidity and death after HAART initiation. These findings support the use of TLC to guide decision-making for HAART initiation and suggest that further study of TLC, hemoglobin level, and DTH responses as an indication to provide HAART may be useful in resource-limited settings. C1 Montefiore Med Ctr, Womens Interagcy HIV Study, Bronx, NY 10467 USA. Lincoln Med & Mental Hlth Ctr, Bronx, NY 10451 USA. New York Med Coll, Valhalla, NY 10595 USA. Cook Cty Hosp, Rush Med Coll, Chicago, IL USA. Univ So Calif, Los Angeles, CA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NIAID, NIH, Bethesda, MD USA. Hlth Sci Ctr, Brooklyn, NY USA. Howard Univ, Med Ctr, Washington, DC USA. Rutgers State Univ, Dept Stat, New Brunswick, NJ USA. Rutgers State Univ, Inst Hlth, Hlth Care Policy & Aging Res, New Brunswick, NJ USA. RP Anastos, K (reprint author), Montefiore Med Ctr, Womens Interagcy HIV Study, 3311 Bainbridge Ave, Bronx, NY 10467 USA. EM kanastos@montefiore.org FU NCRR NIH HHS [M01-RR-00079, M01-RR-00083]; NIAID NIH HHS [N01-AI-35161, U01-AI-31834, U01-AI-34989, U01-AI-34993, U01-AI-34994, U01-AI-35004, U01-AI-42590]; NICHD NIH HHS [U01-HD-32632] NR 37 TC 33 Z9 35 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD APR 1 PY 2004 VL 35 IS 4 BP 383 EP 392 DI 10.1097/00126334-200404010-00008 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 805PV UT WOS:000220379100008 PM 15097155 ER PT J AU Ialongo, N McCreary, BK Pearson, JL Koenig, AL Schmidt, NB Poduska, J Kellam, SG AF Ialongo, N McCreary, BK Pearson, JL Koenig, AL Schmidt, NB Poduska, J Kellam, SG TI Major depressive disorder in a population of urban, African-American young adults: prevalence, correlates, comorbidity and unmet mental health service need SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE major depression; African-Americans; young adults ID PSYCHIATRIC-DISORDERS; SOCIOECONOMIC-STATUS; UNITED-STATES; BLACKS; WHITES AB Background: The U.S. Surgeon General recently highlighted the relative dearth of research on the mental health of minority populations in the U.S. The present report describes the prevalence of major depressive disorder (MDD) in an epidemiologically-defined population of 1197, predominately poor, African-American 19-22-year-olds, living in the greater Baltimore, MD metropolitan area. Method: The prevalence and correlates of MDD, its comorbidity with other mental and substance disorders, and unmet mental health service need were assessed via a structured clinical interview administered by lay interviewers. Results: Using DSM-IV criteria, the overall prevalence of lifetime MDD for the study population was 9.4%, whereas the last year and last month prevalences were 6.2 and 2.7%, respectively. Females were approximately 1.6 times more likely to report a lifetime episode of MDD than males. MDD was highly comorbid with substance disorders. Just under 10% of those who had experienced an episode of MDD within the last year reported receiving mental health specialty services within the last year. Limitations: A major limitation was the reliance on a single interview conducted by a lay interviewer as opposed to a comprehensive psychiatric assessment carried out by a highly trained clinician, integrating information on symptoms and functioning from multiple sources. Conclusions: The lifetime prevalence of MDD found in the present study suggests that it is a significant mental health problem in the African-American young adults studied, particularly amongst women. Moreover, most episodes of MDD went untreated. (C) 2003 Elsevier B.V. All rights reserved. C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hyg, Baltimore, MD 21205 USA. Ohio State Univ, Dept Psychol, Columbus, OH USA. Natl Inst Mental Hlth, Bethesda, MD USA. Amer Inst Res, Washington, DC USA. RP Ialongo, N (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hyg, 624 N Broadway,Room 809, Baltimore, MD 21205 USA. EM nialongo@jhsph.edu FU NIMH NIH HHS [R01 MH42968, T32MH18834] NR 17 TC 21 Z9 22 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD APR PY 2004 VL 79 IS 1-3 BP 127 EP 136 DI 10.1016/S0165-0327(02)00456-1 PG 10 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 806BM UT WOS:000220409400013 PM 15023487 ER PT J AU Preston, GA Marchant, BK Reimherr, FW Strong, RE Hedges, DW AF Preston, GA Marchant, BK Reimherr, FW Strong, RE Hedges, DW TI Borderline personality disorder in patients with bipolar disorder and response to lamotrigine SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE lamotrigine; bipolar; borderline personality disorder ID DEFICIT HYPERACTIVITY DISORDER; DOUBLE-BLIND; DIVALPROEX SODIUM; EFFICACY; ANTICONVULSANTS; PHARMACOTHERAPY; COMORBIDITY; DEPRESSION; DYSTHYMIA; ONSET AB Background: Recent reports suggesting lamotrigine as an effective treatment in bipolar disorder, and perhaps borderline personality disorder, a common comorbid personality disorder in bipolar patients, led us to retrospectively examine patients from two bipolar studies to investigate this pattern of comorbidity, and to determine whether lamotrigine effected the dimensions of borderline personality. Methods: Fifteen months following entry into either study, we retrospectively assessed DSM-IV dimensions of borderline personality disorder pre- and post-treatment with lamotrigine in 35 bipolar patients. Results: Forty percent met criteria for borderline personality disorder; this subgroup had a more frequent history of substance abuse and childhood symptoms of attention deficit hyperactivity disorder (ADHD). Dimensions of borderline personality improved significantly with treatment in both patient groups, and corresponded with response of bipolar symptoms. Six (43%) comorbid bipolar patients endorsed three or fewer criteria of borderline personality during treatment with lamotrigine. There was a trend for comorbid bipolar patients to require a second psychoactive medication in addition to lamotrigine during extended treatment. Limitations: Criteria for borderline personality and improvement were assessed retrospectively in an open manner. Conclusions: Dimensions of borderline personality disorder may respond to lamotrigine in comorbid bipolar patients, controlled studies appear warranted. Bipolar studies should assess and specify the number of patients with personality disorders in the trial. (C) 2002 Elsevier B.V. All rights reserved. C1 Univ Utah, Sch Med, Dept Psychiat, Mood Disorders Clin, Salt Lake City, UT 84112 USA. RP Preston, GA (reprint author), NIMH, Clin Brain Disorders Branch, 10 Ctr Dr,Room 4S235,MSC1379, Bethesda, MD 20892 USA. EM prestong@intra.nimh.nih.gov NR 23 TC 44 Z9 45 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD APR PY 2004 VL 79 IS 1-3 BP 297 EP 303 DI 10.1016/S0165-0327(02)00358-0 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 806BM UT WOS:000220409400037 PM 15023511 ER PT J AU Chinen, J Puck, JM AF Chinen, J Puck, JM TI Successes and risks of gene therapy in primary immunodeficiencies SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE primary immunodeficiency; gene therapy; insertional mutagenesis; retroviral vector; LMO2; X-linked severe combined immunodeficiency; adenosine deaminase; severe combined immunodeficiency ID WISKOTT-ALDRICH-SYNDROME; CHRONIC GRANULOMATOUS-DISEASE; STEM-CELL TRANSPLANTATION; ADENOSINE-DEAMINASE DEFICIENCY; HEMATOPOIETIC PROGENITOR CELLS; X-CHROMOSOME INACTIVATION; T-CELL; BONE-MARROW; SUSTAINED CORRECTION; CD34(+) CELLS AB Several primary immunodeficiencies are under consideration for gene therapy approaches because of limitations of current standard treatment. Many primary immunodeficiencies are caused by defects in single genes expressed in blood cells; thus addition of a correct copy of the gene to hematopoietic stem cells (HSCs) can generate immune cells with restored function. HSCs can be removed from a patient, treated outside the body, and reinfused. In the last decade, significant improvements have been made in transferring genes by means of retroviruses to HSCs in vitro, and gene therapy trials for patients with X-linked severe combined immunodeficiency (XSCID) and adenosine deaminase-deficient severe combined immunodeficiency have restored immune competence. Gene therapy is actively being pursued in other immunodeficiency disorders, including chronic granulomatous disease and Wiskott-Aldrich syndrome. However, enthusiasm for the correction of XSCID by means of gene therapy has been tempered by the occurrence of 2 cases of leukemia in gene therapy recipients caused by insertion of the retroviral vector in or near the oncogene LMO2. The likelihood of retroviral insertional mutagenesis was estimated to be very low in the past on the basis of theoretic calculations and the absence of observed malignancies in animal studies and early clinical trials. Emerging new findings on retroviral integration both in the patients with XSCID and experimental animals now indicate that the insertion of retroviral sequences into the genome carries significant risk. Understanding the magnitude of risk is now a priority so that safety can be improved for future gene therapy clinical trials. C1 NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Puck, JM (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, Bldg 49,Rm 4A14,49 Convent Dr, Bethesda, MD 20892 USA. NR 85 TC 19 Z9 20 U1 0 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD APR PY 2004 VL 113 IS 4 BP 595 EP 603 DI 10.1016/j.jaci.2004.01.765 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA 814DY UT WOS:000220956600002 PM 15100660 ER PT J AU Seeborg, FO Paul, ME Abramson, SL Kearney, DL Dorfman, SR Holland, SM Shearer, WT AF Seeborg, FO Paul, ME Abramson, SL Kearney, DL Dorfman, SR Holland, SM Shearer, WT TI A 5-week-old HIV-1-exposed girl with failure to thrive and diffuse nodular pulmonary infiltrates SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE chronic granulomatous disease; HIV; pulmonary infiltrates; failure to thrive; infant ID CHRONIC GRANULOMATOUS-DISEASE; IMMUNODEFICIENCY-VIRUS INFECTION; LYMPHOID INTERSTITIAL PNEUMONIA; ACQUIRED HIV-INFECTION; CHILDREN BORN; ASPERGILLUS-NIDULANS; AFRICAN CHILDREN; LUNG; INFANTS; MANIFESTATIONS AB A 5-week-old female infant with vertical HIV-1 exposure, progressive cough, and failure to thrive was given a diagnosis of bilateral diffuse nodular lung lesions. The child was without fever, leukocytosis, anemia, peripheral adenopathy, or hepatosplenomegaly, and the results of repeated blood tests for HIV-1 DNA were negative. A needle biopsy of the lungs revealed granulomatous inflammation and giant cells, with fungal organisms suggestive of Aspergillus species. A nitroblue tetrazolium dye test performed on the patient's blood specimen demonstrated absence of dye reduction, suggesting a diagnosis of chronic granulomatous disease. Further analysis revealed that the child had a deficiency of the p47(phox) component of the nicotinamide adenine dinucleotide phosphate oxidase system. Thus this child with vertical HIV-1 exposure and diffuse pulmonary nodules actually had an autosomal recessive form of chronic granulomatous disease. This case study clearly demonstrates that children with suspected HIV-1 infection might also need evaluation for primary immunodeficiency and that the clinical immunology laboratory is a powerful adjunct in coming to a correct diagnosis. C1 Texas Childrens Hosp, Houston, TX 77030 USA. Baylor Coll Med, Dept Pediat, Sect Allergy & Immunol, Houston, TX 77030 USA. Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. Baylor Coll Med, Dept Radiol, Houston, TX 77030 USA. NIAID, Host Def Lab, Bethesda, MD 20892 USA. RP Seeborg, FO (reprint author), Texas Childrens Hosp, 6621 Fannin St, Houston, TX 77030 USA. FU NCRR NIH HHS [RR 0188]; NHLBI NIH HHS [HL 72705]; NIAID NIH HHS [AI 27551, AI 36211]; NICHD NIH HHS [HD 41983] NR 44 TC 4 Z9 4 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD APR PY 2004 VL 113 IS 4 BP 627 EP 634 DI 10.1016/j.jaci.2004.01.763 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 814DY UT WOS:000220956600007 PM 15100665 ER PT J AU Orange, JS Jain, A Ballas, ZK Schneider, LC Geha, RS Bonilla, FA AF Orange, JS Jain, A Ballas, ZK Schneider, LC Geha, RS Bonilla, FA TI The presentation and natural history of immunodeficiency caused by nuclear factor kappa B essential modulator mutation SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE nuclear factor kappa B essential modulator; primary immunodeficiency; nuclear factor kappa B; innate immunity; ectodermal dysplasia; hypogammaglobulinemia; mycobacteria; natural killer cells; combined immunodeficiency ID ANHIDROTIC ECTODERMAL DYSPLASIA; INCONTINENTIA PIGMENTI; CELL CYTOTOXICITY; IMMUNE-DEFICIENCY; MICE LACKING; IKK-ALPHA; PROTEIN; GENE; NEMO; IGM AB Background: An increasing number of rare genetic defects are associated with immunodeficiency and impaired ability to activate gene transcription through nuclear factor (NF) kappaB. Hypomorphic mutations in the NFkappaB essential modulator (NEMO) impair NFkappaB function and are linked to both immunodeficiency and ectodermal dysplasia (ED), as well as susceptibility to atypical mycobacterial infections. Objective: We sought to investigate the clinical and immunologic natural history of patients with NEMO mutation with immunodeficiency (NEMO-ID). Methods: Patients with severe bacterial infection and ED or unexplained mycobacterial sensitivity were evaluated for NEMO mutation. Laboratory investigations and clinical data were retrospectively and prospectively accumulated and reviewed. Results: We have given a diagnosis of NEMO-ID to 7 boys; 6 had ED, and 5 had gene mutations in the 10th exon of NEMO. Our resulting estimated incidence of NEMO-ID is 1:250,000 live male births. All patients had serious pyogenic bacterial illnesses early in life, and the median age of first infection was 8.1 months. Most boys had mycobacterial disease (median age, 84 months), and a minority had herpesviral infections. Initial immunologic assessments showed hypogammaglobulinemia (median IgG, 170 mg/dL) with variable IgM (median, 41 mg/dL) and IgA (median, 143 mg/dL) levels. Two patients had increased IgM levels, and 5 had increased IgA levels. All patients evaluated had normal lymphocyte subsets with impaired proliferative responses, specific antibody production, and natural killer cell function. Two patients died from complications of mycobacterial disease (ages 21 and 33 months). Conclusion: NEMO-ID is a combined immunodeficiency with early susceptibility to pyogenic bacteria and later susceptibility to mycobacterial infection. Specific features of particular NEMO mutations in these patients provide insight into the role of this gene in immune function. C1 Childrens Hosp, Div Immunol, Boston, MA 02115 USA. NIH, Bethesda, MD 20892 USA. Univ Iowa, Iowa City, IA USA. RP Bonilla, FA (reprint author), Childrens Hosp, Div Immunol, 300 Longwood Ave, Boston, MA 02115 USA. RI Orange, Jordan/D-5239-2009; OI orange, jordan/0000-0001-7117-7725 FU NCRR NIH HHS [M01 RR 02172]; NIAID NIH HHS [AI 55602, AI 31541, AI 31136] NR 36 TC 108 Z9 112 U1 0 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD APR PY 2004 VL 113 IS 4 BP 725 EP 733 DI 10.1016/j.jaci.2004.01.762 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA 814DY UT WOS:000220956600022 PM 15100680 ER PT J AU Gustafson, RA Kim, I Stout, PR Klette, KL George, MP Moolchan, ET Levine, B Huestis, MA AF Gustafson, RA Kim, I Stout, PR Klette, KL George, MP Moolchan, ET Levine, B Huestis, MA TI Urinary pharmacokinetics of 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol after controlled oral Delta(9)-tetrahydrocannabinol administration SO JOURNAL OF ANALYTICAL TOXICOLOGY LA English DT Article ID EXCRETION HALF-LIFE; CANNABIS SEED OIL; MARIJUANA USERS; FOOD-PRODUCTS; GC-MS; TETRAHYDROCANNABINOL; METABOLISM; INGESTION; DELTA-9-TETRAHYDROCANNABINOL; CONSUMPTION C1 NIDA, CDM, IRP, NIH, Baltimore, MD 21224 USA. Aegis Sci Corp, Nashville, TN 37210 USA. Navy Drug Screening Lab, Jacksonville, FL 32212 USA. Quest Diagnost Inc, Schaumburg, IL 60173 USA. Univ Maryland, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. RP Huestis, MA (reprint author), NIDA, CDM, IRP, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov NR 36 TC 25 Z9 27 U1 3 U2 9 PU PRESTON PUBLICATIONS INC PI NILES PA 7800 MERRIMAC AVE PO BOX 48312, NILES, IL 60648 USA SN 0146-4760 J9 J ANAL TOXICOL JI J. Anal. Toxicol. PD APR PY 2004 VL 28 IS 3 BP 160 EP 167 PG 8 WC Chemistry, Analytical; Toxicology SC Chemistry; Toxicology GA 809XX UT WOS:000220670500003 PM 15107145 ER PT J AU Masse, LC Fulton, JE Watson, KL Mahar, MT Meyers, MC Wong, WW AF Masse, LC Fulton, JE Watson, KL Mahar, MT Meyers, MC Wong, WW TI Influence of body composition on physical activity validation studies using doubly labeled water SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE accelerometer; physical activity diary; energy expenditure; physical activity energy expenditure ID RESTING METABOLIC-RATE; ENERGY-EXPENDITURE; ACTIVITY QUESTIONNAIRES; MOVEMENT REGISTRATION; ACTIVITY DIARY; WOMEN AB This study investigated the influence of two approaches ( mathematical transformation and statistical procedures), used to account for body composition [ body mass or fat-free mass (FFM)], on associations between two measures of physical activity and energy expenditure determined by doubly labeled water (DLW). Complete data for these analyses were available for 136 African American (44.1%) and Hispanic (55.9%) women ( mean age 50 +/- 7.3 yr). Total energy expenditure ( TEE) by DLW was measured over 14 days. Physical activity energy expenditure (PAEE) was computed as 0.90 x TEE - resting metabolic rate. During week 2, participants wore an accelerometer for 7 consecutive days and completed a 7-day diary. Pearson's product-moment correlations and three statistical procedures ( multiple regressions, partial correlations, and allometric scaling) were used to assess the effect of body composition on associations. The methods-comparison analysis was used to study the effect of body composition on agreement. The statistical procedures demonstrated that associations improved when body composition was included in the model. The accelerometer explained a small but meaningful portion of the variance in TEE and PAEE after body mass was accounted for. The methods-comparison analysis confirmed that agreement with DLW was affected by the transformation. Agreement between the diary ( transformed with body mass) and TEE reflected the association that exists between body mass and TEE. These results suggest that the accelerometer and diary accounted for a small portion of TEE and PAEE. Most of the variance in DLW-measured energy expenditure was explained by body mass or FFM. C1 NCI, Behav Res Program, Hlth Promot Res Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Atlanta, GA 30341 USA. Baylor Coll Med, Houston, TX 77030 USA. E Carolina Univ, Greenville, NC 27858 USA. W Texas A&M Univ, Canyon, TX 79016 USA. RP Masse, LC (reprint author), NCI, Behav Res Program, Hlth Promot Res Branch, Div Canc Control & Populat Sci, EPN 4076,MSC 7335,6130 Execut Blvd, Bethesda, MD 20892 USA. FU ODCDC CDC HHS [U48/CC609653] NR 34 TC 31 Z9 31 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD APR 1 PY 2004 VL 96 IS 4 BP 1357 EP 1364 DI 10.1152/japplphysiol.00901.2003 PG 8 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 801YE UT WOS:000220130400014 PM 14660509 ER PT J AU Ostberg, Y Carroll, JA Pinne, M Krum, JG Rosa, P Bergstrom, S AF Ostberg, Y Carroll, JA Pinne, M Krum, JG Rosa, P Bergstrom, S TI Pleiotropic effects of inactivating a carboxyl-terminal protease, CtpA, in Borrelia burgdorferi SO JOURNAL OF BACTERIOLOGY LA English DT Article ID II REACTION-CENTER; PENICILLIN-BINDING PROTEIN-3; SYNECHOCYSTIS SP PCC-6803; LYME-DISEASE SPIROCHETE; OUTER-MEMBRANE PROTEIN; TAIL-SPECIFIC PROTEASE; PHOTOSYSTEM-II; PROCESSING PROTEASE; D1 PROTEIN; SCENEDESMUS-OBLIQUUS AB A gene encoding a putative carboxyl-terminal protease (CtpA), an unusual type of protease, is present in the Borrelia burgdorferi B31 genome. The B. burgdorferi CtpA amino acid sequence exhibits similarities to the sequences of the CtpA enzymes of the cyanobacterium Synechocystis sp. strain PCC 6803 and higher plants and also exhibits similarities to the sequences of putative CtpA proteins in other bacterial species. Here, we studied the effect of ctpA gene inactivation on the B. burgdorferi protein expression profile. Total B. burgdorferi proteins were separated by two-dimensional gel electrophoresis, and the results revealed that six proteins of the wild type were not detected in the ctpA mutant and that nine proteins observed in the ctpA mutant were undetectable in the wild type. Immunoblot analysis showed that the integral outer membrane protein P13 was larger and had a more acidic pI in the ctpA mutant, which is consistent with the theoretical change in pI for P13 not processed at the carboxyl terminus. Matrix-assisted laser desorption ionization-time of flight data indicated that in addition to P13, the BB0323 protein may serve as a substrate for carboxyl-terminal processing by CtpA. Complementation analysis of the ctpA mutant provided strong evidence that the observed effect on proteins depended on inactivation of the ctpA gene alone. We show that CtpA in B. burgdorferi is involved in the processing of proteins such as P13 and BB0323 and that inactivation of ctpA has a pleiotropic effect on borrelial protein synthesis. To our knowledge, this is the first analysis of both a CtpA protease and different substrate proteins in a pathogenic bacterium. C1 Umea Univ, Dept Biol Mol, SE-90187 Umea, Sweden. Univ Pittsburgh, Sch Med, Dept Mol Genet & Biochem, Pittsburgh, PA 15261 USA. NIAID, Lab Human Bacteriol Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Bergstrom, S (reprint author), Umea Univ, Dept Biol Mol, SE-90187 Umea, Sweden. EM sven.bergstrom@molbiol.umu.se NR 62 TC 27 Z9 28 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD APR PY 2004 VL 186 IS 7 BP 2074 EP 2084 DI 10.1128/JB.186.7.2074-2084.2004 PG 11 WC Microbiology SC Microbiology GA 805JS UT WOS:000220363200019 PM 15028692 ER PT J AU Brendler, T Reaves, L Austin, S AF Brendler, T Reaves, L Austin, S TI Interplay between plasmid partition and postsegregational killing systems SO JOURNAL OF BACTERIOLOGY LA English DT Article ID LARGE VIRULENCE PLASMID; PROGRAMMED CELL-DEATH; BACTERIAL PLASMIDS; SHIGELLA-FLEXNERI; MAINTENANCE; SEQUENCE; REGION; SITE; DNA; P1 AB Active partition systems and postsegregational killing (PSK) systems are present together in naturally occurring low-copy-number plasmids. Theory suggests that PSK may act as the ultimate determinant of plasmid retention, whereas the partition system may minimize the growth penalty to the host, resulting in a near-ideal symbiosis when the systems combine. Here, we prove the validity of this principle for a specific case involving the P1par system and the mvp PSK system. C1 GRCBL, NCI Frederick, NCI, Ft Detrick, MD 21702 USA. RP Austin, S (reprint author), GRCBL, NCI Frederick, NCI, PO Box B, Ft Detrick, MD 21702 USA. EM austin@ncifcrf.gov NR 14 TC 10 Z9 11 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD APR PY 2004 VL 186 IS 8 BP 2504 EP 2507 DI 10.1128/JB.186.8.2504-2507.2004 PG 4 WC Microbiology SC Microbiology GA 809ZE UT WOS:000220673800035 PM 15060057 ER PT J AU Shikanov, A Vaisman, B Krasko, MY Nyska, A Domb, AJ AF Shikanov, A Vaisman, B Krasko, MY Nyska, A Domb, AJ TI Poly(sebacic acid-co-ricinoleic acid) biodegradable carrier for paclitaxel: In vitro release and in vivo toxicity SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A LA English DT Article DE biodegradable polymer; implant; paclitaxel; poly(ester anhydride); toxicity ID DRUG-DELIVERY; FORMULATIONS; POLYANHYDRIDES; BIOPOLYMERS; TAXOL AB Polyesteranhyd rides synthesized by the transesterification of ricinoleic acid and sebacic acid followed by anhydride polymerization were examined as potential controlled delivery carrier for paclitaxel. Solid and liquid polymers were used. Polymers containing 30% ricinoleic acid are solid whereas polymers containing 70% ricinoleic acid are liquid at body temperature and semisolid at room temperature. It was found that upon addition of the liquid polymer to water it solidifies to form a stable semisolid. Paclitaxel, a potent antitumor agent, was incorporated in the polymers (5-20% w/w) and its release in buffer solution was monitored. Paclitaxel was released for over 100 days while the polymer carrier was being degraded. The release rate was affected by the paclitaxel content; the higher the content, the slower was the release. The toxicity of the polymers and formulations with paclitaxel was examined by subcutaneous injection of liquid polymer samples or implantation of solid polymer specimens to mice for different time periods. Histopathological examination of the tissue surrounding the implant showed minor inflammation 1 week after the injection and no inflammation 3 weeks after implantation. Injection of the polymer without paclitaxel showed no adverse effects. (C) 2004 Wiley Periodicals, Inc. C1 Hebrew Univ Jerusalem, Fac Med, Sch Pharm, Dept Med Chem & Nat Prod, IL-91120 Jerusalem, Israel. