FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Tokita, K Hocart, SJ Coy, DH Jensen, RT AF Tokita, K Hocart, SJ Coy, DH Jensen, RT TI Molecular basis of the selectivity of the gastrin-releasing peptide receptor (GRPR) for the neurotransmitter, GRP SO GASTROENTEROLOGY LA English DT Meeting Abstract C1 Tulane Univ, Hlth Sci Ctr, New Orleans, LA 70118 USA. NIH, Bethesda, MD 20892 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 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD APR PY 2001 VL 120 IS 5 SU 1 MA 532 BP A100 EP A101 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 429KA UT WOS:000168514700492 ER PT J AU Wu, SG Morin, PJ Maouyo, D Sears, CL AF Wu, SG Morin, PJ Maouyo, D Sears, CL TI Bacteroides fragilis entertoxin induces c-Myc expression and cellular proliferation SO GASTROENTEROLOGY LA English DT Meeting Abstract C1 NIA, Baltimore, MD 21224 USA. Johns Hopkins Univ, Baltimore, MD 21218 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 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD APR PY 2001 VL 120 IS 5 SU 1 MA 1679 BP A325 EP A325 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 429KA UT WOS:000168514701615 ER PT J AU Adams, TL Tio, TL Mayoral, W Lewis, JH Al-Kawas, F Mehrotra, A Wilson, W Hegde, U Jaffee, E Cassarino, D AF Adams, TL Tio, TL Mayoral, W Lewis, JH Al-Kawas, F Mehrotra, A Wilson, W Hegde, U Jaffee, E Cassarino, D TI Endoscopic features of mantel cell lymphoma involving the gastrointestinal tract SO GASTROINTESTINAL ENDOSCOPY LA English DT Meeting Abstract C1 Georgetown Univ Hosp, Washington, DC 20007 USA. NCI, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0016-5107 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD APR PY 2001 VL 53 IS 5 SU S MA 4247 BP AB182 EP AB182 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 429XG UT WOS:000168542800435 ER PT J AU Filiberti, R Bertario, L Sala, P Blanchi, S Giacosa, SA AF Filiberti, R Bertario, L Sala, P Blanchi, S Giacosa, SA TI The role of chromoendoscopy in the surveillance of the duodenum of patients with familial adenomatous polyposis. SO GASTROINTESTINAL ENDOSCOPY LA English DT Meeting Abstract C1 Natl Canc Inst, Genoa, Italy. Natl Canc Inst, I-20133 Milan, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0016-5107 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD APR PY 2001 VL 53 IS 5 SU S MA 394 BP AB64 EP AB64 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 429XG UT WOS:000168542800030 ER PT J AU Padilla-Nash, HM Heselmeyer-Haddad, K Wangsa, N Zhang, HG Ghadimi, BM Macville, M Augustus, M Schrock, E Hilgenfeld, E Ried, T AF Padilla-Nash, HM Heselmeyer-Haddad, K Wangsa, N Zhang, HG Ghadimi, BM Macville, M Augustus, M Schrock, E Hilgenfeld, E Ried, T TI Jumping translocations are common in solid tumor cell lines and result in recurrent fusions of whole chromosome arms SO GENES CHROMOSOMES & CANCER LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; HERPES-SIMPLEX VIRUS; VIRAL INTEGRATION; FRAGILE SITES; CYTOGENETIC ANALYSIS; MAMMALIAN GENOME; HUMAN NEOPLASIA; REARRANGEMENTS; CARCINOMA; SEQUENCES AB Jumping translocations (JTs) and segmental jumping translocations (SJTs) are unbalanced translocations involving a donor chromosome arm or chromosome segment that has fused to multiple recipient chromosomes. In leukemia, where JTs have been predominantly observed. the donor segment (usually Iq) preferentially fuses to the telomere regions of recipient chromosomes. In this study, spectral karyotyping (SKY) and FISH analysis revealed 188 JTs and JJTs in 10 cell lines derived from carcinomas of the bladder, prostate, breast, cervix, and pancreas. Multiple JTs and SJTs were detected in each cell line and contributed to recurrent unbalanced whole-arm translocations involving chromosome arms 5p, 14q, 15q, 20q, and 21q. Sixty percent (113/188) of JT breakpoints occurred within centromere or pericentromeric regions of the recipient chromosomes, whereas only 12% of the breakpoints were located in the telomere regions. JT breakpoints of both donor and recipient chromosomes coincided with numerous fragile sites as well as viral integration sites for human DNA viruses. The JTs within each tumor cell line promoted clonal progression, leading to the acquisition of extra copies of the donated chromosome segments that often contained oncogenes (MYC, ABL, HER2/NEU, etc.), consequently resulting in tumor-specific genomic imbalances. Published 2001 Wiley-Liss, Inc.dagger. C1 NCI, Dept Genet, Div Clin Sci, NIH, Bethesda, MD 20892 USA. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Nijmegen, Lab In Situ Hybridizat, Inst Pathol, Nijmegen, Netherlands. RP Padilla-Nash, HM (reprint author), NCI, Dept Genet, Div Clin Sci, NIH, 9 Mem Dr,Bldg 9,Room 1N-105, Bethesda, MD 20892 USA. NR 45 TC 63 Z9 63 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 2001 VL 30 IS 4 BP 349 EP 363 DI 10.1002/gcc.1101 PG 15 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 407LJ UT WOS:000167272800004 PM 11241788 ER PT J AU Mathias, RA Freidhoff, LR Blumenthal, MN Meyers, DA Lester, L King, R Xu, JF Solway, J Barnes, KC Pierce, J Stine, OC Togias, A Oetting, W Marshik, PL Hetmanski, JB Huang, SK Ehrlich, E Dunston, GM Malveaux, F Banks-Schlegel, S Cox, NJ Bleecker, E Ober, C Beaty, TH Rich, SS AF Mathias, RA Freidhoff, LR Blumenthal, MN Meyers, DA Lester, L King, R Xu, JF Solway, J Barnes, KC Pierce, J Stine, OC Togias, A Oetting, W Marshik, PL Hetmanski, JB Huang, SK Ehrlich, E Dunston, GM Malveaux, F Banks-Schlegel, S Cox, NJ Bleecker, E Ober, C Beaty, TH Rich, SS CA CSGA TI Genome-wide linkage analyses of total serum IgE using variance components analysis in asthmatic families SO GENETIC EPIDEMIOLOGY LA English DT Article DE total IgE levels; asthma; variance components; linkage; Allergy Index ID IMMUNOGLOBULIN-E; QUANTITATIVE-TRAIT; SEGREGATION ANALYSIS; ASSOCIATION; MARKERS; ALLERGY; ASCERTAINMENT; SENSITIVITY; INHERITANCE; PEDIGREES AB Variance components models were used to analyze total IgE levels in families ascertained though the Collaborative Study of the Genetics of Asthma (CSGA) using a genome-wide array of polymorphic markers. While IgE levels are known to be associated with clinical asthma and recognized to be under strong genetic control (here the heritability was estimated at 44-60% in the three racial groups), specific genes influencing this trait are still largely unknown. Multipoint analysis of 323 markers yielded little indication of specific regions containing a trait locus controlling total serum IgE levels (adjusted for age and gender). Although a number of regions showed LOD statistics above 1.5 in Caucasian families (chromosome 4) and in African-American families (chromosomes 2 and 4), none yielded consistent evidence in all three racial groups. Analysis of total IgE adjusted for gender, age and Allergy Index (a quantitative score of skin test sensitivity to 14 common aeroallergens) was conducted on these data. In this analysis, a much stronger signal for a trait locus controlling adjusted log[total IgE] was seen on the telomeric end of chromosome 18, but only in Caucasian families. This region accounted for most of the genetic variation in log[total IgE], and may represent a quantitative trait locus for IgE levels independent of atopic response. Oligogenic analysis accounting simultaneously for the contribution of this locus on chromosome 18 and other chromosomal regions showing some evidence of linkage in these Caucasian families (on chromosomes 2, 4 and 20) failed to yield significant evidence for interaction. (C) 2001 Wiley-Liss, inc. C1 Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. Univ Maryland, Ctr Genet Asthma & Complex Dis, Baltimore, MD 21201 USA. Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. Univ Chicago, Dept Med, Chicago, IL 60637 USA. Bowman Gray Sch Med, Dept Publ Hlth Sci, Winston Salem, NC USA. Univ New Mexico, Coll Pharm, Albuquerque, NM 87131 USA. Howard Univ, Dept Microbiol, Washington, DC 20059 USA. NHLBI, Div Lung Dis, Bethesda, MD 20892 USA. Univ Chicago, Dept Human Genet, Chicago, IL USA. RP Beaty, TH (reprint author), Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, 615 N Wolfe St, Baltimore, MD 21205 USA. RI Beaty, Terri/A-6032-2008; Solway, Julian/B-1116-2008; Huang, Shau-Ku/F-5509-2010 OI Solway, Julian/0000-0002-0898-8530; FU NHLBI NIH HHS [HL-49612, HL-49609, HL-58977, HL-49602, HL-49596, HV-48141]; NIDDK NIH HHS [DK595522] NR 37 TC 61 Z9 61 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 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD APR PY 2001 VL 20 IS 3 BP 340 EP 355 DI 10.1002/gepi.5 PG 16 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 417EB UT WOS:000167821500005 PM 11255243 ER PT J AU Kerscher, O Hieter, P Winey, M Basrai, MA AF Kerscher, O Hieter, P Winey, M Basrai, MA TI Novel role for a Saccharomyces cerevisiae nucleoporin, nup170p, in chromosome segregation SO GENETICS LA English DT Article ID NUCLEAR-PORE COMPLEX; CELL-CYCLE PROGRESSION; SISTER-CHROMATID COHESION; SPINDLE POLE BODY; IN-VIVO; KINETOCHORE PROTEIN; YEAST; GENE; TRANSMISSION; ORGANIZATION AB We determined that a mutation in the nucleoporin gene NUP170 leads to defects in chromosome transmission fidelity (ctf) and kinetochore integrity in Saccharomyces cerevisiae. A ctf mutant strain, termed s141, shows a transcription readthrough phenotype and stabilizes a dicentric chromosome fragment in two assays for kinetochore integrity. Previously, these assays led to the identification of two essential kinetochore components, Ctf13p and Ctf14p. Thus, s141 represents another ctf mutant involved in the maintenance of kinetochore integrity. We cloned and mapped the gene complementing the ctf mutation of s141 and showed that it is identical to the S. cerevisiae NUP170 gene. A deletion strain of NUP170 (nup170 Delta::HIS3) has a Ctf(-) phenotype similar to the s141 mutant (nup170-141) and also exhibits a kinetochore integrity defect. We identified a second nucleoporin, NUP157, a homolgue of NUP170, as a suppressor of the Ctf(-) phenotype of nup170-141 and nup170 Delta::HIS3 strains. However, a deletion of NUP157 or several other nucleoporins did not affect chromosome segregation. Our data suggest that NUP170 encodes a specialized nucleoporin with a unique role in chromosome segregation and possibly kinetochore function. C1 NCI, Dept Genet, NIH, Natl Naval Med Ctr, Bethesda, MD 20889 USA. Univ British Columbia, Ctr Mol Med & Therapeut, Vancouver, BC V5Z 4H4, Canada. Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA. RP Basrai, MA (reprint author), NCI, Dept Genet, NIH, Natl Naval Med Ctr, Bldg 8,Rm 5101,8901 Wisconsin Ave, Bethesda, MD 20889 USA. FU NCI NIH HHS [CA15916]; NIGMS NIH HHS [GM59992] NR 51 TC 38 Z9 40 U1 0 U2 1 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD APR PY 2001 VL 157 IS 4 BP 1543 EP 1553 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 424GD UT WOS:000168223400014 PM 11290711 ER PT J AU Jordan, IK Makarova, KS Spouge, JL Wolf, YI Koonin, EV AF Jordan, IK Makarova, KS Spouge, JL Wolf, YI Koonin, EV TI Lineage-specific gene expansions in bacterial and archaeal genomes SO GENOME RESEARCH LA English DT Letter ID MYCOBACTERIUM-TUBERCULOSIS; DEINOCOCCUS RADIODURANS; HELICOBACTER-PYLORI; PROTEIN FAMILIES; SEQUENCE; EVOLUTION; DATABASE; NUMBER; ENTRY; CELLS AB Gene duplication is an important mechanistic antecedent to the evolution of new genes and novel biochemical functions. In an attempt to assess the contribution of gene duplication to genome evolution in archaea and bacteria, clusters of related genes that appear to have expanded subsequent to the diversification of the major prokaryotic lineages (lineage-specific expansions) were analyzed. Analysis of 21 completely sequenced prokaryotic genomes shows that lineage-specific expansions comprise a substantial fraction (similar to5%-33%) of their coding capacities. A positive correlation exists between the fraction of the genes taken up by lineage-specific expansions and the total number of genes in a genome. Consistent with the notion that lineage-specific expansions are made up of relatively recently duplicated genes, >90% of the detected clusters consists of only two to four genes. The more common smaller clusters tend to include genes with higher pairwise similarity (as reflected by average score density) than larger clusters. Regardless of size, cluster members tend to be located more closely on bacterial chromosomes than expected by chance, which could reflect a history of tandem gene duplication. In addition to the small clusters, almost all genomes also contain rare large clusters of size greater than or equal to 20. Several examples of the potential adaptive significance of these large clusters are explored. The presence or absence of clusters and their related genes was used as the basis for the construction of a similarity graph for completely sequenced prokaryotic genomes. The topology of the resulting graph seems to reflect a combined effect of common ancestry, horizontal transfer,and lineage-specific gene loss. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20894 USA. Russian Acad Sci, Inst Cytol & Genet, Novosibirsk 630090, Russia. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. FU NIGMS NIH HHS [5R01-GM39933-09] NR 51 TC 114 Z9 121 U1 1 U2 12 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD APR PY 2001 VL 11 IS 4 BP 555 EP 565 DI 10.1101/gr.GR-1660R PG 11 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 418HT UT WOS:000167885400007 PM 11282971 ER PT J AU Durkin, ME Keck-Waggoner, CL Popescu, NC Thorgeirsson, SS AF Durkin, ME Keck-Waggoner, CL Popescu, NC Thorgeirsson, SS TI Integration of a c-myc transgene results in disruption of the mouse Gtf2ird1 gene, the homologue of the human GTF2IRD1 gene hemizygously deleted in Williams-Beuren syndrome SO GENOMICS LA English DT Article ID GROWTH-FACTOR-ALPHA; PUTATIVE TRANSCRIPTION FACTOR; TFII-I; BINDING PROTEIN; MICE; LIVER; IDENTIFICATION; 7Q11.23; EXPRESSION; REGION AB Transgenic mice expressing c-myc under the control of the albumin promoter and enhancer develop liver tumors and have served as a useful model for studying the progression of hepatocarcinogenesis. The chromosomes of one line of c-myc transgenic mice carry the reciprocal translocation t(5;6)(G1;F2) adjacent to the transgene insertion site an the 5G1-ter segment translocated to chromosome 6, To characterize the genomic alterations in the c-myc transgenic animals, we have cloned the mouse DNA flanking the transgene array. By linkage mapping, the transgene integration site was localized to the region of distal chromosome 5 syntenic to the region on human chromosome 7q11.23 that is hemizgygously deleted in Williams-Beuren syndrome, a multisystemic developmental disorder. Comparison of the genomic DNA structure in wildtype and transgenic mice revealed that the transgene integration had induced an similar to 40-kb deletion, starting downstream of the Cyln2 gene and including the first exon of the Gtf2ird1 gene. Gtf2ird1 encodes a polypeptide related to general transcription factor TFII-I, and it is the mouse orthologue of GTF2IRD1 (WBSCR11), one of the genes commonly deleted in Williams-Beuren syndrome patients. Loss of the 5 ' end of the Gtf2ird1 gene resulted in greatly reduced expression of Gtf2ird1 mRNA in mice homozygous for the transgene. C1 NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Durkin, ME (reprint author), NCI, Expt Carcinogenesis Lab, NIH, Bldg 37,Room 3C28,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 31 TC 24 Z9 25 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD APR 1 PY 2001 VL 73 IS 1 BP 20 EP 27 DI 10.1006/geno.2001.6507 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 425XN UT WOS:000168317100003 PM 11352562 ER PT J AU Lee, EC Yu, DG de Velasco, JM Tessarollo, L Swing, DA Court, DL Jenkins, NA Copeland, NG AF Lee, EC Yu, DG de Velasco, JM Tessarollo, L Swing, DA Court, DL Jenkins, NA Copeland, NG TI A highly efficient Escherichia coli-based chromosome engineering system adapted for recombinogenic targeting and subcloning of BAC DNA SO GENOMICS LA English DT Article ID RECOMBINATION SYSTEM; GENE; MUTAGENESIS AB Recently, a highly efficient recombination system for chromosome engineering in Escherichia coli was described that uses a defective A prophage to supply functions that protect and recombine a linear DNA targeting cassette with its substrate sequence (Yu ct al., 2000, Proc. Natl. Acad. Sci. USA 97, 5978-5983). Importantly, the recombination is proficient with DNA homologies as short as 30-50 bp, making it possible to use PCR-amplified fragments as the targeting cassette. Here, we adapt this prophage system for use in bacterial artificial chromosome (BAC) engineering by transferring it to DH1OB cells, a BAC host strain. In addition, arabinose inducible cre and flpe genes are introduced into these cells to facilitate BAC modification using loxP and FRT sites. Next, we demonstrate the utility of this recombination system by using it to target cre to the 3 ' end of the mouse neuron-specific enolase (Eno2) gene carried on a 250-kb BAG, which made it possible to generate BAC transgenic mice that specifically express Cre in all mature neurons. In addition, we show that fragments as large as 80 kb can be subcloned from BACs by gap repair using this recombination system, obviating the need for restriction enzymes or DNA Ligases. Finally, we show that BACs can be modified with this recombination system in the absence of drug selection. The ability to modify or subclone large fragments of genomic DNA with precision should facilitate many kinds of genomic experiments that were difficult or impossible to perform previously and aid in studies of gene function in the postgenomic era. (C) 2001 Academic Press. C1 NCI, Frederick Canc Res & Dev Ctr, Mouse Canc Genet Program, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. RP Copeland, NG (reprint author), NCI, Frederick Canc Res & Dev Ctr, Mouse Canc Genet Program, Bldg 539,Room 229, Frederick, MD 21702 USA. NR 13 TC 801 Z9 830 U1 4 U2 38 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD APR 1 PY 2001 VL 73 IS 1 BP 56 EP 65 DI 10.1006/geno.2000.6451 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 425XN UT WOS:000168317100007 PM 11352566 ER PT J AU Etzioni, R Ramsey, SD Berry, K Brown, M AF Etzioni, R Ramsey, SD Berry, K Brown, M TI The impact of including future medical care costs when estimating the costs attributable to a disease: A colorectal cancer case study SO HEALTH ECONOMICS LA English DT Article DE cost-effectiveness analysis; future medical care costs; survival ID HEALTH AB A source of controversy in the economic literature concerns whether to include or exclude future medical care costs when computing attributable costs for lifesaving interventions. Although it is hypothesized that including future medical care costs will offset the cost savings achieved through prevention, the magnitude of the effect is not known. The objectives of the present study are to develop a methodology for estimating the excess costs of care among colorectal cancer patients, including and excluding future costs of care, and comparing these results with previous studies that do not include costs in added years of life. Subjects in the study included those identified with colorectal cancer drawn from the Surveillance, Epidemiology and End Results (SEER)-Medicare database and an age- and gender-matched control group drawn from the general Medicare population. Using the Kaplan-Meier Sample Average estimator, we directly estimate expected 11-year costs, and then, with the addition of some simple extrapolating assumptions, determine expected 25-year costs. The latter time horizon captures lifetime costs for over 90% of the cohort. Males results for discounted, stage-specific 11- versus 25-year excess costs: in situ, $22411 versus $23494; Stage 1, $29365 versus $32510; Stage 2, $28114 versus $25263; Stage 3, $27397 versus $19647; Stage 4, $3006 versus $7837. Trends were similar for females. It can be concluded that adding costs of care in future years for those whose colorectal cancer is prevented owing to screening greatly alters the estimate of lifetime excess costs for colorectal cancer patients, and can produce negative results for advanced stage disease. The results emphasize the need to adopt a standard approach for dealing with future costs when evaluating lifesaving interventions for cost-effectiveness analyses. Copyright (C) 2001 John Wiley & Sons, Ltd. C1 Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. Univ Washington, Dept Med, Seattle, WA USA. NCI, Rockville, MD USA. RP Ramsey, SD (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave N,Box 19024,MP 804, Seattle, WA 98109 USA. NR 15 TC 31 Z9 32 U1 1 U2 4 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 1057-9230 J9 HEALTH ECON JI Health Econ. PD APR PY 2001 VL 10 IS 3 BP 245 EP 256 DI 10.1002/hec.580 PG 12 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 425QH UT WOS:000168302300005 PM 11288190 ER PT J AU Rimer, BK Glanz, K Rasband, G AF Rimer, BK Glanz, K Rasband, G TI Searching for evidence about health education and health behavior interventions SO HEALTH EDUCATION & BEHAVIOR LA English DT Article; Proceedings Paper CT 1999 Mid-Year SOPHE Meeting CY 1999 CL MINNEAPOLIS, MINNESOTA SP SOPHE ID COMMUNITY PREVENTIVE SERVICES; EVIDENCE-BASED MEDICINE; SYSTEMATIC REVIEWS; FUTURE-DIRECTIONS; DECISION-MAKING; SOCIAL VALIDITY; PROMOTION; GUIDE; CARE; OUTCOMES AB Evidence is fundamental to science, but finding the right evidence in health education and health behavior (HEHB) is often a challenge. The authors discuss some of the controversies about the types of evidence that should be considered acceptable in HEHB, the tension between the use of qualitative versus quantitative data, the need for measures of important but neglected constructs, and interpretation of data from experimental and nonexperimental research. This article discusses some of the challenges to the use of evidence and describes a number of strategies and some forces encouraging the use of evidence-based interventions. Finally, the authors suggest ways to improve the practice and dissemination of evidence-based HEHB. Ultimately, if evidence-based interventions am not disseminated, the interventions will not achieve their potential. The goal should be to develop more effective interventions and disseminate them to improve the public's health. C1 NCI, Bethesda, MD 20892 USA. Univ Hawaii, Canc Res Ctr Hawaii, Honolulu, HI 96822 USA. RP Rimer, BK (reprint author), NCI, Bethesda, MD 20892 USA. NR 63 TC 42 Z9 43 U1 3 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1090-1981 J9 HEALTH EDUC BEHAV JI Health Educ. Behav. PD APR PY 2001 VL 28 IS 2 BP 231 EP 248 DI 10.1177/109019810102800208 PG 18 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 409PA UT WOS:000167391000007 PM 11265831 ER PT J AU Hoover, R AF Hoover, R TI The future of cancer control SO HEALTH PHYSICS LA English DT Meeting Abstract DE National Council on Radiation Protection and; Measurements; cancer; health effects; patient protection C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD APR PY 2001 VL 80 IS 4 BP 362 EP 362 DI 10.1097/00004032-200104000-00012 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 414WM UT WOS:000167689200011 ER PT J AU Bissell, DM Gores, GJ Laskin, DL Hoofnagle, JH AF Bissell, DM Gores, GJ Laskin, DL Hoofnagle, JH TI Drug-induced liver injury: Mechanisms and test systems SO HEPATOLOGY LA English DT Editorial Material ID HEPATIC-FAILURE; MITOCHONDRIAL-DNA; RAT-LIVER; DISEASE; TROGLITAZONE; DEPLETION; HEPATOTOXICITY; CHOLESTASIS; CELLS; CHOLANGIOCYTES C1 Univ Calif San Francisco, Div Gastroenterol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Ctr Liver, San Francisco, CA 94143 USA. Mayo Clin, Rochester, MN USA. Rutgers State Univ, Dept Pharmacol & Toxicol, Piscataway, NJ 08854 USA. NIDDK, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. RP Bissell, DM (reprint author), Univ Calif San Francisco, Div Gastroenterol, Box 0538, San Francisco, CA 94143 USA. NR 44 TC 121 Z9 129 U1 1 U2 3 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD APR PY 2001 VL 33 IS 4 BP 1009 EP + DI 10.1053/jhep.2001.23505 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 416DA UT WOS:000167763900033 PM 11283870 ER PT J AU Danilkovitch-Miagkova, A Leonard, EJ AF Danilkovitch-Miagkova, A Leonard, EJ TI Cross-talk between RON receptor tyrosine kinase and other transmembrane receptors SO HISTOLOGY AND HISTOPATHOLOGY LA English DT Review DE RON; transmembrane receptors; cross-talk ID MACROPHAGE-STIMULATING PROTEIN; GROWTH-FACTOR RECEPTOR; MULTIFUNCTIONAL DOCKING SITE; EPITHELIAL-CELL MIGRATION; BETA-CATENIN; SIGNAL-TRANSDUCTION; HGF RECEPTOR; C-SRC; ERYTHROPOIETIN RECEPTOR; ACTIVATING MUTATIONS AB RON is a transmembrane receptor tyrosine kinase that mediates biological activities of Macrophage Stimulating Protein (MSP). MSP is a multifunctional factor regulating cell adhesion, motility, growth and survival. MSP binding to RON causes receptor tyrosine phosphorylation leading to up-regulation of RON catalytic activity and subsequent activation of downstream signaling molecules. Recent studies show that RON is spatially and functionally associated with other transmembrane molecules including adhesion receptors integrins and cadherins, and cytokine and growth factor receptors IL-3 betac, EPOR and MET. For example, MSP-induced cell shape change is mediated via RON-activated IL-3 betac receptor. Activation of integrins causes MSP-independent RON phosphorylation, and the integrin/RON collaboration regulates cell survival. Thus, RON can be activated without MSP by ligand stimulation of RON-associated receptors, and MSP-activated RON can cause ligand-independent activation of RON-associated receptors. As a result of the receptor cross-activation RON-specific pathways become a part of a signal transduction network of other receptors, and conversely signaling pathways activated by other receptors can be used by RON. This receptor collaboration extends the spectrum of cellular responses generated by MSP and by putative ligands of RON-associated receptors. However signaling pathways involved in the receptor cross-talk and underlying activation mechanisms remain to be investigated. The purpose of this review is to summarize data and to discuss a role of cross-talk between RON and other transmembrane receptors. C1 NCI, Immunobiol Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Danilkovitch-Miagkova, A (reprint author), NCI, Immunobiol Lab, Frederick Canc Res & Dev Ctr, Bldg 560,Room 12-46,Ft Detrick, Frederick, MD 21702 USA. NR 95 TC 18 Z9 18 U1 2 U2 3 PU F HERNANDEZ PI MURCIA PA PLAZA FUENSANTA 2-7 C, 30008 MURCIA, SPAIN SN 0213-3911 J9 HISTOL HISTOPATHOL JI Histol. Histopath. PD APR PY 2001 VL 16 IS 2 BP 623 EP 631 PG 9 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 421LC UT WOS:000168065000030 PM 11332718 ER PT J AU Donahue, RE Dunbar, CE AF Donahue, RE Dunbar, CE TI Update on the use of nonhuman primate models for preclinical testing of gene therapy approaches targeting hematopoietic cells SO HUMAN GENE THERAPY LA English DT Review ID COLONY-STIMULATING FACTOR; GREEN FLUORESCENT PROTEIN; APE LEUKEMIA-VIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; MARROW REPOPULATING CELLS; LONG-TERM ENGRAFTMENT; HUMAN GLUCOCEREBROSIDASE GENE; PERIPHERAL-BLOOD LYMPHOCYTES; LETHALLY IRRADIATED BABOONS; COAGULATION-FACTOR-IX AB Transfer of genes into hematopoietic stem cells or primary lymphocytes has been a primary focus of the gene therapy field for more than a decade because of the wide variety of congenital and acquired diseases that potentially could be cured by successful gene transfer into these cell populations. However, despite success in murine models and in vitro, progress has been slow, and early clinical trials were disappointing due to inefficient gene transfer into long-term repopulating cells. The unique predictive value of nonhuman primate or other large animal models has become more apparent, and major advances in gene transfer efficiency have been made by utilizing these powerful but expensive and complex systems. This review summarizes more recent findings from nonhuman primate investigations focusing on hematopoietic stem cells or lymphocytes as target populations, and highlights specific preclinical issues, including safety. Results from studies using standard retroviral vectors, lentiviral vectors, adenoviral vectors, and adeno-associated viral vectors are discussed. Judicious application of these models should continue to be a priority, and advances should now be tested in proof-of-concept clinical trials. C1 NHLBI, Hematol Branch, Bethesda, MD 20892 USA. RP Donahue, RE (reprint author), NHLBI, Hematol Branch, Room 1B-05,5 Res Court, Rockville, MD 20850 USA. NR 103 TC 59 Z9 59 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD APR PY 2001 VL 12 IS 6 BP 607 EP 617 DI 10.1089/104303401300057289 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 419XA UT WOS:000167973000001 PM 11426461 ER PT J AU Xu, JF Zheng, SL Chang, BL Smith, JR Carpten, JD Stine, OC Isaacs, SD Wiley, KE Henning, L Ewing, C Bujnovszky, P Bleeker, ER Walsh, PC Trent, JM Meyers, DA Isaacs, WB AF Xu, JF Zheng, SL Chang, BL Smith, JR Carpten, JD Stine, OC Isaacs, SD Wiley, KE Henning, L Ewing, C Bujnovszky, P Bleeker, ER Walsh, PC Trent, JM Meyers, DA Isaacs, WB TI Linkage of prostate cancer susceptibility loci to chromosome 1 SO HUMAN GENETICS LA English DT Article ID FAMILIES; 1Q42.2-43; 1Q24-25; HPC1; HUMANS; TESTS; 1P36; GENE; SCAN AB Three prostate cancer susceptibility genes have been reported to be linked to different regions on chromosome 1: HPC1 at 1q24-25, PCAP at 1q42-43, and CAPB at 1p36. Replication studies analyzing each of these regions have yielded inconsistent results. To evaluate link age across this chromosome systematically, we performed multipoint linkage analyses with 50 microsatellite markers spanning chromosome 1 in 159 hereditary prostate cancer families (HPC), including 79 families analyzed in the original report describing HPC1 linkage, The highest lod scores for the complete dataset of 159 families were observed at 1q24-25 at which the parametric lod score assuming heterogeneity (hlod) was 2.54 (P=0.0006) with sin allele sharing lod of 2.34 (P=0.001) at marker D1S413, although only weak evidence was observed in the 80 families not previously analyzed for this region (hlod-0.44, P=0.14, and allele sharing lod=0.67, P=0.08). In the complete data set, the evidence for linkage across this region was very broad, with allele sharing lod scores greater than 0.5 extending approximately 100 cM from 1p13 to 1q32, possibly indicating the presence of multiple susceptibility genes. Elsewhere on chromosome 1, some evidence of linkage was observed at 1q42-43, with a peak allele sharing lod of 0.56 (P=0.11) and hlod of 0.24 (P=0.25) at D1S235. For analysis of the CAPB locus at 1p36, we focused on six HPC families in our collection with a history of primary brain cancer; four of these families had positive linkage results at 1p36, with a peak allele sharing lod of 0.61 (P=0.09) and hlod of 0.39 (P=0.16) at D1S407 in all six families. These results are consistent with the heterogeneous nature of hereditary prostate cancer, and the existence of multiple loci on chromosome 1 for this disease. C1 Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21205 USA. Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Genome, Winston Salem, NC USA. Univ Maryland, Sch Med, Dept Epidemiol, Baltimore, MD 21201 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Johns Hopkins Hosp, Baltimore, MD 21287 USA. RP Isaacs, SD (reprint author), Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21205 USA. RI Smith, Jeff/C-3484-2012 FU NCI NIH HHS [CA58236] NR 33 TC 57 Z9 58 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD APR PY 2001 VL 108 IS 4 BP 335 EP 345 DI 10.1007/s004390100488 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 429MW UT WOS:000168522100009 PM 11379880 ER PT J AU Hollenbach, JA Thomson, G Cao, K Fernandez-Vina, M Erlich, HA Bugawan, TL Winkler, C Winter, M Klitz, J AF Hollenbach, JA Thomson, G Cao, K Fernandez-Vina, M Erlich, HA Bugawan, TL Winkler, C Winter, M Klitz, J TI HLA diversity, differentiation, and haplotype evolution in mesoamerican natives SO HUMAN IMMUNOLOGY LA English DT Article DE Amerindian; HLA; haplotype; linkage disequilibrium ID CLASS-II POLYMORPHISM; AMERICAN INDIAN TRIBES; LINKAGE DISEQUILIBRIUM; PCR AMPLIFICATION; OLIGONUCLEOTIDE PROBES; EXPEDICION-HUMANA; AMERINDIAN GROUPS; B ALLELES; A-LOCUS; POPULATIONS AB Genetic variation of the Human Leukocyte Antigen region (HLA) in three Amerindian populations from the Southern Mexican state of Oaxaca, the Zapotec, Mixtec and the Mire is examined. Individuals were typed using PCR-SSOP for four class II loci (DRB1, DQA1, DQB1, DPB1)and three class I loci (HLA-A, -B, and -C). Based on known HLA distributions, European admixture ranged from 1% to 10%. Individuals with European alleles were excluded from subsequent analysis. New alleles were revealed at each of the class I loci. In general, genotype frequencies were in Hardy-Weinberg equilibrium, although some deviations were detected. Allele frequency distributions at the DRB1. DQA1, DQB1 and HLA-A loci in all populations were more even than expected under neutrality, supporting a model of balancing selection at these loci. A history of directional selection for DPB1 in all three populations was indicated, as homozygosity values were significantly above expected values. Allele frequency distributions at HLA-B and HLA-C did not differ significantly from neutrality expectations. The data also provide evidence from linkage disequilibrium that strong haplotypic associations are present across the entire HLA region in each of the populations. Significant overall linkage disequilibrium exists between all pairs of loci typed in these populations, except those which include the DPB1 locus. These associations exist despite the fact that the recombination fraction between HLA-A, in the class I region, and DQB1, in the class II region, may exceed 0.02. One explanation is that selective pressures are maintaining the relationships between particular alleles at these loci in these populations. These relationships are maintained in general across the entire HLA region in the Oaxacan Amerindians, with the exception of DPB1. (C) American Society for Histocompatibility and Immunogenetics, 2001. Published by Elsevier Science Inc. C1 Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA. Amer Red Cross, Baltimore, MD USA. Roche Mol Syst, Alameda, CA USA. NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, SAIC Frederick, Frederick, MD USA. Inst Nacl Anthropol & Hist, Oaxaca, Mexico. Univ Calif Berkeley, Calif Sch Publ Hlth, Childrens Hosp, Oakland Res Inst, Berkeley, CA 94720 USA. RP Hollenbach, JA (reprint author), Univ Calif Berkeley, Dept Integrat Biol, 3060 VLSB, Berkeley, CA 94720 USA. FU NCI NIH HHS [N01-CO-5600]; NIGMS NIH HHS [GM35326] NR 41 TC 51 Z9 56 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0198-8859 J9 HUM IMMUNOL JI Hum. Immunol. PD APR PY 2001 VL 62 IS 4 BP 378 EP 390 DI 10.1016/S0198-8859(01)00212-9 PG 13 WC Immunology SC Immunology GA 421KE UT WOS:000168062900010 PM 11295471 ER PT J AU Kallioniemi, OP Wagner, U Kononen, J Sauter, G AF Kallioniemi, OP Wagner, U Kononen, J Sauter, G TI Tissue microarray technology for high-throughput molecular profiling of cancer SO HUMAN MOLECULAR GENETICS LA English DT Article ID PROSTATE-CANCER; GENE AMPLIFICATION; COMPLEMENTARY-DNA; CDNA MICROARRAY; BREAST-CANCER; TUMOR TYPES; EXPRESSION; OVEREXPRESSION; PROGRESSION; GLIOMAS AB Tissue microarray (TMA) technology allows rapid visualization of molecular targets in thousands of tissue specimens at a time, either at the DNA, RNA or protein level, The technique facilitates rapid translation of molecular discoveries to clinical applications. By revealing the cellular localization, prevalence and clinical significance of candidate genes, TMAs are ideally suitable for genomics-based diagnostic and drug target discovery. TMAs have a number of advantages compared with conventional techniques. The speed of molecular analyses is increased by more than 100-fold, precious tissues are not destroyed and a very large number of molecular targets can be analyzed from consecutive TMA sections, The ability to study archival tissue specimens is an important advantage as such specimens are usually not applicable in other high-throughput genomic and proteomic surveys, Construction and analysis of TMAs can be automated, increasing the throughput even further, Most of the applications of the TMA technology have come from the field of cancer research, Examples include analysis of the frequency of molecular alterations in large tumor materials, exploration of tumor progression, identification of predictive or prognostic factors and validation of newly discovered genes as diagnostic and therapeutic targets. C1 NHGRI, Canc genet Branch, Nihon Univ, Bethesda, MD 20892 USA. Tampere Univ, Canc Genet Lab, FIN-33520 Tampere, Finland. Tampere Univ Hosp, FIN-33520 Tampere, Finland. Univ Basel, Inst Pathol, CH-4003 Basel, Switzerland. RP Kallioniemi, OP (reprint author), NHGRI, Canc genet Branch, Nihon Univ, 49 Convent Dr,Room 4A24,MSC 4465, Bethesda, MD 20892 USA. RI Kallioniemi, Olli/H-5111-2011; Kallioniemi, Olli/H-4738-2012 OI Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332 NR 24 TC 377 Z9 410 U1 0 U2 19 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 2001 VL 10 IS 7 SI SI BP 657 EP 662 DI 10.1093/hmg/10.7.657 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 424GH UT WOS:000168224100002 PM 11257096 ER PT J AU Riggins, GJ Strausberg, RL AF Riggins, GJ Strausberg, RL TI Genome and genetic resources from the Cancer Genome Anatomy Project SO HUMAN MOLECULAR GENETICS LA English DT Article ID SERIAL ANALYSIS; EXPRESSION; NEOPLASIA; LIBRARIES; DATABASE; INDEX; MAPS AB The Cancer Genome Anatomy Project (CGAP) is a collaborative network of cancer researchers with a common goal: to decipher the genetic changes that occur during cancer formation and progression. The project brings together several recent technologies capable of high-throughput analysis to help achieve this goal. Automated sequencing of cDNA libraries is a primary focus and is geared towards providing a comprehensive and annotated set of human and mouse transcribed sequences, This effort includes full-length transcript sequence generated by CGAP's new Mammalian Gene Collection initiative, Single nucleotide polymorphisms (SNPs) within human gene sequences (Genetic Annotation Initiative) and chromosomal rearrangements within cancer cells (Cancer Chromosome Aberration Project) are also being cataloged as part of CGAP. Finally, to help determine gene expression patterns related to cancer, CGAP provides a quantitative catalog of data through its SAGEmap initiative. The genome and genetic analysis tools listed in this review are all freely distributed by CGAP (http://cgap.nci.nih.gov/) without restriction. C1 Duke Univ, Med Ctr, Durham, NC 27710 USA. NCI, Canc Genom Off, Bethesda, MD 20892 USA. RP Riggins, GJ (reprint author), Duke Univ, Med Ctr, Durham, NC 27710 USA. NR 26 TC 57 Z9 63 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 2001 VL 10 IS 7 SI SI BP 663 EP 667 DI 10.1093/hmg/10.7.663 PG 5 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 424GH UT WOS:000168224100003 PM 11257097 ER PT J AU Brown, LY Odent, S David, V Blayau, M Dubourg, C Apacik, C Delgado, MA Ha, BD Reynolds, JF Sommer, A Wieczorek, D Brown, SA Muenke, M AF Brown, LY Odent, S David, V Blayau, M Dubourg, C Apacik, C Delgado, MA Ha, BD Reynolds, JF Sommer, A Wieczorek, D Brown, SA Muenke, M TI Holoprosencephaly due to mutations in ZIC2: alanine tract expansion mutations may be caused by parental somatic recombination SO HUMAN MOLECULAR GENETICS LA English DT Article ID SONIC-HEDGEHOG GENE; HOXD13; DEFINITION; PATTERN; REGION AB We report on the prevalence of mutations in the zinc finger transcription factor gene, ZIC2, in a group of 509 unrelated individuals with isolated holoprosencephaly (HPE) and normal chromosomes, Overall, we encountered 16 HPE patients (from 15 unrelated families) with ZIC2 mutations, Thus, ZIC2 mutation was the apparent cause of HPE in 3-4% of cases. Seven mutations were frameshifts that were predicted to result in loss of function, further supporting the idea that ZIC2 haploinsufficiency can result in HPE, One mutation, an alanine tract expansion which is caused by the expansion of an imperfect trinucleotide repeat, occurred in seven patients from six different families. In three of those families, the father was found to be apparently mosaic for the mutation, We hypothesize that this mutation can arise through errors in somatic recombination, an extremely unusual mutation mechanism. In addition, one mutation resulted in a single amino acid change and one mutation was an in-frame deletion of 12 amino acids, The central nervous system malformations seen in patients with ZIC2 mutations ranged from alobar HPE (most common) to middle interhemispheric fusion defect tone case). Although severe facial anomalies are common in HPE, all of the patients with ZIC2 mutations had relatively normal faces, suggesting that ZIC2 mutations represent a large proportion of HPE cases without facial malformation. C1 Columbia Univ, Dept Obstet & Gynecol, New York, NY 10032 USA. Hop Pontchaillou, Rennes, France. Kinderzentrum Munchen, Munich, Germany. Texas Scottish Rite Hosp Children, Dallas, TX 75219 USA. Univ Kentucky, Coll Med, Dept Pediat, Lexington, KY USA. Univ Kentucky, Coll Med, Dept Genet, Lexington, KY USA. Shodair Hosp, Helena, MT USA. Childrens Hosp, Dept Clin Genet, Columbus, OH 43205 USA. Univ Essen Gesamthsch, Inst Humangenet, Essen, Germany. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Brown, SA (reprint author), Columbia Univ, Dept Obstet & Gynecol, PH16, New York, NY 10032 USA. FU NICHD NIH HHS [HD29862, R29 HD32467] NR 32 TC 96 Z9 99 U1 0 U2 5 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 2001 VL 10 IS 8 BP 791 EP 796 DI 10.1093/hmg/10.8.791 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 424GF UT WOS:000168223900001 PM 11285244 ER PT J AU Nishimura, DY Searby, CC Carmi, R Elbedour, K Van Maldergem, L Fulton, AB Lam, BL Powell, BR Swiderski, RE Bugge, KE Haider, NB Kwitek-Black, AE Ying, LH Duhl, DM Gorman, SW Heon, E Iannaccone, A Bonneau, D Biesecker, LG Jacobson, SG Stone, EM Sheffield, VC AF Nishimura, DY Searby, CC Carmi, R Elbedour, K Van Maldergem, L Fulton, AB Lam, BL Powell, BR Swiderski, RE Bugge, KE Haider, NB Kwitek-Black, AE Ying, LH Duhl, DM Gorman, SW Heon, E Iannaccone, A Bonneau, D Biesecker, LG Jacobson, SG Stone, EM Sheffield, VC TI Positional cloning of a novel gene on chromosome 16q causing Bardet-Biedl syndrome (BBS2) SO HUMAN MOLECULAR GENETICS LA English DT Article ID SYNDROME LOCUS; 5TH LOCUS; DNA; HETEROGENEITY; POPULATION; MUTATIONS; LINKAGE; OBESITY; MAP AB Bardet-Biedl syndrome (BBS) is a genetically heterogeneous autosomal recessive disorder with the primary clinical features of obesity, pigmented retinopathy, polydactyly, hypogenitalism, mental retardation and renal anomalies. Associated features of the disorder include diabetes mellitus, hypertension and congenital heart disease. There are six known BBS loci, mapping to chromosomes 2, 3, 11, 15, 15 and 20. The BBS2 locus was initially mapped to an 18 cM interval on chromosome 16q21 with a large inbred Bedouin kindred. Further analysis of the Bedouin population allowed for the fine mapping of this locus to a 2 cM region distal to marker D16S408. Physical mapping and sequence analysis of this region resulted in the identification of a number of known genes and expressed sequence tag clusters. Mutation screening of a novel gene (BBS2) with a wide pattern of tissue expression revealed homozygous mutations in two inbred pedigrees, including the large Bedouin kindred used to initially identify the BBS2 locus. In addition, mutations were found in three of 18 unrelated BBS probands from small nuclear families. C1 Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. Univ Iowa, Howard Hughes Med Inst, Iowa City, IA 52242 USA. Ben Gurion Univ Negev, Soroka Med Ctr, IL-84105 Beer Sheva, Israel. Inst Pathol & Genet, Ctr Genet Humaine, Loverval, Belgium. Harvard Univ, Sch Med, Boston, MA USA. Childrens Hosp, Dept Ophthalmol, Boston, MA 02115 USA. Bascom Palmer Eye Inst, Miami, FL 33136 USA. Valley Childrens Hosp, Madera, CA 93638 USA. Jackson Lab, Bar Harbor, ME 04609 USA. Med Coll Wisconsin, Milwaukee, WI 53226 USA. Chiron Corp, Emeryville, CA 94608 USA. Toronto Western Res Inst, Vis Sci Res Program, Toronto, ON, Canada. Univ Tennessee, Hlth Sci Ctr, Dept Ophthalmol, Memphis, TN 38103 USA. Univ Poitiers, Dept Med Genet, Poitiers, France. NHGRI, NIH, Bethesda, MD 20892 USA. Scheie Eye Inst, Philadelphia, PA 19104 USA. Univ Iowa, Dept Ophthalmol, Iowa City, IA 52242 USA. RP Sheffield, VC (reprint author), Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. RI Bonneau, Dominique/K-6110-2015 FU NEI NIH HHS [R01-EY-11298] NR 23 TC 168 Z9 173 U1 0 U2 8 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 2001 VL 10 IS 8 BP 865 EP 874 DI 10.1093/hmg/10.8.865 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 424GF UT WOS:000168223900009 PM 11285252 ER PT J AU Meiri, G Ben-Zion, IZ Greenberg, BD Murphy, DL Benjamin, J AF Meiri, G Ben-Zion, IZ Greenberg, BD Murphy, DL Benjamin, J TI Influence of the serotonin antagonist, metergoline, on the anxiogenic effects of carbon dioxide, and on heart rate and neuroendocrine measures, in healthy volunteers SO HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL LA English DT Article DE anxiety; carbon dioxide; metergoline; noradrenaline; pharmacology; serotonin ID OBSESSIVE-COMPULSIVE DISORDER; ACUTE TRYPTOPHAN DEPLETION; PANIC DISORDER; M-CHLOROPHENYLPIPERAZINE; CO2-INDUCED ANXIETY; 35-PERCENT CO2; 5-HT2C RECEPTORS; D-FENFLURAMINE; M-CPP; CHALLENGE AB The mechanism of action of carbon dioxide (CO2) angiogenesis is unknown; only recently have possible serotonergic (5-HT) influences begun to be studied. In separate double-blind challenges 1 week apart, 14 healthy volunteers received two vital capacity inhalations each of 35% CO2 and of air. once after a single capsule of placebo and once after a single capsule containing 4 mg of the 5-HT antagonist metergoline in a randomized crossover design. The inhalations were repeated 1 and 2 days after the ingestion of capsules, to investigate possible delayed effects of metergoline, and possible tolerance to repeated CO2 after placebo. We observed increased anxiety, and a trend for increased plasma noradrenaline (NA). after CO2. CO2 anxiogenesis was significantly enhanced by metergoline. Heart rate increased after both gas mixtures following metergoline administration. Plasma prolactin levels were lower after metergoline. Responses to CO2 did not differ between the day of placebo administration and the two subsequent days; on the days following metergoline administration there were almost no delayed effects. We hypothesize that 5-HT may function as an inhibitor of CO2 anxiogenesis, and that this is opposed by the 5-HT antagonist, metergoline. Absence of tolerance after repeated CO2 argues against psychological explanations of tolerance after other panicogens. Copyright (C) 2001 John Wiley & Sons, Ltd. C1 Soroka Med Ctr, Dept Psychiat, Div Psychiat, Kupat Holim Sick Fund, IL-84101 Beersheba, Israel. Ben Gurion Univ Negev, IL-84105 Beersheba, Israel. NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. RP Benjamin, J (reprint author), Soroka Med Ctr, Dept Psychiat, Div Psychiat, Kupat Holim Sick Fund, POB 151, IL-84101 Beersheba, Israel. NR 62 TC 6 Z9 6 U1 1 U2 3 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0885-6222 J9 HUM PSYCHOPHARM CLIN JI Hum. Psychopharmacol.-Clin. Exp. PD APR PY 2001 VL 16 IS 3 BP 237 EP 245 DI 10.1002/hup.259 PG 9 WC Clinical Neurology; Pharmacology & Pharmacy; Psychiatry; Psychology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry; Psychology GA 427QL UT WOS:000168416900004 ER PT J AU Bosselut, R Feigenbaum, L Sharrow, SO Singer, A AF Bosselut, R Feigenbaum, L Sharrow, SO Singer, A TI Strength of signaling by CD4 and CD8 coreceptor tails determines the number but not the lineage direction of positively selected thymocytes SO IMMUNITY LA English DT Article ID T-CELL DEVELOPMENT; IMMATURE CD4+CD8+ THYMOCYTES; CLASS-I MOLECULES; TRANSGENIC MICE; CYTOPLASMIC DOMAIN; TYROSINE PHOSPHORYLATION; CD4(+)CD8(+) THYMOCYTES; THYMIC MATURATION; ANTIGEN RECEPTOR; KINASE P56LCK AB The present study has assessed the impact of the intracellular domains of CD4 and CD8 on positive selection and lineage direction of MHC class I-restricted thymocytes. Contrary to current presumption, we found that the CD4 tail promotes the generation of both CD4' and CD8(+) T cells without preference for the CD4' T cell lineage. We also found that the identity of the coreceptor tail and hence the strength of coreceptor signaling determine the number of thymocytes undergoing positive selection but not their ultimate CD4/ CD8 phenotype. These findings demonstrate that the strength of coreceptor signaling has a significant quantitative but not qualitative impact on positive selection and provide a simple explanation for the greater numbers of CD4(+) than CD8(+) T cells selected in the normal thymus. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Frederick, MD 21702 USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 46 TC 39 Z9 39 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD APR PY 2001 VL 14 IS 4 BP 483 EP 494 DI 10.1016/S1074-7613(01)00128-5 PG 12 WC Immunology SC Immunology GA 424TB UT WOS:000168246700015 PM 11336693 ER PT J AU Mermel, LA Farr, BM Sherertz, RJ Raad, II O'Grady, N Harris, JS Craven, DE AF Mermel, LA Farr, BM Sherertz, RJ Raad, II O'Grady, N Harris, JS Craven, DE TI Guidelines for the management of intravascular catheter-related infections SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Review ID STAPHYLOCOCCUS-AUREUS BACTEREMIA; CENTRAL-VENOUS-CATHETER; ANTIBIOTIC-LOCK TECHNIQUE; BLOOD-STREAM INFECTION; DEVICE-RELATED INFECTIONS; CRITICALLY ILL PATIENTS; LONG-TERM HEMODIALYSIS; SUPPURATIVE PERIPHERAL THROMBOPHLEBITIS; COAGULASE-NEGATIVE STAPHYLOCOCCI; PROSTHETIC VALVE ENDOCARDITIS C1 Brown Univ, Rhode Isl Hosp, Sch Med, Div Infect Dis, Providence, RI 02903 USA. Univ Virginia, Charlottesville, VA USA. Wake Forest Univ, Sch Med, Infect Dis Sect, Winston Salem, NC 27109 USA. Univ Texas, MD Anderson Canc Ctr, Dept Internal Med Specialties, Houston, TX 77030 USA. NIH, Crit Care Med Dept, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Sect Pediat Infect Dis, Boston, MA 02215 USA. Boston Univ, Sch Med, Boston Med Ctr, Infect Dis Sect, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Boston Med Ctr, Infect Dis Sect, Boston, MA 02118 USA. Lahey Clin Med Ctr, Burlington, MA 01803 USA. RP Craven, DE (reprint author), Lahey Clin Med Ctr, Burlington, MA 01806 USA. NR 208 TC 76 Z9 83 U1 0 U2 1 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0899-823X J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD APR PY 2001 VL 22 IS 4 BP 222 EP 242 DI 10.1086/501893 PG 21 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 433WP UT WOS:000168783900010 PM 11379714 ER PT J AU Nakabayashi, T Sakata, KM Sakata, A Kong, L Lau, CA Letterio, JJ Vela-Roch, N Talal, N Dang, H AF Nakabayashi, T Sakata, KM Sakata, A Kong, L Lau, CA Letterio, JJ Vela-Roch, N Talal, N Dang, H TI TGF-beta 1 null mutation leads to CD154 upregulated expression in affected tissues SO INFLAMMATION LA English DT Article DE transforming growth factor (TGF-beta 1); CD154; interleukin (IL-12); tissue inflammation ID HUMAN ENDOTHELIAL-CELLS; MHC CLASS-II; CD40 LIGAND; KNOCKOUT MICE; SALIVARY-GLANDS; TGF-BETA; LUPUS; RESPONSES; NEPHRITIS; CYTOKINES AB The TGF-beta1(-/-) mouse is a murine model for systemic autoimmune disease. The aim of this study is to elucidate the immunological mechanism that leads to multifocal tissue inflammation and autoantibody production in TGF-beta1(-/-) mice. Heart, lung, liver, and salivary gland from TGF-beta1(-/-) were assessed for CD154 expression by RT-PCR and immunohistochemistry. Compared to wild-type littermates, CD154 expression was elevated in all tissues studied. Furthermore, IL-12 mRNA was expressed in the salivary gland and heart of TGF-beta1(-/-) mice and not in wildtype littermates. This suggests that the CD154 pathway is activated in these tissues. This shows that TGF-beta1 regulates CD154 expression leading to spontaneous IL-12 production and autoimmunity. C1 Univ Texas, Hlth Sci Ctr, Dept Med, Div Clin Immunol, San Antonio, TX 78229 USA. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. Columbia Univ, Coll Phys & Surg, New York, NY USA. Harcourt Brace Educ Measurement, San Antonio, TX USA. RP Nakabayashi, T (reprint author), Univ Texas, Hlth Sci Ctr, Dept Med, Div Clin Immunol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. FU NIDCR NIH HHS [DE12203] NR 27 TC 2 Z9 2 U1 0 U2 0 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0360-3997 J9 INFLAMMATION JI Inflammation PD APR PY 2001 VL 25 IS 2 BP 69 EP 73 DI 10.1023/A:1007158219974 PG 5 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 419QR UT WOS:000167960600002 PM 11321361 ER PT J AU Martikainen, P Lahelma, E Ripatti, S Albanes, D Virtamo, J AF Martikainen, P Lahelma, E Ripatti, S Albanes, D Virtamo, J TI Educational differences in lung cancer mortality in male smokers SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE lung cancer; mortality; education; smoking; confounding ID RADON; RISK AB Background To assess the extent of lung cancer mortality differentials by education while adjusting for exposure to tobacco smoke and asbestos based on survey questions. Methods Alpha-Tocopherol, Beta Carotene Cancer Prevention (ATBC) Study of 50-69-year-old Finnish male smokers enrolled 1985-1988. These analyses are based on the placebo group and the alpha-tocopherol supplementation group, altogether 14 011 men, with full information on tobacco smoking. Mortality follow-up was to the end of April 1993 and it was based on the complete death certificate register of the Statistics Finland, Results Lung cancer mortality of basic-educated men was 32% (rate ratio [RR] = 1.32; 95% CI : 0.93-1.87) higher than that of better-educated men in the ATBC Study. The excess is practically unchanged when additional adjustment was made for age at initiation, duration of smoking, current smoking at baseline and at first follow-up, smoke inhalation, occupational exposure to asbestos and interactions between asbestos exposure and all smoking variables. This excess mortality was about 40% of the similar excess observed in the general population of men of similar age. Conclusions Educational differences in lung cancer mortality in the total Finnish population are likely to be mainly caused by differences in exposure, particularly to active smoking. Further understanding of the determinants and consequences of socio-economic differences in smoking behaviour are of major scientific and public health importance. C1 Natl Publ Hlth Inst, Dept Nutr, FIN-00300 Helsinki, Finland. NCI, Div Clin Sci, Canc Prevent Studies Branch, Bethesda, MD 20892 USA. Univ Helsinki, Rolf Nevanlinna Inst, FIN-00014 Helsinki, Finland. Univ Helsinki, Dept Publ Hlth, FIN-00014 Helsinki, Finland. Univ Helsinki, Dept Sociol, Populat Res Unit, FIN-00014 Helsinki, Finland. UCL, Dept Epidemiol & Publ Hlth, Int Ctr Hlth & Soc, London WC1E 6BT, England. RP Martikainen, P (reprint author), UCL, Dept Epidemiol & Publ Hlth, Int Ctr Hlth & Soc, 1-19 Torrington Pl, London WC1E 6BT, England. EM pekka@public-health.ucl.ac.uk RI Albanes, Demetrius/B-9749-2015; Ripatti, Samuli/H-9446-2014; OI Ripatti, Samuli/0000-0002-0504-1202; Lahelma, Eero/0000-0002-1064-1333 FU NCI NIH HHS [N01-CN-45165] NR 18 TC 15 Z9 17 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD APR PY 2001 VL 30 IS 2 BP 264 EP 267 DI 10.1093/ije/30.2.264 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 433YZ UT WOS:000168789500013 PM 11369725 ER PT J AU Lacey, JV Deng, J Dosemeci, M Gao, YT Mostofi, FK Sesterhenn, IA Xie, T Hsing, AW AF Lacey, JV Deng, J Dosemeci, M Gao, YT Mostofi, FK Sesterhenn, IA Xie, T Hsing, AW TI Prostate cancer, benign prostatic hyperplasia and physical activity in Shanghai, China SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE physical activity; prostate cancer; MET; energy expended; BPH; China ID UNITED-STATES; COLLEGE ALUMNI; RISK; RELIABILITY; ASSOCIATION; PREVENTION; PATTERNS; RECALL; HEALTH; TRENDS AB Background Studies suggest that increased levels of physical activity might decrease the risk of prostate cancer. We ascertained lifetime measures of activity in a population-based case-control study of prostate cancer in Shanghai, China to investigate physical activity in a population where the incidence of prostate cancer is low but rising. Methods In all, 238 men with prostate cancer, diagnosed 1993-1995, were identified through a rapid reporting system. A second group of 206 men with benign prostatic hyperplasia (BPH) was matched to prostate cancer cases, and 471 age-matched and population-based controls were identified from urban Shanghai. Through personal interviews, we ascertained all daily, occupational, and recreational activities at ages 20-29, ages 40-49, and in 1988 to generate hours spent sleeping, sitting, in moderate activity, and in vigorous activity. Time spent per week in different activities was converted to metabolic equivalents (MET-h) and energy expended. Results Time spent in, MET-h of, and energy expended in physical activities were not consistently related to either prostate cancer or BPH when compared to controls. Few men reported regular vigorous activity. Occupational activity, based on an energy expenditure index using job titles, was suggestively associated with a decreased risk of BPH, but not associated with prostate cancer. Associations did not vary according to age or stage of prostate cancer at diagnosis. Conclusions Our results, based on regular physical activity. occupational activity hours in activities, MET-h, and energy expended, did not support a protective role of physical activity in prostate cancer or BPH for men in a low-risk population. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20852 USA. Shanghai Canc Inst, Shanghai, Peoples R China. Armed Forces Inst Pathol, Washington, DC 20306 USA. RP Lacey, JV (reprint author), NCI, Div Canc Epidemiol & Genet, Room 7056,6120 Execut Blvd,MSC 7234, Bethesda, MD 20852 USA. NR 34 TC 42 Z9 45 U1 2 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD APR PY 2001 VL 30 IS 2 BP 341 EP 349 DI 10.1093/ije/30.2.341 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 433YZ UT WOS:000168789500028 PM 11369740 ER PT J AU Leonard, WJ AF Leonard, WJ TI Role of Jak kinases and STATS in cytokine signal transduction SO INTERNATIONAL JOURNAL OF HEMATOLOGY LA English DT Article DE Jak kinase; STAT; cytokine; receptor; signaling ID SEVERE COMBINED IMMUNODEFICIENCY; DNA-BINDING ACTIVITY; T-CELLS; CONSTITUTIVE ACTIVATION; TARGETED DISRUPTION; NATURAL-KILLER; TH2 CELLS; GENE; RESPONSES; RECEPTOR AB The Janus family tyrosine kinase-signal transducer and activator of transcription (Jak-STAT) signaling pathway is broadly used by interferons and type I cytokines. These cytokines and interferons activate Janus family tyrosine kinases (Jak kinases), which in turn phosphorylate and thereby activate STAT proteins. Before activation, STAT proteins are cytosolic proteins. after activation, however. they are translocated to the nucleus where they function as transcription factors. This review summarizes salient features of the Jak-STAT pathway and focuses on the functional role of the different Jak kinases and STATs in vivo. (C) 2001 The Japanese Society of Hematology. C1 NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Leonard, WJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. NR 50 TC 121 Z9 133 U1 3 U2 10 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 0925-5710 J9 INT J HEMATOL JI Int. J. Hematol. PD APR PY 2001 VL 73 IS 3 BP 271 EP 277 DI 10.1007/BF02981951 PG 7 WC Hematology SC Hematology GA 430YZ UT WOS:000168604200001 PM 11345192 ER PT J AU Blagosklonny, MV Dixon, SC Robey, R Figg, WD AF Blagosklonny, MV Dixon, SC Robey, R Figg, WD TI Resistance to growth inhibitory and apoptotic effects of phorbol ester and UCN-01 in aggressive cancer cell lines SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE prostate cancer; experimental therapy; UCN-01; PMA; p21; cyclin D1 ID PROTEIN-KINASE-C; PROMYELOCYTIC LEUKEMIA-CELLS; ANTICANCER DRUG TARGETS; PROSTATE-CANCER; SELECTIVE INHIBITOR; 12-O-TETRADECANOYLPHORBOL-13-ACETATE-INDUCED APOPTOSIS; CHECKPOINT CONTROL; CERAMIDE SYNTHASE; LUNG-CARCINOMA; CYCLE ARREST AB 7-Hydroxystaurosporine (UCN-01), a nonselective inhibitor of protein kinase C (PKC), and phorbol ester (PMA), a PKC activator, are undergoing clinical evaluations. We investigated the effects of UCN-01 and PMA on a panel of prostate cancer cell lines. While PMA induced p21(WAFI/CPI) and arrest growth of LNCaP cancer cells (IC50 = 0.5-1 nM), aggressive cancer cell lines (DU145, PC3, and PC3M) were resistant to PMA (IC50 >5000 nM). Low concentrations (25-50 nM) of UCN-01 abrogated PMA-induced p21 and growth arrest in LNCaP cells. These low doses of UCN-01 however did not inhibit proliferation of any prostate cancer cell line. PMA-sensitive LNCaP cells were resistant to clinically relevant concentrations of UCN-01 (IC50 = 1.2 muM), but UCN-01 inhibited growth of DU145 and PC3/3M with an IC50 of 200-400 nM. For comparison, PMA-sensitive HL60 leukemia cells were sensitive to UCN-01 due to rapid apoptosis caused by UCN-01. In PMA-resistant prostate cancer cells, UCN-01 downregulated cyclin D1, induced p21, caused morphological differentiation, and G1-phase arrest leading to slow cell death without caspase activation. Importantly, normal prostate epithelial cells (PrEC) were very sensitive to both PMA (IC50 = 0.2 nM) and UCN-01. In PrEC, UCN-01 downregulated cyclin D1 and arrest growth with an IC50 less than 100 nM. We conclude that loss of sensitivity to either UCN-01 or PMA accompanies progression of prostate cancer. C1 NCI, Med Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Blagosklonny, MV (reprint author), NCI, Med Branch, Div Clin Sci, NIH, Bldg 10,R 12N226, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 53 TC 20 Z9 20 U1 0 U2 1 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 2001 VL 18 IS 4 BP 697 EP 704 PG 8 WC Oncology SC Oncology GA 413TN UT WOS:000167628200004 PM 11251163 ER PT J AU Russo, P Ottoboni, C Crippa, A Riou, JF O'Connor, PM AF Russo, P Ottoboni, C Crippa, A Riou, JF O'Connor, PM TI RPR-115135, a new non peptidomimetic farnesyltransferase inhibitor, induces G(0)/G(1) arrest only in serum starved cells SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE farnesyltransferase; RPR-115135; Ras; cell cycle; cyclin A; serum starvation; G(0)/G(1) arrest; p53; p21(waf-1) ID RAS FARNESYLTRANSFERASE; PHASE-I; CANCER; P53; LINES; SENSITIVITY; APOPTOSIS; GENE; PRENYLATION; EXPRESSION AB A new non peptidomimetic farnesyltransferase inhibitor, RPR-115135, was studied in an isogenic cell model system consisting of human colon cancer HCT-116 line. HCT-116 cells were transfected with an empty control pCMV vector or with a dominant-negative mutated p53 transgene to disrupt p53 function. Growth inhibitory effects of RPR-115135 were evaluated on cells growing under different conditions (serum starvation, serum starvation and recovery, nocodazole treatment). The cytotoxic activity of RPR-115135 was independent of the cell cycle status of the target cells. Addition of RPR-115135 only to cells exposed to reduced serum conditions (0.1% FCS) resulted in an enhanced ability of HCT-116 cells to arrest in the G(0)/G(1), phase. This arrest response appeared independent of p53/p21(cip1/waf-1) function. A reduction of Cyclin A protein amount by RPR-115135 was observed in both clones. These latter results suggest that RPR-115135 migth down-regulate the cell cycle factor that would normally impede G(0)/G(1) arrest. C1 Natl Canc Res Inst, Mol Pathol Sect, Expt Oncol Lab, I-16132 Genoa, Italy. NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Aventis Pharma, Ctr Rech Rhone Poulenc Rorer, Anticanc Res Program, F-94403 Vitry, France. RP Russo, P (reprint author), Natl Canc Res Inst, Mol Pathol Sect, Expt Oncol Lab, Largo Rosanna Benzi 10, I-16132 Genoa, Italy. NR 41 TC 12 Z9 12 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 2001 VL 18 IS 4 BP 855 EP 862 PG 8 WC Oncology SC Oncology GA 413TN UT WOS:000167628200026 PM 11251185 ER PT J AU Liu, J Grogan, L Nau, MM Allegra, CJ Chu, E Wright, JJ AF Liu, J Grogan, L Nau, MM Allegra, CJ Chu, E Wright, JJ TI Physical interaction between p53 and primary response gene Egr-1 SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE Egr-1; p53; interaction ID WILMS-TUMOR LOCUS; ZINC-FINGER PROTEIN; CELL LUNG-CANCER; TATA-BINDING PROTEIN; TRANSCRIPTION FACTORS; NGFI-A; SUPPRESSOR PROTEIN; MUTANT P53; FUNCTIONAL INTERACTION; GROWTH-FACTORS AB The tumor suppressor p53 and primary response gene Egr-1 are nuclear transcription factors with regulatory roles in signal transduction pathways mediating cellular proliferation and growth arrest as well as the complex genetic programs controlling differentiation and programmed cell death. We identified a physical association between these regulatory proteins in vitro and in vivo. Recombinant p53 and Egr-1 fusion proteins complexed with in vitro translates of Egr-1 or p53, respectively, or with these respective proteins in cell lysates. This protein-protein interaction was detected in vivo by immunoprecipitation and Western blot analysis of serum-activated cellular lysates with high levels of induced Egr-1 and of human Lung cancer cell lines with constitutive overexpression of Egr-1 and mutant p53. A p53 mutant at codon 154 did not bind Egr-1, while p53 proteins with point mutations at residues 156, 246, 247, and 273 associated with this zinc finger transcription factor. p53 bound full-length Egr-1 and an Egr-1 mutant with a deletion of the 5' transactivation region but did not associate with Egr-1 protein lacking an internal segment that included the first two zinc finger domains, suggesting that binding may require the presence of intact zinc finger motifs. A variant-sized Egr-1 protein expressed by lung fibroblast cell line MRC-9 was also bound by p53. The interaction of these regulatory proteins may alter multiple features of their biological activity especially with regard to the specificity of transcriptional control. C1 Yale Univ, Sch Med, Ctr Canc, Dept Med & Pharmacol, New Haven, CT 06520 USA. VA Connecticut Healthcare Syst, New Haven, CT 06520 USA. NCI, Div Clin Sci, Bethesda, MD 20892 USA. RP Liu, J (reprint author), VA CT Healthcare Syst, Canc Ctr 111D, 950 Campbell Ave, W Haven, CT 06516 USA. FU NCI NIH HHS [CA 16359, CA 75712] NR 54 TC 36 Z9 37 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 2001 VL 18 IS 4 BP 863 EP 870 PG 8 WC Oncology SC Oncology GA 413TN UT WOS:000167628200027 PM 11251186 ER PT J AU Coleman, CN AF Coleman, CN TI Investing in our future: Listening to those who will take us where we need to go SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material C1 NCI, Radiat Oncol Serv Program, Bethesda, MD 20892 USA. RP Coleman, CN (reprint author), NCI, Radiat Oncol Serv Program, Bldg 10,B3B69, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD APR 1 PY 2001 VL 49 IS 5 BP 1211 EP 1211 DI 10.1016/S0360-3016(01)01449-3 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 417EZ UT WOS:000167823600001 PM 11286824 ER PT J AU Matsui, K Travis, WD Gonzalez, R Terzian, JA Rosai, J Moss, J Ferrans, VJ AF Matsui, K Travis, WD Gonzalez, R Terzian, JA Rosai, J Moss, J Ferrans, VJ TI Association of lymphangioleiomyomatosis (LAM) with endosalpingiosis in the retroperitoneal lymph nodes: Report of two cases SO INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE endosalpingiosis; lymphangioleiomyomatosis; lymph node; retroperitoneum; immunohistochemistry; confocal microscopy ID PULMONARY LYMPHANGIOLEIOMYOMATOSIS; TRANSBRONCHIAL BIOPSY; SMOOTH-MUSCLE; INCLUSIONS; DIAGNOSIS; LYMPHANGIOMYOMATOSIS; ANGIOMYOLIPOMA; PROLIFERATION; PATHOGENESIS; RECEPTORS AB We report 2 patients in whom pulmonary lymphangioleiomyomatosis (LAM) affected the retroperitoneal lymph nodes and was associated with endosalpingiosis. These lesions were large, encapsulated masses with multiple cysts containing chylous fluid. Both were characterized by proliferating LAM cells that formed fascicles separated by slit-like channels. Some cysts were lined by ciliated epithelium resembling that of Fallopian tubes. Other cysts were lined either by flattened endothelial cells or by a mixture of these cells and epithelial cells. Many LAM cells gave a positive reaction with HMB-45 antibody. Most LAM cells in fascicles were reactive for a-smooth muscle actin and desmin. In 1 patient, many of the epithelial cells and some of the subjacent LAM cells were positive for estrogen and progesterone receptors. In conclusion, immunostaining with HMB-45 antibody and markers for smooth muscle cells can be helpful in the evaluation of problems in the differential diagnosis of lesions of extrapulmonary LAM, particularly those involving the genital system. C1 NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. Armed Forces Inst Pathol, Dept Pulm & Mediastinal Pathol, Washington, DC 20306 USA. Morristown Mem Hosp, Dept Pathol, Morristown, NJ USA. Lourdes Hosp, Dept Pathol, Binghamton, NY USA. Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. RP Ferrans, VJ (reprint author), NHLBI, Pathol Sect, NIH, 10 Ctr Dr,MSC 1518,Bldg 10-2N240, Bethesda, MD 20892 USA. NR 25 TC 11 Z9 12 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 2001 VL 9 IS 2 BP 155 EP 162 DI 10.1177/106689690100900212 PG 8 WC Pathology; Surgery SC Pathology; Surgery GA 450XK UT WOS:000169770000012 PM 11484504 ER PT J AU Russell, P Tamm, ER Grehn, FJ Picht, G Johnson, M AF Russell, P Tamm, ER Grehn, FJ Picht, G Johnson, M TI The presence and properties of myocilin in the aqueous humor SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID OPEN-ANGLE GLAUCOMA; PROTEIN; GENE; OLFACTOMEDIN; CLONING; MYOSIN; FLOW; TIGR; EYE AB PURPOSE. To determine whether myocilin is present in the aqueous humor (AH) and to examine certain properties of this protein. METHODS. Human AH was obtained at the time of either glaucoma surgery or cataract extraction. Monkey AH was obtained at the time of death, and bovine aqueous was obtained from eyes delivered from an abattoir. Column chromatography was performed on aqueous samples to determine the approximate size of the myocilin present. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and western blot analysis were performed using antibody prepared against a peptide sequence in myocilin. Analysis of the bovine proteins present in AH that were retained by a microporous filter was also performed using western blot analysis. RESULTS. By western blot analysis, myocilin was present in human, monkey, and bovine AH. The apparent molecular size of the myocilin present in the AH were greater than 250,000 Da, when quantified with a gel filtration column. Myocilin appeared to be hydrophobic and was one of the proteins that was retained on microporous filters that were obstructed by AH. CONCLUSIONS. Myocilin is a constituent in the AH. It appears that myocilin is a hydrophobic protein that ma;v exist in an oligomeric state or in association with other proteins. Myocilin is retained by microporous filters and may be involved in the obstruction of these filters that occurs when AW is perfused through them. C1 NEI, NIH, Bethesda, MD 20892 USA. Univ Erlangen Nurnberg, D-8520 Erlangen, Germany. Univ Wurzburg, D-97070 Wurzburg, Germany. Northwestern Univ, Evanston, IL USA. RP Russell, P (reprint author), NEI, NIH, Bldg 6,Room 228,Ctr Dr,MSC2735, Bethesda, MD 20892 USA. RI Johnson, Mark/B-6921-2009 FU NEI NIH HHS [R01EY09699] NR 16 TC 62 Z9 67 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2001 VL 42 IS 5 BP 983 EP 986 PG 4 WC Ophthalmology SC Ophthalmology GA 417TJ UT WOS:000167850000013 PM 11274075 ER PT J AU Veech, RL Chance, B Kashiwaya, Y Lardy, HA Cahill, GR AF Veech, RL Chance, B Kashiwaya, Y Lardy, HA Cahill, GR TI Ketone bodies, potential therapeutic uses SO IUBMB LIFE LA English DT Article DE D-beta-hydroxybutyrate; ketone bodies; ketosis; metabolic control analysis; neurologic disease ID AMYLOID-BETA; FUNCTIONAL GENOMICS; ALZHEIMERS-DISEASE; KETOGENIC DIET; BRAIN; METABOLISM; DEFICIENCY; MUTATIONS; INSULIN; PROTEIN AB Ketosis, meaning elevation of D-beta -hydroxybutyrate (R-3-hydroxybutyrate) and acetoacetate, has been central to starving man's survival by providing nonglucose substrate to his evolutionarily hypertrophied brain, sparing muscle from destruction for glucose synthesis. Surprisingly, D-beta -hydroxybutyrate (abbreviated "beta OHB") may also provide a more efficient source of energy for brain per unit oxygen, supported by the same phenomenon noted in the isolated working perfused rat heart and in sperm. It has also been shown to decrease cell death in two human neuronal cultures, one a model of Alzheimer's and the other of Parkinson's disease. These observations raise the possibility that a number of neurologic disorders, genetic and acquired, might benefit by ketosis. Other beneficial effects from beta OHB include an increased energy of ATP hydrolysis (AG) and its linked ionic gradients. This maybe significant in drug-resistant epilepsy and in injury and anoxic states. The ability of beta OHB to oxidize co-enzyme Q and reduce NADP(+) may also be important in decreasing free radical damage. Clinical maneuvers for increasing blood levels of beta OHB to 2-5 mmol may require synthetic esters or polymers of beta OHB taken orally, probably 100 to 150 g or more daily. This necessitates advances in food-science technology to provide at least enough orally acceptable synthetic material for animal and possibly subsequent clinical testing. The other major need is to bring the technology for the analysis of multiple metabolic "phenotypes" up to the level of sophistication of the instrumentation used, for example, in gene science or in structural biology. This technical strategy will be critical to the characterization of polygenic disorders by enhancing the knowledge gained from gene analysis and from the subsequent steps and modifications of the protein products themselves. C1 NIAAA, LMMB, Unit Metab Control, Rockville, MD 20852 USA. Univ Penn, Johnson Res Fdn, Philadelphia, PA 19104 USA. Tottori Univ, Fac Med, Div Neurol, Yanago, Japan. Univ Wisconsin, Enzyme Inst, Madison, WI 53706 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Cahill, GR (reprint author), POB 367, Stoddard, NH 03464 USA. EM cahill@cheshire.net NR 52 TC 171 Z9 173 U1 4 U2 16 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1521-6543 J9 IUBMB LIFE JI IUBMB Life PD APR PY 2001 VL 51 IS 4 BP 241 EP 247 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 473DG UT WOS:000171024300007 PM 11569918 ER PT J AU Biggar, RJ Engels, EA Frisch, M Goedert, JJ AF Biggar, RJ Engels, EA Frisch, M Goedert, JJ TI Risk of T-cell lymphomas in persons with AIDS SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE AIDS; HIV; T-cell lymphoma; mycosis fungoides; non-Hodgkin's lymphoma; adult T-cell leukemia/lymphoma ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; HIV-INFECTION; VIRUS INFECTION; PATIENT; DISEASE AB Lymphomas in persons with AIDS are mostly B-cell types, but T-cell lymphomas have also been reported. We examined T-cell lymphoma risk in the 2-year period after AIDS onset by linking 302,834 adults with AIDS to cancer registry data. Of 6,788 cases of non-Hodgkin's lymphoma (NHL) with specified histologies, 96 (1.4%) were T-cell lymphomas. Assessment was based on clinical diagnosis and histology because T-cell marker data were inadequate, but when present, marker data supported the T-cell diagnosis. The relative risk of T-cell lymphoma, estimated by standardized incidence ratio, was 15.0 (95% confidence interval: 10.0-21.7). Risks were increased for all subtypes, including mycosis fungoides, peripheral lymphomas, cutaneous lymphomas, and adult T-cell leukemia/lymphoma (ATLL). HIV-related immunodeficiency could be important, but differences between the population developing AIDS and the general population (e. g., immigration from the Caribbean region for ATLL) might independently increase T-cell lymphoma risk. C1 NCI, Viral Epidemiol Branch, Rockville, MD 20852 USA. Danish Epidemiol Sci Ctr, Dept Epidemiol Res, Statens Serum Inst, Copenhagen, Denmark. RP Biggar, RJ (reprint author), NCI, Viral Epidemiol Branch, 6120 Room,8014 Execut Blvd, Rockville, MD 20852 USA. RI Frisch, Morten/E-9206-2016 OI Frisch, Morten/0000-0002-3864-8860 NR 20 TC 47 Z9 52 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. PD APR 1 PY 2001 VL 26 IS 4 BP 371 EP 376 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 426NG UT WOS:000168354800013 PM 11317081 ER PT J AU Wootton, JC Sparber, A AF Wootton, JC Sparber, A TI Surveys of complementary and alternative medicine: Part I. General trends and demographic groups SO JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE LA English DT Article ID LOW-INCOME POPULATION; UNITED-STATES; UNCONVENTIONAL THERAPIES; FOLK REMEDIES; PREVALENCE; SATISFACTION; PREDICTORS; SERVICES; HEALERS; CANCER AB Data from the surveys of the Harvard team, led by David Eisenberg, M.D., are frequently used as a summary first paragraph introduction to the status of complementary and alternative medicine (CAM) in the United States. However, there is now a substantial body of literature on various facets of CAM use. Six national surveys to date are briefly discussed and summarized in a table. Some surveys have been conducted at a regional level. Three are summarized but there are too few data yet to draw any conclusions, Eighteen more exploratory surveys of specific subpopulations are presented to help draw a clearer picture of income, ethnic, and age groups. The search strategy is provided. The changing terminology in the field, the development of the CAM survey, and some common shortcomings are also addressed. C1 Alternat Med Fdn Inc, Bethesda, MD 20814 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Wootton, JC (reprint author), Alternat Med Fdn Inc, 5411 W Cedar Lane,205A, Bethesda, MD 20814 USA. NR 32 TC 78 Z9 80 U1 1 U2 4 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1075-5535 J9 J ALTERN COMPLEM MED JI J. Altern. Complement Med. PD APR PY 2001 VL 7 IS 2 BP 195 EP 208 DI 10.1089/107555301750164307 PG 14 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA 423LM UT WOS:000168177800010 PM 11327525 ER PT J AU Roth, SM Schrager, MA Ferrell, RE Riechman, SE Metter, EJ Lynch, NA Lindle, RS Hurley, BF AF Roth, SM Schrager, MA Ferrell, RE Riechman, SE Metter, EJ Lynch, NA Lindle, RS Hurley, BF TI CNTF genotype is associated with muscular strength and quality in humans across the adult age span SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE ciliary neurotrophic factor; aging; concentric strength; eccentric strength; muscle power; muscle quality ID CILIARY NEUROTROPHIC FACTOR; SKELETAL-MUSCLE; ALPHA COMPONENT; NULL MUTATION; PEAK TORQUE; POWER; WOMEN; MEN; RECEPTOR; GENE AB The relationship between ciliary neurotrophic factor (CNTF) genotype and muscle strength was examined in 494 healthy men and women across the entire adult age span (20-90 yr). Concentric (Con) and eccentric (Ecc) peak torque were assessed using a Kin-Corn isokinetic dynamometer for the knee extensors (KE) and knee flexors (KF) at slow (0.52 rad/s) and faster (3.14 rad/s) velocities. The results were covaried for age, gender, and body mass or fat-free mass (FFM). Individuals heterozygous for the CNTF null (A allele) mutation (G/A) exhibited significantly higher Con peak torque of the KE and KF at 3.14 rad/s than G/G homozygotes when age, gender, and body mass were covaried (P < 0.05). When the dominant leg FFM (estimated muscle mass) was used in place of body mass as a covariate, Con peak torque of the KE at 3.14 rad/s was also significantly greater in the G/A individuals (P < 0.05). In addition, muscle quality of the KE (peak torque at 3.14 rad(.)s(-1.)leg muscle mass(-1)) was significantly greater in the G/A heterozygotes (P < 0.05). Similar results were seen in a subanalysis of subjects 60 yr and older, as well as in Caucasian subjects. In contrast, A/A homozygotes demonstrated significantly lower Ece peak torque at 0.52 rad/s for both KE and KF compared with G/G and G/A groups (P < 0.05). No significant relation ships were observed at 0.52 rad/s between genotype and Con peak torque. These data indicate that individuals exhibiting the G/A genotype possess significantly greater muscular strength and muscle quality at relatively fast contraction speeds than do G/G individuals. Because of high positive correlations between fast-velocity peak torque and muscular power, these findings suggest that further investigations should address the relationship between CNTF genotype and muscular power. C1 Univ Maryland, Dept Kinesiol, Coll Hlth & Human Performance, College Pk, MD 20742 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Univ Maryland, Sch Med, Div Gerontol, Baltimore Vet Affairs Med Ctr, Baltimore, MD 21201 USA. Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA 15261 USA. RP Hurley, BF (reprint author), Univ Maryland, Dept Kinesiol, Coll Hlth & Human Performance, College Pk, MD 20742 USA. OI Roth, Stephen/0000-0002-7841-3695 FU NIA NIH HHS [AG-05893, AG-00268, AG-16205] NR 31 TC 60 Z9 68 U1 0 U2 3 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 PY 2001 VL 90 IS 4 BP 1205 EP 1210 PG 6 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 411HD UT WOS:000167491500004 PM 11247915 ER PT J AU Bernstein, KD Hyndman, JB AF Bernstein, KD Hyndman, JB TI Physiological basis for conservation of the signal recognition particle targeting pathway in Escherichia coli SO JOURNAL OF BACTERIOLOGY LA English DT Article ID INNER MEMBRANE-PROTEINS; HEAT-SHOCK RESPONSE; 4.5S RNA; ENDOPLASMIC-RETICULUM; NASCENT PREPROLACTIN; SEQUENCE RECOGNITION; DOCKING PROTEIN; TRIGGER FACTOR; CELL-GROWTH; GTP-BINDING AB The Escherichia coli signal recognition particle (SRP) is a ribonucleoprotein complex that targets nascent inner membrane proteins (IMPs) to transport sites in the inner membrane (IM). Since SRP depletion only partially inhibits IMP insertion under some growth conditions, however, it is not clear why the particle is absolutely essential for viability. Insights into this question emerged from experiments in which we analyzed the physiological consequences of reducing the intracellular concentration of SRP below the wild-type level. We found that even moderate SRP deficiencies that have little effect on cell growth led to the induction of a heat shock response. Genetic manipulations that suppress the heat shock response were lethal in SRP-deficient cells, indicating that the elevated synthesis of heat shock proteins plays an important role in maintaining cell viability. Although it is conceivable that the heat shock response serves to increase the capacity of cells to target IMPs via chaperone-based mechanisms, SRP deficient cells did not show an increased dependence on either GroEL or DnaK. By contrast, the heat shock regulated proteases Lon and ClpQ became essential for viability when SRP levels were reduced, These results suggest that the heat shock response protects SRP-deficient cells by increasing their capacity to degrade mislocalized IMPs. Consistent with this notion, a model IMP that was mislocalized in the cytoplasm as the result of SRP depletion appeared to be more stable in a Delta lon Delta clpQ strain than in control cells. Taken together, the data provide direct evidence that SRP is essential in E. coli and possibly conserved throughout prokaryotic evolution as well partly because efficient IMP targeting prevents a toxic accumulation of aggregated proteins in the cytoplasm. C1 NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Bernstein, KD (reprint author), NIDDKD, Genet & Biochem Branch, NIH, Bldg 10,Room 9D-20, Bethesda, MD 20892 USA. EM harris_bernstein@nih.gov NR 59 TC 6 Z9 6 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD APR PY 2001 VL 183 IS 7 BP 2187 EP 2197 PG 11 WC Microbiology SC Microbiology GA 411RH UT WOS:000167512700005 ER PT J AU Kaji, M Ikari, M Hashiguchi, S Ito, Y Matsumoto, R Yoshimura, T Kuratsu, J Sugimura, K AF Kaji, M Ikari, M Hashiguchi, S Ito, Y Matsumoto, R Yoshimura, T Kuratsu, J Sugimura, K TI Peptide mimics of monocyte chemoattractant protein-1 (MCP-1) with an antagonistic activity SO JOURNAL OF BIOCHEMISTRY LA English DT Article DE inhibition; MCP-1; molecular design; peptide mimic; phage library ID SITE-DIRECTED MUTAGENESIS; T-CELL PROLIFERATION; ATHEROSCLEROTIC LESIONS; RECEPTOR ACTIVATION; CHEMOKINES; DOMAIN; IDENTIFICATION AB In this study, we attempted to analyze the peptide motifs recognized by 24822.111 and F9, monoclonal antibodies (mAbs) that inhibit the chemotactic activity of monocyte chemoattractant protein-1 (MCP-1), a member of the CC subfamily of chemokines, We isolated phage clones from a phage display library and identified six peptide motifs, One of these clones, C27, was strongly and specifically recognized by 24822.111 mAb, while another, G25, was similarly recognized by F9 mAb, Both the C27 motif and the G25 motif contain two cysteines in their sequences and have little homology to the primary amino acid sequence of MCP-1, These clones, however, bound to THP-1 cells, and the binding was: competitively inhibited by MCP-1, The clones strongly inhibited the MCP-1-induced chemotaxis of human monocytes, The synthetic and intramolecularly disulfide-linked peptides of C27 and G25 (sC27 and sG25) also inhibited the chemotaxis induced by MCP-1, while their derivatives with serine in place of cysteine did not, suggesting the importance of the loop structure for the inhibition. These results suggest that sC27 and sG25 may mimic the MCP-1-binding domain to the MCP-1 receptor. C1 Kagoshima Univ, Fac Engn, Dept Bioengn, Kagoshima 8900065, Japan. Kagoshima Univ, Fac Med, Dept Neurosurg, Kagoshima 8908544, Japan. NCI, Immunobiol Lab, Immunopathol Sect, Frederick, MD 21701 USA. RP Sugimura, K (reprint author), Kagoshima Univ, Fac Engn, Dept Bioengn, 1-21-40 Korimoto, Kagoshima 8900065, Japan. NR 25 TC 11 Z9 12 U1 0 U2 2 PU JAPANESE BIOCHEMICAL SOC PI TOKYO PA ISHIKAWA BLDG-3F, 25-16 HONGO-5-CHOME, BUNKYO-KU, TOKYO, 113, JAPAN SN 0021-924X J9 J BIOCHEM-TOKYO JI J. Biochem. (Tokyo) PD APR PY 2001 VL 129 IS 4 BP 577 EP 583 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 418XP UT WOS:000167920000012 PM 11275557 ER PT J AU Daan, S Albrecht, U van der Horst, GTJ Illnerova, H Roenneberg, T Wehr, TA Schwartz, WJ AF Daan, S Albrecht, U van der Horst, GTJ Illnerova, H Roenneberg, T Wehr, TA Schwartz, WJ TI Assembling a clock for all seasons: Are there M and E oscillators in the genes? SO JOURNAL OF BIOLOGICAL RHYTHMS LA English DT Article DE evening/morning oscillators; circadian clock genes; pacemaker; photoperiodism; seasonal adjustment ID RAT SUPRACHIASMATIC NUCLEUS; MAMMALIAN CIRCADIAN CLOCK; FUNCTIONAL-ANALYSIS; NOCTURNAL RODENTS; PHASE-SHIFTS; COUPLED OSCILLATORS; UNILATERAL LESIONS; PHOTIC REGULATION; SIBERIAN HAMSTER; ACTIVITY RHYTHMS AB The hypothesis is advanced that the circadian pacemaker in the mammalian suprachiasmatic nucleus (SCN) is composed at the molecular level of a nonredundant double complex of circadian genes (per1, cry1, and per2, cry2). Each one of these sets would be sufficient for the maintenance of endogenous rhythmicity and thus constitute an oscillator. Each would have slightly different temporal dynamics and light responses. The per1/cry1 oscillator is accelerated by light and decelerated by darkness and thereby tracks dawn when day length changes. The per2/cry2 oscillator is decelerated by light and accelerated by darkness and thereby tracks dusk. These M (morning) and E (evening) oscillators would give rise to the SCN's neuronal activity in an M and an E component. Suppression of behavioral activity by SCN activity in nocturnal mammals would give rise to adaptive tuning of the endogenous behavioral program to day length. The proposition-which is a specification of Pittendrigh and Daan's E-M oscillator model-yields specific nonintuitive predictions amenable to experimental testing in animals with mutations of circadian genes. C1 Univ Groningen, Zool Lab, NL-9750 AA Haren, Netherlands. Max Planck Inst Expt Endocrinol, D-30625 Hannover, Germany. Erasmus Univ, Dept Cell Biol & Genet, NL-3000 DR Rotterdam, Netherlands. Acad Sci Czech Republic, Inst Physiol, CR-14220 Prague 4, Czech Republic. Univ Munich, Inst Med Physiol, D-80336 Munich, Germany. NIMH, Sect Biol Rhythms, Bethesda, MD 20892 USA. Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01655 USA. RP Daan, S (reprint author), Univ Groningen, Zool Lab, POB 14, NL-9750 AA Haren, Netherlands. RI Albrecht, Urs/A-9831-2011; Illnerova, Helena/G-3898-2014; van der Horst, Gijsbertus/E-3661-2015 NR 77 TC 149 Z9 157 U1 0 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0748-7304 J9 J BIOL RHYTHM JI J. Biol. Rhythms PD APR PY 2001 VL 16 IS 2 BP 105 EP 116 DI 10.1177/074873001129001809 PG 12 WC Biology; Physiology SC Life Sciences & Biomedicine - Other Topics; Physiology GA 482WF UT WOS:000171599700003 PM 11302553 ER PT J AU Wu, ZR Ono, A Kainosho, M Bax, A AF Wu, ZR Ono, A Kainosho, M Bax, A TI H center dot center dot center dot N hydrogen bond lengths in double stranded DNA from internucleotide dipolar couplings SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Dickerson dodecamer; dipolar coupling; E.COSY; hydrogen bond; liquid crystal; Watson-Crick ID BASE-PAIRS; NMR; DODECAMER; SPECTROSCOPY; (3H)J(NC'); CONSTANTS; PROTEINS; REVEALS AB The ratio of the internucleotide dipolar coupling and the corresponding one-bond imino N-15-H-1 dipolar coupling provides a measure for the N . . .H/H-N distance ratio. Measurements were carried out for a dodecamer, d(CGCGAATTCGCG)(2), in which a C-G and an A-T basepair were uniformly enriched in N-15. When assuming H-bonds to be perfectly linear, dipolar data indicate time-averaged hydrogen bond lengths of 1.80 +/-0.03 Angstrom for A-T and 1.86 +/-0.02 Angstrom for C-G. When using H-bond orientations from high resolution X-ray data, H-bond lengths are about 0.1 Angstrom shorter. C1 NIDDKD, NIH, Chem Phys Lab, Bethesda, MD 20892 USA. Tokyo Metropolitan Univ, Tokyo 1920397, Japan. RP Wu, ZR (reprint author), NIDDKD, NIH, Chem Phys Lab, Bethesda, MD 20892 USA. NR 21 TC 15 Z9 16 U1 0 U2 3 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD APR PY 2001 VL 19 IS 4 BP 361 EP 365 DI 10.1023/A:1011250219293 PG 5 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 419BB UT WOS:000167928500007 PM 11370782 ER PT J AU Wu, ZR Tjandra, N Bax, A AF Wu, ZR Tjandra, N Bax, A TI Measurement of (1)H3 '-P-31 dipolar couplings in a DNA oligonucleotide by constant-time NOESY difference spectroscopy SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE constant-time NOESY; Dickerson dodecamer; dipolar coupling; liquid crystal; Pf1 ID C-13-LABELED NUCLEIC-ACIDS; QUANTITATIVE J-CORRELATION; HYDROGEN-BONDS; NMR; PROTEIN; MACROMOLECULES; COMPLEXES; DODECAMER; FRAGMENTS; REFINEMENT AB The ratios of cross peak intensities in a selective constant-time NOESY experiment, recorded with and without P-31 decoupling, yield values for the sum of the H3'-P scalar and dipolar couplings. The selective refocusing of H3' resonances in this experiment results in excellent resolution and sensitivity, even in the liquid crystalline phase where the H-1 spectrum is broadened by unresolved homonuclear dipolar couplings. The vicinal H3'-P scalar and dipolar couplings in the DNA oligomer d(CGCGAATTCGCG)(2) were measured in both isotropic solution, and in a liquid crystalline phase. Isotropic values are in good agreement with values reported previously. Dipolar couplings are in excellent agreement with the NMR structure for this dodecamer, and to a somewhat lesser extent with the X-ray structures. C1 NIDDKD, NIH, Chem Phys Lab, Bethesda, MD 20892 USA. NHLBI, NIH, Biophys Chem Lab, Bethesda, MD 20892 USA. RP Wu, ZR (reprint author), NIDDKD, NIH, Chem Phys Lab, Bethesda, MD 20892 USA. NR 27 TC 28 Z9 29 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD APR PY 2001 VL 19 IS 4 BP 367 EP 370 DI 10.1023/A:1011292803363 PG 4 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 419BB UT WOS:000167928500008 PM 11370783 ER PT J AU Zhang, XP Morham, SG Langenbach, R Young, DA Xing, LP Boyce, BF Puzas, EJ Rosier, RN O'Keefe, RJ Schwarz, EM AF Zhang, XP Morham, SG Langenbach, R Young, DA Xing, LP Boyce, BF Puzas, EJ Rosier, RN O'Keefe, RJ Schwarz, EM TI Evidence for a direct role of cyclo-oxygenase 2 in implant wear debris-induced osteolysis SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE prostaglandin G/H synthase; cyclo-oxygenase 2; prostaglandin E-2; osteolysis; inflammation; aseptic loosening ID OSTEOCLAST DIFFERENTIATION FACTOR; PROSTAGLANDIN G/H SYNTHASE-2; TOTAL HIP-REPLACEMENT; BONE-RESORPTION; RHEUMATOID-ARTHRITIS; PARATHYROID-HORMONE; INHIBITORY FACTOR; GENE DISRUPTION; DEFICIENT MICE; CYCLOOXYGENASE AB Aseptic loosening is a major complication of prosthetic joint surgery and is manifested as chronic inflammation,, pain, and osteolysis at the bone implant interface. The osteolysis is believed to be driven by a host inflammatory response to wear debris generated from the implant. In our current study, we use a selective inhibitor (celecoxib) of cyclo-oxygenase 2 (COX-2) and mice that lack either COX-1 (COX-1-/-) or COX-2 (COX-2-/-) to show that COX-2, but not COX-1, plays an important role in wear debris-induced osteolysis. Titanium (Ti) wear debris was implanted surgically onto the calvaria of the mice. An intense inflammatory reaction and extensive bone resorption, which closely resembles that observed in patients with aseptic loosening, developed within 10 days of implantation in wild-type and COX-1-/- mice. COX-2 and prostaglandin E-2 (PGE(2)) production increased in the calvaria and inflammatory tissue overlying it after Ti implantation. Celecoxib (25 mg/kg per day) significantly reduced the inflammation, the local PGE, production, and osteolysis, In comparison with wild-type and COX-1-/- mice, COX-2-/- mice implanted with Ti had a significantly reduced calvarial bone resorption response, independent of the inflammatory response, and significantly fewer osteoclasts were formed from cultures of their bone marrow cells. These results provide direct evidence that COX-2 is an important mediator of wear debris-induced osteolysis and suggests that COX-2 inhibitors are potential therapeutic agents for the prevention of wear debris-induced osteolysis. C1 Univ Rochester, Med Ctr, Dept Orthoped, Sch Med & Dent, Rochester, NY 14642 USA. Myriad Genet Inc, Salt Lake City, UT USA. NIEHS, Lab Expt Carcinogenesis & Mutagenesis, Res Triangle Pk, NC 27709 USA. Univ Rochester, Sch Med & Dent, Dept Med Endocrinol, Rochester, NY 14642 USA. Univ Rochester, Sch Med & Dent, Dept Pathol, Rochester, NY 14642 USA. RP Univ Rochester, Med Ctr, Dept Orthoped, Sch Med & Dent, 601 Elmwood Ave,Box 665, Rochester, NY 14642 USA. FU NIAMS NIH HHS [AR45971] NR 51 TC 76 Z9 79 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD APR PY 2001 VL 16 IS 4 BP 660 EP 670 DI 10.1359/jbmr.2001.16.4.660 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 413JV UT WOS:000167610000007 PM 11315993 ER PT J AU Schonherr, E Schaefer, L O'Connell, BC Kresse, H AF Schonherr, E Schaefer, L O'Connell, BC Kresse, H TI Matrix metalloproteinase expression by endothelial cells in collagen lattices changes during co-culture with fibroblasts and upon induction of decorin expression SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID ANGIOGENESIS IN-VITRO; NECROSIS-FACTOR-ALPHA; LEUCINE-RICH REPEAT; GENE-EXPRESSION; GROWTH-FACTOR; INTERSTITIAL COLLAGENASE; PLASMINOGEN ACTIVATORS; SULFATE PROTEOGLYCANS; TISSUE INHIBITOR; PROGELATINASE-A AB EA.hy 926 cells, a derivative of human umbilical vein endothelial cells, in the presence of fibroblasts show the phenomena of angiogenesis, express the proteoglycan decorin and escape apoptosis, when they are maintained in collagen lattices, while fibroblast-free cultures do not show these changes, Virus-mediated decorin expression can substitute for the presence of fibroblasts. Since the expression of matrix metalloproteinases (MMPs) is an essential step in the formation of capillaries, several MMPs and tissue inhibitors of metalloproteinases (TIMPs) were investigated. MMP-1, MMP-2, MMP-9, and the cell-associated MMP-14 were augmented on the protein level in the presence of fibroblasts. No effect was seen with respect to MMP-3, TIMP-1, and TIMP-2, Semiquantitative RT-PCRs of endothelial cells in co-culture revealed a 7-, 19-, and 11-fold increase for mRNAs of MMP-1, MMP-2, and MMP-14 after six days, respectively. Virus-mediated decorin expression also was accompanied by an up-regulation of these MMPs. The expression of MMP-1 mRNAs increased 5-fold after 2 days and gradually declined thereafter. In contrast, MMP-2 and MMP-14 showed a 7-fold acid a 14-Told increase on day two which returned to basal levels within 24 h, indicating that the expression of MMP-1 is differentially regulated from MMP-2 and MMP-14. In spite of the upregulation of the proteases, an enhanced degradation of decorin was not observed. These results indicate that the expression of decorin is a sufficient signal in EA.hy 926 cells for a finely tuned induction of selected MMPs which are involved in angiogenesis whereas the up-regulation of MMPs does not lead to the degradation of the responsible proteoglycan. (C) 2001 Wiley-Liss, inc. C1 Univ Munster, Inst Physiol Chem & Pathobiochem, D-48149 Munster, Germany. Univ Munster, Dept Internal Med, D-48149 Munster, Germany. NIDCR, NIH, Bethesda, MD USA. RP Schonherr, E (reprint author), Univ Munster, Inst Physiol Chem & Pathobiochem, Waldeyerstr 15, D-48149 Munster, Germany. OI O'Connell, Brian/0000-0003-4529-7664 NR 56 TC 32 Z9 32 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 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD APR PY 2001 VL 187 IS 1 BP 37 EP 47 DI 10.1002/1097-4652(2001)9999:9999<::AID-JCP1048>3.0.CO;2-W PG 11 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 408BE UT WOS:000167306000004 PM 11241347 ER PT J AU Culmsee, C Zhu, Y Krieglstein, J Mattson, MP AF Culmsee, C Zhu, Y Krieglstein, J Mattson, MP TI Evidence for the involvement of Par-4 in ischemic neuron cell death SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE apoptosis; antisense; caspase; hippocampus; stroke ID PROSTATE APOPTOSIS RESPONSE-4; FOCAL CEREBRAL-ISCHEMIA; TRANSIENT FOREBRAIN ISCHEMIA; MITOCHONDRIAL DYSFUNCTION; HIPPOCAMPAL-NEURONS; OXIDATIVE STRESS; RAT-BRAIN; NEURODEGENERATIVE DISORDERS; CASPASE ACTIVATION; PROTEIN EXPRESSION AB After a stroke many neurons in the ischemic brain tissue die by a process called apoptosis, a form of cell death that may be preventable. The specific molecular cascades that mediate ischemic neuronal death are not well understood. The authors recently identified prostate apoptosis response-3 (Par-4) as a protein that participates in the death of cultured hippocampal neurons induced by trophic factor withdrawal and exposure to glutamate. Here, the authors show that Par-4 levels increase in vulnerable populations of hippocampal and striatal neurons in rats after transient forebrain ischemia; Par-4 levels increased within 6 hours of reperfusion and remained elevated in neurons undergoing apoptosis 3 days later. After transient focal ischemia in mice, Par-4 levels were increased 6 to 12 hours after reperfusion in the infarcted cortex and the striatum, and activation of caspase-8 occurred with a similar time course. Par-4 immunoreactivity was localized predominantly in cortical neurons at the border of the infarct area. A Par-4 antisense oligonucleotide protected cultured hippocampal neurons against apoptosis induced by chemical hypoxia and significantly reduced focal ischemic damage in mice. The current data suggest that early up-regulation of Par-4 plays a pivotal role in ischemic neuronal death in animal models of stroke and cardiac arrest. C1 NIA, Gerontol Res Ctr, Neurosci Lab, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD USA. Univ Marburg, Inst Pharmakol & Toxikol, Marburg, Germany. RP Mattson, MP (reprint author), NIA, Gerontol Res Ctr, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 57 TC 30 Z9 41 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD APR PY 2001 VL 21 IS 4 BP 334 EP 343 PG 10 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 421PT UT WOS:000168073300002 PM 11323519 ER PT J AU Vgontzas, AN Bixler, EO Wittman, AM Zachman, K Lin, HM Vela-Bueno, A Kales, A Chrousos, GP AF Vgontzas, AN Bixler, EO Wittman, AM Zachman, K Lin, HM Vela-Bueno, A Kales, A Chrousos, GP TI Middle-aged men show higher sensitivity of sleep to the arousing effects of corticotropin-releasing hormone than young men: Clinical implications SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID BIOCHEMICAL MANIFESTATIONS; CORTISOL; DEPRESSION; SECRETION; STRESS; ADRENOCORTICOTROPIN; NEUROBIOLOGY; HUMANS; SYSTEM AB The prevalence of insomnia associated with emotional stress increases markedly in middle-age. Both the top and end hormones of the hypothalamic-pituitary-adrenal axis, i.e. CRH and glucocorticoids, stimulate arousal/wakefulness and inhibit slow wave (deep) sleep in experimental animals and man. The objective of this study was to test the hypothesis that middle-age is characterized by increased sensitivity to the sleep-disturbing effects of the hypothalamic-pituitary-adrenal axis. We studied 12 healthy middle-aged (45.1 +/- 1.9) and 12 healthy young (22.7 +/- 2.8) men by monitoring their sleep by polysomnography for 4 consecutive nights, including in tandem 1 adaptation and 2 baseline nights and a night during which we administered equipotent doses of ovine CRH (1 mug/kg, iv bolus) 10 min after sleep onset. Analyses included comparisons within and between groups using multiple ANOVA and regression analysis. Although both middle-aged and young men responded to CRH with similar elevations of ACTH and cortisol, the former had significantly more wakefulness and suppression of slow wave sleep compared with baseline sleep; in contrast, the latter showed no change. Also, comparison of the change in sleep patterns from baseline to the CRH night in the young men to the respective change observed in middle-aged men showed that middle-age was associated with significantly higher wakefulness and significantly greater decrease in slow wave sleep than in young age. We conclude that middle-aged men show increased vulnerability of sleep to stress hormones, possibly resulting in impairments in the quality of sleep during periods of stress. We suggest that changes in sleep physiology associated with middle-age play a significant role in the marked increase of prevalence of insomnia in middle-age. C1 Penn State Univ, Coll Med, Dept Psychiat, Sleep Res & Treatment Ctr, Hershey, PA 17033 USA. Penn State Univ, Dept Hlth Evaluat Sci, Hershey, PA 17033 USA. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Autonomous Univ Madrid, Dept Psychiat, E-28049 Madrid, Spain. RP Vgontzas, AN (reprint author), Penn State Univ, Coll Med, Dept Psychiat, Sleep Res & Treatment Ctr, 500 Univ Dr, Hershey, PA 17033 USA. EM axv3@psu.edu NR 26 TC 71 Z9 72 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2001 VL 86 IS 4 BP 1489 EP 1495 DI 10.1210/jc.86.4.1489 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 424QM UT WOS:000168243000009 PM 11297573 ER PT J AU Bergh, FT Kumpfel, T Grasser, A Rupprecht, R Holsboer, F Trenkwalder, C AF Bergh, FT Kumpfel, T Grasser, A Rupprecht, R Holsboer, F Trenkwalder, C TI Combined treatment with corticosteroids and moclobemide favors normalization of hypothalamo-pituitary-adrenal axis dysregulation in relapsing-remitting multiple sclerosis: A randomized, double blind trial SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; CORTICOTROPIN-RELEASING HORMONE; DEXAMETHASONE-CRH TEST; ADRENOCORTICAL SYSTEM; DEPRESSED-PATIENTS; SHORT-TERM; THERAPY; RAT; DISORDERS; SUPPRESSION AB Hyperresponsiveness of the hypothalamo-pituitary-adrenal (HPA) axis in multiple sclerosis (MS), an autoimmune inflammatory disease of the central nervous system, is presumably due to diminished corticosteroid receptor function. It probably influences the immune response, but its clinical significance is not clear. Similar HPA dysregulation occurs in depression and is reversible with successful antidepressant treatment. We conducted a double blind, placebo-controlled trial to evaluate the neuroendocrine effect of cotreatment with the antidepressant moclobemide as an adjunct to oral corticosteroids in MS. Twenty-one patients with definite relapsing-remitting MS (11 females, aged 33.9 +/- 2.0 yr; Expanded Disability Status Scale score of neurological impairment. 2.0-6.5) in acute relapse were treated with placebo (n = 13) or 300 mg moclobemide (reversible monoamine oxidase A inhibitor; n = 8) for 75 days. All received oral fluocortolone from day 7 on, and the dose was tapered until day 29. Effects were evaluated using the combined dexamethasone-CRH test and clinically on days 1, 30, and 75. At baseline, the HPA axis was mildly activated, comparably for treatment groups [area under the curve for cortisol (AUC-Cort), 213.8 +/- 76.8 arbitrary units in the moclobemide group us. 225.8 +/- 65.1 in the steroid alone group; mean +/- SEM]. In a group of healthy controls with comparable demographic characteristics, the AUC-Cort was 107.4 +/- 14.1. Moclobemide cotreatment resulted in normalization of the HPA axis response, whereas the HPA system hyperresponse was maintained with steroids alone (AUC-Cort on day 30, 85.9 +/- 22.8 us. 177.1 +/- 68.5; on day 75, 111.0 +/- 46.0 us. 199.2 +/- 64.6). The change in Expanded Disability Status Scale was comparable for both groups. Although corticosteroids alone had no effect on the HPA response using the dexamethasone-CRH test, treatment with moclobemide combined with corticosteroids favors normalization of the HPA response in relapsing-remitting MS. C1 Max Planck Inst Psychiat, Dept Neurol, D-80804 Munich, Germany. RP Bergh, FT (reprint author), NINDS, Mol Biol Lab, NIH, 36 Convent Dr,Room 3C11, Bethesda, MD 20892 USA. EM thenberf@ninds.nih.gov NR 43 TC 17 Z9 17 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 2001 VL 86 IS 4 BP 1610 EP 1615 DI 10.1210/jc.86.4.1610 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 424QM UT WOS:000168243000029 ER PT J AU Harik-Khan, RI Wise, RA Fleg, JL AF Harik-Khan, RI Wise, RA Fleg, JL TI The effect of gender on the relationship between body fat distribution and lung function SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE WHR; FEV1; FVC; lung function; body fat distribution; obesity ID PULMONARY-FUNCTION; CARDIOVASCULAR-DISEASE; RESPIRATORY-FUNCTION; ADIPOSE-TISSUE; WEIGHT-GAIN; RISK FACTOR; OBESITY; MORTALITY; FOLLOW; WOMEN AB Although abdominal obesity, as measured by waist-to-hip ratio (WHR), has long been recognized as a risk factor for metabolic and cardiovascular diseases, little is known about the effect of WHR on pulmonary function, especially in women. In this study of 1094 men and 540 women (18-102 years) from the Baltimore Longitudinal Study of Aging (BLSA), we examined the effect of WHR on forced expiratory volume in 1 s (FEV1). Cross-sectional analyses, after accounting for body mass index (BMI) and other variables, showed a strong inverse association of WHR with FEV, in men (beta = -1.338, P = .0001) but not in women. Furthermore, larger values of WHR were associated with greater reductions of forced vital capacity (FVC) in men (beta = -1.383, P = .0005) compared to women (beta = -0.679, P = .02). Thus, body fat distribution has independent effects on lung function that are more prominent in men than women. (C) 2001 Elsevier Science Inc. All rights reserved. C1 NIA, Gerontol Res Ctr, Longitudinal Studies Sect, Clin Invest Lab, Baltimore, MD 21224 USA. Johns Hopkins Sch Med, Dept Med, Baltimore, MD 21205 USA. RP Harik-Khan, RI (reprint author), NIA, Gerontol Res Ctr, Longitudinal Studies Sect, Clin Invest Lab, 5600 Nathan Shock Dr,Box 06, Baltimore, MD 21224 USA. OI Wise, Robert/0000-0002-8353-2349 NR 30 TC 71 Z9 77 U1 2 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD APR PY 2001 VL 54 IS 4 BP 399 EP 406 DI 10.1016/S0895-4356(00)00318-8 PG 8 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 417KX UT WOS:000167835100010 PM 11297889 ER PT J AU Baddeley, AD Vargha-Khadem, F Mishkin, M AF Baddeley, AD Vargha-Khadem, F Mishkin, M TI Preserved recognition in a case of developmental amnesia: Implications for the acquisition of semantic memory? SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Article ID EPISODIC MEMORY; PEOPLE TEST; RECALL; ORGANIZATION; PATHOLOGY; ABSENCE; DAMAGE; DOORS; CONSCIOUSNESS; INFORMATION AB We report the performance on recognition memory tests of Jon, who, despite amnesia from early childhood, has developed normal levels of performance on tests of intelligence, language, and general knowledge. Despite impaired recall, he performed within the normal range on each of six recognition tests, but he appears to lack the recollective phenomenological experience normally associated with episodic memory. His recall of previously unfamiliar newsreel events was impaired, but gained substantially from repetition over a 2-day period. Our results are consistent with the hypothesis that the recollective process of episodic memory is not necessary either for recognition or for the acquisition of semantic knowledge. C1 Univ Bristol, Dept Expt Psychol, Bristol BS8 1TN, Avon, England. UCL, London WC1E 6BT, England. Great Ormond St Hosp Sick Children, London WC1N 3JH, England. NIMH, Bethesda, MD 20892 USA. RP Baddeley, AD (reprint author), Univ Bristol, Dept Expt Psychol, 8 Woodland Rd, Bristol BS8 1TN, Avon, England. EM alan.baddeley@bristol.ac.uk RI Vargha-Khadem, Faraneh/C-2558-2008 NR 60 TC 143 Z9 145 U1 3 U2 23 PU MIT PRESS PI CAMBRIDGE PA 55 HAYWARD STREET, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD APR 1 PY 2001 VL 13 IS 3 BP 357 EP 369 DI 10.1162/08989290151137403 PG 13 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 425DR UT WOS:000168273500007 PM 11371313 ER PT J AU Jeffcoat, MK Lewis, CE Reddy, MS Wang, CY Redford, MA AF Jeffcoat, MK Lewis, CE Reddy, MS Wang, CY Redford, MA TI From benchtop to clinic: osteoporosis and oral bone loss. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Univ Alabama Sch, Fred Hutchinson Canc Res Ctr, Natl Inst Dent & Craniofacial Res, Birmingham, AL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD APR PY 2001 VL 80 IS 4 BP 982 EP 982 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 497VL UT WOS:000172476100307 ER PT J AU Goldberg, M Dunglas, C Septier, D Paine, ML Snead, ML Qasba, P Sreenath, T Kulkarni, AB AF Goldberg, M Dunglas, C Septier, D Paine, ML Snead, ML Qasba, P Sreenath, T Kulkarni, AB TI Transgenic mice as tools for understanding dental tissue formation. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Univ Paris 05, Lab Biol Physiopathol Craniofacial, Paris, France. Univ So Calif, Ctr Craniofacial Mol Biol, Los Angeles, CA 90033 USA. NIDCR, Funct Gen Unit, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD APR PY 2001 VL 80 IS 4 BP 1147 EP 1147 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 497VL UT WOS:000172476101429 ER PT J AU Grzesik, W Kuznetsov, S Yamauchi, M AF Grzesik, W Kuznetsov, S Yamauchi, M TI Cementum forming cells can be cultured from human soft peridontal tissues. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Univ N Carolina, Sch Dent, Dent Res Ctr, Chapel Hill, NC 27599 USA. NIDCR, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD APR PY 2001 VL 80 IS 4 BP 1278 EP 1278 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 497VL UT WOS:000172476102307 ER PT J AU Grzesik, W Robey, F Wojtowicz, A Yamauchi, M AF Grzesik, W Robey, F Wojtowicz, A Yamauchi, M TI Interactions of integrin receptors with their synthetic ligands increase bone formation in vivo SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Univ N Carolina, Dent Res Ctr, Chapel Hill, NC 27599 USA. NIDR, Pharyngeal Canc Branch, Bethesda, MD 20892 USA. Med Univ Warsaw, Dept Oral Surg, Warsaw, Poland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD APR PY 2001 VL 80 IS 4 BP 1285 EP 1285 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 497VL UT WOS:000172476102360 ER PT J AU Umansky, R Watson, JS Hoffbuhr, K Painter, KM Devaney, J Hoffman, E AF Umansky, R Watson, JS Hoffbuhr, K Painter, KM Devaney, J Hoffman, E TI Social facilitation of object-oriented hand use in a Rett syndrome variant girl: Implications for partial preservation of an hypothesized specialized cerebral network SO JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS LA English DT Article DE Rett; MeCP2; hand; social facilitation AB Partial preservation of object-oriented hand use (OOHU) was studied behaviorally in a 6-1/2-year-old girl with the preserved speech variant (PSV) of Rett syndrome (RS), associated with a T 158 missense MeCP2 mutation and favorably skewed X-inactivation. At home, OOHU was limited except for self-feeding. When examined, overall time invested in toy play was only 38% of that of healthy subjects, and also, by comparison with healthy subjects, less when autonomous than when socially-facilitated (13% vs 63%). Good interest in and responsiveness to people translated into better motivation for OOHU. She responded to others' requests for grasping and handling objects and used them to reinforce affiliations with people. Results were discussed in terms of a disruption of the formation of a specialized OOHU cerebral network in RS, partially compensated for by the favorably skewed X-inactivation, which among other effects permitted functional retention of the network segment incorporating social influence and motivation. C1 Childrens Hosp, Child Dev Ctr, Oakland, CA 94609 USA. Univ Calif Berkeley, Dept Psychol, Berkeley, CA 94720 USA. Childrens Res Inst, Res Ctr Genet Med, Washington, DC USA. NICHHD, Bethesda, MD 20892 USA. Transgenom Inc, Gaithersburg, MD USA. Childrens Res Inst, Res Ctr Genet Med, Washington, DC USA. RP Umansky, R (reprint author), 6433 Regent St, Oakland, CA 94618 USA. NR 17 TC 4 Z9 4 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-206X J9 J DEV BEHAV PEDIATR JI J. Dev. Behav. Pediatr. PD APR PY 2001 VL 22 IS 2 BP 119 EP 122 PG 4 WC Behavioral Sciences; Psychology, Developmental; Pediatrics SC Behavioral Sciences; Psychology; Pediatrics GA 420GB UT WOS:000167996300005 PM 11332781 ER PT J AU Stein, MT Zentall, S Shaywitz, SE Shaywitz, BA AF Stein, MT Zentall, S Shaywitz, SE Shaywitz, BA TI A school-aged child with belayed reading skills SO JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS LA English DT Editorial Material DE dyslexia; phonetic code; learning disabilities C1 Univ Calif San Diego, San Diego, CA 92103 USA. Purdue Univ, W Lafayette, IN 47907 USA. Yale Univ, Sch Med, NICHD, Yale Ctr Study Learning & Attent, New Haven, CT USA. RP Stein, MT (reprint author), Univ Calif San Diego, San Diego, CA 92103 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-206X J9 J DEV BEHAV PEDIATR JI J. Dev. Behav. Pediatr. PD APR PY 2001 VL 22 IS 2 SU S BP S111 EP S115 PG 5 WC Behavioral Sciences; Psychology, Developmental; Pediatrics SC Behavioral Sciences; Psychology; Pediatrics GA 423NV UT WOS:000168183100022 PM 11332789 ER PT J AU Panchenko, VA Glasser, CR Mayer, ML AF Panchenko, VA Glasser, CR Mayer, ML TI Structural similarities between glutamate receptor channels and K+ channels examined by scanning mutagenesis SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Article DE AMPA receptor; kainate receptor; polyamines; pore helix; ion channel block ID LIGAND-BINDING CORE; GATED ION CHANNELS; POTASSIUM CHANNELS; INTRACELLULAR POLYAMINES; MOLECULAR-BASIS; PORE; KAINATE; BLOCK; AMPA; MODULATION AB The pores of glutamate receptors and K+ channels share sequence homology suggesting a conserved secondary structure. Scanning mutagenesis with substitution of alanine and trytptophan in GluR6 channels was performed based on the structure of KcsA. Our assay used disruption of voltage-dependent polyamine block to test for changes in the packing of pore-forming regions. Alanine scanning from D567 to R603 revealed reduced rectification resulting from channel block in two regions. A pel-iodic pattern from F575 to M589 aligned with the pore helix in KcsA, whereas a cluster of sensitive positions around Q590. a site regulated by RNA editing, mapped to the selectivity filter in KcsA. Tryptophan scanning from D56T to R603 revealed similar patterns, but with a complete disruption of spermine block for 7 out of the 3T positions and a phl dissociation constant for Q590W Molecular modeling with KcsA coordinates showed that GluR6 pol e helix mutants disrupting polyamine block pack against M1 and M2, and are not exposed in the ion channel pore. In the selectivity filter tryptophan creates an aromatic cage consistent with the pM dissociation constant for Q590W A scan with glutamate substitution was used to map the cytoplasmic entrance to the pore based on charge neutralization experiments, which established that E594 was uniquely required fur high affinity polyamine block. In E594Q mutants, introduction of glutamate at positions S593-L600 restored pol) amine block at positions corresponding to surface-exposed residues in KcsA. Our results reinforce proposals that the pore region of glutamate receptors contains a helix and pore loop analogous to that found in K+ channels. At the cytoplasmic entrance of the channel, a negatively charged amino acid, located in an extended loop with solvent-exposed side chains, is required for high affinity polyamine block and probably attracts cations via a through space electrostatic mechanism. C1 NICHHD, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. RP Mayer, ML (reprint author), Bldg 49,Room 5A78,Convent Dr MSC 4495, Bethesda, MD 20892 USA. RI Mayer, Mark/H-5500-2013 NR 49 TC 77 Z9 78 U1 0 U2 0 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 2001 VL 117 IS 4 BP 345 EP 359 DI 10.1085/jgp.117.4.345 PG 15 WC Physiology SC Physiology GA 419HR UT WOS:000167943700004 PM 11279254 ER PT J AU Henkler, F Hoare, J Waseem, N Goldin, RD McGarvey, MJ Koshy, R King, IA AF Henkler, F Hoare, J Waseem, N Goldin, RD McGarvey, MJ Koshy, R King, IA TI Intracellular localization of the hepatitis B virus HBx protein SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID X-PROTEIN; HEPATOCELLULAR-CARCINOMA; TRANSCRIPTIONAL ACTIVITY; TRANSACTIVATOR PROTEIN; EXCISION-REPAIR; DNA-BINDING; IN-VIVO; ACTIVATION; P53; EXPRESSION AB The hepatitis B virus (HBV) X protein (HBx) was originally suggested to be a viral transcriptional activator, but its functional mechanisms are still unclear. In this study we have analysed the intracellular localization of HBx in transfected cells and demonstrate that its compartmentalization is dependent on overall expression levels. HBx was exclusively or predominantly localized in the nuclei in weakly expressing cells. However, elevated cellular levels correlated with its accumulation in the cytoplasm, suggesting that the capacity of HBx for nuclear compartmentalization might be limited. Cytoplasmic HBx was detected either as punctate granular staining or in dispersed, finely granular patterns. We have further analysed the detailed cytoplasmic compartmentalization, using confocal microscopy, and show no association with the endoplasmic reticulum, plasma membrane or lysosomes, but a substantial association of HBx with mitochondria. However, a major fraction of cytoplasmic HBx did not localize in mitochondria, indicating the presence of two distinctly compartmentalized cytoplasmic populations. Furthermore, high levels of HBx expression led to an abnormal mitochondrial distribution, involving clumping and organelle aggregation, which was not observed at lower expression levels. The data presented here provide novel insights into the compartmentalization of HBx and may prove important for future evaluations of its functions, both in the viral life-cycle and in the pathology of HBV-related liver disease. C1 Natl Inst Med Res, Div Membrane Biol, London NW7 1AA, England. Univ London Imperial Coll Sci Technol & Med, Sch Med, Dept Med, London W2 1NY, England. Univ London Imperial Coll Sci Technol & Med, Sch Med, Dept Histopathol, London W2 1NY, England. NIAID, Hepatitis Viruses Sect, LID, NIH, Bethesda, MD 20892 USA. Guys Kings & St Thomass Sch Med, Div Med & Mol Genet, London SE1 9RT, England. RP Henkler, F (reprint author), Univ Stuttgart, Inst Cell Biol & Immunol, Allmandring 31, D-70569 Stuttgart, Germany. RI Waseem, Naushin/C-9573-2013 NR 43 TC 89 Z9 108 U1 0 U2 1 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AE, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD APR PY 2001 VL 82 BP 871 EP 882 PN 4 PG 12 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 413PW UT WOS:000167621800020 PM 11257193 ER PT J AU Wedemeyer, H He, XS Nascimbeni, M Davis, AR Greenberg, HB Alter, H Rehermann, B AF Wedemeyer, H He, XS Nascimbeni, M Davis, AR Greenberg, HB Alter, H Rehermann, B TI Impaired effector function of HCV-specific CD8+T cells in chronic hepatitis C virus infection SO JOURNAL OF HEPATOLOGY LA English DT Meeting Abstract C1 NIDDK, NIH, Bethesda, MD 20892 USA. NIH, Dept Transfus Med, Bethesda, MD 20892 USA. Stanford Univ, Sch Med, Stanford, CA USA. 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 2001 VL 34 SU 1 BP 24 EP 25 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 441RM UT WOS:000169243400074 ER PT J AU Yablonka-Reuveni, Z Paterson, BM AF Yablonka-Reuveni, Z Paterson, BM TI MyoD and myogenin expression patterns in cultures of fetal and adult chicken myoblasts SO JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY LA English DT Article DE chicken; fetal myoblasts; adult myoblasts; satellite cells; MyoD; myogenin; MEF2A ID MUSCLE SATELLITE CELLS; SKELETAL-MUSCLE; GENE-EXPRESSION; STEM-CELL; DIFFERENTIATION; TRANSITION; PROTEINS; PROLIFERATION; ACTIVATION; LINEAGES AB Isolated chicken myoblasts had previously been utilized in many studies aiming at understanding the emergence and regulation of the adult myogenic precursors (satellite cells). However, in recent years only a small number of chicken satellite cell studies have been published compared to the increasing number of studies with rodent satellite cells. In large part this is due to the lack of markers for tracing avian myogenic cells before they become terminally differentiated and express muscle-specific structural proteins. We previously demonstrated that myoblasts isolated from fetal and adult chicken muscle display distinct schedules of myosin heavy-chain isoform expression in culture. We further showed that myoblasts isolated from newly hatched and young chickens already possess the adult myoblast phenotype. in this article, we report on the use of polyclonal antibodies against the chicken myogenic regulatory factor proteins MyoD and myogenin for monitoring fetal and adult chicken myoblasts as they progress from proliferation to differentiation in culture. Fetal-type myoblasts were isolated from Ii-day-old embryos and adult-type myoblasts were isolated from 3-week-old chickens. We conclude that fetal myoblasts express both MyoD and myogenin within the first day in culture and rapidly transit into the differentiated myosin-expressing state. In contrast, adult myoblasts are essentially negative for MyoD and myogenin by culture Day 1 and subsequently express first MyoD and then myogenin before expressing sarcomeric myosin. The delayed MyoD-to-myogenin transition in adult myoblasts is accompanied by a lag in the fusion into myotubes, compared to fetal myoblasts. We also report on the use of a commercial antibody against the myocyte enhancer factor ZA (MEF2A) to detect terminally differentiated chicken myoblasts by their MEF2+ nuclei. Collectively, the results support the hypothesis that fetal and adult myoblasts represent different phenotypic populations. The fetal myoblasts may already be destined for terminal differentiation at the time of their isolation, and the adult myoblasts may represent progenitors that reside in an earlier compartment of the myogenic lineage. C1 Univ Washington, Sch Med, Dept Biol Struct, Seattle, WA 98195 USA. NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Yablonka-Reuveni, Z (reprint author), Univ Washington, Sch Med, Dept Biol Struct, Box 357420, Seattle, WA 98195 USA. FU NIA NIH HHS [AG13798] NR 43 TC 49 Z9 51 U1 0 U2 1 PU HISTOCHEMICAL SOC INC PI SEATTLE PA UNIV WASHINGTON, DEPT BIOSTRUCTURE, BOX 357420, SEATTLE, WA 98195 USA SN 0022-1554 J9 J HISTOCHEM CYTOCHEM JI J. Histochem. Cytochem. PD APR PY 2001 VL 49 IS 4 BP 455 EP 462 PG 8 WC Cell Biology SC Cell Biology GA 422TR UT WOS:000168135800005 PM 11259448 ER PT J AU Skapenko, A Lipsky, PE Kraetsch, HG Kalden, JR Schulze-Koops, H AF Skapenko, A Lipsky, PE Kraetsch, HG Kalden, JR Schulze-Koops, H TI Antigen-independent Th2 cell differentiation by stimulation of CD28: Regulation via IL-4 gene expression and mitogen-activated protein kinase activation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ACCESSORY MOLECULE CD28; CYTOKINE MESSENGER-RNA; RESTING T-CELLS; RHEUMATOID-ARTHRITIS; PERIPHERAL-CIRCULATION; SIGNAL INTEGRATION; MULTIPLE-MYELOMA; EFFECTOR-CELLS; IN-VIVO; COSTIMULATION AB To delineate the molecular mechanisms regulating Th2 cell differentiation, CD28-mediated generation of Th2 effectors was analyzed. In the absence of TCR ligation CD28 stimulation induced Th2 differentiation of memory but not of naive CD4+ T cells, whereas costimulation via CD28 and the TCR enhanced Th2 differentiation from naive T cells but suppressed it from memory T cells. Stimulation of T cells via the CD28 pathway, therefore, provided critical signals facilitating Th2 cell differentiation. By comparing the responses to CD28 stimulation in memory and naive T cells and by using specific inhibitors, signaling pathways were defined that contributed to Th2 differentiation. CD28-induced Th2 differentiation required IL-4 stimulation and the activation of the mitogen-activated protein kinases p38 and extracellular signal-regulated kinases 1/2. CD28 engagement directly initiated IL-4 gene transcription in memory T cells and induced activation of phosphatidylinositol 3-kinase, p38, and c-Jun NH2-terminal kinase/stress-activated protein kinase pathways. Extracellular signal-regulated kinase phosphorylation that was necessary for Th2 differentiation, however, required stimulation by IL-2. These results indicate that optimal TCR-independent generation of Th2 effectors requires coordinate signaling via the CD28 and IL-2 pathways. TCR-independent generation of Th2 effectors might provide a mechanism to control Th1-dominated cellular inflammation. C1 Univ Erlangen Nurnberg, Dept Internal Med 3, Clin Res Grp 3, Nikolaus Fiebiger Ctr Mol Med, D-91054 Erlangen, Germany. Univ Erlangen Nurnberg, Inst Clin Immunol, D-91054 Erlangen, Germany. NIAMSD, Bethesda, MD 20892 USA. RP Schulze-Koops, H (reprint author), Univ Erlangen Nurnberg, Dept Internal Med 3, Clin Res Grp 3, Nikolaus Fiebiger Ctr Mol Med, Glueckstr 6, D-91054 Erlangen, Germany. NR 53 TC 28 Z9 33 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 2001 VL 166 IS 7 BP 4283 EP 4292 PG 10 WC Immunology SC Immunology GA 471UZ UT WOS:000170948200003 PM 11254680 ER PT J AU Norbury, CC Princiotta, MF Bacik, I Brutkiewicz, RR Wood, P Elliott, T Bennink, JR Yewdell, JW AF Norbury, CC Princiotta, MF Bacik, I Brutkiewicz, RR Wood, P Elliott, T Bennink, JR Yewdell, JW TI Multiple antigen-specific processing pathways for activating naive CD8(+) T cells in vivo SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; CLASS-I MOLECULES; PROTEIN DISULFIDE-ISOMERASE; ENDOPLASMIC-RETICULUM; DENDRITIC CELLS; APOPTOTIC CELLS; LYMPHOCYTE-T; PEPTIDES; TAP; MICE AB Current knowledge of the processing of viral Ags into MHC class I-associated ligands is based almost completely on in vitro studies using nonprofessional APCs (pAPCs). This is two steps removed from real immune responses to pathogens and vaccines, in which pAPCs activate naive CD8+ T cells in vivo. Rational vaccine design requires answers to numerous questions surrounding the function of pAPCs in vivo, including their abilities to process and present peptides derived from endogenous and exogenous viral Ags. In the present study, we characterize the in vivo dependence of Ag presentation on the expression of TAP by testing the immunogenicity of model Ags synthesized by recombinant vaccinia viruses in TAP1(-/-) mice. We show that the efficiency of TAP-independent presentation in vitro correlates with TAP-independent activation of naive T cells in vivo and provide the first in vivo evidence for proteolytic processing of antigenic peptides in the secretory pathway. There was, however, a clear exception to this correlation; although the presentation of the minimal SIINFEKL determinant from chicken egg OVA in vitro was strictly TAP dependent, it was presented in a TAP-independent manner in vivo. In vivo presentation of the same peptide from a fusion protein retained its TAP dependence. These results show that determinant-specific processing pathways exist in vivo for the generation of antiviral T cell responses. We present additional findings that point to cross-priming as the likely mechanism for these protein-specific differences. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. Southampton Gen Hosp, CRC, Med Oncol Unit, Southampton SO9 4XY, Hants, England. RP Bennink, JR (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RI yewdell, jyewdell@nih.gov/A-1702-2012 NR 47 TC 73 Z9 73 U1 1 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 2001 VL 166 IS 7 BP 4355 EP 4362 PG 8 WC Immunology SC Immunology GA 471UZ UT WOS:000170948200012 PM 11254689 ER PT J AU Fukao, T Frucht, DM Yap, G Gadina, M O'Shea, JJ Koyasu, S AF Fukao, T Frucht, DM Yap, G Gadina, M O'Shea, JJ Koyasu, S TI Inducible expression of Stat4 in dendritic cells and macrophages and its critical role in innate and adaptive immune responses SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MHC CLASS-II; IFN-GAMMA PRODUCTION; IN-VIVO; TYROSINE PHOSPHORYLATION; INTERFERON-GAMMA; DEVELOPMENTAL REGULATION; IL-12 PRODUCTION; TH1 CELLS; T-CELLS; INTERLEUKIN-12 AB Autocrine activation of APC by IL-12 has recently been revealed; we demonstrate here that inducible expression of Stat4 in APC is central to this process. Stat4 is induced in dendritic cells (DC) in a maturation-dependent manner and in macrophages in an activation-dependent manner. Stat4 levels directly correlate with IL-12-dependent IFN-gamma production by APC as well as IFN-gamma production by DC during Ag presentation. The Th2 cytokines IL-4 and IL-10 suppress Stat4 induction in DC and macrophages when present during maturation and activation, respectively, diminishing IFN-gamma production. In contrast, IL-4 has no effect on Stat4 levels in mature DC and actually augments IFN-gamma production by DC during Ag presentation, indicating that IL-4 acts differently in a spatiotemporal manner. The functional importance of Stat4 is evident in Stat4(-/-) DC and macrophages, which fail to produce IFN-gamma. Furthermore, Stat4(-/-) macrophages are defective in NO production in response to IL-12 and are susceptible to Toxoplasma. Autocrine IL-12 signaling is required for high-level IFN-T production by APC at critical stages in both innate and adaptive immunity, and the control of Stat4 expression is likely an important regulator of this process. C1 Keio Univ, Sch Med, Dept Microbiol & Immunol, Shinjuku Ku, Tokyo 1608582, Japan. NIAMSD, Lymphocyte Cell Biol Sect, Arthrit & Rheumatism Branch, Bethesda, MD 20892 USA. NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Koyasu, S (reprint author), Keio Univ, Sch Med, Dept Microbiol & Immunol, Shinjuku Ku, 35 Shinanomachi, Tokyo 1608582, Japan. RI Fukao, Taro/I-3246-2014; Koyasu, Shigeo/J-5583-2015 OI Koyasu, Shigeo/0000-0001-9585-3038 NR 50 TC 129 Z9 133 U1 1 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD APR 1 PY 2001 VL 166 IS 7 BP 4446 EP 4455 PG 10 WC Immunology SC Immunology GA 471UZ UT WOS:000170948200023 PM 11254700 ER PT J AU Okayama, Y Hagaman, DD Metcalfe, DD AF Okayama, Y Hagaman, DD Metcalfe, DD TI A comparison of mediators released or generated by IFN-gamma-treated human mast cells following aggregation of Fc gamma RI or Fc epsilon RI SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TYROSINE KINASE P72(SYK); AFFINITY IGG RECEPTOR; EXPRESSION; PHAGOCYTOSIS; ASSOCIATION; SUBUNIT; VASCULITIS; POPULATION; IMMUNITY; CHAIN AB The high affinity receptor for IgG (Fc gamma RI, CD64) is expressed on human mast cells, where it is up-regulated by IFN-gamma and, thus, may allow mast cells to be recruited through IgG-dependent mechanisms in IFN-gamma -rich tissue inflammation. However, the mediators produced by human mast cells after aggregation of Fc gamma RI are incompletely described, and it is unknown whether these mediators are distinct from those produced after activation of human mast cells via Fc epsilon RI. Thus, we investigated the release of histamine and arachidonic acid metabolites and examined the chemokine and cytokine mRNA profiles of IFN-gamma -treated cultured human mast cells after Fc gamma RI or Fc epsilon RI aggregation. Aggregation of Fc gamma RI resulted in histamine release and PGD(2) and LTC4 generation. These responses were qualitatively indistinguishable from responses stimulated via Fc epsilon RI. Aggregation of Fc epsilon RI or Fc gamma RI led to an induction or accumulation of 22 cytokine and chemokine mRNAs. Among them, seven cytokines (TNF-alpha, IL-1 beta, IL-5, IL-6, IL-13, IL-IR antagonist, and GM-CSF) were significantly up-regulated via aggregation of Fc gamma RI compared with Fc epsilon RI. TNF-alpha mRNA data were confirmed by quantitative RT-PCR and ELISA. Furthermore, we confirmed histamine and TNF-alpha data using IFN-gamma -treated purified human lung mast cells. Thus, aggregation of Fc gamma RI on mast cells led to up-regulation and/or release of three important classes of mediators: biogenic amines, lipid mediators, and cytokines. Some cytokines, such as TNF-alpha, were released and generated to a greater degree after Fc gamma RI aggregation, suggesting that selected biologic responses of mast cells maybe preferentially generated through Fc gamma RI in an IFN-gamma -rich environment. C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Okayama, Y (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C206,10 Ctr Dr MSC 1881, Bethesda, MD 20892 USA. NR 41 TC 69 Z9 74 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD APR 1 PY 2001 VL 166 IS 7 BP 4705 EP 4712 PG 8 WC Immunology SC Immunology GA 471UZ UT WOS:000170948200054 PM 11254731 ER PT J AU Pinto, LA Blazevic, V Anderson, SA Venzon, DJ Mac Trubey, C Rowe, T Katz, JM Liewehr, D Dolan, MJ Shearer, GM AF Pinto, LA Blazevic, V Anderson, SA Venzon, DJ Mac Trubey, C Rowe, T Katz, JM Liewehr, D Dolan, MJ Shearer, GM TI Influenza virus-stimulated generation of anti-human immunodeficiency virus (HIV) activity after influenza vaccination in HIV-infected individuals and healthy control subjects SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID BLOOD MONONUCLEAR-CELLS; CD8(+) T-CELLS; PERIPHERAL-BLOOD; REVERSE TRANSCRIPTION; IFN-GAMMA; SEROPOSITIVE PATIENTS; SUPPRESSIVE FACTORS; CYTOKINE PRODUCTION; INTERFERON-GAMMA; DENDRITIC CELLS AB Influenza virus stimulation of leukocytes induces factors that suppress human immunodeficiency virus (HIV). The effect of influenza vaccination on influenza-induced anti-HIV activity was investigated. Influenza vaccine was administered to 25 control subjects and 20 HIV-infected patients. Antiviral activity, cytokine production, and influenza antibodies were assessed before and 2 and 6 weeks after vaccination. Immunization induced a statistically significant increase in antiviral activity in control subjects but not in HIV patients, although the number of patients who generated this activity increased. Pre- and postvaccination levels of anti-HIV activity were significantly lower in HIV patients. Vaccination of control subjects and HIV patients induced increases in production of interleukin-2 and interferon (IFN)-gamma, but not of IFN-alpha. Virus load and CD4 cell counts were not significantly altered. This study demonstrates impairment of antiviral activity in HIV patients, in addition to deficiencies in antibody responses and cytokine production. In summary, influenza vaccination can induce an increase in multiple immunologic components that remained impaired in HIV patients. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. NCI, Intramural Res Support Program, Sci Applicat Int Corp Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. Henry M Jackson Fdn, San Antonio, TX USA. Wilford Hall USAF Med Ctr, Infect Dis Serv, Lackland AFB, San Antonio, TX 78236 USA. Ctr Dis Control & Prevent, Influenza Branch, Atlanta, GA USA. RP Shearer, GM (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Rm 4B36, Bethesda, MD 20892 USA. RI Venzon, David/B-3078-2008 FU NCI NIH HHS [N01-CA-56000] NR 39 TC 14 Z9 14 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 2001 VL 183 IS 7 BP 1000 EP 1008 DI 10.1086/319277 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 409CL UT WOS:000167366900002 PM 11237823 ER PT J AU Jankelevich, S Mueller, BU Mackall, CL Smith, S Zwerski, S Wood, LV Zeichner, SL Serchuck, L Steinberg, SM Nelson, RP Sleasman, JW Nguyen, BY Pizzo, PA Yarchoan, R AF Jankelevich, S Mueller, BU Mackall, CL Smith, S Zwerski, S Wood, LV Zeichner, SL Serchuck, L Steinberg, SM Nelson, RP Sleasman, JW Nguyen, BY Pizzo, PA Yarchoan, R TI Long-term virologic and immunologic responses in human immunodeficiency virus type 1-infected children treated with indinavir, zidovudine, and lamivudine SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 6th Conference on Retroviruses and Opportunistic Infections CY JAN 31-FEB 04, 1999 CL CHICAGO, ILLINOIS ID COMBINATION ANTIRETROVIRAL THERAPY; PROTEASE INHIBITOR; HIV-INFECTION; FITNESS; AIDS AB Virologic and immunologic responses were examined for 33 human immunodeficiency virus (HIV)-infected children who participated for greater than or equal to 96 weeks in a phase 1/2 protocol of 16 weeks of indinavir monotherapy, followed by the addition of zidovudine and lamivudine. At week 96, a median increase of 199 CD4(+) T cells/mL and a median decrease of 0.74 log(10) HIV RNA copies/mL were observed. The relationship between control of viral replication and CD4(+) T cell count was examined. Patients were categorized into 3 response groups on the basis of duration and extent of control of viral replication. Of 21 children with a transient decrease in virus load of greater than or equal to0.7 log(10) HIV RNA copies/mL from baseline, 7 experienced sustained increases in CD4(+), CD4(+) CD45RA(+), and CD4(+) CD45RO(+) T cell counts. CD4(+) CD45RA(+) (naive) T cells were the major contributor to CD4(+) T cell expansion. Continued long-term immunologic benefit may be experienced by a subset of children, despite only transient virologic suppression. C1 NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Data Management Sect, Div Clin Sci, NIH, Bethesda, MD 20892 USA. Univ S Florida, All Childrens Hosp, St Petersburg, FL 33701 USA. Univ Florida, Gainesville, FL USA. Merck Res Labs, Rahway, NJ USA. RP Yarchoan, R (reprint author), NIH, Bldg 10,Rm 10S255,MSC 1868,10 Ctr Dr, Bethesda, MD 20892 USA. NR 15 TC 23 Z9 24 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 2001 VL 183 IS 7 BP 1116 EP 1120 DI 10.1086/319274 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 409CL UT WOS:000167366900018 PM 11237839 ER PT J AU Greenblatt, RM Jacobson, LP Levine, AM Melnick, S Anastos, K Cohen, M DeHovitz, J Young, MA Burns, D Miotti, P Koelle, DM AF Greenblatt, RM Jacobson, LP Levine, AM Melnick, S Anastos, K Cohen, M DeHovitz, J Young, MA Burns, D Miotti, P Koelle, DM TI Human herpesvirus 8 infection and Kaposi's sarcoma among human immunodeficiency virus-infected and -uninfected women SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 12th International Conference on AIDS CY JUN-JUL -, 1998 CL GENEVA, SWITZERLAND ID SEXUAL TRANSMISSION; INTERAGENCY HIV; RISK GROUPS; HERPESVIRUS; ANTIBODIES; AIDS; PREVALENCE; POPULATION; COHORT AB Little is known about the epidemiology of human herpesvirus 8 (HHV- 8) infections among women. A cross- sectional study was conducted of HHV- 8 infection among human immunodeficiency virus (HIV)- infected and high- risk HIV- uninfected women. Serological tests with noninduced (latent) and induced (lytic) HHV- 8 antigens were used to detect infection among 2483 participants of a multisite cohort. Reactivity to latent antigen was present in 4.1% and to induced antigens in 12.0% of women. Seven of 8 women who reported Kaposi's sarcoma had HHV- 8 antibodies. Among HIV- positive women, HHV- 8 infection was associated with use of crack, cocaine, or heroin (76% vs. 65%; P < .001), past syphilis (29% vs. 20%; P < .001), an injection drug-using male sex partner (61% vs. 53%; P = .014), black race (P = .010), and enrollment site (P = .015). In multivariate analysis, HIV infection, older age, past syphilis, black race, and enrollment site were independently associated with HHV- 8 infection. In this cohort of North American women, HHV- 8 infection was associated with HIV infection, drug use, and risky sexual behavior. C1 Univ Calif San Francisco, Div Infect Dis, San Francisco, CA 94122 USA. Univ So Calif, Los Angeles, CA USA. Johns Hopkins Univ, Baltimore, MD USA. NICHHD, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NIAID, Bethesda, MD 20892 USA. Univ Washington, Seattle, WA 98195 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Montefiore Med Ctr, Bronx, NY 10467 USA. SUNY, Brooklyn, NY USA. Georgetown Univ, Washington, DC USA. Cook Cty Hosp, Chicago, IL 60612 USA. RP Greenblatt, RM (reprint author), Univ Calif San Francisco, Div Infect Dis, 405 Irving St,2d Floor, San Francisco, CA 94122 USA. EM ruthg@itsa.ucsf.edu RI Koelle, David/Q-6529-2016 OI Koelle, David/0000-0003-1255-9023 FU NCRR NIH HHS [5-MO1-RR-00079, 5-MO1-RR-00083-379] NR 18 TC 37 Z9 39 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD APR 1 PY 2001 VL 183 IS 7 BP 1130 EP 1134 DI 10.1086/319270 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 409CL UT WOS:000167366900021 PM 11237842 ER PT J AU Dunbar, CE AF Dunbar, CE TI The use of nonhuman primate models to improve gene transfer into haematopoietic stem cells SO JOURNAL OF INTERNAL MEDICINE LA English DT Review DE clonality; haematopoiesis; lentiviral vectors; retroviral vectors; rhesus macaque ID MARROW REPOPULATING CELLS; COLONY-STIMULATING FACTOR; HUMAN HEMATOPOIETIC STEM; RHESUS PERIPHERAL-BLOOD; LONG-TERM ENGRAFTMENT; IN-VIVO EXPRESSION; BONE-MARROW; EX-VIVO; RETROVIRAL VECTOR; PROGENITOR CELLS AB Primitive haematopoietic progenitor and stem cells (HSC) have been pursued as highly desirable targets for genetic therapy as technology allowing safe and controllable transfer of exogenous genes into eukaryotic cells was developed a decade ago, Retroviral vectors have been used for the majority of preclinical and clinical studies directed at these cells, because these vectors have a number of the necessary properties, including chromosomal integration, helper-free production systems, and lack of toxicity. Until recently, however, results with these vectors in clinical trials and large animal models indicated efficiency of gene transfer as a major hurdle to be overcome. We have focused on using the rhesus macaque autologous transplantation model to optimize gene transfer to primitive haematopoietic cells, and investigate questions regarding in vivo stem cell behaviour, in a system with proven predictive value for human haematopoiesis. By optimization of transduction conditions using standard vectors, gene transfer efficiency to primitive repopulating cells has reached the clinically relevent range of 5-20% long-term. Alternative vector systems, have also yielded promising results. We have also found that relatively simple manipulation of cell cycle status prior to reinfusion of marked cells results in significantly improved engraftment of transduced cells: this finding may have an impact particularly in the nonablative setting, The high level marking has permitted insertion site analysis and clonal tracking in vivo. Inverse PCR and/or a ligation-mediated PCR procedure have demonstrated that a large number of transduced clones (over 50) contribute to multiple lineages in vivo for up to at least 2 years posttransplantation. Thus far we have little evidence for rapid clonal succession or lineage-restricted engraftment of transduced cells. These and other advances should result in successful gene therapy for a variety of acquired and congenital disorders affecting HSCs and their progeny lineages. C1 NHLBI, Hematol Branch, Mol Hematopoiesis Sect, NIH, Bethesda, MD 20892 USA. RP Dunbar, CE (reprint author), Bldg 10,Room 7C103,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 53 TC 14 Z9 16 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD APR PY 2001 VL 249 IS 4 BP 329 EP 338 DI 10.1046/j.1365-2796.2001.00805.x PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 424WK UT WOS:000168256800007 PM 11298853 ER PT J AU Sprecher, E Ishida-Yamamoto, A Becker, OM Marekov, L Miller, CJ Steinert, PM Nelder, K Richard, G AF Sprecher, E Ishida-Yamamoto, A Becker, OM Marekov, L Miller, CJ Steinert, PM Nelder, K Richard, G TI Evidence for novel functions of the keratin tail emerging from a mutation causing ichthyosis hystrix SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article DE cornified cell envelope; desmosomes; keratin intermediate filaments; loricrin; palmoplantar keratoderma ID CORNIFIED CELL-ENVELOPE; INTERMEDIATE FILAMENTS; CURTH-MACKLIN; PROTEINS; LORICRIN; DYNAMICS; SKIN; IDENTIFICATION; KERATODERMA; EXPRESSION AB Unraveling the molecular basis of inherited disorders of epithelial fragility has led to understanding of the complex structure and function of keratin intermediate filaments. Keratins are organized as a central alpha -helical rod domain flanked by nonhelical, variable end domains. Pathogenic mutations in 19 different keratin genes have been identified in sequences corresponding to conserved regions at the beginning and end of the rod. These areas have been recognized as zones of overlap between aligned keratin proteins and are thought to be crucial for proper assembly of keratin intermediate filaments. Consequently, all keratin disorders of skin, hair, nail, and mucous membranes caused by mutations in rod domain sequences are characterized by perinuclear clumping of fragmented keratin intermediate filaments, thus compromising mechanical strength and cell integrity. We report here the first mutation in a keratin gene (KRT1) that affects the variable tail domain (V2) and results in a profoundly different abnormality of the cytoskeletal architecture leading to a severe form of epidermal hyperkeratosis known as ichthyosis hystrix Curth-Macklin, Structural analyses disclosed a failure in keratin intermediate filament bundling, retraction of the cytoskeleton from the nucleus, and failed translocation of loricrin to the desmosomal plaques. These data provide the first in vivo evidence for the crucial role of a keratin tail domain in supramolecular keratin intermediate filament organization and barrier formation. C1 Thomas Jefferson Univ, Jefferson Med Coll, Dept Dermatol & Cutaneous Biol, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Jefferson Med Coll, Jefferson Inst Mol Med, Philadelphia, PA 19107 USA. Asahikawa Med Coll, Dept Dermatol, Asahikawa, Hokkaido 078, Japan. Tel Aviv Univ, Sch Chem, IL-69978 Tel Aviv, Israel. NIAMS, Skin Biol Lab, NIH, Bethesda, MD USA. Texas Tech Univ, Dept Dermatol, Lubbock, TX 79409 USA. RP Richard, G (reprint author), Thomas Jefferson Univ, Jefferson Med Coll, Dept Dermatol & Cutaneous Biol, 233 S 10th St,BLSB Suite 409, Philadelphia, PA 19107 USA. FU NIAMS NIH HHS [P01-AR38923] NR 40 TC 72 Z9 74 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD APR PY 2001 VL 116 IS 4 BP 511 EP 519 DI 10.1046/j.1523-1747.2001.01292.x PG 9 WC Dermatology SC Dermatology GA 421EA UT WOS:000168048100005 PM 11286616 ER PT J AU Selleri, C Maciejewski, JP AF Selleri, C Maciejewski, JP TI Nitric oxide and cell survival: Megakaryocytes say "NO" SO JOURNAL OF LABORATORY AND CLINICAL MEDICINE LA English DT Editorial Material ID NECROSIS-FACTOR-ALPHA; MITOCHONDRIAL RESPIRATION; INDUCED APOPTOSIS; CASPASE ACTIVATION; INTERFERON-GAMMA; CYTOCHROME-C; SYNTHASE; MECHANISMS; DEATH; INHIBITION C1 Univ Naples Federico II, Div Hematol, Naples, Italy. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Selleri, C (reprint author), Univ Naples Federico II, Div Hematol, Naples, Italy. NR 58 TC 6 Z9 6 U1 2 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0022-2143 J9 J LAB CLIN MED JI J. Lab. Clin. Med. PD APR PY 2001 VL 137 IS 4 BP 225 EP 230 DI 10.1067/mlc.2001.113660 PG 6 WC Medical Laboratory Technology; Medicine, General & Internal; Medicine, Research & Experimental SC Medical Laboratory Technology; General & Internal Medicine; Research & Experimental Medicine GA 420KB UT WOS:000168003200001 PM 11283517 ER PT J AU Tang, DC Fucharoen, S Ding, I Rodgers, GP AF Tang, DC Fucharoen, S Ding, I Rodgers, GP TI Rapid differentiation of five common alpha-thalassemia genotypes by polymerase chain reaction SO JOURNAL OF LABORATORY AND CLINICAL MEDICINE LA English DT Article ID PRENATAL-DIAGNOSIS; DETERMINANTS; DETECT AB The alpha -thalassemias are common genetic disorders that arise from reduced synthesis of the alpha -globin chains. At present, large-scale carrier screening and clinically valuable antenatal detection programs have not been established for the congenital disorder alpha -thalassemia (alpha -thal). We have developed a simple nonradioactive polymerase chain reaction (PCR) approach that can detect and differentiate several common alpha -globin gene deletional alpha -thals regardless of the break points. When three primer sets were used-two gene-specific sets for the alpha (1)- and alpha (2)-globin genes and one set for the beta -actin gene (serving as an internal control)-PCR products from genomic DNA were simultaneously amplified and analyzed after coamplification and gel electrophoresis. The number of a-globin genes present in the subjects was determined by the intensity of alpha (1) and alpha (2) bands normalized with that of beta -actin when using densitometry, Our results demonstrate that five common genotypes of deletional a-thal are differentiated by the ratios of alpha (1)/beta -actin and alpha (2)/beta -actin. We also examined the feasibility of coupling this allele-specific amplification to a color-complementary assay. This easy and reproducible PCR assay is suitable for identifying a-thal carriers in screenings of large populations and improving genetic counseling. C1 NIDDKD, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. Mahidol Univ, Inst Sci & Technol Res & Dev, Thalassemia Ctr, Nakhonpathom, Thailand. RP Rodgers, GP (reprint author), NIDDK, Mol & Clin Hematol Branch, NIH, Bldg 10,Room 9N119,10 Ctr Dr, Bethesda, MD 20892 USA. NR 15 TC 4 Z9 4 U1 1 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0022-2143 J9 J LAB CLIN MED JI J. Lab. Clin. Med. PD APR PY 2001 VL 137 IS 4 BP 290 EP 295 DI 10.1067/mlc.2001.113947 PG 6 WC Medical Laboratory Technology; Medicine, General & Internal; Medicine, Research & Experimental SC Medical Laboratory Technology; General & Internal Medicine; Research & Experimental Medicine GA 420KB UT WOS:000168003200008 PM 11283524 ER PT J AU Schwieters, CD Clore, GM AF Schwieters, CD Clore, GM TI The VMD-XPLOR visualization package for NMR structure refinement SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article ID PROTEIN-STRUCTURE DETERMINATION; MACROMOLECULAR STRUCTURE DETERMINATION; INTERPROTON DISTANCE RESTRAINTS; RIGID-BODY MINIMIZATION; DIPOLAR COUPLINGS; MOLECULAR-DYNAMICS; 3-DIMENSIONAL STRUCTURES; CHEMICAL-SHIFTS; CYANOVIRIN-N; IMPACT AB In this paper we present the VMD-XPLOR package combining the XPLOR refinement program and the VMD visualization program and including extensions for use in the determination of biomolecular structures from NMR data. The package allows one to pass structures to and to control VMD from the XPLOR scripting level. The VMD graphical interface has been customized for NMR structure refinement, including support to manipulate coordinates interactively while graphically visualizing NMR experimental information in the context of a molecular structure. Finally, the VMD-XPLOR interface is modular so that it is readily transferable to other refinement programs (such as CNS). C1 NIH, Ctr Informat Technol, Computat Biosci & Engn Lab, Bethesda, MD 20892 USA. NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Schwieters, CD (reprint author), NIH, Ctr Informat Technol, Computat Biosci & Engn Lab, Bldg 12A, Bethesda, MD 20892 USA. RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 NR 35 TC 96 Z9 96 U1 1 U2 4 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD APR PY 2001 VL 149 IS 2 BP 239 EP 244 DI 10.1006/jmre.2001.2300 PG 6 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 431JN UT WOS:000168628200008 PM 11318623 ER PT J AU Spencer, RGS Fishbein, KW Galban, CJ AF Spencer, RGS Fishbein, KW Galban, CJ TI Pitfalls in the measurement of metabolite concentrations using the one-pulse experiment in in vivo NMR: Commentary on "On neglecting chemical exchange effects when correcting in vivo P-31 MRS data for partial saturation" SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article ID LATTICE RELAXATION-TIMES; IN-VIVO; HEART; SPECTROSCOPY; SYSTEMS AB In an article in a previous issue of the Journal of Magnetic Resonance, Ouwerkerk and Bottomley (J. Magn. Reson. 148, pp. 425-435, 2001) show that even in the presence of chemical exchange, the dependence of saturation factors on repetition time in the one-pulse experiment is approximately monoexponential. They conclude from this fact that the effect of chemical exchange on the use of saturation factors when correcting for partial saturation is negligible. We take issue with this conclusion and demonstrate that because saturation factors in the presence of chemical exchange are strongly dependent upon all of the chemical parameters of the system, that is, upon all T-1's and M-0's of resonances in the exchange network and upon the reaction rates themselves, it is problematic to apply saturation factor corrections in situations in which any of these parameters may change. The error criterion we establish reflects actual errors in quantitation, rather than departures from monoexponentiality. C1 NIA, NIH, Baltimore, MD 21224 USA. RP Spencer, RGS (reprint author), NIA, NIH, GRC 4D-08,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Fishbein, Kenneth/0000-0002-6353-4603 NR 17 TC 10 Z9 10 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD APR PY 2001 VL 149 IS 2 BP 251 EP 257 DI 10.1006/jmre.2000.2251 PG 7 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 431JN UT WOS:000168628200010 PM 11318625 ER PT J AU Delaglio, F Wu, ZR Bax, A AF Delaglio, F Wu, ZR Bax, A TI Measurement of homonuclear proton couplings from regular 2D COSY spectra SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article ID LEAST-SQUARES FITS; DIPOLAR COUPLINGS; ACCURATE MEASUREMENTS; NMR EXPERIMENTS; CONSTANTS; PROTEINS; ANGLES; SPECTROSCOPY; POLYPEPTIDES; EXTRACTION AB An interactive computer procedure is described which determines H-1-H-1 couplings from fitting the cross-peak multiplets in regular phase-sensitive COSY spectra. The robustness and simplicity of the method rely on the fact that a given cross-peak intensity is not an independent variable in the fitting procedure, making it possible to measure couplings accurately even from individual cross peaks with unresolved multiplet structure. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Delaglio, F (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NR 29 TC 55 Z9 55 U1 0 U2 6 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD APR PY 2001 VL 149 IS 2 BP 276 EP 281 DI 10.1006/jmre.2001.2297 PG 6 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 431JN UT WOS:000168628200015 PM 11318630 ER PT J AU Du Val, G Sartorius, L Clarridge, B Gensler, G Danis, M AF Du Val, G Sartorius, L Clarridge, B Gensler, G Danis, M TI What triggers requests for ethics consultations? SO JOURNAL OF MEDICAL ETHICS LA English DT Article DE ethics consultation; resolution of ethical problems; ethical conflicts ID GOALS AB Objectives-While clinical practice is complicated by many ethical dilemmas, clinicians do not often request ethics consultations. We therefore investigated what triggers clinicians' requests for ethics consultation. Design-Cross-sectional telephone survey. Setting-internal medicine practices throughout the United States. Participants-Randomly selected physicians practising in internal medicine, oncology and critical care. Main measurements-Socio-demographic characteristics, training in medicine and ethics, and practice characteristics; types of ethical problems that prompt requests for consultation, and factors triggering consultation requests. Results-One hundred and ninety of 344 responding physicians (55%) reported requesting ethics consultations. Physicians most commonly reported requesting ethics consultations for ethical dilemmas related to end-of-life decision making, patient autonomy issues, and conflict. The most common triggers that led to consultation requests were: 1) wanting help resolving a conflict; 2) wanting assistance interacting with a difficult family, patient, or surrogate; 3) wanting help making a decision or planning care, and 4) emotional triggers. Physicians who were ethnically in the minority, practised in communities under 500,000 population, or who were trained in the US were more likely to request consultations prompted by conflict. Conclusions-Conflicts and other emotionally charged concerns trigger consultation requests more commonly than other cognitively based concerns. Ethicists need to be prepared to mediate conflicts and handle sometimes difficult emotional situations when consulting. The data suggest that ethics consultants might serve clinicians well by consulting on a more proactive basis to avoid conflicts and by educating clinicians to develop mediation skills. C1 Univ Toronto, Toronto, ON, Canada. Natl Inst Hlth, Bethesda, MD USA. Univ Massachusetts, Boston, MA USA. EMMES Corp, Potomac, MD USA. RP Du Val, G (reprint author), Univ Toronto, Toronto, ON, Canada. NR 12 TC 20 Z9 21 U1 0 U2 2 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 J9 J MED ETHICS JI J. Med. Ethics PD APR PY 2001 VL 27 SU 1 BP I24 EP I29 DI 10.1136/jme.27.suppl_1.i24 PG 6 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 422KZ UT WOS:000168118200006 PM 11314608 ER PT J AU Black, A Tilmont, EM Baer, DJ Rumpler, DK Roth, GS Lane, MA AF Black, A Tilmont, EM Baer, DJ Rumpler, DK Roth, GS Lane, MA TI Accuracy and precision of dual-energy X-ray absorptiometry for body composition measurements in rhesus monkeys SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Article DE BMC; chemical analysis; DXA; fat; lean; nonhuman primates ID SOFT-TISSUE COMPOSITION; CHEMICAL-ANALYSIS; CARCASS ANALYSIS; PIGS; VALIDATION; PIGLETS; INFANTS; INVIVO; RATS AB Accuracy of body composition measurements by dual-energy X-ray absorptiometry (DXA) was compared with direct chemical analysis in 10 adult rhesus monkeys. DXA was highly correlated (r-values > 0.95) with direct analyses of body fat mass (FM), lean mass (LM) and lumbar spine bone mineral content (BMC). DXA measurements of total body BMC were not as strongly correlated (r-value = 0.58) with total carcass ash content. DXA measurements of body FM, LM and lumbar spine BMC were not different from data obtained by direct analyses (P-values > 0.30). In contrast, DXA determinations of total BMC (TBMC) averaged 15% less than total carcass ash measurements (P = 0.002). In conclusion, this study confirms the accurate measurement of fat and lean tissue mass by DXA in rhesus monkeys. DXA also accurately measured lumbar spine BMC but underestimated total body BMC as compared with carcass ash determinations. C1 NIA, Nutr Mol Physiol Unit, Neurosci Lab,Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. USDA ARS, Beltsville Human Nutr Res Ctr, Diet & Human Performance Lab, Beltsville, MD 20705 USA. RP Black, A (reprint author), NIA, Nutr Mol Physiol Unit, Neurosci Lab,Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 25 TC 15 Z9 16 U1 0 U2 3 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD APR PY 2001 VL 30 IS 2 BP 94 EP 99 DI 10.1034/j.1600-0684.2001.300204.x PG 6 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 452UR UT WOS:000169878500004 PM 11491410 ER PT J AU Kim, SY Lee, CH Kim, YJ Kim, YS AF Kim, SY Lee, CH Kim, YJ Kim, YS TI Expression of the functional recombinant interleukin-16 in E-coli and mammalian cell lines SO JOURNAL OF MICROBIOLOGY AND BIOTECHNOLOGY LA English DT Article DE interleukin-16; E. coli; mammalian cells; retrovirus producer cells; lymphocyte migration activity; HIV-1 LTR suppression ID LYMPHOCYTE CHEMOATTRACTANT FACTOR; CD4(+) T-CELLS; HUMAN LYMPHOKINES; LEUKEMIA-VIRUS; MESSENGER-RNA; TAT PROTEIN; IL-16; REPLICATION; ACTIVATION; MIGRATION AB The C-terminal 393 bp region of the human interleukin-16 (IL-16) gene was cloned and expressed in E. coli along with mammalian cell lines. Recombinant IL-16 expressed from E. coli was 22 kDa on SDS-PAGE and showed 260% of chemoattractant activity at a concentration of 0.1 mug/ml. HeLa, COS, and Neuro-2a cells were transduced by recombinant retrovirus vector pLNC/IL-16/IRES/TK and the intracellular and secreted amounts of IL-16 produced by HeLa/IL-16/TK, COS/IL-I6/TK, and Neuro-2a/IL-16/TK cells were determined by enzyme-linked immunosorbent assay (ELISA). HeLa/IL-16/TK (1x10(5)) and COS/IL-16/TK(1x10(5)) cells secreted 36.1 and 13.3 ng of IL-16 for 48 h, respectively. Forty-nine ng and 86.4 ng of IL-16 remained in the cell lysates of HeLa/IL-16/ TK and COS/IL-16/TK. Intracellular and secreted amounts of IL-16 from Neuro-2a/IL-16/TK (5x10(5)) cells during 24h cultivation were 50 ng and 3.3 ng, respectively. Also, HeLa and COS cells were stably transfected with mammalian expression vector pCRIII/IL-16. Both culture media and cell lysates prepared from HeLa/IL-16 cells and COS/IL-16 cells showed chemoattractant activity ranging from 190% to 460% as compared to the control experiment Expression of the herpes simplex virus thymidine kinase (HSV-tk) gene in pLNC/IL-16/ IRES/TK bicistronic retroviral expression vector was verified by performing a ganciclovir (GCV) sensitivity assay. Finally, IL-16 repressed Tat-transactivated human immunodeficiency virus type 1 long terminal repeat (HIV-1 LTR) promoter activity. C1 Korea Res Inst Biosci & Biotechnol, Cell Biol Lab, Taejon 305333, South Korea. NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Kim, YS (reprint author), Korea Res Inst Biosci & Biotechnol, Cell Biol Lab, 52 Eoundong, Taejon 305333, South Korea. NR 34 TC 3 Z9 3 U1 0 U2 2 PU KOREAN SOC APPLIED MICROBIOLOGY PI SEOUL PA KOREA SCI TECHNOL CENTER #507, 635-4 YEOGSAM-DONG, KANGNAM-GU, SEOUL 135-703, SOUTH KOREA SN 1017-7825 J9 J MICROBIOL BIOTECHN JI J. Microbiol. Biotechnol. PD APR PY 2001 VL 11 IS 2 BP 234 EP 241 PG 8 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 430QV UT WOS:000168587800011 ER PT J AU Smith, QR Nagura, H AF Smith, QR Nagura, H TI Fatty acid uptake and incorporation in brain - Studies with the perfusion model SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article; Proceedings Paper CT International Workshop on Brain Uptake and Utilization of Fatty Acids CY MAR 02-04, 2000 CL BETHESDA, MARYLAND DE blood-brain barrier; protein binding; cerebrovascular; palmitate; capillary; lipid metabolism ID RAT-BRAIN; PALMITATE; BARRIER; TRANSPORT; ALBUMIN; LIPIDS; AWAKE AB The contributions of individual components of blood to brain [C-14]palmitate uptake and incorporation were studied with the ill situ brain perfusion technique in the pentobarbital-anesthetized rat. With whole-blood perfusate, brain unacylated [C-14]palmitate uptake was linear with time and extrapolated to zero at T = 0 s of perfusion. Tracer accumulated in brain with a blood-to-brain transfer coefficient of 1.8 +/- 0.1 x 10(-1) mL/s/g (whole cerebral hemisphere). Incorporation into brain lipids was rapid such that similar to 40% of tracer in brain at 45 s of perfusion was in cerebral phospholipids and neutral lipids. Similar rates of uptake were obtained during unacylated [C-14]palmitate perfusion in whole rat plasma, serum, or artificial saline containing 2-3 % albumin, suggesting that albumin has a key role in determining [C-14]palmitate uptake in brain. The excellent match in brain uptake rates between whole blood and albumin-containing saline fluid suggests that the perfusion technique will be useful method for quantifying the individual contributions of blood constituents and albumin binding on brain [C-14]palmitate uptake. C1 Texas Tech Univ, Hlth Sci Ctr, Dept Pharmaceut Sci, Amarillo, TX 79106 USA. NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. RP Smith, QR (reprint author), Texas Tech Univ, Hlth Sci Ctr, Dept Pharmaceut Sci, 1300 Coulter Dr, Amarillo, TX 79106 USA. NR 24 TC 43 Z9 44 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD APR-JUN PY 2001 VL 16 IS 2-3 BP 167 EP 172 DI 10.1385/JMN:16:2-3:167 PG 6 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 453YK UT WOS:000169945600011 PM 11478371 ER PT J AU Kim, HY Akbar, M Kim, KY AF Kim, HY Akbar, M Kim, KY TI Inhibition of neuronal apoptosis by polyunsaturated fatty acids SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article; Proceedings Paper CT International Workshop on Brain Uptake and Utilization of Fatty Acids CY MAR 02-04, 2000 CL BETHESDA, MARYLAND DE docosahexaenoic acid; arachidonic acid; apoptosis; neuronal cells; phosphatidylserine; serum starvation; caspase-3 ID DOCOSAHEXAENOIC ACID; LIPID-PEROXIDATION; GLIOMA-CELLS; PHOSPHATIDYLSERINE; ACCUMULATION; 22/6N-3 AB The effect of polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (22:6n-3; DHA) and arachidonic acid (20 :4n-6; AA), on apoptotic cell death was evaluated based on DNA fragmentation and caspase-3 activity induced by serum starvation using Neuro-2A and PC-12 cells. The presence of 20:4n-6 in the medium during serum starvation decreased DNA fragmentation and this initial protective effect was diminished with prolonged serum starvation. The observed protective effect of 20:4n-6 was not affected by the inhibitors of cyclooxygenase (COX) and lipoxygenase. Conversely 22:6n-3 became protective only after the enrichment of cells with this fatty acid at least for 24 h prior to the serum deprivation. DNA fragmentation as well as caspase-3 activity was reduced in 22:6n-3 enriched cells with a concomitant decrease in protein and mRNA levels. During the enrichment period, 22:6n-3 steadily increased its incorporation into PS leading to a significant increase in the total PS content; the protective effect of 22:6n-3 paralleled the PS accumulation. Neither direct exposure of cells to nor enrichment with 18:1n-9 had any protective effect. In conclusion, it is proposed that 20:4n-6 prevents neuronal apoptosis primarily due to the action of nonesterified 20:4n-6 but 22:6n-3, at least in part, through PS accumulation. C1 NIAAA, Sect Mass Spectrometry, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. RP Kim, HY (reprint author), NIAAA, Sect Mass Spectrometry, Lab Membrane Biochem & Biophys, NIH, 12420 Parklawn Dr, Rockville, MD 20852 USA. NR 19 TC 50 Z9 52 U1 1 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD APR-JUN PY 2001 VL 16 IS 2-3 BP 223 EP 227 DI 10.1385/JMN:16:2-3:223 PG 5 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 453YK UT WOS:000169945600018 PM 11478377 ER PT J AU Litman, BJ Niu, SL Polozova, A Mitchell, DC AF Litman, BJ Niu, SL Polozova, A Mitchell, DC TI The role of docosahexaenoic acid containing phospholipids in modulating G protein-coupled signaling pathways - Visual transduction SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article; Proceedings Paper CT International Workshop on Brain Uptake and Utilization of Fatty Acids CY MAR 02-04, 2000 CL BETHESDA, MARYLAND DE docosahexaenoic acid; DHA; G protein-coupled signaling; visual transduction; microdomains; receptor activation ID POLYUNSATURATED FATTY-ACIDS; SERUM-CHOLESTEROL; DEFICIENCY; SUICIDE AB In order to understand the role of the high levels of docosahexaenoic acid (DHA) in neuronal and retinal tissue, a study of the effect of membrane lipid composition on the visual pathway, a G protein-coupled system, was undertaken. The level of metarhodopsin II (MII) formation was determined to be a function of phospholipid acyl-chain unsaturation, with the highest levels seen in DHA-containing bilayers. Similarly, the rate of coupling of MII to the retinal G protein, G(t), to form a MII-G(t) complex, was enhanced in DHA bilayers relative to less unsaturated phospholipids. Complex formation initiates the first stage of amplification in the visual pathway. The activation of the cGMP phosphodiesterase (PDE), the effector enzyme, represents the integrated pathway function. DHA-containing bilayers were found to support PDE levels comparable to those of the rod outer segment (ROS) disk membranes. Inclusion of 30 mol% cholesterol in the reconstituted bilayers had an inhibitory effect on each step in the visual pathway studied. Inclusion of cholesterol reduced MII formation and PDE activity and increased the lag time between the appearance of MII and the formation of the MII-C, complex. However, signaling in DHA bilayers was far less affected by the addition of cholesterol than in bilayers containing less unsaturated phospholipids. These studies point up the importance of DHA acyl chains in promoting optimal function in G protein-coupled signaling pathways. The results reported here suggest that visual and cognitive deficits observed in n-3 deficiency may result from decreased efficiency in related neurotransmitter and visual signaling pathways in the absence of DHA. C1 NIAAA, Sect Fluorescence Studies, Lab Membrane Biochem & Biophys, Div Intramural Clin & Biol Res,NIH, Rockville, MD 20852 USA. RP Litman, BJ (reprint author), 12420 Parklawn Dr,Room 158, Rockville, MD 20852 USA. RI Polozova, Alla/C-2395-2008 NR 22 TC 114 Z9 116 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD APR-JUN PY 2001 VL 16 IS 2-3 BP 237 EP 242 DI 10.1385/JMN:16:2-3:237 PG 6 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 453YK UT WOS:000169945600020 PM 11478379 ER PT J AU Rapoport, SI AF Rapoport, SI TI In vivo fatty acid incorporation into brain phosholipids in relation to plasma availability, signal transduction and membrane remodeling SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article; Proceedings Paper CT International Workshop on Brain Uptake and Utilization of Fatty Acids CY MAR 02-04, 2000 CL BETHESDA, MD DE brain; fatty acids; neuroplasticity; signaling; turnover; phospholipids; imaging; lithium ID POSITRON-EMISSION-TOMOGRAPHY; NUCLEUS BASALIS MAGNOCELLULARIS; STIMULATED HUMAN-PLATELETS; CHRONIC LITHIUM TREATMENT; ACYL-COA CONCENTRATIONS; CENTRAL-NERVOUS-SYSTEM; RAT-BRAIN; ARACHIDONIC-ACID; DOCOSAHEXAENOIC ACID; PHOSPHOLIPASE A(2) AB A method, model, and "operational equations" are described to quantify in vivo turnover rates and half-lives of fatty acids within brain phospholipids, as well as rates of incorporation of these fatty acids into brain from plasma. In awake rats, recycling of fatty acids within brain phospholipids, due to deesterification and reesterification, is very rapid, with half-lives in some cases of minutes to hours. Plasma fatty acids make only a small contribution (2-4%) to the net quantity of fatty acids that are reesterified. This explains why many weeks are necessary to recover normal brain n-3 polyunsaturated fatty acid concentrations following their prolonged dietary deprivation. Changes in recycling of specific fatty acids in response to centrally acting drugs can help to identify enzyme targets for drug action. For example, recycling of arachidonate is specifically reduced by 80% in rats treated chronically with lithium, a drug effective against bipolar disorder; the effect reflects downregulation of gene expression of an arachidonate-specific phospholipase A,. When combined with neuroimaging (quantitative autoradiography in rodents or positron-emission tomography [PET] in macaques or humans), intravenously injected radiolabeled fatty acids can be used to localize and quantify brain PLA(2)-mediated signal transduction, and to examine neuroplastic remodeling of brain lipid membranes. C1 NIA, Sect Brain Physiol & Metab, NIH, Bethesda, MD 20892 USA. RP NIA, Sect Brain Physiol & Metab, NIH, Bldg 10,Rm 6N-202, Bethesda, MD 20892 USA. EM SIR@HELIX.NIH.GOV NR 125 TC 135 Z9 140 U1 0 U2 7 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 EI 1559-1166 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD APR-JUN PY 2001 VL 16 IS 2-3 BP 243 EP 261 DI 10.1385/JMN:16:2-3:243 PG 19 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 453YK UT WOS:000169945600021 PM 11478380 ER PT J AU Salem, N Moriguchi, T Greiner, RS McBride, K Ahmad, A Catalan, JN Slotnick, B AF Salem, N Moriguchi, T Greiner, RS McBride, K Ahmad, A Catalan, JN Slotnick, B TI Alterations in brain function after loss of docosahexaenoate due to dietary restriction of n-3 fatty acids SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article; Proceedings Paper CT International Workshop on Brain Uptake and Utilization of Fatty Acids CY MAR 02-04, 2000 CL BETHESDA, MARYLAND DE docosahexaenoic acid; brain development; essential fatty acids; behavior; spatial task; Morris water maze; olfactory discrimination; n-3 fatty acid deficiency; hippocampus; neuro-anatomy ID VISUAL-ACUITY DEVELOPMENT; HEALTHY PRETERM INFANTS; ALPHA-LINOLENIC ACID; FULL-TERM INFANTS; ARACHIDONIC-ACID; RESOLUTION ACUITY; CONTROLLED TRIAL; LEARNING-TASKS; WATER-MAZE; HUMAN-MILK AB The concentration of the major polyunsaturated fatty acid (PUFA) in brain, docosahexaenoate, may be markedly reduced by two or more generations of dietary restriction of sources of n-3 fatty acids in the diet. Such a deficiency was induced through the feeding of safflower oil as the principal source of essential fatty acids. The reference point for this diet was an n-3 adequate diet to which alpha-linoleate and docosahexaenoate were added through the addition of a small quantity of flax seed or algael oils, respectively. The loss of brain DHA was associated with poorer performance in spatial tasks and an olfactory-cued reversal learning task. No difference could be observed in the hippocampal gross morphology. This study demonstrates the importance of providing a source of n-3 fatty acids during mammalian growth and development. C1 NIAAA, Sect Nutrit Neurosci, Lab Membrane Biochem & Biophys, Div Intramural Clin & Biol Res,NIH, Rockville, MD 20852 USA. American Univ, Dept Psychol, Washington, DC 20016 USA. RP Salem, N (reprint author), 12420 Parklawn Dr,Room 158, Rockville, MD 20852 USA. NR 59 TC 69 Z9 70 U1 2 U2 5 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD APR-JUN PY 2001 VL 16 IS 2-3 BP 299 EP 307 DI 10.1385/JMN:16:2-3:299 PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 453YK UT WOS:000169945600027 PM 11478385 ER PT J AU Garraffo, HM Jain, P Spande, TF Daly, JW Jones, TH Smith, LJ Zottig, VE AF Garraffo, HM Jain, P Spande, TF Daly, JW Jones, TH Smith, LJ Zottig, VE TI Structure of alkaloid 275A, a novel 1-azabicyclo[5.3.0]decane from a dendrobatid frog, Dendrobates lehmanni: Synthesis of the tetrahydrodiastereomers SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID VENOM CHEMISTRY; PYRROLIDINES; MONOMORIUM; REDUCTION; KETONES; ANTS AB The principal alkaloid 275A in skins of the Colombian poison frog Dendrobates lehmanni has been identified as the pyrrolo[1,2-alpha ]azepane (1), the first occurrence in nature of this "izidine" system. Tetrahydro-l proved identical to one of the four synthetic diastereomers, 2a-2d, thereby establishing that 1 has the 5Z,10E relative stereochemistry. Alkaloid 1 is often accompanied by other congeners, in particular a 5Z,10Z diastereomer 15, a dihydro analogue 16, and a ketone 17. Such izidines in frogs may arise from dietary ants, as do other classes of izidines. C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Virginia Mil Inst, Dept Chem, Lexington, VA 24450 USA. RP Garraffo, HM (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NR 39 TC 27 Z9 27 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD APR PY 2001 VL 64 IS 4 BP 421 EP 427 DI 10.1021/np0005098 PG 7 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 431ZH UT WOS:000168661300005 PM 11325220 ER PT J AU Meragelman, KM McKee, TC Boyd, MR AF Meragelman, KM McKee, TC Boyd, MR TI Anti-HIV prenylated flavonoids from Monotes africanus SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID FLAVANONES; ENGLERI; INFECTION; PLANTS AB Six flavonoids, among them a new dihydroflavonol, 6,8-diprenylaromadendrin (1), and the flavonol. 6,8-diprenylkaempferol (3), have been isolated from the organic extract of Monotes africanus. The isolated compounds containing a 5,7-dihydroxy-6,8-diprenyl system in the A ring of the flavonoid (1, 3, and 6) exhibited HIV-inhibitory activity in the XTT-based, whole-cell screen. In addition, several C-13 NMR assigments of lonchocarpol A (6) were corrected. C1 NCI, Div Basic Sci, Lab Drug Discovery Res & Dev, Frederick, MD 21702 USA. RP Boyd, MR (reprint author), NCI, Div Basic Sci, Lab Drug Discovery Res & Dev, Frederick, MD 21702 USA. NR 21 TC 48 Z9 52 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD APR PY 2001 VL 64 IS 4 BP 546 EP 548 DI 10.1021/np0005457 PG 3 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 431ZH UT WOS:000168661300033 PM 11325248 ER PT J AU Liu, B Wang, K Gao, HM Mandavilli, B Wang, JY Hong, JS AF Liu, B Wang, K Gao, HM Mandavilli, B Wang, JY Hong, JS TI Molecular consequences of activated microglia in the brain: overactivation induces apoptosis SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE activation; apoptosis; caspase; lipopolysaccharide; microglia; TNF alpha ID CENTRAL-NERVOUS-SYSTEM; LIPOPOLYSACCHARIDE-INDUCED NEUROTOXICITY; NITRIC-OXIDE; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; CELL-DEATH; IN-VITRO; CULTURES; GLIA; CYTOKINES AB Microglia, the resident immune cells in the brain, play a pivotal role in immune surveillance, host defense, and tissue repair in the CNS. In response to immunological challenges, microglia readily become activated as characterized by morphological changes, expression of surface antigens, and production of immune modulators that impact on neurons to induce neurodegeneration. However, little is known concerning the fate of activated microglia. In the present study, stimulation of cultured rat primary microglia with 1 ng/mL of the inflammagen lipopolysaccharide (LPS) resulted in a maximal activation as measured by the release of tumor necrosis factor alpha (TNF alpha). However, treatment with higher concentrations of LPS resulted in significantly lower quantities of detectable TNF alpha. Further analysis revealed that overactivation of microglia with higher concentrations of LPS (> 1 ng/mL) resulted in a time- and dose-dependent apoptotic death of microglia as defined by DNA strand breaks, surface expression of apoptosis-specific markers (phosphatidylserine), and activation of caspase-3. In contrast, astrocytes were insensitive to LPS-induced cytotoxicity. In light of the importance of microglia and the limited replenishment mechanism, depletion of microglia from the brain may severely hamper its capacity for combating inflammatory challenges and tissue repair. Furthermore, overactivation-induced apoptosis of microglia may be a fundamental self-regulatory mechanism devised to limit bystander killing of vulnerable neurons. C1 NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. Natl Def Med Ctr, Dept Physiol, Taipei, Taiwan. NIEHS, Genet Mol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Liu, B (reprint author), NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, F1-01,POB 12233, Res Triangle Pk, NC 27709 USA. RI gao, huiming/C-8454-2012; liu, Bin/A-7695-2009; OI Wang, Kevin/0000-0002-9343-6473 NR 37 TC 190 Z9 194 U1 1 U2 8 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD APR PY 2001 VL 77 IS 1 BP 182 EP 189 DI 10.1046/j.1471-4159.2001.00216.x PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 417KY UT WOS:000167835200019 PM 11279274 ER PT J AU Culmsee, C Zhu, XX Yu, QS Chan, SL Camandola, S Guo, ZH Greig, NH Mattson, MP AF Culmsee, C Zhu, XX Yu, QS Chan, SL Camandola, S Guo, ZH Greig, NH Mattson, MP TI A synthetic inhibitor of p53 protects neurons against death induced by ischemic and excitotoxic insults, and amyloid beta-peptide SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE Alzheimer's disease; apoptosis; glutamate; hippocampus; ischemic stroke; mitochondria ID BREAK-INDUCED APOPTOSIS; TUMOR-SUPPRESSOR GENE; CELL-DEATH; BRAIN INJURY; MITOCHONDRIAL DYSFUNCTION; HIPPOCAMPAL-NEURONS; PRECURSOR PROTEIN; TRANSGENIC MICE; EXPRESSION; BAX AB The tumor suppressor protein p53 is essential for neuronal death in several experimental settings and may participate in human neurodegenerative disorders. Based upon recent studies characterizing chemical inhibitors of p53 in preclinical studies in the cancer therapy field, we synthesized the compound pifithrin-alpha and evaluated its potential neuroprotective properties in experimental models relevant to the pathogenesis of stroke and neurodegenerative disorders. Pifithrin-alpha protected neurons against apoptosis induced by DNA-damaging agents, amyloid beta -peptide and glutamate, Protection by pifithrin-alpha was correlated with decreased p53 DNA-binding activity, decreased expression of the p53 target gene Bax and suppression of mitochondrial dysfunction and caspase activation. Mice given pifithrin-alpha exhibited increased resistance of cortical and striatal neurons to focal ischemic injury and of hippocampal neurons to excitotoxic damage. These preclinical studies demonstrate the efficacy of a p53 inhibitor in models of stroke and neurodegenerative disorders, and suggest that drugs that inhibit p53 may reduce the extent of brain damage in related human neurodegenerative conditions. C1 NIA, Neurosci Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. Univ Marburg, Inst Pharmakol & Toxikol, D-3550 Marburg, Germany. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Gerontol Res Ctr, GRC 4F01,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 45 TC 231 Z9 243 U1 0 U2 4 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD APR PY 2001 VL 77 IS 1 BP 220 EP 228 DI 10.1046/j.1471-4159.2001.00220.x PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 417KY UT WOS:000167835200023 PM 11279278 ER PT J AU Connaughton, VP Dyer, KD Nadi, NS Behar, TN AF Connaughton, VP Dyer, KD Nadi, NS Behar, TN TI The expression of GAD(67) isoforms in zebrafish retinal tissue changes over the light/dark cycle SO JOURNAL OF NEUROCYTOLOGY LA English DT Article ID GLUTAMIC-ACID DECARBOXYLASE; GAMMA-AMINOBUTYRIC-ACID; MESSENGER-RNA; ENDOGENOUS DOPAMINE; TELEOST RETINA; MICE LACKING; FISH RETINA; DARK CYCLES; RAT-BRAIN; GABA AB We show the levels of glutamic acid decarboxylase (GAD), the enzyme catalyzing the conversion of glutamic acid to GABA, changes in zebrafish retinal tissue during the light/dark cycle. Further, we identify two transcripts of the GAD(67) gene, full-length GAD(67) and the truncated 25 kDa alternative splice variant (ES), as the major GAD isoforms in this tissue. GAD-positive neurons were identified immunocytochemically by probing retinal sections with K2, an antibody to the GAD(67) isoform, and with an antibody specific for the 25 kDa splice variant. For both antibodies, GAD-immunoreactivity was observed in horizontal cells in the distal retina and amacrine cells in the proximal retina, with both cell bodies and processes labeled. No apparent difference in K2 labeling pattern was observed in tissue harvested 8 hrs after light offset or onset, whereas ES label was identified in more structures in dark tissue. Quantification of GAD levels was determined by densitometry of Western Blots. The protein content of GAD(67) and ES varied between tissue harvested during the light and the dark. ES expression was up-regulated in dark tissue; whereas, full-length GAD(67) expression increased in light tissue. In vivo GABA content, measured with high performance liquid chromatography (HPLC), was found to increase in light tissue, paralleling the expression of full-length GAD(67) transcripts. Expression of ES did not correlate with measured GABA levels, suggesting this isoform, which lacks the catalytic domain necessary for enzymatic activity, may have a different physiological role in retinal tissue. The inverse expression patterns of full-length GAD(67) and ES suggest that alternative splicing of GAD(67) may be triggered by the light and/or dark cycle, resulting in a change in inhibitory neurotransmitter content in retinal tissue. C1 American Univ, Dept Biol, Washington, DC 20016 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Dept Physiol, Washington, DC USA. Naval Med Res Ctr, Bethesda, MD USA. George Washington Univ, Sch Med, Washington, DC USA. NINCDS, Neurophysiol Lab, Bethesda, MD USA. RP Connaughton, VP (reprint author), American Univ, Dept Biol, Washington, DC 20016 USA. NR 31 TC 7 Z9 7 U1 1 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0300-4864 J9 J NEUROCYTOL JI J. Neurocytol. PD APR PY 2001 VL 30 IS 4 BP 303 EP 312 DI 10.1023/A:1014404328905 PG 10 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 527GB UT WOS:000174177400003 PM 11875278 ER PT J AU Foundas, AL Weisberg, A Browning, CA Weinberger, IR AF Foundas, AL Weisberg, A Browning, CA Weinberger, IR TI Morphology of the frontal operculum: A volumetric magnetic resonance imaging study of the pars triangularis SO JOURNAL OF NEUROIMAGING LA English DT Article DE cerebral laterality; Broca's area; pars triangularis; magnetic resonance imaging ID PLANUM TEMPORALE ASYMMETRY; ANTERIOR SPEECH REGION; MRI FINDINGS; HANDEDNESS; SCHIZOPHRENIA; BOYS AB Objective. Broca's area, which includes the pars triangularis (PTR), is a neuroanatomical region important in speech and language production. Linear measures of the PTR have been found to be asymmetric, with the direction of the asymmetry correlating with language dominance determined by Wada testing. It is unclear, however, whether these linear measurements correlate with volumetric measures, and it is also unknown whether white matter and/or gray matter contribute differentially to these asymmetries. To investigate these issues, volumetric magnetic resonance imaging methodologies were used to measure the PTR in a group of healthy right-handed men (n = 12). There was a significant leftward asymmetry of the PTR using linear and volumetric measures. Linear measures of the left and right hemispheres were highly correlated with volumetric measures. Underlying gray and white matter both contributed to PTR asymmetry. Anatomical boundaries and four configurations (V, U, Y, and J) are discussed with reference to potential interhemispheric differences. C1 Tulane Univ, Hlth Sci Ctr, Dept Psychiat & Neurol, New Orleans, LA 70112 USA. Neurol Serv Vet Affairs Med Ctr, New Orleans, LA USA. NIMH, Clin Brain Disorders Branch, Neurosci Ctr St Elizabeths, Intramural Res Program, Washington, DC 20032 USA. RP Foundas, AL (reprint author), Tulane Univ, Hlth Sci Ctr, Dept Psychiat & Neurol, 1430 Tulane Ave, New Orleans, LA 70112 USA. FU NIDCD NIH HHS [DC00135] NR 30 TC 22 Z9 23 U1 1 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1051-2284 J9 J NEUROIMAGING JI J. Neuroimaging PD APR PY 2001 VL 11 IS 2 BP 153 EP 159 PG 7 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 455FT UT WOS:000170017400009 PM 11296585 ER PT J AU Lebedev, MA Douglass, DK Moody, SL Wise, SP AF Lebedev, MA Douglass, DK Moody, SL Wise, SP TI Prefrontal cortex neurons reflecting reports of a visual illusion SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID FRONTAL EYE FIELD; SIZE-CONTRAST ILLUSIONS; WORKING-MEMORY; FUNCTIONAL-ORGANIZATION; BINOCULAR-RIVALRY; NEURAL ACTIVITY; UNIT-ACTIVITY; MACAQUE; OBJECT; PERCEPTION AB When a small, focally attended visual stimulus and a larger background frame shift location at the same time, the frame's new location can affect spatial perception. For horizontal displacements on the order of 1-2 degrees, when the frame moves more than the attended stimulus, human subjects may perceive that the attended stimulus has shifted to the right or left when it has not done so. However, that misapprehension does not disable accurate eye movements to the same stimulus. We trained a rhesus monkey to report the direction that an attended stimulus had shifted by making an eye movement to one of the two report targets. Then, using conditions that induce displacement illusions in human subjects, we tested the hypothesis that neuronal activity in the prefrontal cortex (PF) would reflect the displacement directions reported by the monkey, even when they conflicted with the actual displacement, if any, of the attended stimulus. We also predicted that these cells would have directional selectivity for movements used to make those reports, but not for similar eye movements made to fixate the attended stimulus. A population of PF neurons showed the predicted properties, which could not be accounted for on the basis of either eye-movement or frame-shift parameters. This activity, termed report-related, began approximately 150 ms before the onset of the reporting saccade. Another population of PF neurons showed greater directional selectivity for saccadic eye movements made to fixate the attended stimulus than for similar saccades made to report its displacement. In view of the evidence that PF functions to integrate inputs and actions occurring at different times and places, the present findings support the idea that such integration involves movements to acquire response targets, directly, as well as actions guided by less direct response rules, such as perceptual reports. C1 NIMH, Lab Syst Neurosci, NIH, Bethesda, MD 20892 USA. RP Wise, SP (reprint author), NIMH, Lab Syst Neurosci, NIH, 49 Convent Dr,Bldg 49,Rm B1EE17,MSC 4401, Bethesda, MD 20892 USA. RI Lebedev, Mikhail/H-5066-2016 OI Lebedev, Mikhail/0000-0003-0355-8723 NR 62 TC 10 Z9 10 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD APR PY 2001 VL 85 IS 4 BP 1395 EP 1411 PG 17 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 418AB UT WOS:000167866700006 PM 11287464 ER PT J AU Sommer, MA Wurtz, RH AF Sommer, MA Wurtz, RH TI Frontal eye field sends delay activity related to movement, memory, and vision to the superior colliculus SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID PREFRONTAL UNIT-ACTIVITY; GO/NO-GO DISCRIMINATION; ANTI-SACCADE TASK; NEURONAL-ACTIVITY; GUIDED SACCADES; MOTOR PREPARATION; VISUAL RESPONSES; RHESUS-MONKEYS; PRO-SACCADES; CORTEX AB Many neurons within prefrontal cortex exhibit a tonic discharge between visual stimulation and motor response. This delay activity may contribute to movement, memory, and vision. We studied delay activity sent from the frontal eye field (FEF) in prefrontal cortex to the superior colliculus (SC). We evaluated whether this efferent delay activity was related to movement, memory, or vision, to establish its possible functions. Using antidromic stimulation, we identified 66 FEF neurons projecting to the SC and we recorded from them while monkeys performed a Go/Nogo task. Early in every trial, a monkey was instructed as to whether it would have to make a saccade (Go) or not (Nogo) to a target location, which permitted identification of delay activity related to movement. In half of the trials (memory trials), the target disappeared, which permitted identification of delay activity related to memory. In the remaining trials (visual trials), the target remained visible, which permitted identification of delay activity related to vision. We found that 77% (51/66) of the FEF output neurons had delay activity. In 53% (27/51) of these neurons, delay activity was modulated by Go/Nogo instructions. The modulation preceded saccades made into only part of the visual field, indicating that the modulation was movement-related. In some neurons, delay activity was modulated by Go/Nogo instructions in both memory and visual trials and seemed to represent where to move in general. In other neurons, delay activity was modulated by Go/Nogo instructions only in memory trials, which suggested that it was a correlate of working memory, or only in visual trials, which suggested that it was a correlate of visual attention. In 47% (24/51) of FEF output neurons, delay activity was unaffected by Go/Nogo instructions, which indicated that the activity was related to the visual stimulus. In some of these neurons, delay activity occurred in both memory and visual trials and seemed to represent a coordinate in visual space. In others, delay activity occurred only in memory trials and seemed to represent transient visual memory. In the remainder, delay activity occurred only in visual trials and seemed to be a tonic visual response. In conclusion, the FEF sends diverse delay activity signals related to movement, memory, and vision to the SC, where the signals may be used for saccade generation. Downstream transmission of various delay activity signals may be an important, general way in which the prefrontal cortex contributes to the control of movement. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Sommer, MA (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Room 2A50,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 57 TC 91 Z9 91 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD APR PY 2001 VL 85 IS 4 BP 1673 EP 1685 PG 13 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 418AB UT WOS:000167866700032 PM 11287490 ER PT J AU Johnson, SM Koshiya, N Smith, JC AF Johnson, SM Koshiya, N Smith, JC TI Isolation of the kernel for respiratory rhythm generation in a novel preparation: The pre-Botzinger complex "island" SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID IN-VITRO; PACEMAKER; MAMMALS; NETWORK AB The pre-Botzinger complex (pre-BotC), a bilaterally distributed network of rhythmogenic neurons within the ventrolateral medulla, has been proposed to be the critical locus for respiratory rhythm generation in mammals. To date, thin transverse medullary slice preparations that capture the pre-BotC have served as the optimal experimental model to study the region's inherent cellular and network properties. We have reduced the thin slices to isolated pre-BotC "islands" to further establish whether the pre-BotC has intrinsic rhythmicity and is the kernel for rhythmogenesis in the slice. We recorded neuron population activity locally in the pre-BotC with macroelectrodes and fluorescent imaging of Ca2+ activities with Calcium Green-1AM dye before and after excising the island. The isolated island remained rhythmically active with a population burst profile similar to the inspiratory burst in the slice. Rhythmic population activity persisted in islands after block of GABA(A) ergic and glycinergic synaptic inhibition. The loci of pre-BotC Ca2+ activity imaged in thin slices and islands were similar, and imaged pre-BotC neurons exhibited synchronized flashing after blocking synaptic inhibition. Population burst frequency increased monotonically as extracellular potassium concentration was elevated, consistent with mathematical models consisting entirely of an excitatory network of synaptically coupled pacemaker neurons with heterogeneous, voltage-dependent bursting properties. Our results provide further evidence for a rhythmogenic kernel in the pre-BotC in vitro and demonstrate that the islands are ideal preparations for studying the kernel's intrinsic properties. C1 NINDS, Cellular & Syst Neurobiol Sect, Neural Control Lab, NIH, Bethesda, MD 20892 USA. RP Smith, JC (reprint author), NINDS, Cellular & Syst Neurobiol Sect, Neural Control Lab, NIH, 49 Convent Dr,Rm 3A50 MSC 4455, Bethesda, MD 20892 USA. NR 9 TC 82 Z9 85 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD APR PY 2001 VL 85 IS 4 BP 1772 EP 1776 PG 5 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 418AB UT WOS:000167866700040 PM 11287498 ER PT J AU Maric, D Liu, QY Maric, I Chaudry, S Chang, YH Smith, SV Sieghart, W Fritschy, JM Barker, JL AF Maric, D Liu, QY Maric, I Chaudry, S Chang, YH Smith, SV Sieghart, W Fritschy, JM Barker, JL TI GABA expression dominates neuronal lineage progression in the embryonic rat neocortex and facilitates neurite outgrowth via GABA(A) autoreceptor/Cl- channels SO JOURNAL OF NEUROSCIENCE LA English DT Article DE embryonic; rat development; cortical; neuritogenesis; GABA; GAD; FACS ID SUBUNIT MESSENGER-RNAS; CENTRAL-NERVOUS-SYSTEM; A-RECEPTOR; HIPPOCAMPAL-NEURONS; POSTNATAL-DEVELOPMENT; GROWTH CONES; PRENATAL DEVELOPMENT; CORTICAL-NEURONS; PROGENITOR CELLS; CEREBRAL-CORTEX AB GABA emerges as a trophic signal during rat neocortical development in which it modulates proliferation of neuronal progenitors in the ventricular/subventricular zone (VZ/SVZ) and mediates radial migration of neurons from the VZ/VZ to the cortical plate/subplate (CP/SP) region. In this study we investigated the role of GABA in the earliest phases of neuronal differentiation in the CP/SP. GABAergic-signaling components emerging during neuronal lineage progression were comprehensively characterized using flow cytometry and immunophenotyping together with physiological indicator dyes. During migration from the VZ/SVZ to the CP/SP, differentiating cortical neurons became predominantly GABAergic, and their dominant GABA(A) receptor subunit expression pattern changed from alpha4 beta1 gamma1 to alpha3 beta3 gamma2 gamma3 coincident with an increasing potency of GABA on GABA(A) receptor-mediated depolarization. GABA(A) autoreceptor/Cl- channel activity in cultured CP/SP neurons dominated their baseline potential and indirectly their cytosolic Ca2+ (Ca-c(2+)) levels via Ca2+ entry through L-type Ca2+ channels, Block of this autocrine circuit at the level of GABA synthesis, GABA(A) receptor activation, intracellular Cl- ion homeostasis, or L-type Ca2+ channels attenuated neurite outgrowth in most GABAergic CP/SP neurons. In the absence of autocrine GABAergic signaling, neuritogenesis could be preserved by depolarizing cells and elevating Ca-c(2+). These results reveal a morphogenic role for GABA during embryonic neocortical neuron development that involves GABA, autoreceptors and L-type Ca2+ channels. C1 NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. Univ Vienna, Psychiat Clin, Dept Biochem Psychiat, A-1090 Vienna, Austria. Univ Zurich, Inst Pharmacol, CH-8057 Zurich, Switzerland. RP Maric, D (reprint author), NINDS, Neurophysiol Lab, NIH, Bldg 36,Room 2C-02, Bethesda, MD 20892 USA. RI Sieghart, Werner/A-4877-2013 OI Sieghart, Werner/0000-0002-0443-0302 NR 62 TC 102 Z9 108 U1 1 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD APR 1 PY 2001 VL 21 IS 7 BP 2343 EP 2360 PG 18 WC Neurosciences SC Neurosciences & Neurology GA 415RU UT WOS:000167737100018 PM 11264309 ER PT J AU Rausch, DM Davis, MR AF Rausch, DM Davis, MR TI HIV in the CNS: Pathogenic relationships to systemic HIV disease and other CNS diseases SO JOURNAL OF NEUROVIROLOGY LA English DT Review DE HIV; dementia; Alzheimer's disease; multiple sclerosis; trafficking; chemokines ID HUMAN-IMMUNODEFICIENCY-VIRUS; CENTRAL-NERVOUS-SYSTEM; ACTIVE ANTIRETROVIRAL THERAPY; BLOOD-BRAIN-BARRIER; AIDS DEMENTIA COMPLEX; NECROSIS-FACTOR-ALPHA; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; MARROW-DERIVED ELEMENTS; AMYLOID BETA-PROTEIN; CD4(+) T-CELLS AB Research on the pathogenesis of the human immunodeficiency virus (HIV) infection of the central nervous system (CNS) has reached a pivotal stage. While the incidence of HIV dementia appears to be declining, the prevalence of milder, yet debilitating, neuropsychological impairments may rise as individuals infected with HIV live longer. There are also concerns about CNS reservoirs of latently infected cells. Building upon progress in understanding HIV neuropathogenesis, the time is ideal to expand research on the interrelationships between the CNS and systemic HIV disease, and extend the boundaries of this research to the neuropathogenic similarities between HIV and other CNS inflammatory diseases. Neuropathogenic insights gained from these pursuits can spawn new treatment strategies for HIV/CNS disease as well as potentially other diseases of the nervous system. C1 NIMH, Ctr Mental Hlth Res AIDS, Bethesda, MD 20892 USA. George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Epidemiol & Biostat, Washington, DC USA. RP Rausch, DM (reprint author), NIMH, Ctr Mental Hlth Res AIDS, 6100 Execut Blvd,Room 6212,MSC 9623, Bethesda, MD 20892 USA. NR 151 TC 14 Z9 16 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD APR PY 2001 VL 7 IS 2 BP 85 EP 96 PG 12 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 454TJ UT WOS:000169987600001 PM 11517381 ER PT J AU Dixon, LB Winkleby, MA Radimer, KL AF Dixon, LB Winkleby, MA Radimer, KL TI Dietary intakes and serum nutrients differ between adults from food-insufficient and food-sufficient families: Third National Health and Nutrition Examination Survey, 1988-1994 SO JOURNAL OF NUTRITION LA English DT Article DE biomarker; dietary intake; food insecurity; food insufficiency; hunger; NHANES III ID ALPHA-TOCOPHEROL; UNITED-STATES; ADIPOSE-TISSUE; ENERGY-INTAKE; FATTY-ACIDS; HUNGER; CAROTENOIDS; INSECURITY; PLASMA; WOMEN AB Approximately 10.2 million persons in the United States sometimes or often do not have enough food to eat, a condition known as food insufficiency. Using cross-sectional data from the Third National Health and Nutrition Examination Survey (NHANES III), we examined whether dietary intakes and serum nutrients differed between adults from food-insufficient families (FIF) and adults from food-sufficient families (FSF). Results from analyses, stratified by age group and adjusted for family income and other important covariates, revealed several significant findings (P < 0.05). Compared with their food-sufficient counterparts, younger adults (aged 20-59 y) from FIF had lower intakes of calcium and were more likely to have calcium and vitamin E intakes below 50% of the recommended amounts on a given day. Younger adults from FIF also reported lower 1-mo frequency of consumption of milk/milk products, fruits/fruit juices and vegetables. In addition, younger adults from FIF had lower serum concentrations of total cholesterol, vitamin A and three carotenoids (-carotene, beta -cryptoxanthin and lutein/zeaxanthin). Older adults (aged greater than or equal to 60 y) from FIF had lower intakes of energy, vitamin B-6, magnesium, iron and zinc and were more likely to have iron and zinc intakes below 50% of the recommended amount on a given day. Older adults from FIF also had lower serum concentrations of high-density lipoprotein cholesterol, albumin, vitamin A, beta -cryptoxanthin and vitamin E. Both younger and older adults from FIF were more likely to have very low serum albumin (<35 g/L) than were adults from FSF. Our findings show that adults from FIF have diets that may compromise their health. C1 Natl Canc Inst, Div Canc Prevent, Bethesda, MD USA. Stanford Univ, Ctr Res Dis Prevent, Stanford, CA 94305 USA. Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. RP Dixon, LB (reprint author), NCI, Appl Res Program, 6130 Execut Blvd,MSC 7344,EPN 4005, Bethesda, MD 20892 USA. NR 55 TC 119 Z9 124 U1 3 U2 15 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD APR PY 2001 VL 131 IS 4 BP 1232 EP 1246 PG 15 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 421TK UT WOS:000168079500021 PM 11285332 ER PT J AU Picciano, MF Raiten, DJ AF Picciano, MF Raiten, DJ TI Bioavailability of nutrients and other bioactive components from dietary supplements - Introduction SO JOURNAL OF NUTRITION LA English DT Editorial Material C1 Penn State Univ, University Pk, PA 16802 USA. NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. NICHHD, Off Prevent Res & Int Programs, NIH, Bethesda, MD 20892 USA. RP Picciano, MF (reprint author), Penn State Univ, University Pk, PA 16802 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD APR PY 2001 VL 131 SU 4 BP 1329S EP 1330S PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 423HU UT WOS:000168170600001 ER PT J AU DiSaia, PJ Tewari, KS AF DiSaia, PJ Tewari, KS TI Recent advancements in the treatment of epithelial ovarian cancer SO JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH LA English DT Article DE ovarian cancer; chemotherapy; management ID GYNECOLOGIC-ONCOLOGY-GROUP; PHASE-II TRIAL; 2ND-LINE THERAPY; PLATINUM-RESISTANT; RANDOMIZED TRIALS; DEBULKING SURGERY; ORAL ETOPOSIDE; FREE INTERVAL; FOLLOW-UP; STAGE-III AB bImportant advances in the management of advanced epithelial ovarian cancer have been made in recent years, with much of the knowledge emanating from clinical trials conducted by the Gynecological Oncology Group (GOG). This monograph reviews the trials that have defined current clinical practice and summarizes some innovative techniques and promising new drugs for the future. C1 Univ Calif Irvine, Ctr Med, Div Gynecol Oncol, Chao Family NCI Designated Comprehens Canc Ctr, Orange, CA 92868 USA. RP DiSaia, PJ (reprint author), Univ Calif Irvine, Ctr Med, Div Gynecol Oncol, Chao Family NCI Designated Comprehens Canc Ctr, 101 City Dr, Orange, CA 92868 USA. NR 72 TC 7 Z9 7 U1 0 U2 1 PU BLACKWELL PUBLISHING ASIA PI CARLTON PA 54 UNIVERSITY ST, P O BOX 378, CARLTON, VICTORIA 3053, AUSTRALIA SN 1341-8076 J9 J OBSTET GYNAECOL RE JI J. Obstet. Gynaecol. Res. PD APR PY 2001 VL 27 IS 2 BP 61 EP 75 PG 15 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 512PY UT WOS:000173333800003 PM 11396641 ER PT J AU Zheng, TZ Cantor, KP Zhang, YW Keim, S Lynch, CF AF Zheng, TZ Cantor, KP Zhang, YW Keim, S Lynch, CF TI Occupational risk factors for brain cancer: A population-based case-control study in Iowa SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; UTILITY WORKERS; EXPOSURE; TUMORS; MORTALITY; FARMERS; GLIOMAS; DEATH; HYDROCARBONS; CARCINOGENS AB A number of occupations and industries have been inconsistently associated with the risk of brain cancer. To further explore possible relationships, we conducted a population-based case-control study of brain glioma in the state of Iowa, involving 375 histologically confirmed incident cases and 2434 population-based controls, Among men, the industries and/or occupations that had a significantly increased risk for employment of more than 10 years included roofing; siding; and sheet metalworking; newspaper work; rubber and plastics products, particularly tires and inner tubes; miscellaneous manufacturing industries; wholesale trade of durable goods, grain, and field beans, cleaning and building service occupations; miscellaneous mechanics and repairers; and janitors and cleaners. Subjects who worked in plumbing, heating and air conditioning; electrical services; gasoline service stations; and military occupations also experienced a significantly increased risk. Among women, significant excess risk was observed for occupations in agricultural services and farming; apparel and textile products, electrical and electronic equipment manufacturing, various retail sales, record-keeping, and restaurant service. Workers in industries with a potential for gasoline or motor exhaust exposures experienced a non-significant excess risk of brain glioma. C1 Yale Univ, Sch Publ Hlth, New Haven, CT USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA 52242 USA. RP Zheng, TZ (reprint author), 129 Church St,Suite 700-703, New Haven, CT 06510 USA. RI Keim, Sarah/F-8929-2013 OI Keim, Sarah/0000-0003-3490-3649 NR 45 TC 26 Z9 28 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-2752 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD APR PY 2001 VL 43 IS 4 BP 317 EP 324 DI 10.1097/00043764-200104000-00005 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 423AB UT WOS:000168151800005 PM 11322092 ER PT J AU Khasar, SG Isenberg, WM Miao, FJP Gear, RW Green, PG Levine, JD AF Khasar, SG Isenberg, WM Miao, FJP Gear, RW Green, PG Levine, JD TI Gender and gonadal hormone effects on vagal modulation of tonic nociception SO JOURNAL OF PAIN LA English DT Article DE androgen; estrogen; tonic nociception; vagus nerve ID FORMALIN TEST; MECHANICAL HYPERALGESIA; BEHAVIORAL-RESPONSE; SEX-DIFFERENCES; FEMALE RATS; PAIN; TESTOSTERONE; INHIBITION; AFFERENTS; VAGOTOMY AB We studied the influence of gender and gonadal hormones on modulation of tonic nociception exerted by vagal activity. In male rats, subdiaphragmatic vagotomy resulted in significantly reduced nociceptive behavior during phase 2 of the formalin test. Whereas gonadectomy alone had no effect, it completely eliminated the suppressive effect of subdiaphragmatic vagotomy; however, sex hormone replacement with either testosterone or dihydrotestosterone did not restore the ability of subdiaphragmatic vagotomy to suppress nociceptive behavior. These results suggest that, in males, a gonad-dependent but androgenic gonadal hormone-independent mechanism contributes to pronociceptive effects of vagal afferent activity. Although neither gonadectomy nor subdiaphragmatic vagotomy alone affected the response to formalin in females, gonadectomy plus vagotomy resulted in significantly reduced nociceptive behavior during phase 2. Reconstitution with 17 beta -estradiol implants in gonadectomized females not only prevented suppression of nociceptive behavior seen with gonadectomy plus vagotomy, but also led to increased nociceptive behavior in the interphase between phases 1 and 2. However, placement of 17 beta -estradiol implants in gonad-intact females had no effect on formalin-induced nociceptive behavior. The finding that estrogen produced an increase in nociceptive behavior in gonadectomized female rats after vagotomy but not in normal female rats (with intact gonads and subdiaphragmatic vagus) suggests that the interaction between estrogen and nociceptive afferent activity is suppressed by vagal function. In conclusion, a nonandrogenic action of testicular function in male rats and estrogen in females seems to influence the effect of vagal activity on formalin-induced nociceptive behavior. C1 Univ Calif San Francisco, NIH, Pain Ctr, Dept Med Oral & Maxillofacial Surg, San Francisco, CA 94143 USA. Univ Calif San Francisco, NIH, Pain Ctr, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94143 USA. Univ Calif San Francisco, NIH, Pain Ctr, Div Neurosci, San Francisco, CA 94143 USA. Univ Calif San Francisco, NIH, Pain Ctr, Program Biomed Sci, San Francisco, CA 94143 USA. Univ Calif San Francisco, NIH, Pain Ctr, Ctr Orofacial Pain, San Francisco, CA 94143 USA. RP Levine, JD (reprint author), Univ Calif San Francisco, NIH, Pain Ctr, Dept Med Oral & Maxillofacial Surg, Box 0440,C522, San Francisco, CA 94143 USA. RI Green, Paul/C-5943-2011 NR 30 TC 16 Z9 17 U1 0 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD APR PY 2001 VL 2 IS 2 BP 91 EP 100 DI 10.1054/jpai.2000.19295 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 421PV UT WOS:000168073500002 PM 14622830 ER PT J AU Caudle, RM Mannes, AJ Benoliel, R Eliav, E Iadarola, MJ AF Caudle, RM Mannes, AJ Benoliel, R Eliav, E Iadarola, MJ TI Intrathecally administered cholera toxin blocks allodynia and hyperalgesia in persistent pain models SO JOURNAL OF PAIN LA English DT Article DE chronic pain; opioids; cholera toxin; spinal cord ID MU-OPIOID RECEPTOR; RAT SPINAL-CORD; ENKEPHALIN-LIKE MATERIAL; LONG-LASTING ALLODYNIA; DYNORPHIN-A; PERIPHERAL MONONEUROPATHY; PRODYNORPHIN PROMOTER; CDNA HYBRIDIZATION; SEGMENTAL RELEASE; NEUROPATHIC PAIN AB In persistent pain, the spinal cord concentration of the opioid peptide dynorphin increases dramatically, yet the function of dynorphin remains unknown. If prodynorphin expression could be manipulated in vivo, it might be possible to determine what role dynorphin plays in persistent pain. Previous work in our laboratory showed that prodynorphin expression is regulated through the cyclic adenosine monophosphate pathway. Therefore, we attempted to enhance prodynorphin expression in the spinal cord of rats by stimulating adenylate cyclase with cholera toxin; however, contrary to our hypothesis, intrathecally administered cholera toxin did not enhance prodynorphin expression. Rather, cholera toxin suppressed the increase in prodynorphin produced by inflammation. Cholera toxin also inhibited the allodynia and hyperalgesia associated with inflammation and nerve injury. Interestingly, the antiallodynic and antihyperalgesic actions of cholera toxin were reversed with the opioid receptor antagonist, naloxone. These findings suggest that cholera toxin enhances or unmasks an endogenous opioid pathway to produce its antiallodynic and antihyperalgesic effects. Furthermore, these data indicate that the suppression of the inflammation-induced increase in spinal cord prodynorphin is caused by the opioid-mediated decrease in the nociceptive stimulus. C1 Univ Florida, Coll Dent, Dept Oral Surg, Gainesville, FL 32610 USA. Univ Penn, Coll Med, Dept Anesthesia, Philadelphia, PA USA. Hadassah Sch Dent Med, Oral Diag Oral Med & Radiol Dept, Jerusalem, Israel. Natl Inst Dent & Craniofacial Res, Pain & Neurosensory Mechanisms Branch, NIH, Bethesda, MD USA. RP Caudle, RM (reprint author), Univ Florida, Coll Dent, Dept Oral Surg, Gainesville, FL 32610 USA. OI Mannes, Andrew/0000-0001-5834-5667 NR 56 TC 12 Z9 13 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD APR PY 2001 VL 2 IS 2 BP 118 EP 127 DI 10.1054/jpai.2000.19948 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 421PV UT WOS:000168073500005 PM 14622833 ER PT J AU O'Mara, AM Arenella, C AF O'Mara, AM Arenella, C TI Minority representation, prevalence of symptoms, and utilization of services in a large metropolitan hospice SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE hospice care; health services accessibility; minority groups AB Minority access to and utilization of hospice services is gaining increasing attention in the field of health case delivery systems. This case study describes the 1997 ethnic and racial make-up of a large metropolitan hospice facility located in Arlington, Virginia and compares its composition with the regional community. Demographic data; aggregate physical and psychosocial problems; utilization of services; and admission, discharge, and mortality data were collected and summarized by race and ethnicity. The state provided 1997 regional mortality data by race and ethnicity. When hospice deaths were compared with regional deaths, the hospice provided service to 30% of Caucasians decedents. By using mortality data rather than census data, the discrepancy between minority and Caucasian populations is not as large as has been reported in previous research. (C) U.S. Cancer Pain Relief Committee, 2001. C1 NCI, DCP, EDCOP, Bethesda, MD 20892 USA. Hospice No Virginia, Falls Church, VA USA. RP O'Mara, AM (reprint author), NCI, DCP, EDCOP, 6130 Execut Blvd,Suite 305, Bethesda, MD 20892 USA. NR 24 TC 16 Z9 16 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0885-3924 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD APR PY 2001 VL 21 IS 4 BP 290 EP 297 DI 10.1016/S0885-3924(01)00256-1 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA 421BP UT WOS:000168042500006 PM 11312043 ER PT J AU Charmandari, E Meadows, N Patel, M Johnston, A Benjamin, N AF Charmandari, E Meadows, N Patel, M Johnston, A Benjamin, N TI Plasma nitrate concentrations in children with infectious and noninfectious diarrhea SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Article DE plasma nitrate concentrations; chronic diarrhea; gastroenteritis; nitric oxide ID NITRIC-OXIDE SYNTHASE; L-ARGININE; ULCERATIVE-COLITIS; CROHNS-DISEASE; GASTROENTERITIS; CELLS; TUBERCULOSIS; MACROPHAGES; INHIBITION; EXCRETION AB Background: In patients with intact renal function and low dietary nitrate intake, plasma nitrate concentrations reflect endogenous nitric oxide production and are shown to be increased during inflammatory processes. The aim of this study was to compare plasma nitrate concentrations and hence endogenous nitric oxide production in children with infectious and noninfectious diarrhea and to determine whether plasma nitrate concentrations could serve as a discriminant test between acute and chronic diarrhea in children. Methods: Three groups of patients were identified: 14 patients with acute gastroenteritis, 13 patients with chronic noninfectious diarrhea, and 14 patients with no evidence of gastrointestinal pathology and no underlying infectious process, who served as control subjects. Plasma nitrate concentrations were determined spectrophotometrically using the Greiss reaction before reduction to nitrite with a copper-coated cadmium column. Results: Mean plasma nitrate concentrations were 405.3 mu mol/L +/- 281.6 mu mol/L (standard deviation) in patients with infectious diarrhea, 134.7 mu mol/L +/- 77.0 mu moI/L inpatients with chronic diarrhea, and 54.1 mu mol/L +/- 20.1 mu mol/L in control subjects (F = 42.6, P < 0.0001; analysis of variance). Plasma nitrate concentrations were significantly higher in the infectious diarrhea group compared with the noninfectious diarrhea and control groups (Student-Newman-Keuls test, P < 0.5). Conclusions: Although an optimal cutoff concentration cannot be defined, plasma nitrate concentrations in excess of 300 mu mol/L, are suggestive of an infectious process whereas values less than 100 mu mol/L are indicative of noninfectious diarrhea. C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. St Bartholomews & Royal London Sch Med, Dept Paediat Gastroenterol, London, England. St Bartholomews & Royal London Sch Med, Dept Clin Pharmacol, London, England. RP Charmandari, E (reprint author), NICHHD, Pediat & Reprod Endocrinol Branch, NIH, 10 Ctr Dr,Bldg 10,Suite 9D42, Bethesda, MD 20892 USA. RI Charmandari, Evangelia/B-6701-2011 NR 31 TC 12 Z9 12 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-2116 J9 J PEDIATR GASTR NUTR JI J. Pediatr. Gastroenterol. Nutr. PD APR PY 2001 VL 32 IS 4 BP 423 EP 427 DI 10.1097/00005176-200104000-00006 PG 5 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA 436ZW UT WOS:000168966600005 PM 11396807 ER PT J AU Nguyen, TT Keil, MF Russell, DL Pathomvanich, A Uwaifo, GI Sebring, NG Reynolds, JC Yanovski, JA AF Nguyen, TT Keil, MF Russell, DL Pathomvanich, A Uwaifo, GI Sebring, NG Reynolds, JC Yanovski, JA TI Relation of acanthosis nigricans to hyperinsulinemia and insulin sensitivity in overweight African American and white children SO JOURNAL OF PEDIATRICS LA English DT Article ID CLINICAL RESEARCH-CENTER; BONE-MINERAL DENSITY; GROWTH-HORMONE; RESISTANCE; SECRETION; PREVALENCE; POPULATION; RECEPTOR; BLACK; RISK AB Objectives: Acanthosis nigricans (AN) has been proposed as a reliable marker of hyperinsulinemia but its utility for predicting hyperinsulinism has not been systematically evaluated in overweight children. We examined the relationship of AN to hyperinsulinemia and body adiposity. Study design: One hundred thirty-nine children underwent physical examination for AN, body composition studies, an oral glucose tolerance test, and a hyperglycemic clamp. Results: Thirty-five children (25%) had AN. AN was more prevalent in African Americans (50.1%) than in white subjects (8.2%, P < .001). Independent of race, children with AN had greater body weight and body fat mass (P < .001); greater basal and glucose-stimulated insulin levels during oral glucose tolerance test (P < .001); greater first-phase, second-phase, and steady-state insulin levels (P < .001); and lower insulin sensitivity (P < .001) during the hyperglycemic clamp. After adjusting for body fat mass and age. none of these differences remained significant. When categorized by fasting insulin, 35% with fasting insulin levels >20 muU/mL and 50% with fasting insulin levels >15 muU/mL did not have AN. Eighty-eight percent of children with fasting insulin levels greater than or equal to 15 muU/mL had a body mass index SE score greater than or equal to3.0. Conclusions: AN is not a reliable marker for hyperinsulinemia in over-weight children. Children with a race-, sex-, and age-specific body mass index SD scores greater than or equal to3.0 should be screened for hyperinsulinemia, whether or not they have AN. C1 NICHHD, Unit Growth & Obes, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIH, Dept Nutr, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. NIH, Dept Nucl Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD USA. RP Yanovski, JA (reprint author), NICHHD, Unit Growth & Obes, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N262,MSC 1862,10 Ctr Dr, Bethesda, MD 20892 USA. RI Uwaifo, Gabriel/M-2361-2016; OI Uwaifo, Gabriel/0000-0002-6962-9304; Yanovski, Jack/0000-0001-8542-1637 FU NICHD NIH HHS [HD-00641] NR 27 TC 62 Z9 65 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD APR PY 2001 VL 138 IS 4 BP 474 EP 480 DI 10.1067/mpd.2001.112657 PG 7 WC Pediatrics SC Pediatrics GA 423KL UT WOS:000168175400012 PM 11295708 ER PT J AU Altarescu, G Hill, S Wiggs, E Jeffries, N Kreps, C Parker , CC Brady, RO Barton, NW Schiffmann, R Bannarjee, TK Crutchfield, K Frei, K McKee, MA Moore, DF Tournay, A AF Altarescu, G Hill, S Wiggs, E Jeffries, N Kreps, C Parker , CC Brady, RO Barton, NW Schiffmann, R Bannarjee, TK Crutchfield, K Frei, K McKee, MA Moore, DF Tournay, A TI The efficacy of enzyme replacement therapy in patients with chronic neuronopathic Gaucher's disease SO JOURNAL OF PEDIATRICS LA English DT Article ID MACROPHAGE-TARGETED GLUCOCEREBROSIDASE; PULMONARY-HYPERTENSION; TYPE-1; ALGLUCERASE; INVOLVEMENT AB Objective: To assess the long-term systemic and neurologic responses to enzyme replacement therapy (ERT) with macrophage-targeted glucocerebrosidase in patients with type 3 Gaucher's disease. Study design: Patients with type 3 Gaucher's disease (n = 21), aged 8 months to 35 years, were enrolled in a prospective study. Enzyme dose was adjusted to control systemic manifestations. Clinical and laboratory evaluations were performed at baseline and every 6 to 12 months thereafter. Patients were followed up for 2 to 8 years. Results: Significant improvement in hemoglobin levels, platelet count, and acid phosphatase values occurred. Liver and spleen volume markedly decreased, and bone structure improved. Nineteen patients bad asymptomatic interstitial lung disease unresponsive to ERT. Supranuclear gaze palsy remained stable in 19 patients, worsened in one patient, and improved in one. Cognitive function remained unchanged or improved over time in 13 patients but decreased in 8 patients, 3 of whom developed progressive myoclonic encephalopathy accompanied by cranial magnetic resonance imaging and electroencephalographic deterioration. Conclusions: At relatively high doses, ERT reverses almost all the systemic manifestations in patients with type 3 Gaucher's disease. Most treated patients do not deteriorate neurologically, Novel therapeutic strategies are required to reverse the pulmonary and neuronopathic aspects of the disease. C1 NINDS, Dev & Metab Neurol Branch, Biometry & Field Studies Branch, NIH, Bethesda, MD 20892 USA. NIH, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Schiffmann, R (reprint author), NINDS, Dev & Metab Neurol Branch, Biometry & Field Studies Branch, NIH, Bldg 10,Room 3D03,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 37 TC 91 Z9 95 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD APR PY 2001 VL 138 IS 4 BP 539 EP 547 DI 10.1067/mpd.2001.112171 PG 9 WC Pediatrics SC Pediatrics GA 423KL UT WOS:000168175400022 PM 11295718 ER PT J AU Yanovski, JA Arioglu, E AF Yanovski, JA Arioglu, E TI When a child can't clean her neck SO JOURNAL OF PEDIATRICS LA English DT Article C1 NICHD, Unit Growth & Obes, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Diabet Branch, NIH, Bethesda, MD USA. US PHS, Washington, DC 20201 USA. RP Yanovski, JA (reprint author), NICHD, Unit Growth & Obes, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. OI Oral, Elif/0000-0002-9171-1144; Yanovski, Jack/0000-0001-8542-1637 NR 0 TC 2 Z9 2 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD APR PY 2001 VL 138 IS 4 BP 608 EP 608 DI 10.1067/mpd.2001.114227 PG 1 WC Pediatrics SC Pediatrics GA 423KL UT WOS:000168175400039 PM 11295735 ER PT J AU McCrae, RR Yang, J Costa, PT Dai, XY Yao, SQ Cai, TS Gao, BL AF McCrae, RR Yang, J Costa, PT Dai, XY Yao, SQ Cai, TS Gao, BL TI Personality profiles and the prediction of categorical personality disorders SO JOURNAL OF PERSONALITY LA English DT Article ID REPUBLIC-OF-CHINA; 5-FACTOR MODEL; AXIS-II; CONSTRUCT-VALIDITY; DIMENSIONS; RATINGS; SAMPLE AB Personality disorders (PDs) are usually construed as psychiatric categories characterized by a unique configuration of traits and behaviors. To generate clinical hypotheses from normal personality trait scores, profile agreement statistics can be calculated using a prototypical personality profile for each PD. Multimethod data from 1.909 psychiatric patients in the People's Republic of China were used to examine the accuracy of such hypotheses in the Interpretive Report of the Revised NEO Personality Inventory. Profile agreement indices from both self-reports and spouse ratings were significantly related to PD symptom scores derived from questionnaires and clinical interviews. However, accuracy of diagnostic classification was only modest to moderate, probably because PDs are not discrete categorical entities. Together with other literature, these data suggest that the current categorical system should be replaced by a more comprehensive system of personality traits and personality-related problems. C1 NIA, Gerontol Res Ctr, Personal Stress & Coping Sect, NIH, Baltimore, MD 21224 USA. Cent S Univ, Affiliated Hosp 2, Clin Psychol Res Ctr, Changsha, Peoples R China. RP McCrae, RR (reprint author), Ctr Addict & Mental Hlth, Toronto, ON, Canada. EM jeffm@mvx.grc.nia.nih.gov OI Costa, Paul/0000-0003-4375-1712 NR 40 TC 29 Z9 29 U1 2 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3506 J9 J PERS JI J. Pers. PD APR PY 2001 VL 69 IS 2 BP 155 EP 174 DI 10.1111/1467-6494.00140 PG 20 WC Psychology, Social SC Psychology GA 421AN UT WOS:000168040100002 PM 11339794 ER PT J AU Qin, ZH Wang, YM Chen, RW Wang, XX Ren, M Chuang, DM Chase, TN AF Qin, ZH Wang, YM Chen, RW Wang, XX Ren, M Chuang, DM Chase, TN TI Prostaglandin A(1) protects striatal neurons against excitotoxic injury in rat striatum SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID NF-KAPPA-B; PROGRAMMED CELL-DEATH; D-ASPARTATE RECEPTORS; HEAT-SHOCK PROTEIN; CYCLIN D1; CYCLOPENTENONE PROSTAGLANDINS; NUCLEAR TRANSLOCATION; DOPAMINERGIC-NEURONS; HIPPOCAMPAL-NEURONS; INDUCED APOPTOSIS AB Prostaglandin A(1) (PGA(1)) reportedly inhibits NF-kappaB activation and induces expression of heat shock proteins. Since both these effects could be neuroprotective, the therapeutic potential of PGA(1) in neurodegenerative disorders, where excitotoxicity may contribute to pathogenesis, was evaluated in rat striatal neurons exposed to the N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid (QA). Intrastriatal administration of PGA(1) (5-80 nmol) attenuated QA (60 nmol)-induced internucleosomal DNA fragmentation. The inhibitory effects of a single dose of PGA(1) (80 nmol) on QA (60 nmol)-induced DNA fragmentation were observed 12 to 48 h after treatment. PGA(1) (80 nmol) also attenuated QA-induced DNA fragmentation when administered up to 4 h after QA exposure. PGA(1) significantly decreased the loss of D-1 dopamine receptors and GAD(67) mRNA in QA-injected striatum as measured by quantitative receptor autoradiography and in situ hybridization histochemistry, suggesting that it reduced the neuronal loss induced by QA. Protection of striatal neurons against QA-induced death by PGA(1) was further indicated by Nissl staining 10 days after QA administration. PGA(1) (5-80 nmol) significantly inhibited QA-induced NF-kappaB activation by blocking inhibitory kappaB-alpha degradation but had no effect on activator protein-1 binding activity. PGA(1) (80 nmol) treatment substantially increased 70- and 72-kDa heat shock protein levels in striatum. These results indicate that PGA(1) blunts NMDA receptor-mediated neuronal apoptosis by a mechanism possibly involving the up-regulation of neuroprotective heat shock proteins and inhibition of NF-kappaB activation. In view of its potent neuroprotective activity, PGA(1) could prove useful in the treatment of certain neurodegenerative disorders related to excitotoxicity. C1 Natl Inst Neurodegenerat Disorders & Stroke, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. NIMH, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Chase, TN (reprint author), Natl Inst Neurodegenerat Disorders & Stroke, Expt Therapeut Branch, NIH, Bldg 10,Room 5C103,10 Ctr Dr,MSC 1406, Bethesda, MD 20892 USA. NR 45 TC 28 Z9 32 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD APR PY 2001 VL 297 IS 1 BP 78 EP 87 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 416AX UT WOS:000167756700010 PM 11259530 ER PT J AU Boyd, MR Farina, C Belfiore, P Gagliardi, S Kim, JW Hayakawa, Y Beutler, JA McKee, TC Bowman, BJ Bowman, EJ AF Boyd, MR Farina, C Belfiore, P Gagliardi, S Kim, JW Hayakawa, Y Beutler, JA McKee, TC Bowman, BJ Bowman, EJ TI Discovery of a novel antitumor benzolactone enamide class that selectively inhibits mammalian vacuolar-type (H+)-ATPases SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID CHONDROMYCES SPECIES MYXOBACTERIA; H+-ATPASE; CYTOTOXIC MACROLIDES; STRUCTURAL ELUCIDATION; ANTIRESORPTIVE AGENTS; APICULAREN-A; PROTON PUMP; BAFILOMYCINS; EXPRESSION; CONCANAMYCINS AB A series of naturally occurring compounds reported recently by multiple laboratories defines a new small-molecule class sharing a unique benzolactone enamide core structure and diverse biological actions, including inhibition of growth of tumor cells and oncogene-transformed cell lines. Here we show that representative members of this class, including salicylihalamide A, lobatamides A-F, and oximidines I and II inhibit mammalian vacuolar-type (H+)-ATPases (V-ATPases) with unprecedented selectivity. Data derived from the NCl 60-cell antitumor screen critically predicted the V-ATPase molecular target, while specific biochemical assays provided confirmation and further illumination. The compounds potently blocked representative V-ATPases from human kidney, liver, and osteoclastic giant-cell tumor of bone but were essentially inactive against V-ATPases of Neurospora crassa and Saccharomyces cerevisiae and other membrane ATPases. Essential regulation of pH in cytoplasmic, intraorganellar, and local extracellular spaces is provided by V-ATPases, which are ubiquitously distributed among eukaryotic cells and tissues. The most potent and selective V-ATPase inhibitors heretofore known were the bafilomycins and concanamycins, which do not discriminate between mammalian and nonmammalian V-ATPases. Numerous physiological processes are mediated by V-ATPases, and aberrant V-ATPase functions are implicated in many different human diseases. Previous efforts to develop therapeutic pharmacological modulators of V-ATPases have been frustrated by a lack of synthetically tractable and biologically selective leads. Therefore, availability of the unique benzolactone enamide inhibitor class may enable further elucidation of functional and architectural features of mammalian versus nonmammalian V-ATPase isoforms and provide new opportunities for targeting V-ATPase-mediated processes implicated in diverse pathophysiological phenomena, including cancer. C1 NCI, Frederick Canc Res & Dev Ctr, Lab Nat Prod, Div Basic Sci, Frederick, MD 21702 USA. SmithKline Beecham SpA, Milan, Italy. Univ Tokyo, Inst Mol & Cellular Biosci, Bunkyo Ku, Tokyo, Japan. SAIC Frederick, Frederick, MD USA. Univ Calif Santa Cruz, Dept Biol, Santa Cruz, CA 95064 USA. RP Boyd, MR (reprint author), NCI, Frederick Canc Res & Dev Ctr, Lab Nat Prod, Div Basic Sci, Bldg 1052,Rm 121, Frederick, MD 21702 USA. RI Beutler, John/B-1141-2009 OI Beutler, John/0000-0002-4646-1924 FU NCI NIH HHS [N01-CO-56000]; NIGMS NIH HHS [GM28703] NR 40 TC 134 Z9 140 U1 3 U2 15 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD APR PY 2001 VL 297 IS 1 BP 114 EP 120 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 416AX UT WOS:000167756700014 PM 11259534 ER PT J AU Taniuchi, H Shi, Y Miguel, GIS Ferretti, JA Mack, JW Fisher, A Shah, M Schechter, AN Shiloach, J AF Taniuchi, H Shi, Y Miguel, GIS Ferretti, JA Mack, JW Fisher, A Shah, M Schechter, AN Shiloach, J TI A study of the influence of the of yeast iso-2-cytochrome c on hydrophobic core residues phosphate binding: A probe of the hydrophobic core-surface charge interactions SO JOURNAL OF PROTEIN CHEMISTRY LA English DT Article DE modulation of phosphate bindings; influence of hydrophobic core residues; electrostatic core-surface interactions; polarizable domain model; cytochrome c chimeras ID HEART CYTOCHROME-C; FERRICYTOCHROME-C; PROTEIN STABILITY; LONG-RANGE; GUANIDINE-HYDROCHLORIDE; 3-FRAGMENT COMPLEX; FERROCYTOCHROME-C; FRAGMENT-COMPLEX; OXIDATION STATE; ION-BINDING AB To gain insight into the role of hydrophobic core-surface charge interactions in stabilizing cytochrome c, we investigated the influence of hydrophobic core residues on phosphate binding by mutating residues in yeast iso-2-cytochrome c to those corresponding to iso-l-cytochrome c in various combinations. Heat transition of ultraviolet CD was followed as a function of pH in the presence and absence of phosphate. Thermodynamic parameters were deduced. It was found that the 120V/V43A/M98L mutation in the hydrophobic core, whose locations are remote from the putative phosphate sites, modulates phosphate interactions, The modulation is pH dependent. The 120V/M98L and V43A mutation effects are nonadditive. The results lead to a model analogous to that of Tsao, Evans, and Wennerstrom, where a domain associated with the ordered hydrophobic core is sensitive to the fields generated by the surface charges. Such an explanation would be in accord with the observed difference in thermal stability between iso-2 and horse cytochromes c. C1 NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. Howard Univ, Coll Med, Dept Biochem, Washington, DC 20059 USA. NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Taniuchi, H (reprint author), NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. NR 82 TC 3 Z9 3 U1 1 U2 2 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0277-8033 J9 J PROTEIN CHEM JI J. Protein Chem. PD APR PY 2001 VL 20 IS 3 BP 203 EP 215 DI 10.1023/A:1010906929793 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 467GH UT WOS:000170693700003 PM 11565900 ER PT J AU Lucas, CP Zhang, HY Fisher, PW Shaffer, D Regier, DA Narrow, WE Bourdon, K Dulcan, MK Canino, G Rubio-Stipec, M Lahey, BB Friman, P AF Lucas, CP Zhang, HY Fisher, PW Shaffer, D Regier, DA Narrow, WE Bourdon, K Dulcan, MK Canino, G Rubio-Stipec, M Lahey, BB Friman, P TI The DISC Predictive Scales (DPS): Efficiently screening for diagnoses SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article; Proceedings Paper CT 44th Annual Meeting of the American-Academy-of-Child-and-Adolescent-Psychiatry CY OCT 14-19, 1997 CL TORONTO, CANADA SP Amer Acad Child & Adolescent Psychiat DE diagnostic screening; DISC Predictive Scales; Diagnostic Interview Schedule for Children; diagnostic interview ID CHILD PSYCHOPATHOLOGY; INTERVIEW SCHEDULE; DISORDERS; VALIDITY; DEPRESSION; PREVALENCE; AGREEMENT; LIFETIME; SYMPTOM AB Objective: To derive and test a series of brief diagnosis-specific scales to identify subjects who are at high probability of meeting diagnostic criteria and those who may safely be spared more extensive diagnostic inquiry. Method: Secondary data analysis of a large epidemiological data set (n = 1,286) produced a series of gate and contingent items for each diagnosis. Findings were replicated in a second retrospective analysis from a residential care sample (n = 884). The DISC Predictive Scales (DPS) were then used prospectively as a self-report questionnaire in two studies, in which parents (n = 128) and/or adolescents (n = 208) had subsequent diagnostic interviewing with the Diagnostic Interview Schedule for Children or the Schedule for Affective Disorders and Schizophrenia for School-Age Children. Results: All analyses showed that gate item selection was valid and that any missed cases were due solely to inconsistent reports on the same questions. Screening performance of the full scales was shown to be good, and substantial reductions in scale length were not associated with significant changes in discriminatory power. Conclusions: The DPS can accurately determine subjects who can safely be spared further diagnostic inquiry in any diagnostic area. This has the potential to speed up structured diagnostic interviewing considerably. The full DPS can be used to screen accurately for cases of specific DSMIII-R disorders. C1 Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, New York, NY 10032 USA. NIMH, Rockville, MD 20857 USA. Northwestern Univ, Childrens Mem Hosp, Chicago, IL 60614 USA. Univ Puerto Rico, San Juan, PR 00936 USA. Univ Chicago, Chicago, IL 60637 USA. Univ Nevada, Reno, NV 89557 USA. RP Lucas, CP (reprint author), Columbia Univ Coll Phys & Surg, Div Child Psychiat, 1051 Riverside Dr Box 78, New York, NY 10032 USA. FU NIMH NIH HHS [K01 MH01298, U01 MH46718, U01 MH46725, U01 MH46732, P30 MH34878, U01 MH46717] NR 24 TC 221 Z9 223 U1 3 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD APR PY 2001 VL 40 IS 4 BP 443 EP 449 DI 10.1097/00004583-200104000-00013 PG 7 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 415HT UT WOS:000167716000013 PM 11314570 ER PT J AU Pennesi, G Morellini, M Lulli, P Cappellacci, S Brioli, G Franceschi, C Trabace, S AF Pennesi, G Morellini, M Lulli, P Cappellacci, S Brioli, G Franceschi, C Trabace, S TI TCR V beta repertoire in an Italian longeval population including centenarians. SO JOURNAL OF THE AMERICAN AGING ASSOCIATION LA English DT Article ID T-CELL REPERTOIRE; PRIMERS PCR-SSP; HEALTHY CENTENARIANS; ANTIGEN; CHAIN; OLIGOCLONALITY; AMPLIFICATION; RECOGNITION; LYMPHOCYTES; ARTHRITIS AB During the last years, the hypothesis that aging and diseases are two distinct phenomena, and that successful aging is possible for most humans, has been put forward. We studied the TCR VP repertoire of T lymphocytes of healthy longevals and centenarians as crossing point of genetic predisposition and environmental effects to longevity, using the Spectra-typing method. TCR V beta1, V beta8, and V beta 20 were found to be expanded in the longeval population, compared with the younger control population. This repertoire can have been shaped by the selective action of particular HLA alleles, or by the clonal expansion of specific T cell clones, able to modulate the immune response to endogenous and exogenous antigens. Moreover, the skewed VP usage and the clonal expansion seem to be the effects of physiological changes occurring with aging and not pathological signs of malignity. C1 NEI, NIH, Bethesda, MD 20892 USA. Univ Rome La Sapienza, Dept Expt Med & Pathol, Genet Sect, L Spallanzani Hosp, I-00128 Rome, Italy. INRCA, Dept Gerontol Res, Ancona, Italy. RP Pennesi, G (reprint author), NEI, NIH, 10 Ctr Dr,Bldg 10,Room 10N218, Bethesda, MD 20892 USA. NR 29 TC 4 Z9 4 U1 0 U2 0 PU AMER AGING ASSOC PI MEDIA PA SALLY BALIN MEDICAL CENTER, 110 CHESLEY DR, MEDIA, PA 19063 USA SN 0161-9152 J9 J AM AGING ASSOC JI J. Am. Aging Assoc. PD APR PY 2001 VL 24 IS 2 BP 63 EP 70 PG 8 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 454BQ UT WOS:000169952900004 PM 23604877 ER PT J AU Blazer, DG Landerman, LR Hays, JC Grady, TA Havlik, R Corti, MC AF Blazer, DG Landerman, LR Hays, JC Grady, TA Havlik, R Corti, MC TI Blood pressure and mortality risk in older people: Comparison between African Americans and whites SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE aging; blood pressure; hypertension; longitudinal study; mortality; race; African American ID HEART-DISEASE MORTALITY; SYSTOLIC HYPERTENSION; NORTH-CAROLINA; PREDICTORS AB OBJECTIVES: To determine the risk from hypertension for all-cause mortality in a racially mixed sample of community-dwelling older adults. DESIGN: Baseline blood pressure was assessed between 1985 and 1986 in a sample of persons 65 years of age and older from five counties of the Piedmont of North Carolina (N = 4,162). All-cause mortality was monitored annually over the subsequent 6 years as part of the Established Populations for Epidemiologic Studies of the Elderly (EPESE) sponsored by the National Institute on Aging. SETTING: Eighteen percent of all respondents in the sample had a systolic blood pressure of >160 (17% for whites and 18% for African Americans) and 16% had a diastolic blood pressure of >90 (14% for whites and 20% for African Americans). During the 6 years of follow-up, 29% of the sample died (with no difference in mortality rates between whites and African Americans). PARTICIPANTS: 4,000 community-dwelling people age 65 years and older; 1,846 were white and 2,154 were African American. MEASUREMENTS: Systolic and diastolic blood pressure and all-cause mortality. RESULTS: Systolic blood pressure positively related to mortality during the 6 years of follow-up (relative risk = 1.05). Among whites the relationship of diastolic pressure to mortality was nonlinear, with those at the upper and lower ends of the distribution at increased risk. Among African Americans, diastolic pressure was unrelated to mortality. The analyses were controlled for age; gender; education; body mass index (BMI); smoking history; taking a medication to manage blood pressure; a history of cancer, diabetes mellitus, heart attack, or stroke; poor subjective health; impaired functional status; and cognitive impairment. CONCLUSIONS: The findings confirm that among older adults there is a significant relationship overall between systolic blood pressure and mortality over 6 years of follow-up in both whites and African Americans. Diastolic pressure was a risk factor for whites only. C1 Duke Univ, Med Ctr, Durham, NC USA. Duke Univ, Ctr Aging & Human Dev, Durham, NC USA. Univ Rochester, Sch Med, Rochester, NY USA. NIA, Epidemiol Demog & Biometry Program, NIH, Bethesda, MD USA. Univ Padua, Padua, Italy. RP Blazer, DG (reprint author), Box 3003 DUMC, Durham, NC 27710 USA. FU NIA NIH HHS [N01-AG-4-2110] NR 20 TC 8 Z9 8 U1 1 U2 2 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2001 VL 49 IS 4 BP 375 EP 381 DI 10.1046/j.1532-5415.2001.49079.