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. RP Domb, AJ (reprint author), Hebrew Univ Jerusalem, Fac Med, Sch Pharm, Dept Med Chem & Nat Prod, IL-91120 Jerusalem, Israel. EM adomb@md.huji.ac.il NR 19 TC 56 Z9 59 U1 0 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9304 J9 J BIOMED MATER RES A JI J. Biomed. Mater. Res. Part A PD APR 1 PY 2004 VL 69A IS 1 BP 47 EP 54 DI 10.1002/jbm.a.20101 PG 8 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 803IK UT WOS:000220224600006 PM 14999750 ER PT J AU Leet, AI Chebli, C Kushner, H Chen, CC Kelly, MH Brillante, BA Robey, PG Bianco, P Wientroub, S Collins, MT AF Leet, AI Chebli, C Kushner, H Chen, CC Kelly, MH Brillante, BA Robey, PG Bianco, P Wientroub, S Collins, MT TI Fracture incidence in polyostotic fibrous dysplasia and the McCune-Albright Syndrome SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article ID STIMULATORY G-PROTEIN; INTRAVENOUS PAMIDRONATE; ACTIVATING MUTATIONS; NATURAL-HISTORY; BONE; GENE; ABNORMALITIES; DYSFUNCTION; CALCITONIN; CHILDREN AB In patients with polyostotic fibrous dysplasia of bone, the peak incidence of fractures is during the first decade of life, followed by a decrease thereafter. Phosphaturia is associated with an earlier incidence and increased frequency of fractures. Introduction: Fibrous dysplasia (FD) is a disorder involving either one (monostotic) or several bones (polyostotic FD [PFD] and sometimes is associated with cafe-au-lait hyperpigmentation of the skin and one or more hyperfunctioning endocrinopathies (McCune-Albright syndrome [MAS]). Both PFD and MAS are often associated with phosphaturia. Although fractures occur frequently in PFD/MAS, fracture incidence and the effect of age and co-existing metabolic abnormalities (endocrinopathy and/or phosphaturia) on fractures are ill defined. Materials and Methods: We reviewed the medical records and examined the endocrine and phosphorus metabolism of 35 patients with PFD/MAS. We report on the age at which extremity fractures occurred and their location and treatment. The results of endocrine and phosphorus metabolism testing and associations between age of first fractures, number of fractures, fracture rate, and metabolic abnormalities were noted. Results: The average follow-up was 14.2 years (range, 2-39 years), during which 172 fractures occurred. The number and sites of fractures were 103 femoral, 25 tibial, 33 humeral, and 11 forearm. Twenty-seven patients had PFD with one or more endocrinopathies and/or phosphaturia, and eight had PFD alone. The endocrinopathies included precocious puberty (n = 19), hyperthyroidism (n = 9), growth hormone excess (n = 6), and one patient each with Cushing syndrome and primary hyperparathyroidism. Twelve patients had phosphaturia. The peak rate of fractures occurred between 6 and 10 years of age and decreased thereafter. Patients with metabolic abnormalities sustained their first fracture at an earlier age (6.9 versus 16.6 years, p < 0.005) and had a higher lifetime rate of fractures (0.29 versus 0.08 fractures/year), relative to patients with PFD alone. Phosphaturia was the single metabolic dysfunction associated with both an earlier age of first fracture (5.1 versus 16.6 years, p < 0.05) and a greater lifetime fracture rate (0.35 versus 0.08 fractures/year, p < 0.05). Conclusions: The occurrence of extremity fractures in FD peaks between 6 and 10 years of age and declines thereafter. Fractures occur earlier and more frequently in the presence of phosphaturia. These data have implications for long-term prognosis, clinical management, and interpretation of therapeutic interventions. C1 NIDCR, CSDB, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Johns Hopkins Univ, Div Pediat Orthoped, Dept Orthoped, Baltimore, MD USA. Univ Maryland, Dept Orthopaed Surg, Baltimore, MD 21201 USA. Biomed Comp Res Inst, Philadelphia, PA USA. NIH, Dept Nucl Med, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIH, Nursing Serv, Warren Grant Magnuson Clin Ctr, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Roma La Sapienza, Dipartimento Med Sperimentale & Patol, Rome, Italy. Tel Aviv Univ, Ctr Med, Dana Childrens Hosp, Dept Pediat Orthopaed Surg, IL-69978 Tel Aviv, Israel. RP Collins, MT (reprint author), NIDCR, CSDB, NIH, Dept Hlth & Human Serv, Bldg 30,Room 228,MSC 4320, Bethesda, MD 20892 USA. EM mc247k@nih.gov RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 44 TC 56 Z9 63 U1 2 U2 2 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD APR PY 2004 VL 19 IS 4 BP 571 EP 577 DI 10.1359/JBMR.0301262 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 804ZD UT WOS:000220335700008 PM 15005844 ER PT J AU Hu, JX Mora, S Weber, G Zamproni, I Proverbio, MC Spiegel, AM AF Hu, JX Mora, S Weber, G Zamproni, I Proverbio, MC Spiegel, AM TI Autosomal dominant hypocalcemia in monozygotic twins caused by a De Novo germline mutation near the amino-terminus of the human calcium receptor SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE autosomal dominant hypocalcemia; human calcium receptor; activating mutation; Venus flytrap-like domain; loop 2 ID NEONATAL SEVERE HYPERPARATHYROIDISM; SENSING RECEPTOR; CA2+-SENSING RECEPTOR; EXTRACELLULAR DOMAIN; GENE; HYPERCALCEMIA AB To define the molecular pathogenesis of severe postnatal hypocalcemia in monozygotic twin sisters, we sequenced their CaR gene and identified a missense mutation, K29E. Expression of the mutant receptor in vitro showed a marked increase in Ca2+ sensitivity explaining the observed phenotype. Additional mutagenesis studies lead us to speculate concerning a novel mechanism whereby the K29E mutation may lead to receptor activation. Introduction: Activating mutations of the Ca2+-sensing receptor (CaR) gene have been identified in subjects with autosomal dominant hypocalcemia. Study of such mutations has provided insight into the mechanism of activation of the CaR. Materials and Methods: We performed biochemical and molecular genetic studies on monozygotic twin sisters who presented with early postnatal hypocalcemia and on their unaffected sister and parents. Functional characterization of mutant CaRs transfected in HEK-293 cells included immunoblots to monitor protein expression and Ca2+ stimulation of phosphoinositide hydrolysis to measure Ca2+ sensitivity. Results: We identified a K29E missense mutation in the twin sisters but not in their parents or unaffected sister. The K29E mutant CaR showed a marked increase in Ca2+ sensitivity, including when it was co-transfected with wildtype CaR cDNA, consistent with a dominant effect. Substitution of K 29 by aspartate equivalently increased CaR sensitivity, whereas conservative substitution by arginine did not. Conclusions: Severe postnatal hypocalcemia in the twin sisters was caused by a de novo germline activating mutation. In a model of the Venus flytrap-like domain of the extracellular amino-terminus of the CaR, K 29 is located close to a peptide loop, "loop 2," that forms part of the dimer interface and is the site of 10 of the previously reported naturally occurring activating CaR mutations. We speculate that K29E increases Ca2+ sensitivity of the CaR by disrupting a salt bridge between K 29 and an acidic residue in loop 2 and thereby changes the normal structure of loop 2 that maintains the CaR in its inactive conformation. C1 Natl Inst Deafness & Other Commun Disorders, Mol Pathophysiol Sect, NIH, Bethesda, MD 20892 USA. Vita Salute San Raffaele Univ, Lab Pediat Endocrinol, Milan, Italy. Vita Salute San Raffaele Univ, Dept Pediat, Milan, Italy. Univ Milan, Dipartimento Sci & Tecnol Biomed, Milan, Italy. RP Hu, JX (reprint author), Natl Inst Deafness & Other Commun Disorders, Mol Pathophysiol Sect, NIH, Bldg 10,Room 8C-101,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jianxinh@intra.niddk.nih.gov RI Mora, Sefano/B-2143-2013; OI WEBER, Giovanna/0000-0002-2172-381X NR 17 TC 21 Z9 21 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD APR PY 2004 VL 19 IS 4 BP 578 EP 586 DI 10.1359/JBMR.040106 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 804ZD UT WOS:000220335700009 PM 15005845 ER PT J AU Kozloff, KM Carden, A Bergwitz, C Forlino, A Uveges, TE Morris, MD Marini, JC Goldstein, SA AF Kozloff, KM Carden, A Bergwitz, C Forlino, A Uveges, TE Morris, MD Marini, JC Goldstein, SA TI Brittle IV mouse model for osteogenesis imperfecta IV demonstrates postpubertal adaptations to improve whole bone strength SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE biomechanics; osteogenesis imperfecta; collagen; knock-in; mouse model ID CORTICAL BONE; MECHANICAL-PROPERTIES; PARATHYROID-HORMONE; MINERALIZED TISSUES; FATIGUE BEHAVIOR; MICE; COLLAGEN; FORM; MUTATION; OSTEOPOROSIS AB The Brtl mouse model for type IV osteogenesis imperfecta improves its whole bone strength andstiffness between 2 and 6 months of age. This adaptation is accomplished without a corresponding improvement in geometric resistance to bending, suggesting an improvement in matrix material properties. Introduction: The Brittle IV (Brtl) mouse was developed as a knock-in model for osteogenesis imperfecta (OI) type IV. A Gly349Cys substitution was introduced into one col1a1 allele, resulting in a phenotype representative of the disease. In this study, we investigate the effect of the Brtl mutation on whole bone architecture, strength, and composition across a range of age groups. Materials and Methods: One-, 2-, 6-, and 12-month-old Brtl and wildtype (WT) mice were analyzed. Femurs were assessed at the central diaphysis for cortical geometric parameters using muCT and were subsequently mechanically tested to failure by four-point bending. Matrix material properties were predicted using muCT data to normalize data from mechanical tests. Raman spectroscopy and DXA were used to assess matrix composition. Results: Our findings show a postpubertal adaptation in which Brtl femoral strength and stiffness increase through a mechanism independent of changes in whole bone geometry. These findings suggest an improvement in the material properties of the bone matrix itself, rather than improvements in whole bone geometry, as seen in previous mouse models of OI. Raman spectroscopic results suggest these findings may be caused by changes in mineral/matrix balance rather than improvements in mineral crystallinity. Conclusions: Our findings parallel the currently unexplained clinical observation of decreased fractures in human OI patients after puberty. The Brtl mouse remains an important tool for investigating therapeutic interventions for OI. C1 Univ Michigan, Dept Orthopaed Surg, Orthopaed Res Labs, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA. NICHHD, Bone & Extracellular Matrix Branch, Bethesda, MD 20892 USA. RP Goldstein, SA (reprint author), Univ Michigan, Dept Orthopaed Surg, Orthopaed Res Labs, Room G-161 400 N Ingalls, Ann Arbor, MI 48109 USA. EM stevegld@umich.edu RI Morris, Michael/A-9327-2009; Forlino, Antonella/H-5385-2015 OI Forlino, Antonella/0000-0002-6385-1182 FU NIAMS NIH HHS [AR47969, AR46024] NR 50 TC 77 Z9 79 U1 0 U2 7 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD APR PY 2004 VL 19 IS 4 BP 614 EP 622 DI 10.1359/JBMR.040111 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 804ZD UT WOS:000220335700013 PM 15005849 ER PT J AU Lathrop, DA AF Lathrop, DA TI Clearer connections: Toward improved understanding of neural communications with the heart and their involvement in arrhythmias and sudden death SO JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY LA English DT Editorial Material ID CARDIAC DEATH; MYOCARDIAL-INFARCTION; CIRCADIAN VARIATION; HYPERINNERVATION C1 NHLBI, Div Heart & Vasc Dis, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Lathrop, DA (reprint author), NHLBI, Div Heart & Vasc Dis, NIH, US Dept HHS, 6701 Rockledge Dr, Bethesda, MD 20892 USA. EM lathropd@nhlbi.nih.gov RI LATHROP, David/A-2758-2008 NR 15 TC 1 Z9 1 U1 0 U2 2 PU BLACKWELL FUTURA PUBLISHING, INC PI MALDEN PA 350 MAIN STREET, MALDEN, MA 01248-5018 USA SN 1045-3873 J9 J CARDIOVASC ELECTR JI J. Cardiovasc. Electrophysiol. PD APR PY 2004 VL 15 IS 4 BP 438 EP 439 DI 10.1046/j.1540-8167.2004.03643.x PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 813SM UT WOS:000220926800010 PM 15089993 ER PT J AU Voutetakis, A Wang, JH Baum, BJ AF Voutetakis, A Wang, JH Baum, BJ TI Utilizing endocrine secretory pathways in salivary glands for systemic gene therapeutics SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Review ID RAT SUBMANDIBULAR GLANDS; CELLS IN-VITRO; ADENOASSOCIATED VIRUS; GROWTH-HORMONE; PAROTID-GLAND; CARBOXYPEPTIDASE E; MEDIATED TRANSFER; EUKARYOTIC CELLS; SORTING RECEPTOR; ADENOVIRUS AB Mammalian salivary glands are commonly used models of exocrine secretion. However, there is substantial experimental evidence showing the physiological existence of endocrine secretory pathways in those tissues. The use of gene transfer technology in vivo has allowed the unambiguous demonstration of these endocrine pathways. We and others have exploited such findings and evaluated salivary glands as possible target tissues for systemic applications of gene therapeutics. Salivary glands present numerous advantages for this purpose, including being well encapsulated, which limits extra-glandular vector dissemination, and having the luminal membranes of almost all parenchymal cells accessible via intraoral delivery of vectors through the main excretory ducts. Existing studies suggest that, clinical benefits will result from salivary gland targeted systemic gene therapeutics. Published 2003 Wiley-Liss, Inc.(dagger) C1 NIDCR, GTTB, DHHS, NIH, Bethesda, MD 20892 USA. RP Baum, BJ (reprint author), NIDCR, GTTB, DHHS, NIH, Bldg 10,Rm 1N113,MSC-1190, Bethesda, MD 20892 USA. EM bbaum@dir.nidcr.nih.gov NR 60 TC 11 Z9 11 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD APR PY 2004 VL 199 IS 1 BP 1 EP 7 DI 10.1002/jcp.10429 PG 7 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 773EQ UT WOS:000188885100001 PM 14978729 ER PT J AU Popov, AV Agmon, N Gopich, IV Szabo, A AF Popov, AV Agmon, N Gopich, IV Szabo, A TI Influence of diffusion on the kinetics of excited-state association-dissociation reactions: Comparison of theory and simulation SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID REVERSIBLE BIMOLECULAR REACTIONS; 3-DIMENSIONAL SIMULATIONS; DIFFERENT LIFETIMES; GEMINATE REACTION; TARGET PROBLEM; APPROXIMATION; RELAXATION AB Several recent theories of the kinetics of diffusion influenced excited-state association-dissociation reactions are tested against accurate Brownian dynamics simulation results for a wide range of parameters. The theories include the relaxation time approximation (RTA), multiparticle kernel decoupling approximations and the so-called kinetic theory. In the irreversible limit, none of these theories reduce to the Smoluchowski result. For the pseudo-first-order target problem, we show how the RTA can be modified so that the resulting formalism does reduce correctly in the irreversible limit. We call this the unified Smoluchowski approximation, because it unites modern theories of reversible reactions with Smoluchowski's theory of irreversible reactions. (C) 2004 American Institute of Physics. C1 Hebrew Univ Jerusalem, Dept Phys Chem, IL-91904 Jerusalem, Israel. Hebrew Univ Jerusalem, Fritz Haber Res Ctr, IL-91904 Jerusalem, Israel. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Inst Technol, Kemerovo 650060, Russia. RP Popov, AV (reprint author), Hebrew Univ Jerusalem, Dept Phys Chem, IL-91904 Jerusalem, Israel. RI Popov, Alexander/B-8842-2008; Agmon, Noam/B-2611-2009; Szabo, Attila/H-3867-2012 OI Agmon, Noam/0000-0003-4339-8664; NR 20 TC 24 Z9 24 U1 0 U2 3 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD APR 1 PY 2004 VL 120 IS 13 BP 6111 EP 6116 DI 10.1063/1.1649935 PG 6 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 803ZN UT WOS:000220269100031 PM 15267495 ER PT J AU Casanova, MF Araque, J Giedd, J Rumsey, JM AF Casanova, MF Araque, J Giedd, J Rumsey, JM TI Reduced brain size and gyrification in the brains of dyslexic patients SO JOURNAL OF CHILD NEUROLOGY LA English DT Article ID ANATOMICAL RISK-FACTORS; DEVELOPMENTAL DYSLEXIA; PLANUM TEMPORALE; CEREBRAL-CORTEX; MINICOLUMNAR PATHOLOGY; AUTISM; MAMMALS; MEN AB Dyslexia is a specific learning disability that affects the way in which a person acquires reading skills. The pathologic substrate of the condition has been debated in the literature. Conclusions from postmortem studies remain controversial because series have been based on few and often ill-characterized cases. The present article expands on one of the reported neuropathologic findings in dyslexia, that is, wider minicolumns. Measurements were made of magnetic resonance images in a series of 16 dyslexic and 14 age- and sex-matched controls. Dyslexic patients had significantly smaller total cerebral volume (P = .014) and reduced gyrification index (P = .021). No changes were noted in cortical thickness, the ratio of gray to white matter, or the cross-sectional areas of the corpus callosum and medulla oblongata. The findings, although not conclusive, are in keeping with a minicolumnar defect in dyslexia. The decreased gyrification and preserved cortical thickness can alter the information processing capacity of the brain by providing a greater degree of cortical integration at the expense of a slower response time. The article also emphasizes the contrast between findings in dyslexia and in autism. C1 Univ Louisville, Dept Psychiat, Louisville, KY 40292 USA. Med Coll Georgia, Dept Anat, Augusta, GA 30912 USA. NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. NIMH, Clin Neurosci Branch, Bethesda, MD 20892 USA. RP Casanova, MF (reprint author), Univ Louisville, Dept Psychiat, 500 S Preston St,Bldg A,Rm 217, Louisville, KY 40292 USA. EM m0casa02@louisville.edu RI Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 FU NIMH NIH HHS [MH61606, MH62654] NR 38 TC 50 Z9 51 U1 1 U2 7 PU B C DECKER INC PI HAMILTON PA 20 HUGHSON ST SOUTH, PO BOX 620, L C D 1, HAMILTON, ONTARIO L8N 3K7, CANADA SN 0883-0738 J9 J CHILD NEUROL JI J. Child Neurol. PD APR PY 2004 VL 19 IS 4 BP 275 EP 281 DI 10.1177/088307380401900407 PG 7 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 820VZ UT WOS:000221419000007 PM 15163094 ER PT J AU Cochran, E Young, JR Sebring, N DePaoli, A Oral, EA Gorden, P AF Cochran, E Young, JR Sebring, N DePaoli, A Oral, EA Gorden, P TI Efficacy of recombinant methionyl human leptin therapy for the extreme insulin resistance of the Rabson-Mendenhall syndrome SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID RECEPTOR GENE; SEVERE LIPODYSTROPHY; REPLACEMENT AB Recombinant methionyl human leptin (r-metHuLeptin) therapy has shown clear efficacy in the treatment of severe insulin resistance associated with lipodystrophy syndromes and low leptin levels. We treated two siblings with Rabson-Mendenhall syndrome (severe insulin resistance and presumed insulin receptor mutations). The brother and sister, aged 13 and 11 yr, respectively, had severe acanthosis nigricans, insulin resistance, and diabetes. Both were taking 2000 mg metformin and 2 mg rosiglitazone daily; the brother was also taking 300 U regular insulin daily. In contrast to our lipoatrophic patients treated with r-metHuLeptin, these two patients had a higher percent body fat and low-normal fasting triglycerides [42 mg/dl (0.37 mmol/liter), male sibling, and 33 mg/dl (0.47 mmol/liter), female sibling]. The siblings were treated with r-metHuLeptin therapy for 10-months and demonstrated a 40-60% decrease in fasting serum glucose and insulin levels and improved glycosylated hemoglobin. There was corresponding improvement in glucose and insulin tolerance during leptin therapy. This is the first report of a partial, but significant, effect of r-metHuLeptin administration in patients with extreme insulin resistance with a presumed insulin receptor mutation and low serum triglyceride levels. C1 NIDDKD, CRNP, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Nutr, Bethesda, MD 20892 USA. Amgen Inc, Thousand Oaks, CA 91320 USA. Univ Michigan, Dept Med, Div Endocrinol, Ann Arbor, MI 48109 USA. RP Cochran, E (reprint author), NIDDKD, CRNP, Clin Endocrinol Branch, NIH, Bldg 10,Room 8D20, Bethesda, MD 20892 USA. EM elainec@intra.niddk.nih.gov OI Oral, Elif/0000-0002-9171-1144 NR 17 TC 46 Z9 50 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2004 VL 89 IS 4 BP 1548 EP 1554 DI 10.1210/jc.2003-031952 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 810OV UT WOS:000220714500007 PM 15070911 ER PT J AU Ross, JL Stefanatos, GA Kushner, H Bondy, C Nelson, L Zinn, A Roeltgen, D AF Ross, JL Stefanatos, GA Kushner, H Bondy, C Nelson, L Zinn, A Roeltgen, D TI The effect of genetic differences and ovarian failure: Intact cognitive function in adult women with premature ovarian failure versus Turner syndrome SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID HORMONE-REPLACEMENT THERAPY; SURGICALLY MENOPAUSAL WOMEN; ELDERLY-WOMEN; X-CHROMOSOME; ESTROGEN; BRAIN; MEMORY; PERFORMANCE; DEFICITS; GIRLS AB Premature ovarian failure (POF) is generally defined as amenorrhea, hypoestrogenism, and elevated gonadotropins occurring in a woman before the age of 40 yr. Usually, the etiology is unknown. Turner syndrome (TS, monosomy X), also associated with ovarian failure, has a characteristic neuro-cognitive profile. TS females, as a group, have specific deficits in visual-spatial abilities, visual-perceptual abilities, motor function, nonverbal memory, executive function, and attentional abilities. Observed deficits in TS could be due to endocrine (estrogen deficiency) or genetic factors. If early estrogen deficiency contributes to the cognitive deficits in TS, women with POF would also be at risk for similar findings. The objective of this work was to examine the specific cognitive profile in women with POF and compare it with women with TS and normal female controls. We compared two unique populations (women with POF vs. TS), both with earlier estrogen deficiency. The TS group only had a major genetic deficiency, absence of all or part of one X chromosome. We evaluated the cognitive performance of estrogen-repleted women with POF (n = 89), compared with verbal IQ- and socioeconomic status-matched females with TS (n = 94) and controls (n = 96). Performance by the POF population was similar to that of controls and differed from the TS population. In contrast, TS adults had relative difficulty with measures of spatial/perceptual skills, visual-motor integration, affect recognition, visual memory, attention, and executive function. These deficits are apparent in TS women, despite apparently adequate estrogen treatment. The cognitive phenotypes of women with POF and normal controls are similar and differ from women with TS, indicating that prior estrogen deficiency does not have a major impact on cognitive function in adult females. The genetic deficiencies of women with TS most likely account for their specific cognitive phenotype. C1 Thomas Jefferson Univ, Dept Pediat, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Albert Einstein Med Ctr, MossRehab Res Inst, Philadelphia, PA 19141 USA. Biomed Comp Res Inst, Philadelphia, PA 19115 USA. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Univ Texas, SW Med Sch, Eugene McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA. Univ Texas, SW Med Sch, Dept Internal Med, Dallas, TX 75390 USA. Penn State Coll Med, Dept Med Neurol, Hershey, PA 17033 USA. RP Ross, JL (reprint author), Thomas Jefferson Univ, Dept Pediat, 1025 Walnut St, Philadelphia, PA 19107 USA. EM judith.ross@mail.tju.edu OI Zinn, Andrew/0000-0002-4935-3291 FU NINDS NIH HHS [NS42777] NR 43 TC 30 Z9 33 U1 2 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2004 VL 89 IS 4 BP 1817 EP 1822 DI 10.1210/jc.2003-031463 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 810OV UT WOS:000220714500046 PM 15070950 ER PT J AU Vortmeyer, AO Huang, S Lubensky, I Zhuang, ZP AF Vortmeyer, AO Huang, S Lubensky, I Zhuang, ZP TI Non-islet origin of pancreatic islet cell tumors SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID HIPPEL-LINDAU-DISEASE; HUMAN FETAL PANCREAS; ENDOCRINE PANCREAS; ALLELIC DELETIONS; STEM-CELLS; IN-VITRO; INSULIN; GENE AB The histogenesis of pancreatic islet cell tumors was investigated by morphological identification of putative precursor lesions in pancreatic tissue from patients with multiple endocrine neoplasia type 1 (MEN1), tissue microdissection, and genetic analysis. MEN1 mutation and absence of the MEN1 wild-type allele in different precursor lesions strongly suggest that pancreatic islet cell tumors are derived from the ductal/acinar system but not from pancreatic islet tissue. Pluripotent cells within the exocrine pancreas appear capable of formation into small atypical accumulations of MEN1-deficient cells with both exocrine and endocrine phenotype. The findings suggest presence of multiple developmental aberrations in MEN1 pancreas that potentially serve as precursor material for neuroendocrine tumors. C1 NINDS, Mol Pathogenesis Lab, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Vortmeyer, AO (reprint author), NINDS, Mol Pathogenesis Lab, Surg Neurol Branch, NIH, Bldg 10,Room 5D37,10 Ctr Dr, Bethesda, MD 20892 USA. EM vortmeyera@ninds.nih.gov NR 18 TC 65 Z9 66 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2004 VL 89 IS 4 BP 1934 EP 1938 DI 10.1210/jc.2003-031575 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 810OV UT WOS:000220714500062 PM 15070966 ER PT J AU Charmandari, E Kino, T Souvatzoglou, E Vottero, A Bhattacharyya, N Chrousos, GP AF Charmandari, E Kino, T Souvatzoglou, E Vottero, A Bhattacharyya, N Chrousos, GP TI Natural glucocorticoid receptor mutants causing generalized glucocorticoid resistance: Molecular genotype, genetic transmission, and clinical phenotype SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PRIMARY CORTISOL RESISTANCE; HORMONE-BINDING DOMAIN; NUCLEAR-LOCALIZATION; TRANSCRIPTIONAL COACTIVATOR; DNA-BINDING; MUTATION; PROTEIN; COREGULATORS; MECHANISMS; EXPORT AB Glucocorticoid resistance is a rare, familial, or sporadic condition characterized by partial end-organ insensitivity to glucocorticoids. The clinical spectrum of the condition ranges from completely asymptomatic to severe hyperandrogenism, fatigue, and/or mineralocorticoid excess. The molecular basis of glucocorticoid resistance in several families and sporadic cases has been ascribed to mutations in the human glucocorticoid receptor-alpha (hGRalpha) gene, which impair the ability of the receptor to transduce the glucocorticoid signal. We systematically investigated the molecular mechanisms through which natural, ligand-binding domain hGRalpha mutants, including hGRalphaI559N, hGRalphaV571A, hGRalphaD641V, hGRalphaV729I, and hGRalphaI747M, produce a defective signal and determined whether their differential effects on hGRalpha function might account for the type of genetic transmission of the disorder and the variable clinical phenotype of the affected subjects. Our findings suggest that all five mutant receptors studied have ligand-binding domains with decreased intrinsic transcriptional activity. Unlike hGRalphaI559N and I747M previously shown to exert a dominant negative effect upon the transcriptional activity of hGRalpha, hGRalphaV571A, D641V, and V729I do not have such an effect. All five mutants studied demonstrate varying degrees of decreased affinity for the ligand in a standard dexamethasone binding assay, but preserve their ability to bind DNA. The nondominant negative mutants, hGRalphaV571A, D641V, and V729I, show delayed translocation into the nucleus after exposure to ligand. Finally, hGRalphaI559N, V571A, D641V, and V729I display an abnormal interaction with the glucocorticoid receptor-interacting protein-1 coactivator in vitro, as this was previously shown also for hGRalphaI747M. We conclude that each of the above hGRalpha mutations imparts different functional defects upon the glucocorticoid signal transduction pathway, which explains the autosomal recessive or dominant transmission of the disorder, but might only explain in part its variable clinical phenotype. C1 NICHHD, Pediat Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Charmandari, E (reprint author), NICHHD, Pediat Reprod Endocrinol Branch, NIH, 10 Ctr Dr,Bldg 10,Room 9D42, Bethesda, MD 20892 USA. RI Charmandari, Evangelia/B-6701-2011 NR 45 TC 58 Z9 62 U1 1 U2 6 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2004 VL 89 IS 4 BP 1939 EP 1949 DI 10.1210/jc.2003-030450 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 810OV UT WOS:000220714500063 PM 15070967 ER PT J AU Belyakov, IM Hammond, SA Ahlers, JD Glenn, GM Berzofsky, JA AF Belyakov, IM Hammond, SA Ahlers, JD Glenn, GM Berzofsky, JA TI Transcutaneous immunization induces mucosal CTLs and protective immunity by migration of primed skin dendritic cells SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HEAT-LABILE ENTEROTOXIN; ADP-RIBOSYLATING EXOTOXINS; ANTIGEN-PRESENTING CELLS; CYTOTOXIC T-LYMPHOCYTES; CHOLERA-TOXIN; ESCHERICHIA-COLI; LANGERHANS CELLS; LYMPHOID-TISSUE; CPG OLIGODEOXYNUCLEOTIDES AB Transcutaneous immunization (TO), the application of vaccines on the skin, induces robust systemic and mucosal antibodies in animal models and in humans. The means by which mucosal immune responses to vaccine antigens are elicited by TO has not been well characterized. We examined the effect of TO with an HIV peptide vaccine on the induction of mucosal and systemic CTL responses and protective immunity against mucosal challenge with live virus in mice. Robust HIV-specific CTL responses in the spleen and in the gut mucosa were detected after TCI. The responses were dependent upon the addition of an adjuvant and resulted in protection against mucosal challenge with recombinant vaccinia virus encoding HIV gp160. Although it is clear that adjuvant-activated DCs migrated mainly to draining lymph nodes, coculture with specific T cells and flow cytometry studies with DCs isolated from Peyer's patches after TO suggested that activated DCs carrying skin-derived antigen also migrated from the skin to immune-inductive sites in gut mucosa and presented antigen directly to resident lymphocytes. These results and previous clinical trial results support the observation that TO is a safe and effective strategy for inducing strong mucosal antibody and CTL responses. C1 NCI, Mol Immunogenet & Vaccine Res Sect, Vaccine Branch, NIH, Bethesda, MD 20892 USA. IOMAI Corp, Gaithersburg, MD USA. RP Belyakov, IM (reprint author), NCI, Mol Immunogenet & Vaccine Res Sect, Vaccine Branch, NIH, Bethesda, MD 20892 USA. EM belyakov@mail.nih.gov NR 88 TC 149 Z9 156 U1 1 U2 5 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD APR PY 2004 VL 113 IS 7 BP 998 EP 1007 DI 10.1172/JCI200420261 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 809QR UT WOS:000220651700012 PM 15057306 ER PT J AU Proia, RL Wu, YP AF Proia, RL Wu, YP TI Blood to brain to the rescue SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID ENZYME-REPLACEMENT THERAPY; CENTRAL-NERVOUS-SYSTEM; VII MOUSE-BRAIN; LYSOSOMAL STORAGE; HEMATOPOIETIC-CELLS; BONE-MARROW; ADULT MICE; TRANSPLANTATION; ENGRAFTMENT; DISEASE AB Neurodegeneration occurs in the majority of the more than 40 known lysosomal storage diseases. Since the nervous system in these disorders can be globally affected, effective treatment would require persistent widespread correction. Biffi et al. (see the related article beginning on page 1118) show such correction is possible in a mouse model of metachromatic leukodystrophy by the transplantation of hematopoietic cells genetically modified to overexpress the missing lysosomal enzyme. The results reveal a nervous system damage-response pathway that can be harnessed to provide therapy to the nervous system in these serious disorders. C1 NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Proia, RL (reprint author), NIDDKD, Genet Dev & Dis Branch, NIH, Bldg 10,Room 9N-314,10 Ctr Dr,MSC 1821, Bethesda, MD 20892 USA. EM proia@nih.gov RI Proia, Richard/A-7908-2012 NR 15 TC 23 Z9 23 U1 0 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD APR PY 2004 VL 113 IS 8 BP 1108 EP 1110 DI 10.1172/JCI200421476 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 820CU UT WOS:000221365100007 PM 15085187 ER PT J AU Laeyendecker, O Henson, C Gray, RH Nguyen, RHN Horne, BJ Wawer, MJ Serwadda, D Kiwanuka, N Morrow, RA Hogrefe, W Quinn, TC AF Laeyendecker, O Henson, C Gray, RH Nguyen, RHN Horne, BJ Wawer, MJ Serwadda, D Kiwanuka, N Morrow, RA Hogrefe, W Quinn, TC TI Performance of a commercial, type-specific enzyme-linked immunosorbent assay for detection of herpes simplex virus type 2-specific antibodies in Ugandans SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID GENITAL HERPES; IMMUNOBLOT; INFECTIONS; SERA AB Two hundred forty-eight human immunodeficiency virus (HIV)-positive and 496 HIV-negative subjects in Uganda were tested by HerpeSelect herpes simplex virus type 2 enzyme-linked immunosorbent assay (ELISA) and Western blotting to optimize the ELISA for use in this population. A higher index cutoff value was required for optimal sensitivity and specificity, and overall performance of the assay was not affected by HIV status. C1 NIAID, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21218 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Populat & Family Hlth Sci, Baltimore, MD USA. Columbia Univ, Joseph L Mailman Sch Publ Hlth, Heilbrun Ctr Populat & Family Hlth, New York, NY USA. Makerere Univ, Inst Publ Hlth, Kampala, Uganda. Uganda Virus Res Inst, Rakai Project, Entebbe, Uganda. Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. Focus Technol, Cypress, CA USA. RP Quinn, TC (reprint author), Ross Bldg 1159,720 Rutland Ave, Baltimore, MD 21205 USA. EM tquinn@jhmi.edu RI Laeyendecker, Oliver/B-9331-2009; OI Laeyendecker, Oliver/0000-0002-6429-4760 FU Intramural NIH HHS [Z99 AI999999]; NIAID NIH HHS [AI-30731, AI-3426S, P01 AI030731, R01 AI-34826, U01 AI046745, U01 AI048054, U01-AI-46745, U01-AI-48054]; NICHD NIH HHS [5P30HD06826] NR 14 TC 56 Z9 56 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD APR PY 2004 VL 42 IS 4 BP 1794 EP 1796 DI 10.1128/JCM.42.4.1794-1796.2004 PG 3 WC Microbiology SC Microbiology GA 814GK UT WOS:000220963000076 PM 15071053 ER PT J AU Weil, RJ AF Weil, RJ TI Potential confounding features in p53 gene therapy of recurrent glioma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Weil, RJ (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD APR 1 PY 2004 VL 22 IS 7 BP 1344 EP 1345 DI 10.1200/JCO.2004.99.287 PG 2 WC Oncology SC Oncology GA 808DQ UT WOS:000220550200031 PM 15051789 ER PT J AU Ozerdem, A Schmidt, ME Manji, HK Risinger, RC Potter, WZ AF Ozerdem, A Schmidt, ME Manji, HK Risinger, RC Potter, WZ TI Chronic lithium administration enhances noradrenergic responses to intravenous administration of the alpha(2) antagonist idazoxan in healthy volunteers SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article ID RAT-BRAIN; PLASMA-CATECHOLAMINES; CEREBROSPINAL-FLUID; CARBONATE TREATMENT; NOREPINEPHRINE; INCREASES; YOHIMBINE; RECEPTOR; METABOLISM; MECHANISMS AB The acute and chronic effects of lithium carbonate administration at therapeutic blood levels on peripheral noradrenergic activity and sympathetic responses to alpha(2) adrenoceptor blockade were examined in 10 medically and psychiatrically healthy volunteers. Supine resting levels of plasma norepinephrine and the increases in norepinephrine following intravenous infusion of 200 mug/kg of idazoxan, a selective alpha(2) adrenoceptor antagonist, were determined before lithium (Li+) administration and after 5 days and after 4 weeks of daily Li+ treatment. Chronic Li+ treatment significantly increased mean resting plasma norepinephrine levels by 53.6%. The noradrenergic responses to infusions of idazoxan were slightly enhanced after 5 days of Li+ administration and significantly increased following 4 weeks of Li+ treatment. The possibility that Li+ produces functional alpha(2) subsensitivity causing enhanced peripheral noradrenergic activity in humans is supported by the findings of increased mean resting plasma norepinephrine and increased response to idazoxan following chronic Li+ administration. Alteration of regulatory mechanisms in the noradrenergic system may be relevant to understanding the clinical effects of Li+ in manic-depressive illness. C1 Dokuz Eylul Univ, Sch Med, Dept Psychiat, TR-35340 Izmir, Turkey. Novartis Pharmaceut Corp, Neurosci Therapeut Area, E Hanover, NJ USA. NIMH, Mol Pathophysiol Lab, Bethesda, MD 20892 USA. Med Coll Wisconsin, Dept Psychiat & Behav Med, Milwaukee, WI 53226 USA. Lilly Res Labs, Neurosci Therapeut Area, Indianapolis, IN USA. RP Ozerdem, A (reprint author), Dokuz Eylul Univ, Sch Med, Dept Psychiat, TR-35340 Izmir, Turkey. EM aysegul.ozerdem@deu.edu.tr NR 40 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD APR PY 2004 VL 24 IS 2 BP 150 EP 154 DI 10.1097/01.jcp.0000115667.45074.9f PG 5 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 804PK UT WOS:000220310400006 PM 15206661 ER PT J AU Aldridge, J Lamb, ME Sternberg, KJ Orbach, Y Esplin, PW Bowler, L AF Aldridge, J Lamb, ME Sternberg, KJ Orbach, Y Esplin, PW Bowler, L TI Using a human figure drawing to elicit information from alleged victims of child sexual abuse SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article ID ANATOMICALLY DETAILED DOLLS; INVESTIGATIVE INTERVIEWS; PEDIATRIC EXAMINATION; FORENSIC INTERVIEWS/; EYEWITNESS TESTIMONY; AGE-DIFFERENCES; QUESTION TYPE; WITNESSES; MEMORY; RESPONSES AB Ninety 4- to 13-year-old alleged victims of sexual abuse were interviewed by police officers using the National Institute of Child Health and Human Development (NICHD) investigative interview protocol, following which they were shown a human figure drawing and asked a series of questions. The drawing and associated questions elicited an average of 86 new forensically relevant details. They were especially productive with 4- to 7-year-olds, who provided an average of 95 additional details (27% of their total) after the drawing was introduced despite having previously "exhausted" their memories. Information elicited using the drawing may be less accurate, however, because recognition memory prompts predominated, so such drawings should only be introduced late in investigative interviews. C1 NICHHD, Sect Social & Emot Dev, Rockledge Ctr 1, Bethesda, MD 20892 USA. Univ Leeds, Dept Psychiat, Leeds LS2 9JT, W Yorkshire, England. Derbyshire Constabulary, Ripley, England. RP Lamb, ME (reprint author), NICHHD, Sect Social & Emot Dev, Rockledge Ctr 1, Suite 8048,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM michael_lamb@nih.gov NR 43 TC 32 Z9 33 U1 0 U2 10 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD APR PY 2004 VL 72 IS 2 BP 304 EP 316 DI 10.1037/0022-006X.72.2.304 PG 13 WC Psychology, Clinical SC Psychology GA 806OE UT WOS:000220442400014 PM 15065963 ER PT J AU Dolensky, B Nam, G Deng, WP Narayanan, J Fan, JF Kirk, KL AF Dolensky, B Nam, G Deng, WP Narayanan, J Fan, JF Kirk, KL TI Syntheses of side-chain fluorinated biologically important imidazoles and indoles SO JOURNAL OF FLUORINE CHEMISTRY LA English DT Article; Proceedings Paper CT Symposium on Fluorinated Synthons CY SEP 07-09, 2003 CL New York, NY DE imidazoles; indoles; biogenic amines; "FBr" addition; deoxyfluorination ID HYDROGEN-FLUORIDE; L-HISTIDINOL; FLUOROUROCANIC ACIDS; BUILDING-BLOCKS; STEREOCHEMISTRY; DERIVATIVES; BROMOFLUORINATION; HALOFLUORINATION; ELIMINATION; SUPPRESSION AB We review in this report the preparation of several side-chain fluorinated analogues of biologically important imidazoles and indoles. The building blocks used should also have applications in other synthetic problems. The addition of "FBr" to vinyl imidazole derivatives was used to prepare beta-fluoro- and beta,beta-difluorohistamine and histidinols, as well as beta-fluorourocanic acid. Deoxyfluorination of intermediate acylindoles was used to prepare a series of beta,beta-difluorotryptamine derivative, including the fluorinated analogue of the important neurotransmitter, serotonin. (C) 2004 Elsevier B.V. All rights reserved. C1 NIDDKD, Bioorgan Chem Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Kirk, KL (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Dept Hlth & Human Serv, Bldg 8A,Room B1A-02,8 Ctr Dr,MSC 0810, Bethesda, MD 20892 USA. EM kennethk@bdg8.niddk.nih.gov NR 45 TC 15 Z9 15 U1 2 U2 9 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 0022-1139 J9 J FLUORINE CHEM JI J. Fluor. Chem. PD APR PY 2004 VL 125 IS 4 BP 501 EP 508 DI 10.1016/j.jfluchem.2003.12.013 PG 8 WC Chemistry, Inorganic & Nuclear; Chemistry, Organic SC Chemistry GA 823QW UT WOS:000221629100004 ER PT J AU Shi, PA De Angioletti, M Donahue, RE Notaro, R Luzzatto, L Dunbar, CE AF Shi, PA De Angioletti, M Donahue, RE Notaro, R Luzzatto, L Dunbar, CE TI In vivo gene marking of rhesus macaque long-term repopulating hematopoietic cells using a VSV-G pseudotyped versus amphotropic oncoretroviral vector SO JOURNAL OF GENE MEDICINE LA English DT Article DE hematopoietic stem cells; genetic vectors; Macaca mulatta; VSV-G protein; glucose-6-phosphate dehydrogenase deficiency ID VESICULAR STOMATITIS-VIRUS; STEM-CELLS; PERIPHERAL-BLOOD; HIGH-TITER; NONHUMAN-PRIMATES; MONKEY MODEL; TRANSDUCTION; EXPRESSION; EFFICIENCY; RETROVIRUS AB Background Gene transfer efficiency into primitive hematopoietic cells may be limited by their expression of surface receptors allowing vector entry. Vectors pseudotyped with the vesicular stomatitis virus (VSV-G) envelope do not need receptors to enter cells, and therefore may provide superior transduction efficiency. Methods Using a competitive repopulation model in the rhesus macaque, we examined in vivo gene marking levels of blood cells transduced with two vectors: (i) a VSV-G pseudotyped retrovirus and (ii) a conventional amphotropic retrovirus. The VSV-G vector, containing the human glucose-6-phosphate dehydrogenase (G6PD) gene, was constructed for treatment of severe hemolytic anemia caused by G6PD deficiency. Three myeloablated animals were transplanted with peripheral blood CD34+ cells, half of which were transduced with the VSV-G vector and the other half with the amphotropic vector. Results In all animals post-transplantation, levels of in vivo marking in circulating granulocytes and mononuclear cells were similar: 1% or less with both vectors. In one animal, the human G6PD enzyme transferred by the VSV-G vector was expressed in erythrocytes, early after transplantation, at a level of 45% of the endogenous rhesus G6PD) protein. Conclusions In a clinically relevant animal model we found similar, in vivo marking with a VSV-G pseudotyped and a standard amphotropic oncoretroviral vector. Amphotropic receptor expression may not be a limiting factor in transduction efficiency, but VSV-G pseudotypes possess other practical advantages that may make them advantageous for clinical use. Copyright (C) 2004 John Wiley Sons, Ltd. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. IST, Ist Nazl Ric Canc, Genoa, Italy. RP Dunbar, CE (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,7C103,9000 Rockvill Pke, Bethesda, MD 20892 USA. EM dunbarc@nhlbi.nih.gov OI Notaro, Rosario/0000-0002-9087-9404; DEANGIOLETTI, MARIA/0000-0002-2686-6457 FU Fondazione Telethon NR 21 TC 7 Z9 7 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1099-498X J9 J GENE MED JI J. Gene. Med. PD APR PY 2004 VL 6 IS 4 BP 367 EP 373 DI 10.1002/jgm.514 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 816UM UT WOS:000221134800001 PM 15079811 ER PT J AU Hurst, S Forde, R Pegoraro, D Perrier, A Reiter-Theil, S Slowther, A Danis, M AF Hurst, S Forde, R Pegoraro, D Perrier, A Reiter-Theil, S Slowther, A Danis, M TI An exploration of the interaction of rationing at the provider and system-wide levels. SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT 27th Annual Meeting of the Society-of-General-Internal-Medicine CY MAY 12-15, 2004 CL Chicago, IL SP Soc Gen Internal Med C1 Ctr Med Univ Geneva, Geneva, Switzerland. Norwegian Med Assoc, Oslo, Norway. Fdn Lanza, Padua, Italy. Univ Hosp Geneva, Geneva, Switzerland. Univ Basel, CH-4003 Basel, Switzerland. Ethox Inst Hlth Sci, Headington, England. NIH, Bethesda, MD 20892 USA. RI Hurst, Samia/A-9661-2008; Perrier, Arnaud/M-2263-2014 OI Hurst, Samia/0000-0002-1980-5226; NR 0 TC 1 Z9 1 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2004 VL 19 SU 1 BP 118 EP 118 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 816RA UT WOS:000221125800400 ER PT J AU Reynolds, PP AF Reynolds, PP TI Breaking through the ivory white tower: The racial integration of medical education in the United States, 1950-1970. SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT 27th Annual Meeting of the Society-of-General-Internal-Medicine CY MAY 12-15, 2004 CL Chicago, IL SP Soc Gen Internal Med C1 NIH, Natl Lib Med, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2004 VL 19 SU 1 BP 126 EP 127 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 816RA UT WOS:000221125800434 ER PT J AU McDermott, MM Ferrucci, L Liu, K Chan, C Greenland, P Pearce, WH Criqui, MH Martin, GJ AF McDermott, MM Ferrucci, L Liu, K Chan, C Greenland, P Pearce, WH Criqui, MH Martin, GJ TI D-dimer and inflammatory blood markers predict functional decline in men and women with and without peripheral arterial disease. SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT 27th Annual Meeting of the Society-of-General-Internal-Medicine CY MAY 12-15, 2004 CL Chicago, IL SP Soc Gen Internal Med C1 Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. NIA, Bethesda, MD 20892 USA. Univ Calif San Diego, La Jolla, CA 92093 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2004 VL 19 SU 1 BP 134 EP 135 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 816RA UT WOS:000221125800468 ER PT J AU Eisenstaedt, RS Woodman, RC Klein, HG Ferrucci, L Guralnick, JM AF Eisenstaedt, RS Woodman, RC Klein, HG Ferrucci, L Guralnick, JM TI Epidemiology of anemia in the elderly. SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT 27th Annual Meeting of the Society-of-General-Internal-Medicine CY MAY 12-15, 2004 CL Chicago, IL SP Soc Gen Internal Med C1 Temple Univ, Philadelphia, PA 19122 USA. Ortho Biotech LP, Bridgewater, NJ USA. NIH, Bethesda, MD 20892 USA. NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2004 VL 19 SU 1 BP 150 EP 150 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 816RA UT WOS:000221125800533 ER PT J AU Henrich, JB Hughes, J Kaufman, S Brody, D AF Henrich, JB Hughes, J Kaufman, S Brody, D TI How useful is follicle stimulating hormone in assessing menopausal status? SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT 27th Annual Meeting of the Society-of-General-Internal-Medicine CY MAY 12-15, 2004 CL Chicago, IL SP Soc Gen Internal Med C1 Yale Univ, Hamden, CT USA. Orkland Corp, Falls Church, VA USA. NICHHD, Bethesda, MD 20892 USA. Natl Ctr Hlth Stat, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2004 VL 19 SU 1 BP 161 EP 161 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 816RA UT WOS:000221125800578 ER PT J AU Ryder, KM Tylavsky, FA Bush, AJ Bauer, DC Simonsick, E Strotmeyer, E Harris, T Shorr, RI AF Ryder, KM Tylavsky, FA Bush, AJ Bauer, DC Simonsick, E Strotmeyer, E Harris, T Shorr, RI TI Low initiation of fracture reducing therapy in older women with reduced bone density. SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT 27th Annual Meeting of the Society-of-General-Internal-Medicine CY MAY 12-15, 2004 CL Chicago, IL SP Soc Gen Internal Med C1 Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NIA, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. RI Strotmeyer, Elsa/F-3015-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2004 VL 19 SU 1 BP 176 EP 176 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 816RA UT WOS:000221125800643 ER PT J AU Sudore, R Mehta, K Harris, T Newman, A Simonsick, E Satterfield, S Rosano, C Rooks, R Rubin, S Ayonayon, H Yaffe, K AF Sudore, R Mehta, K Harris, T Newman, A Simonsick, E Satterfield, S Rosano, C Rooks, R Rubin, S Ayonayon, H Yaffe, K TI Low literacy and poor health in the elderly: The health ABC study. SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT 27th Annual Meeting of the Society-of-General-Internal-Medicine CY MAY 12-15, 2004 CL Chicago, IL SP Soc Gen Internal Med C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. NIA, Chevy Chase, MD USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. NIA, Bethesda, MD 20892 USA. Univ Tennessee, Knoxville, TN USA. Kent State Univ, Kent, OH 44242 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2004 VL 19 SU 1 BP 176 EP 176 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 816RA UT WOS:000221125800644 ER PT J AU Danis, M Ginsburg, M Parise, C Goold, SD AF Danis, M Ginsburg, M Parise, C Goold, SD TI Preparing employees to participate in the design of their health insurance benefits. SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT 27th Annual Meeting of the Society-of-General-Internal-Medicine CY MAY 12-15, 2004 CL Chicago, IL SP Soc Gen Internal Med C1 NIH, Bethesda, MD 20892 USA. Sacramento Healthcare Decis, Rancho Cordova, CA USA. Sutter Inst Med Res, Sacramento, CA USA. Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2004 VL 19 SU 1 BP 197 EP 197 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 816RA UT WOS:000221125800731 ER PT J AU Tice, J Kanaya, A Hue, T Rubin, S Buist, D Lacey, J Bauer, D AF Tice, J Kanaya, A Hue, T Rubin, S Buist, D Lacey, J Bauer, D TI Risk factors for 9 year mortality in older women. SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT 27th Annual Meeting of the Society-of-General-Internal-Medicine CY MAY 12-15, 2004 CL Chicago, IL SP Soc Gen Internal Med C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Grp Hlth Cooperat Puget Sound, Seattle, WA 98121 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2004 VL 19 SU 1 BP 206 EP 207 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 816RA UT WOS:000221125800773 ER PT J AU McDermott, MM Liu, K Greenland, P Guralnik, JM Criqui, MH Cheeling, C Pearce, WH Ferrucci, L Celic, L Martin, GJ AF McDermott, MM Liu, K Greenland, P Guralnik, JM Criqui, MH Cheeling, C Pearce, WH Ferrucci, L Celic, L Martin, GJ TI The ankle brachial index and specific leg symptoms predict decline of lower extremity functioning in peripheral arterial disease. SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Meeting Abstract CT 27th Annual Meeting of the Society-of-General-Internal-Medicine CY MAY 12-15, 2004 CL Chicago, IL SP Soc Gen Internal Med C1 Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. NIA, Bethesda, MD 20892 USA. Univ Calif San Diego, La Jolla, CA 92093 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2004 VL 19 SU 1 BP 214 EP 214 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 816RA UT WOS:000221125800805 ER PT J AU Wang, JM Roh, SH Kim, S Lee, CW Il Kim, J Swartz, KJ AF Wang, JM Roh, SH Kim, S Lee, CW Il Kim, J Swartz, KJ TI Molecular surface of tarantula toxins interacting with voltage sensors in K-v channels SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Article DE spider venom; scanning mutagenesis; gating modifier; voltage-activated channels ID GATING MODIFIER TOXINS; OMEGA-GRAMMOTOXIN-SIA; POLYPEPTIDE ANTHOPLEURIN-B; HIGH-AFFINITY BINDING; AMINO-ACID-SEQUENCE; ALPHA-LIKE TOXIN; POTASSIUM CHANNEL; CALCIUM-CHANNELS; SODIUM-CHANNELS; PEPTIDE INHIBITOR AB The venom from spiders, scorpions, and sea anemone contain a rich diversity of protein toxins that interact with ion channel voltage sensors. Although atomic structures have been solved for many of these toxins the surfaces that are critical for interacting with voltage sensors are poorly defined. Hanatoxin and SGTx are tarantula toxins that inhibit activation of K, channels by interacting with each of the four voltage sensors. In this study we set out to identify the active surface of these toxins by alanine-scanning SGTx and characterizing the interaction of each mutant with the K(v)2.1 channel. Examination of the concentration dependence for inhibition identified 15 mutants with little effect on the concentration dependence for toxin inhibition of the K(v)2.1 channel, and 11 Mutants that display moderate to dramatic perturbations. Mapping of these results onto the structure of SGTx identifies one face of the toxin where mutations with pronounced perturbations Cluster together, and a backside of the toxin where Mutations are well tolerated. The active surface of SGTx contains a ring-like assembly of highly, polar residues, with two basic residues that are particularly critical, concentrically arranged around a hydrophobic protrusion containing critical aliphatic and aromatic residues. These results identify the active surface of the toxin and reveal the types of side chains that are important for interacting with voltage sensors. C1 NINDS, Mol Physiol & Biophys Sect, NIH, Bethesda, MD 20892 USA. Kwangju Inst Sci & Technol, Dept Life Sci, Kwangju 500712, South Korea. RP Swartz, KJ (reprint author), NINDS, Mol Physiol & Biophys Sect, NIH, Bld 36 Rm 2C19,36 Convent Dr,MSC 4066, Bethesda, MD 20892 USA. EM swartzk@ninds.nih.gov FU Intramural NIH HHS [ZIA NS002945-13] NR 70 TC 74 Z9 78 U1 2 U2 6 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1295 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD APR PY 2004 VL 123 IS 4 BP 455 EP 467 DI 10.1085/jgp.200309005 PG 13 WC Physiology SC Physiology GA 811TU UT WOS:000220795000011 PM 15051809 ER PT J AU Wagner, M Fickert, P Zollner, G Silbert, D Fuchsbichler, A Gumhold, J Schuetz, JD Gonzalez, FJ Zatloukal, K Marschall, HU Denk, H Trauner, M AF Wagner, M Fickert, P Zollner, G Silbert, D Fuchsbichler, A Gumhold, J Schuetz, JD Gonzalez, FJ Zatloukal, K Marschall, HU Denk, H Trauner, M TI Adaptive renal ABC transporter expression in common bile duct-ligated mice SO JOURNAL OF HEPATOLOGY LA English DT Meeting Abstract CT 39th Annual Meeting of the European-Association-for-the-Study-of-the-Liver CY APR 14-18, 2004 CL Berlin, GERMANY SP European Assoc Study Liver C1 Med Univ, Dept Med, Graz, Austria. Med Univ Graz, Dept Pathol, Graz, Austria. St Jude Childrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. NCI, Bethesda, MD 20892 USA. Huddinge Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD APR PY 2004 VL 40 SU 1 MA 73 BP 26 EP 26 DI 10.1016/S0168-8278(04)90073-6 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 814BS UT WOS:000220950800074 ER PT J AU Wagner, M Fickert, P Zollner, G Fuchsbichler, A Gumhold, J Silbert, D Zatloukal, K Gu, GL Marschall, HU Denk, H Trauner, M AF Wagner, M Fickert, P Zollner, G Fuchsbichler, A Gumhold, J Silbert, D Zatloukal, K Gu, GL Marschall, HU Denk, H Trauner, M TI Role of adaptive hepatobiliary transporter expression and regulation of bile acid synthetic enzymes in MDR2-/- mice: A model for chronic cholestatic liver disease due to sclerosing cholangitis SO JOURNAL OF HEPATOLOGY LA English DT Meeting Abstract CT 39th Annual Meeting of the European-Association-for-the-Study-of-the-Liver CY APR 14-18, 2004 CL Berlin, GERMANY SP European Assoc Study Liver C1 Med Univ, Dept Med, Graz, Austria. Med Univ, Dept Pathol, Graz, Austria. NCI, Bethesda, MD 20892 USA. Huddinge Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden. NR 0 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD APR PY 2004 VL 40 SU 1 MA 557 BP 163 EP 163 DI 10.1016/S0168-8278(04)90557-0 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 814BS UT WOS:000220950800558 ER PT J AU LaMarca, ME Goldstein, M Tayebi, N Arcos-Burgos, M Martin, BM Sidransky, E AF LaMarca, ME Goldstein, M Tayebi, N Arcos-Burgos, M Martin, BM Sidransky, E TI A novel alteration in metaxin 1, F202L, is associated with N370S in Gaucher disease SO JOURNAL OF HUMAN GENETICS LA English DT Article DE Gaucher disease; genotype/phenotype correlation; glucocerebrosidase; haplotype; metaxin; polymorphism ID GLUCOCEREBROSIDASE GENE; COMPLEX; IMPORT AB The gene for glucocerebrosidase (GBA), the enzyme deficient in Gaucher disease, is located in a gene-rich region on 1q21. Metaxin 1(MTX1) is a convergently transcribed gene contiguous to the 3' end of the GBA pseudogene. A single nucleotide alteration in MTX1, 628T-->C, resulting in the amino acid change F202L, was identified in patients with Gaucher disease in association with the common N370S mutation in GBA. The polymorphism was also present on 4.6% of 152 control alleles, but could have functional consequences that have a modifying role in Gaucher disease. C1 NIMH, Sect Mol Neurogenet, Bethesda, MD 20892 USA. NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. NIMH, Lab Neurotoxicol, Bethesda, MD 20892 USA. RP Sidransky, E (reprint author), NIMH, Sect Mol Neurogenet, 49 Convent Dr MSC4405,49-B1EE16, Bethesda, MD 20892 USA. EM sidranse@irp.nimh.nih.gov NR 15 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER-VERLAG TOKYO PI TOKYO PA 3-3-13, HONGO, BUNKYO-KU, TOKYO, 113-0033, JAPAN SN 1435-232X J9 J HUM GENET JI J. Hum. Genet. PD APR PY 2004 VL 49 IS 4 BP 220 EP 222 DI 10.1007/s10038-004-0134-7 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 815SG UT WOS:000221061400008 PM 15024629 ER PT J AU Choi, MS Ray, R Zhang, ZJ Mukherjee, AB AF Choi, MS Ray, R Zhang, ZJ Mukherjee, AB TI IFN-gamma stimulates the expression of a novel secretoglobin that regulates chemotactic cell migration and invasion SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PROSTATIC BINDING-PROTEIN; HUMAN UTEROGLOBIN GENE; 10 KDA PROTEIN; INTERFERON-GAMMA; CANCER-CELLS; BLASTOCYST DEVELOPMENT; SECRETORY PROTEIN; IGA NEPHROPATHY; BREAST-CANCER; AMINO-ACID AB IFNs are a family of cytokines that alert the immune system against viral infections of host cells. The IFNs (IFN-alpha, IFN-beta, and IFN-gamma) interact with specific cellular receptors and stimulate the production of second messengers, leading to the expression of antiviral and immunomodulatory proteins. We report in this study that IFN-gamma stimulates the expression of a novel gene that encodes a protein with 30% amino acid sequence identity with uteroglobin, the founding member of the newly formed Secreto-globin (SCGB) superfamily. We named this protein IFN-gamma-inducible SCGB (IIS), because its expression in lymphoblast cells is augmented by IFN-gamma treatment. IIS is expressed in virtually all tissues, and the highest level of expression is detectable in lymph nodes, tonsil, cultured lymphoblasts, and the ovary. Interestingly, although the expression of IIS mRNA is not significantly different in resting lymphoid cells, it is markedly elevated in activated CD8(+) and CD19(+) cells. Furthermore, treatment of lymphoblast cells with IIS antisense phosphorothioate (S)-oligonucleotides prevents chemotactic migration and invasion. Taken together, these results raise the possibility that this novel SCGB has immunological functions. C1 NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Mukherjee, AB (reprint author), NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bldg 10,Room 9S241, Bethesda, MD 20892 USA. EM mukherja@exchange.nih.gov NR 47 TC 8 Z9 11 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD APR 1 PY 2004 VL 172 IS 7 BP 4245 EP 4252 PG 8 WC Immunology SC Immunology GA 829TO UT WOS:000222072900030 PM 15034037 ER PT J AU McKarns, SC Schwartz, RH Kaminski, NE AF McKarns, SC Schwartz, RH Kaminski, NE TI Smad3 is essential for TGF-beta 1 to suppress IL-2 production and TCR-induced proliferation, but not IL-2-induced proliferation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TRANSFORMING-GROWTH-FACTOR; MEDIATED SIGNAL-TRANSDUCTION; BETA-INDUCED PHOSPHORYLATION; HUMAN LYMPHOCYTES-T; TGF-BETA; TARGETED DISRUPTION; TRANSCRIPTIONAL REGULATION; INTERLEUKIN-2 RECEPTOR; INHIBITOR P15(INK4B); CLONAL EXPANSION AB Transforming growth factor-beta1 is essential to maintain T cell homeostasis, as illustrated by multiorgan inflammation in mice deficient in TGF-beta1 signaling. Despite the physiological importance, the mechanisms that TGF-beta1 uses to regulate T cell expansion remain poorly understood. TGF-beta1 signals through transmembrane receptor serine/threonine kinases to activate multiple intracellular effector molecules, including the cytosolic signaling transducers of the Smad protein family. We used Smad3(-/-) mice to investigate a role for Smad3 in IL-2 production and proliferation in T cells. Targeted disruption of Smad3 abrogated TGF-beta1-mediated inhibition of anti-CD3 plus anti-CD28-induced steady state IL-2 mRNA and IL-2 protein production. CFSE labeling demonstrated that TGF-beta1 inhibited entry of wild-type anti-CD3 plus anti-CD28-stimulated cells into cycle cell, and this inhibition was greatly attenuated in Smad3(-/-) T cells. In contrast, disruption of Smad3 did not affect TGF-beta1-mediated inhibition of IL-2-induced proliferation. These results demonstrate that TGF-beta1 signals through Smad3-dependent and -independent pathways to inhibit T cell proliferation. The inability of TGF-beta1 to inhibit TCR-induced proliferation of Smad3(-/-) T cells suggests that IL-2 is not the primary stimulus driving expansion of anti-CD3 plus anti-CD28-stimulated T cells. Thus, we establish that tGF-beta1 signals through multiple pathways to suppress T cell proliferation. C1 NIAID, Lab Cellular & Mol Immunol, NIH, Bethesda, MD 20892 USA. Michigan State Univ, Dept Pharmacol & Toxicol, E Lansing, MI 48824 USA. RP McKarns, SC (reprint author), NIAID, Lab Cellular & Mol Immunol, NIH, Bethesda, MD 20892 USA. EM smckarns@niaid.nih.gov FU NIEHS NIH HHS [P42 ES504911-08C] NR 58 TC 79 Z9 83 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 APR 1 PY 2004 VL 172 IS 7 BP 4275 EP 4284 PG 10 WC Immunology SC Immunology GA 829TO UT WOS:000222072900034 PM 15034041 ER PT J AU Poltoratsky, VP Wilson, SH Kunkel, TA Pavlov, YI AF Poltoratsky, VP Wilson, SH Kunkel, TA Pavlov, YI TI Recombinogenic phenotype of human activation-induced cytosine deaminase SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CLASS-SWITCH RECOMBINATION; URACIL-DNA-GLYCOSYLASE; SINGLE-STRANDED-DNA; BASE EXCISION-REPAIR; SOMATIC HYPERMUTATION; SACCHAROMYCES-CEREVISIAE; ESCHERICHIA-COLI; ANTIBODY DIVERSIFICATION; IMMUNOGLOBULIN GENES; POLYMERASE-ETA AB Class switch recombination, gene conversion, and somatic hypermutation that diversify rearranged Ig genes to produce various classes of high affinity Abs are dependent on the enzyme activation-induced cytosine deaminase (AID). Evidence suggests that somatic hypermutation is due to error-prone DNA repair that is initiated by AID-mediated deamination of cytosine in DNA, whereas the mechanism by which AID controls recombination remains to be elucidated. In this study, using a yeast model system, we have observed AID-dependent recombination. Expression of human AID in wild-type yeast is mutagenic for G-C to A-T transitions, and as expected, this mutagenesis is increased upon inactivation of uracil-DNA glycosylase. AID expression also strongly induces intragenic mitotic recombination, but only in a strain possessing uracil-DNA glycosylase. Thus, the initial step of base excision repair is required for AID-dependent recombination and is a branch point for either hypermutagenesis or recombination. C1 NIEHS, NIH, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, NIH, Struct Biol Lab, POB 12233,111 TW Alexander Dr,Bldg 101,Room B-246, Res Triangle Pk, NC 27709 USA. EM wilson5@nichs.nih.gov NR 54 TC 34 Z9 35 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 APR 1 PY 2004 VL 172 IS 7 BP 4308 EP 4313 PG 6 WC Immunology SC Immunology GA 829TO UT WOS:000222072900038 PM 15034045 ER PT J AU Lu, J Higashimoto, Y Appella, E Celis, E AF Lu, J Higashimoto, Y Appella, E Celis, E TI Multiepitope Trojan antigen peptide vaccines for the induction of antitumor CTL and Th immune responses SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INDUCED CELL-DEATH; LYMPHOCYTES-T; TOLERANCE INDUCTION; TRANSGENIC MICE; TUMOR-ANTIGENS; RECEPTOR; APOPTOSIS; EPITOPES; CANCER; IDENTIFICATION AB We describe in this study a strategy to produce synthetic vaccines based on a single polypeptide capable of eliciting strong immune responses to a combination CTL and Th epitopes with the purpose of treating malignancies or preventing infectious diseases. This strategy is based on the capacity of Trojan Ags to deliver exogenous Ags into the intracellular compartments, where processing into MHC-binding peptides takes place. Our previous work demonstrated that Trojan Ags containing a CTL epitope localized to intracellular compartments, where MHC class I-binding peptides were generated in a TAP-independent fashion by the action of various exopeptidases and the endopeptidase furin. In this study, we report that Trojan Ags containing several CTL epitopes joined via furin-sensitive linkers generated all of the corresponding MHC class I-binding peptides, which were recognized by CTL. However, Trojan Ags prepared with furin-resistant linkers failed to produce the MHC class I-binding peptides. We also present data indicating that Trojan Ags bearing both CTL and Th epitopes can generate the corresponding MHC class I- and II-binding peptides, which are capable of stimulating T cell responses. Most significantly, in vivo vaccination of mice with a single injection of multiepitope Trojan Ags resulted in strong CTL and Th responses that translated into significant antitumor responses in a model of malignant melanoma. The overall results indicate that Trojan Ags prepared with furin-sensitive linkers are ideal candidates for producing synthetic multiepitope vaccines for the induction of CTL and Th responses that could be used against a variety of diseases, including cancer. C1 Mayo Clin & Mayo Fdn, Dept Immunol, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Dept Canc Ctr, Rochester, MN 55905 USA. NCI, Lab Cell Biol, NIH, Bethesda, MD 20892 USA. RP Celis, E (reprint author), Mayo Clin & Mayo Fdn, Dept Immunol, GU421A, Rochester, MN 55905 USA. EM celis.esteban@mayo.edu FU NCI NIH HHS [CA80782, P50CA91956] NR 31 TC 54 Z9 58 U1 1 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD APR 1 PY 2004 VL 172 IS 7 BP 4575 EP 4582 PG 8 WC Immunology SC Immunology GA 829TO UT WOS:000222072900068 PM 15034075 ER PT J AU Herbeuval, JP Lelievre, E Lambert, C Dy, M Genin, C AF Herbeuval, JP Lelievre, E Lambert, C Dy, M Genin, C TI Recruitment of STAT3 for production of IL-10 by colon carcinoma cells induced by macrophage-derived IL-6 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EPITHELIAL OVARIAN-CANCER; GENE-EXPRESSION; TRANSCRIPTION FACTOR; PROSTATE-CANCER; T-CELL; INTERLEUKIN-6; GROWTH; ACTIVATION; CYTOKINES; DISEASE AB The immunosuppressive cytokine IL-10 is associated with poor prognosis in colon cancer. Although macrophages are involved in antitumor defenses, production of IL-10 by tumor cells may permit malignant cells escape to cell-mediated immune defenses. To investigate interactions between macrophages and tumor cells in humans, we cultured macrophages isolated from patients and tested the effect of these macrophages on the production of IL-10- by several tumor cell lines. Macrophages were isolated from pleural effusions of patients with malignancy and from noncancer control patients. We demonstrated that culture supernatants of macrophages from both sources strongly stimulated IL-10 production by the three different human colon adenocarcinoma cell lines, Colo 205, Colo 320, and HT29. Recombinant IL-6, but not IL-10, TNF-alpha, and IFN-alpha, stimulated the secretion of IL-10 by colon tumor cells. mAbs against IL-6 and IL-6R prevented the effect of macrophage culture supernatants and of rIL-6, respectively, on the production of IL-10 by the three cell lines. Cocultures of macrophages and colon cancer cells showed that these tumor cells first stimulated macrophages to produce IL-6, which was then followed by IL-6-induced IL-10 production by colon cancer cells. Finally, we showed that IL-10 gene regulation was mediated by STAT3, which was phosphorylated after the binding of IL-6 to IL-6R. This is the first demonstration that IL-6, secreted by macrophages, can induce a STAT3-mediated IL-10 production by colon tumor cells. C1 Univ St Etienne, Grp Immunite Muqueuses & Agents Pathogenes, St Etienne, France. Inst Natl Sante & Rech Med, Unite 564, Angers, France. CNRS, Unite Mixte Rech, F-8603 Paris, France. RP Herbeuval, JP (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM herbeuvj@mail.nih.gov RI Lelievre, Eric/M-2878-2015 NR 38 TC 58 Z9 61 U1 2 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD APR 1 PY 2004 VL 172 IS 7 BP 4630 EP 4636 PG 7 WC Immunology SC Immunology GA 829TO UT WOS:000222072900075 PM 15034082 ER PT J AU Kottilil, S Shin, K Planta, M McLaughlin, M Hallahan, CW Ghany, M Chun, TW Sneller, MC Fauci, AS AF Kottilil, S Shin, K Planta, M McLaughlin, M Hallahan, CW Ghany, M Chun, TW Sneller, MC Fauci, AS TI Expression of chemokine and inhibitory receptors on natural killer cells: Effect of immune activation and HIV viremia SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID IMMUNODEFICIENCY-VIRUS-INFECTION; ACTIVE ANTIRETROVIRAL THERAPY; WEGENERS-GRANULOMATOSIS; INNATE IMMUNITY; T-LYMPHOCYTES; NK; IMPAIRMENT; MEMORY AB We examined the cell-surface expression of chemokine and natural killer (NK) cell inhibitory receptors (iNKRs) on NK cells from individuals with human immunodeficiency virus (HIV) infection, chronic hepatitis C infection, and Wegener's granulomatosis (WG), an inflammatory, granulomatous vasculitis. The expression of CCR5 on NK cells was up-regulated in individuals with HIV viremia and in individuals with active WG, indicating that expression of this receptor is modulated by states of immune activation associated with viral infection and inflammatory or immune-mediated diseases. In contrast, iNKRs were shown to be up-regulated only on NK cells of individuals with HIV viremia, and they returned to a normal level when viremia was controlled with effective antiviral therapy. In individuals with HIV-1 viremia, there was a direct correlation between the level of expression of p58.1, p58.2, and CD94 receptors and plasma HIV viremia, suggesting that ongoing active HIV replication has an effect on the expression of such receptors on NK cells. These results suggest that immune activation leads to abnormal cell-surface expression of chemokine receptors on NK cells, whereas HIV-specific processes account for the up-regulation of iNKRs on NK cells; this may explain the NK cell-functional defects seen in HIV infection. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Kottilil, S (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Rm 6A11,9000 Wisconsin Ave, Bethesda, MD 20892 USA. EM skottilil@niaid.nih.gov NR 19 TC 59 Z9 60 U1 0 U2 2 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 APR 1 PY 2004 VL 189 IS 7 BP 1193 EP 1198 DI 10.1086/382090 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 805AC UT WOS:000220338200009 PM 15031787 ER PT J AU Oxenius, A Price, DA Hersberger, M Schlaepfer, E Weber, R Weber, M Kundig, TM Boni, J Joller, H Phillips, RE Flepp, M Opravil, M Speck, RF AF Oxenius, A Price, DA Hersberger, M Schlaepfer, E Weber, R Weber, M Kundig, TM Boni, J Joller, H Phillips, RE Flepp, M Opravil, M Speck, RF CA Swiss HIV Cohort Study TI HIV-specific cellular immune response is inversely correlated with disease progression as defined by decline of CD4(+) T cells in relation to HIV RNA load SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; LONG-TERM NONPROGRESSORS; TYPE-1 INFECTION; VIRAL LOAD; ANTIRETROVIRAL THERAPY; HOST DETERMINANTS; NATURAL-HISTORY; CD8(+); LYMPHOCYTES; VIREMIA AB The average time between infection with human immunodeficiency virus (HIV) and development of acquired immune deficiency syndrome is similar to 8 years. However, progression rates vary widely, depending on several determinants, including HIV-specific immunity, host genetic factors, and virulence of the infecting strain. In untreated HIV-infected patients with different progression rates, we examined HIV-specific T cell responses in combination with host genetic markers, such as chemokine/chemokine- receptor (CCR) polymorphisms and human leukocyte antigen (HLA) genotypes. HIV-specific CD4(+) T cell responses and, to a lesser extent, HIV-specific CD8(+) T cell responses were inversely correlated with progression rate. Slower progression was not related to polymorphisms in CCR genes, HLA genotype, or GB virus C coinfection. These data suggest that HIV-specific T cell responses are involved in protecting the host from disease progression. C1 ETH, Inst Microbiol, CH-8092 Zurich, Switzerland. Univ Zurich Hosp, Inst Clin Chem, CH-8091 Zurich, Switzerland. Univ Zurich Hosp, Div Infect Dis & Hosp Epidemiol, CH-8091 Zurich, Switzerland. Univ Zurich Hosp, Clin Viseral & Transplantat Surg, CH-8091 Zurich, Switzerland. Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland. Univ Zurich Hosp, Dept Med, CH-8091 Zurich, Switzerland. Univ Zurich, Swiss Natl Ctr Retroviruses, Zurich, Switzerland. NIAID, Vaccinse Res Ctr, NIH, Bethesda, MD 20892 USA. John Radcliffe Hosp, Nuffield Dept Med, Oxford OX3 9DU, England. RP Oxenius, A (reprint author), ETH Zentrum, Inst Microbiol, LFV B31,Schmelzbergstr 7, CH-8092 Zurich, Switzerland. EM oxenius@microbiol.ethz.ch RI Infektiologie, USZ/A-6921-2011; Price, David/C-7876-2013; SHCS, all/G-4072-2011; SHCS, ch/G-4077-2011; SHCS, only/G-4080-2011; Weber, Rainer/D-5175-2012; Oxenius, Annette/G-7794-2015; Speck, Roberto/O-2433-2016 OI Price, David/0000-0001-9416-2737; NR 42 TC 17 Z9 18 U1 0 U2 2 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 APR 1 PY 2004 VL 189 IS 7 BP 1199 EP 1208 DI 10.1086/382028 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 805AC UT WOS:000220338200010 PM 15031788 ER PT J AU Gray, RH Li, X Wawer, MJ Serwadda, D Sewankambo, NK Wabwire-Mangen, F Lutalo, T Kiwanuka, N Kigozi, G Nalugoda, F Meehan, MP Robb, M Quinn, TC AF Gray, RH Li, X Wawer, MJ Serwadda, D Sewankambo, NK Wabwire-Mangen, F Lutalo, T Kiwanuka, N Kigozi, G Nalugoda, F Meehan, MP Robb, M Quinn, TC TI Determinants of HIV-1 load in subjects with early and later HIV infections, in a general-population cohort of Rakai, Uganda SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; SEXUALLY-TRANSMITTED-DISEASES; VIRAL LOAD; RNA LEVELS; TYPE-1 INFECTION; SEX-DIFFERENCES; MEN; SEROCONVERSION; TRANSMISSION; WOMEN AB Human immunodeficiency virus (HIV) type 1 RNA loads were determined for 256 subjects with early ( incident) HIV infection and for 1293 subjects with later ( prevalent) HIV infection, in a Ugandan cohort. Prevalent infections were classified as latent ( 0 - 1 symptoms) and midstage disease (greater than or equal to2 symptoms), and deaths were ascribed to acquired immunodeficiency syndrome. Among subjects with incident HIV infection, HIV load did not differ by sex, but, among subjects with prevalent HIV infection, it was higher in males than in females. HIV load was highest in subjects ( 25 - 29 years old) with incident HIV infection but increased with age in subjects with prevalent HIV infection. Viremia was higher after serconversion than in latency and increased with more advanced disease. Viremia was increased with genital ulcer disease (GUD) in both subjects with incident infection and in those with prevalent infection, and with herpes simplex virus type 2 seropositivity in subjects with incident HIV infection. GUD was consistently associated with higher HIV loads in subjects with incident and those with prevalent HIV infection, suggesting that treatment of GUD might reduce HIV viremia. C1 Johns Hopkins Univ, Bloomberg Sch Hyg & Publ Hlth, Dept Populat & Family Hlth Sci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. NIAID, NIH, Bethesda, MD 20892 USA. Henry M Jackson Fdn Advancement Mil Med, Rockville, MD USA. Columbia Univ, Joseph L Mailman Sch Publ Hlth, Heilbrun Ctr Populat & Family Hlth, New York, NY USA. Makerere Univ, Dept Med, Kampala, Uganda. Makerere Univ, Inst Publ Hlth, Kampala, Uganda. Makerere Univ, Fac Med, Kampala, Uganda. Uganda Virus Res Inst, Rakai Project, Entebbe, Uganda. RP Gray, RH (reprint author), Johns Hopkins Univ, Bloomberg Sch Hyg & Publ Hlth, Dept Populat & Family Hlth Sci, Ste 4030,615 N Wolfe St, Baltimore, MD 21205 USA. EM rgray@jhsph.edu OI Sewankambo, Nelson/0000-0001-9362-053X FU FIC NIH HHS [5D43TW00010]; NIAID NIH HHS [R01 AI3426S, R01 AI34826]; NICHD NIH HHS [5P30HD06826] NR 29 TC 60 Z9 64 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD APR 1 PY 2004 VL 189 IS 7 BP 1209 EP 1215 DI 10.1086/382750 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 805AC UT WOS:000220338200011 PM 15031789 ER PT J AU Wright, PF Mestecky, J McElrath, MJ Keefer, MC Gorse, GJ Goepfert, PA Moldoveanu, Z Schwartz, D Spearman, PW El Habib, R Spring, MD Zhu, YW Smith, C Flores, J Weinhold, KJ AF Wright, PF Mestecky, J McElrath, MJ Keefer, MC Gorse, GJ Goepfert, PA Moldoveanu, Z Schwartz, D Spearman, PW El Habib, R Spring, MD Zhu, YW Smith, C Flores, J Weinhold, KJ CA Natl Inst Allergy Infect Dis AIDS TI Comparison of systemic and mucosal delivery of 2 canarypox virus vaccines expressing either HIV-1 genes or the gene for rabies virus G protein SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; RECOMBINANT VACCINE; SEX WORKERS; PHASE-I; ANTIBODIES; INFECTION; SAFETY; MACAQUES; AIDS; IMMUNOGENICITY AB Background. Since the primary routes of human immunodeficiency type 1 (HIV-1) infection are across mucosal barriers, a randomized trial of canarypox virus - based vectors was conducted in 84 individuals, with delivery of vaccine by mucosal routes, and was accompanied by a detailed analysis of humoral, cellular, and mucosal immune responses. Methods. Over the course of 6 months, HIV-1 - specific (vCP 205) and rabies ( vCP 65) canarypox virus vectors were delivered systemically and/or mucosally into the nose, mouth, vagina, or rectum in a 4-dose schedule, followed by 2 doses of HIV-1 MN recombinant glycoprotein (rgp) 120 or subunit rabies vaccine administered by the intramuscular route. Results. Administration of vaccine and collection of samples were well tolerated. Serum IgG HIV-1 - specific antibodies to rgp120 were rarely seen after either systemic or mucosal delivery of canarypox virus vaccine. In contrast, serum IgG rabies and canarypox antibodies were detected in all individuals after systemic, but rarely after mucosal, delivery of vaccine. Suggestions of mucosal recognition of HIV-1 antigen included a cytotoxic T lymphocyte response in 4 of 8 individuals after administration of vaccine by the intrarectal route and a limited immunoglobulin A response at the same site. Conclusions. Each of the routes of vaccine administration was feasible in the context of a phase 1 study with motivated individuals. However, with the doses and routes of administration used, canarypox virus was not an effective mucosal immunogen. C1 Vanderbilt Univ, Med Ctr, Sch Med, Dept Pediat,Sect Infect Dis, Nashville, TN 37232 USA. Univ Alabama, Dept Med, Mucosal Immunol Lab, Birmingham, AL USA. Univ Washington, Sch Med, Seattle, WA USA. Univ Rochester, Sch Med & Dent, Rochester, NY USA. St Louis Dept Vet Affairs Med Ctr, St Louis, MO USA. St Louis Univ, Sch Med, St Louis, MO USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. EMMES Corp, Rockville, MD USA. NIAID, Div AIDS, Bethesda, MD USA. Duke Univ, Med Ctr, Cent Immunol Lab, Durham, NC USA. Pasteur Aventis, Marcy Letoile, France. RP Wright, PF (reprint author), Vanderbilt Univ, Med Ctr, Sch Med, Dept Pediat,Sect Infect Dis, Rm D-7219 MCN, Nashville, TN 37232 USA. EM peter.wright@vanderbilt.edu NR 42 TC 40 Z9 42 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 APR 1 PY 2004 VL 189 IS 7 BP 1221 EP 1231 DI 10.1086/382088 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 805AC UT WOS:000220338200013 PM 15031791 ER EF