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 426CC UT WOS:000168331300004 PM 11347779 ER PT J AU Boyd, CM Xue, Q Guralnik, JM Fried, LP AF Boyd, CM Xue, Q Guralnik, JM Fried, LP TI The association of incident hospitalization with incident and persistent dependence in activities of daily living (ADLS) in a cohort of moderately to severely disabled community-dwelling older women. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract C1 Johns Hopkins Univ, Baltimore, MD USA. NIA, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2001 VL 49 IS 4 MA P398 BP S136 EP S136 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 426CC UT WOS:000168331300472 ER PT J AU Cohen, HJ Pieper, CF Harris, T AF Cohen, HJ Pieper, CF Harris, T TI Markers of inflammation and coagulation predict decline in function and mortality in community dwelling elderly SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract C1 Duke Univ, Med Ctr, Ctr Aging, Durham, NC 27710 USA. NIA, Epidemiol Demography & Biometry Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2001 VL 49 IS 4 MA A3 BP S1 EP S1 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 426CC UT WOS:000168331300036 ER PT J AU Ferrucci, L Pahor, M Penninx, BJ Di Bari, M Guralnik, JM Chen, JM Applegate, WB Furberg, CA AF Ferrucci, L Pahor, M Penninx, BJ Di Bari, M Guralnik, JM Chen, JM Applegate, WB Furberg, CA TI Treatment of systolic hypertension in older patients who should be treated more aggressively. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract C1 INRCA, Dept Geriatr, Lab Clin Epidemiol, Florence, Italy. Wake Forest Univ, Sch Med, Dept Internal Med, Winston Salem, NC USA. NIA, Epidemiol Demog & Biometry Program, NIH, Bethesda, MD USA. RI DI BARI, MAURO/J-1524-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2001 VL 49 IS 4 MA P383 BP S131 EP S132 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 426CC UT WOS:000168331300457 ER PT J AU Guralnik, JM Ferrucci, L Volpato, S Simonsick, EM Fried, LP AF Guralnik, JM Ferrucci, L Volpato, S Simonsick, EM Fried, LP TI Patterns of change in physical function in women who develop ADL and severe mobility disability: Toward a nosologic classification of the disablement process. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract C1 NIA, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Dept Epidemiol, Baltimore, MD 21205 USA. NR 0 TC 6 Z9 6 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2001 VL 49 IS 4 MA A36 BP S12 EP S12 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 426CC UT WOS:000168331300068 ER PT J AU Hu, P Seeman, TE Harris, TB Reuben, DB AF Hu, P Seeman, TE Harris, TB Reuben, DB TI Is serum uric acid level associated with all-cause mortality in high-functioning elderly persons: MacArthur studies of successful aging. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract C1 Univ Calif Los Angeles, Multicampus Program Geriatr Med & Gerontol, Los Angeles, CA USA. NIA, Epidemiol Demography & Biometry Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2001 VL 49 IS 4 MA A34 BP S11 EP S12 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 426CC UT WOS:000168331300066 ER PT J AU Magboo, MC Plassman, BL Havlik, RJ Steffens, DC Helms, MJ Burke, JR Launer, LJ Phillips, C Guralnik, JM Breitner, JC AF Magboo, MC Plassman, BL Havlik, RJ Steffens, DC Helms, MJ Burke, JR Launer, LJ Phillips, C Guralnik, JM Breitner, JC TI Documented head injury in early adulthood and risk of stroke in late life. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract C1 Duke Univ, Dept Psychiat & Behav Sci, Durham, NC USA. Duke Univ, Dept Neurol, Durham, NC USA. Duke Univ, Ctr Aging, Durham, NC USA. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Baltimore, MD USA. RI Burke, James/E-4245-2016 OI Burke, James/0000-0002-3408-7787 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2001 VL 49 IS 4 MA P23 BP S22 EP S22 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 426CC UT WOS:000168331300100 ER PT J AU Pahor, M Kritchevsky, SB Tracy, RP Newman, AB Sutton-Tyrrell, KS Penninx, BW Onder, G Simonsick, EM Harris, TB AF Pahor, M Kritchevsky, SB Tracy, RP Newman, AB Sutton-Tyrrell, KS Penninx, BW Onder, G Simonsick, EM Harris, TB TI Interleukin-6, tumor necrosis factor-alpha, C-reactive protein and subclinical cardiovascular disease in older persons: The Health ABC study. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract C1 Wake Forest Univ, Sch Med, Winston Salem, NC USA. Univ Tennessee, Memphis, TN USA. Univ Vermont, Burlington, VT USA. Univ Pittsburgh, Pittsburgh, PA USA. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD USA. RI DI BARI, MAURO/J-1524-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2001 VL 49 IS 4 MA P230 BP S85 EP S85 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 426CC UT WOS:000168331300305 ER PT J AU Pahor, M Kritchevsky, SB Tracy, RP Newman, AB Di Bari, M Williamson, JD Penninx, BW Harris, TB Cummings, SR AF Pahor, M Kritchevsky, SB Tracy, RP Newman, AB Di Bari, M Williamson, JD Penninx, BW Harris, TB Cummings, SR TI Interleukin-6 and heart rate in older persons: The Health ABC study. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract C1 Wake Forest Univ, Sch Med, Winston Salem, NC USA. Univ Tennessee, Memphis, TN USA. Univ Vermont, Burlington, VT 05405 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. NIA, Epidemiol Biometry & Demog Program, Bethesda, MD USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RI DI BARI, MAURO/J-1524-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2001 VL 49 IS 4 MA P231 BP S85 EP S85 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 426CC UT WOS:000168331300306 ER PT J AU Simpson, C Boyd, C Guralnik, J Kasper, J Fried, LP AF Simpson, C Boyd, C Guralnik, J Kasper, J Fried, LP TI Agreement between self-report of disease diagnoses and medical record validation in disabled, older women: Factors that modify agreement. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract C1 Johns Hopkins Univ, Sch Med, Baltimore, MD USA. NIA, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Publ Hlth, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2001 VL 49 IS 4 MA A35 BP S12 EP S12 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 426CC UT WOS:000168331300067 ER PT J AU Vaitkevicius, PV Shah, MS Lane, M Spurgeon, H Ingram, DK Roth, GS Cerami, A Egan, JJ Vasan, S Lakatta, EG AF Vaitkevicius, PV Shah, MS Lane, M Spurgeon, H Ingram, DK Roth, GS Cerami, A Egan, JJ Vasan, S Lakatta, EG TI A novel cross-link breaker has sustained effects on arterial and ventricular properties in older rhesus monkeys. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract C1 Univ Michigan, Div Geriatr, Ann Arbor, MI USA. Univ Michigan, Div Cardiol, Ann Arbor, MI USA. NIH, NIA, Ctr Gerontol Res, Baltimore, MD USA. Kenneth S Warren Labs, Tarrytown, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2001 VL 49 IS 4 MA P110 BP S49 EP S49 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 426CC UT WOS:000168331300187 ER PT J AU Williamson, JD Penninx, BW Dibari, M Onder, G Guralnik, JM Fried, L Pahor, M AF Williamson, JD Penninx, BW Dibari, M Onder, G Guralnik, JM Fried, L Pahor, M TI Blood pressure control & incident disability in high-risk older women: Data from the Women's Health and Aging Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract C1 Wake Forest Univ, Winston Salem, NC 27109 USA. NIA, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD 21218 USA. RI DI BARI, MAURO/J-1524-2012 NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2001 VL 49 IS 4 MA P401 BP S137 EP S137 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 426CC UT WOS:000168331300475 ER PT J AU Zieman, SJ Gerstenblith, G Fleg, JL Townsend, SN Waldron, MM Cosgriff, RF Risby, TH AF Zieman, SJ Gerstenblith, G Fleg, JL Townsend, SN Waldron, MM Cosgriff, RF Risby, TH TI Breath ethane, a measure of oxidative stress, does not increase with age during aerobic exercise. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract C1 Johns Hopkins Univ, Baltimore, MD USA. NIA, Baltimore, MD 21224 USA. NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2001 VL 49 IS 4 MA P341 BP S118 EP S119 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 426CC UT WOS:000168331300415 ER PT J AU Ornstein, DK Cinquanta, M Weiler, S Duray, PH Emmert-Buck, MR Vocke, CD Linehan, WM Ferretti, JA AF Ornstein, DK Cinquanta, M Weiler, S Duray, PH Emmert-Buck, MR Vocke, CD Linehan, WM Ferretti, JA TI Expression studies and mutational analysis of the androgen regulated homeobox gene NKX3.1 in benign and malignant prostate epithelium SO JOURNAL OF UROLOGY LA English DT Article DE prostate; epithelium; prostatic neoplasms; genes, homeobox; gene expression ID TISSUE-SPECIFIC EXPRESSION; ALLELIC LOSS; INTRAEPITHELIAL NEOPLASIA; CHROMOSOME 8P12-21; MEMBRANE ANTIGEN; 8P SEQUENCES; CANCER; IDENTIFICATION; REGION; CDX1 AB Purpose: The NKX-3.1gene is an androgen regulated prostate specific homeobox gene that is believed to have a vital role in normal prostate development. In mice the homologue NKx3.1 is exclusively expressed in prostate epithelium. In humans NKX3.1 expression is also restricted to the prostate but to our knowledge the cellular location has not been described. Furthermore, since NKX3.1 maps to chromosomal band 8p21, a region with high loss of heterozygosity in prostate cancer, the gene has been proposed to have tumor suppressor function. In this study we demonstrate that in human prostates NKX3.1 is expressed exclusively in secretory epithelial cells and the level of NKX3.1 expression remains invariant in normal tissue and in tissue showing various grades of prostate cancer. In the 19 cases examined the DNA sequences of the NKX3.1 gene were identical and no mutation was detected. Materials and Methods: Frozen tissue from patients who underwent radical prostatectomy was used for this study. For in situ hybridization experiments a 377 bp fragment corresponding to a portion of the 3' untranslated region of the NKX3.1 gene was amplified by polymerase chain reaction and cloned into the pCRII plasmid vector Invitrogen. Antisense or sense [P-33] uridine triphosphate labeled RNA probes were generated with SP6 or T7 RNA polymerase and hybridized to the tissue sections. Slides were exposed to photographic emulsion and visualized on autoradiography. Laser capture microdissection was performed to procure pure populations of malignant epithelium. DNA was isolated by digesting samples in proteinase K buffer. Polymerase chain reaction and direct sequencing was performed using standard protocols. Results: In vitro hybridization showed that NKX3.1 expression was restricted to secretory epithelial cells within benign prostate glands. No expression was detected in stroma or infiltrating lymphocytes. NKX3.1 was expressed in all grades of malignant epithelium in all 25 cases examined. Direct sequencing of the coding region of NKX3.1 revealed the wild-type sequence in all 18 microdissected cancers analyzed. Conclusions: Based on our studies we propose that NKX3.1 gene expression is restricted to benign and malignant secretory epithelium within the prostate but NKX3.1. does not appear to be a classic tumor suppressor gene responsible for prostate cancer initiation. These findings are consistent with the role of NKX3.1 in the development of normal prostate epithelium and maintenance of normal secretory function. Thus, NKX3.1 may represent a useful molecular marker for benign and malignant prostate epithelium. C1 NHLBI, Biophys Chem Lab, Bethesda, MD 20892 USA. NHLBI, Lab Biochem Genet, Bethesda, MD 20892 USA. NCI, Pathol Lab, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Ornstein, DK (reprint author), Univ N Carolina, Dept Surg, Div Urol, 427 Burnett Womack Bldg,CB 7285, Chapel Hill, NC 27599 USA. NR 23 TC 57 Z9 63 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD APR PY 2001 VL 165 IS 4 BP 1329 EP 1334 DI 10.1016/S0022-5347(01)69894-X PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 411MK UT WOS:000167503700097 PM 11257711 ER PT J AU Hvizda, JL Wood, BJ AF Hvizda, JL Wood, BJ TI Selective transcatheter platelet infusion for gastrointestinal bleeding after failed embolization with resistant thrombocytopenia SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Letter C1 NIH, Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Hvizda, JL (reprint author), NIH, Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, Bldg 10,Room 1C660,10 Ctr Dr,MSC 1182, Bethesda, MD 20892 USA. FU Intramural NIH HHS [NIH0010126778]; PHS HHS [NIH0010126778] NR 2 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD APR PY 2001 VL 12 IS 4 BP 549 EP 550 DI 10.1016/S1051-0443(07)61901-0 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 419BC UT WOS:000167928600025 PM 11287549 ER PT J AU An, DS Kung, SKP Bonifacino, A Wersto, RP Metzger, ME Agricola, BA Mao, SH Chen, ISY Donahue, RE AF An, DS Kung, SKP Bonifacino, A Wersto, RP Metzger, ME Agricola, BA Mao, SH Chen, ISY Donahue, RE TI Lentivirus vector-mediated hematopoietic stem cell gene transfer of common gamma-chain cytokine receptor in rhesus macaques SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MURINE LEUKEMIA-VIRUS; IN-VIVO EXPRESSION; BONE-MARROW CELLS; LONG-TERM ENGRAFTMENT; BLOOD CD34(+) CELLS; NONHUMAN-PRIMATES; PERIPHERAL-BLOOD; REPOPULATING CELLS; RETROVIRAL VECTOR AB Nonhuman primate model systems of autologous CD34(+) cell transplant are the most effective means to assess the safety and capabilities of lentivirus vectors. Toward this end,,ve tested the efficiency of marking, gene expression, and transplant of hone marrow and peripheral blood CD34(+) cells using a self-inactivating lentivirus vector (CS-Rh-MLV-E) bearing an internal murine leukemia virus long terminal repeat derived from a murine retrovirus adapted to replicate in rhesus macaques. In vitro cytokine stimulation was not required to achieve efficient transduction of CD34(+) cells resulting in marking and gene expression of the reporter gene encoding enhanced green fluorescent protein (EGFP) following transplant of the CD34(+) cells. Monkeys transplanted with mobilized peripheral blood CD34(+) cells resulted in EGFP expression in 1 to 10% of multilineage peripheral blood cells, including red blood cells and platelets, stable for 15 months to date. The relative level of gene expression utilizing this vector is 2- to 10-fold greater than that utilizing a non-self-inactivating lentivirus vector bearing the cytomegalovirus immediate-early promoter. In contrast, in animals transplanted with autologous bone marrow CD34(+) cells, multilineage EGFP expression was evident initially but diminished over time. We further tested our lentivirus vector system by demonstrating gene transfer of the human common gamma-chain cytokine receptor gene (gamma (c)), deficient in X-linked SCID patients and recently successfully used to treat disease. Marking was 0.42 and .001 HIV-1 vector DNA copy per 100 cells in two animals. To date, all EGFP- and gamma (c)-transplanted animals are healthy. This system may prove useful for expression of therapeutic genes in human hematopoietic cells. C1 Univ Calif Los Angeles, Sch Med, AIDS Inst, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Microbiol & Immunol & Mol Genet, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. NHLBI, Hematol Branch, Rockville, MD 20850 USA. RP Chen, ISY (reprint author), Univ Calif Los Angeles, Sch Med, AIDS Inst, 10833 LeConte Ave,11-934 Factor Bldg, Los Angeles, CA 90095 USA. FU NIAID NIH HHS [AI39975-01, AI36555, R01 AI039975] NR 50 TC 68 Z9 70 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR PY 2001 VL 75 IS 8 BP 3547 EP 3555 DI 10.1128/JVI.75.8.3547-3555.2001 PG 9 WC Virology SC Virology GA 414QN UT WOS:000167677800006 PM 11264344 ER PT J AU Mautino, MR Keiser, N Morgan, RA AF Mautino, MR Keiser, N Morgan, RA TI Inhibition of human immunodeficiency virus type 1 (HIV-1) replication by HIV-1-based lentivirus vectors expressing transdominant Rev SO JOURNAL OF VIROLOGY LA English DT Article ID CONSTITUTIVE TRANSPORT ELEMENT; RETROVIRAL VECTORS; GENE-THERAPY; T-CELLS; PROTEIN EXPRESSION; PARTICLE FORMATION; NONDIVIDING CELLS; CD34(+) CELLS; ANTISENSE-TAR; LYMPHOCYTES AB Retrovirus vectors expressing transdominant-negative mutants of Rev (TdRev) inhibit human immunodeficiency virus type 1 (HIV-1) replication by preventing the nuclear export of unspliced viral transcripts, thus inhibiting the synthesis of Gag-Pol, Env, and genomic RNA. The use of HIV-1-based vectors to express TdRev would have the advantage of allowing access to nondividing hematopoietic cells. It would also provide additional levels of protection by sequestering the viral regulatory proteins Tat and Rev, competing for encapsidation into wild-type virions, and inhibiting reverse transcription. Here we describe HIV-1-based vectors that express TdRev, These vectors contain mutations in the splicing signals or replacement of the Rev-responsive element by the simian retrovirus type 1 constitutive transport element, making them less sensitive to the inhibitory effects of TdRev, In addition, overexpression of Rev and the use of an HIV-1 helper plasmid that drives high levels of Gag-Pol synthesis were used to transiently overcome the inhibition by TdRev of the synthesis of Gag-Pol during vector production. SupT1 cells transduced with these vectors were more resistant to HIV-1 replication than cells transduced with Moloney murine leukemia virus-based vectors expressing TdRev, Furthermore, we show that these vectors can be mobilized by the wild-type virus, reducing the infectivity of virions escaping inhibition and conferring protection against HIV-1 replication to previously untransduced cells. C1 NHGRI, Clin Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. RP Morgan, RA (reprint author), NHGRI, Clin Gene Therapy Branch, NIH, Bldg 10,Room 10C103, Bethesda, MD 20892 USA. NR 44 TC 12 Z9 12 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR PY 2001 VL 75 IS 8 BP 3590 EP 3599 DI 10.1128/JVI.75.8.3590-3599.2001 PG 10 WC Virology SC Virology GA 414QN UT WOS:000167677800010 PM 11264348 ER PT J AU Teterina, NL Egger, D Bienz, K Brown, DM Semler, BL Ehrenfeld, E AF Teterina, NL Egger, D Bienz, K Brown, DM Semler, BL Ehrenfeld, E TI Requirements for assembly of poliovirus replication complexes and negative-strand RNA synthesis SO JOURNAL OF VIROLOGY LA English DT Article ID IN-SITU HYBRIDIZATION; ENDOPLASMIC-RETICULUM; MEMBRANE-PERMEABILITY; VIRAL REPLICATION; PROTEIN 3AB; ENTRY SITE; POLYMERASE; 2C; CELLS; EXPRESSION AB HeLa cells were transfected with several plasmids that encoded all poliovirus (PV) nonstructural proteins. Viral RNAs were transcribed by T7 RNA polymerase expressed from recombinant vaccinia virus. All plasmids produced similar amounts of viral proteins that were processed identically; however, RNAs were designed either to serve as templates for replication or to contain mutations predicted to prevent RNA replication. The mutations included substitution of the entire PV 5' noncoding region (NCR) with the encephalomyocarditis virus (EMCV) internal ribosomal entry site, thereby deleting the 5'-terminal cloverleaf-like structure, or insertion of three nucleotides in the 3D(pol) coding sequence. Production of viral proteins was sufficient to induce the characteristic reorganization of intracellular membranes into heterogeneous-sized vesicles, independent of RNA replication. The vesicles were stably associated,vith viral RNA only when RNA replication could occur. Nonreplicating RNAs localized to distinct, nonoverlapping regions in the cell, excluded from the viral protein-membrane complexes. The absence of accumulation of positive-strand RNA from both mutated RNAs in transfected cells was documented. In addition, no minus-strand RNA was produced from the EMCV chimeric template RNA in vitro. These data show that the 5'-terminal sequences of PV RNA are essential for initiation of minus-strand RNA synthesis at its 3' end. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. Univ Basel, Inst Med Microbiol, Basel, Switzerland. Univ Calif Irvine, Coll Med, Dept Microbiol & Mol Genet, Irvine, CA 92717 USA. RP Ehrenfeld, E (reprint author), NIAID, Viral Dis Lab, NIH, Bldg 9,Room 1 E 100,MSC 0930, Bethesda, MD 20892 USA. FU NIAID NIH HHS [AI 22693, AI07319, T32 AI007319, R01 AI022693] NR 55 TC 59 Z9 61 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR PY 2001 VL 75 IS 8 BP 3841 EP 3850 DI 10.1128/JVI.75.8.3841-3850.2001 PG 10 WC Virology SC Virology GA 414QN UT WOS:000167677800035 PM 11264373 ER PT J AU Parker, JSL Murphy, WJ Wang, D O'Brien, SJ Parrish, CR AF Parker, JSL Murphy, WJ Wang, D O'Brien, SJ Parrish, CR TI Canine and feline parvoviruses can use human or feline transferrin receptors to bind, enter, and infect cells SO JOURNAL OF VIROLOGY LA English DT Article ID PANLEUKOPENIA VIRUS; HOST-RANGE; CAPSID STRUCTURE; MONOCLONAL-ANTIBODIES; MEDIATED ENDOCYTOSIS; TRAFFICKING; EVOLUTION; INVITRO; PATHWAY; MAP AB Canine parvovirus (CPV) enters and infects cells by a dynamin-dependent, clathrin-mediated endocytic pathway, and viral capsids colocalize with transferrin in perinuclear vesicles of cells shortly after entry (J. S. L. Parker and C. R. Parrish, J. Virol. 74:1919-1930, 2000). Here we report that CPV and feline panleukopenia virus (FPV), a closely related parvovirus, bind to the human and feline transferrin receptors (TfRs) and use these receptors to enter and infect cells. Capsids did not detectably bind or enter quail QT35 cells or a Chinese hamster ovary (CHO) cell-derived cell line that lacks any TfR (TRVb cells). However, capsids bound and were endocytosed into QT35 cells and CHO-derived TRVb-1 cells that expressed the human TfR. TRVb-1 cells or TRVb cells transiently expressing the feline TfR were susceptible to infection by CPV and FPV, but the parental TRVb cells were not. We screened a panel of feline-mouse hybrid cells for susceptibility to FPV infection and found that only those cells that possessed feline chromosome C2 were susceptible. The feline TfR gene (TRFC) also mapped to feline chromosome C2. These data indicate that cell susceptibility for these viruses is determined by the TfR. C1 Cornell Univ, Coll Vet Med, James A Baker Inst, Ithaca, NY 14853 USA. Natl Canc Inst, Lab Genom Divers, Frederick, MD 21702 USA. RP Parrish, CR (reprint author), Cornell Univ, Coll Vet Med, James A Baker Inst, Ithaca, NY 14853 USA. OI Parker, John/0000-0003-4487-4175 FU NIAID NIH HHS [AI33468, AI28385, F32 AI010134, F32 AI10134, R01 AI028385, R01 AI033468] NR 36 TC 139 Z9 151 U1 2 U2 15 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR PY 2001 VL 75 IS 8 BP 3896 EP 3902 DI 10.1128/JVI.75.8.3896-3902.2001 PG 7 WC Virology SC Virology GA 414QN UT WOS:000167677800040 PM 11264378 ER PT J AU Imamichi, T Murphy, MA Imamichi, H Lane, HC AF Imamichi, T Murphy, MA Imamichi, H Lane, HC TI Amino acid deletion at codon 67 and Thr-to-Gly change at codon 69 of human immunodeficiency virus type 1 reverse transcriptase confer novel drug resistance profiles SO JOURNAL OF VIROLOGY LA English DT Article ID BETA-3-BETA-4 HAIRPIN LOOP; COMBINATION THERAPY; INHIBITORS; GENE; INSERTION; MUTATIONS; CLEAVAGE; MUTANTS; SITES AB The potential rules of an amino acid deletion at codon 67 (Delta 67) and a Thr-to-Gly change at codon 69 (T69G) in the reverse transcriptase of human immunodeficiency virus (HIV) type 1 in drug sensitivity and relative replication fitness were studied. Our results suggest that the Delta 67 and T69G changes can be categorized as mutations associated with multidrug resistance. The combination of both mutations with an L74I change (Delta 67+T69G/L74I) leads to a novel 3'-azido-3'-deoxythymidine resistance motif and compensates for impaired HIV replication. C1 NCI, Lab Mol Retrovirol, Clin Serv Program, SAIC Frederick, Frederick, MD 21702 USA. NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. RP Imamichi, T (reprint author), NCI, Lab Mol Retrovirol, Clin Serv Program, SAIC Frederick, Bldg 550,Room 126,POB B, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 22 TC 30 Z9 30 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR PY 2001 VL 75 IS 8 BP 3988 EP 3992 DI 10.1128/JVI.75.8.3988-3992.2001 PG 5 WC Virology SC Virology GA 414QN UT WOS:000167677800051 PM 11264389 ER PT J AU Oren, DA Zulman, DM Needham, WE Berman, RM Anand, A Charney, DS AF Oren, DA Zulman, DM Needham, WE Berman, RM Anand, A Charney, DS TI Visual impairment and patterns of winter seasonal depression: Seeing the light? SO JOURNAL OF VISUAL IMPAIRMENT & BLINDNESS LA English DT Article ID AFFECTIVE-DISORDER; MOOD C1 VA Connecticut Healthcare Syst, W Haven, CT 06516 USA. Yale Univ, Sch Med, Dept Psychiat, W Haven, CT 06516 USA. Stanford Univ, Stanford, CA 94305 USA. Pfizer Corp, New York, NY 10017 USA. NIMH, Mood & Anxiety Intramural Programs, Bethesda, MD 20892 USA. RP Oren, DA (reprint author), VA Connecticut Healthcare Syst, Mailstop 116A,950 Campbell Ave, W Haven, CT 06516 USA. RI Anand, Amit/D-4232-2013 NR 15 TC 1 Z9 1 U1 0 U2 0 PU AMER FOUNDATION BLIND PI NEW YORK PA J VISUAL IMPAIRMENT BLINDNESS 11 PENN PLAZA SUITE 300, NEW YORK, NY 10001 USA SN 0145-482X J9 J VISUAL IMPAIR BLIN JI J. Vis. Impair. Blind. PD APR PY 2001 VL 95 IS 4 BP 226 EP 229 PG 4 WC Rehabilitation SC Rehabilitation GA 421PR UT WOS:000168073200004 ER PT J AU Melton, LJ Hesdorffer, DC Malkasian, GD Atkinson, EJ Brinton, LA O'Fallon, WM AF Melton, LJ Hesdorffer, DC Malkasian, GD Atkinson, EJ Brinton, LA O'Fallon, WM TI Long-term fracture risk among infertile women: A population-based cohort study SO JOURNAL OF WOMENS HEALTH & GENDER-BASED MEDICINE LA English DT Article ID BONE MASS; VERTEBRAL FRACTURES; HIP FRACTURE; INVOLUTIONAL OSTEOPOROSIS; REPRODUCTIVE FACTORS; DEFINED POPULATION; EPIDEMIOLOGY; HISTORY; PERIMENOPAUSAL; PREVALENCE AB Nulliparity has been linked to bone loss and fractures, but the contribution of infertility is unclear. The purpose of this study was to assess the long-term risk of fractures among infertile women. In a population-based retrospective cohort study, all 658 Olmsted County, Minnesota, women with infertility (failure to conceive after 1 year despite intercourse without contraception) first diagnosed at Mayo Clinic in 1935-1964 were followed for fractures. Risk was assessed by comparing new fractures of each type to the number expected from sex-specific and age-specific fracture rates in the general population (standardized incidence ratios [SIR]). During 18,130 person-years of follow-up, 184 women experienced at least one fracture when 291 would have been expected on the basis of fracture incidence rates in the general population (SIR 0.6, 95% CI 0.5-0.7). There was no increase in proximal femur fractures (SIR 1.0, 95% CI 0.6-1.6) and a statistically significant decrease in the risk of distal forearm fractures (SIR 0.7, 95% CI 0.5-0.97), two of the three sites traditionally associated with osteoporosis. By contrast, there was a significant increase in subsequent vertebral fractures (SIR 1.9, 95% CI 1.4-2.4) that was consistent across divergent causes of infertility and reported menstrual patterns. Although an apparent increase in the risk of vertebral fractures requires further investigation, we saw no indication of an increase in limb fractures, suggesting that infertility does not have long-term adverse skeletal effects like those reported for athletes and dieters with irregular menses. C1 Mayo Clin & Mayo Fdn, Dept Hlth Sci Res, Clin Epidemiol Sect, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Dept Obstet & Gynecol, Rochester, MN 55905 USA. Columbia Univ, Coll Phys & Surg, Gertrude H Sergievsky Ctr, New York, NY USA. NCI, Environm Epidemiol Branch, Bethesda, MD 20892 USA. RP Melton, LJ (reprint author), Mayo Clin & Mayo Fdn, Dept Hlth Sci Res, Clin Epidemiol Sect, 200 1st St SW, Rochester, MN 55905 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 FU NIA NIH HHS [AG 04875]; NIAMS NIH HHS [AR 30582] NR 43 TC 6 Z9 6 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1524-6094 J9 J WOMEN HEALTH GEN-B JI J. WOMENS HEALTH GENDER-BASED MED. PD APR PY 2001 VL 10 IS 3 BP 289 EP 297 DI 10.1089/152460901300140040 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 430PX UT WOS:000168584700011 PM 11389789 ER PT J AU Maggi, S Minicuci, N Harris, T Motta, L Baldereschi, M Di Carlo, A Inzitari, D Crepaldi, G AF Maggi, S Minicuci, N Harris, T Motta, L Baldereschi, M Di Carlo, A Inzitari, D Crepaldi, G CA ILSA Grp TI High plasma insulin and lipids profile in older individuals: The Italian longitudinal study on aging SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID CORONARY HEART-DISEASE; CHOLESTEROL ABSORPTION; RISK FACTOR; DIABETES-MELLITUS; SERUM-CHOLESTEROL; LDL CHOLESTEROL; ELDERLY MEN; HYPERINSULINEMIA; ASSOCIATION; POPULATION AB Background. The inverse relationship of insulin level to high-density lipoprotein (HDL)-cholesterol and its positive association with hypertriglyceridemia has been demonstrated in several studies: however. the relationship of insulin to low-density lipoprotein (LDL)-cholesterol in elderly persons is not clear. This study investigates the relationships of tasting plasma insulin and selected metabolic and biological risk factors in an aged population. Methods. The present study is based on a cross-sectional analysis of the data collected;It baseline of the Italian Longitudinal Study on Aging in 1992 on a random sample of 5632 Italians aged 65-84 years. Analyses were performed to compare the distribution of risk factors. such as blood level of lipids, creatinine. albumin. fibrinogen, apolipoprotein A-1 and B, blood pressure, and body mass index (BMI). by quartiles of insulin, in both diabetic and nondiabetic participants. Results. Significantly higher levels of triglycerides and BMI and lower levels of HDL-cholesterol were found in the upper quartile of insulin among nondiabetic individuals. In men, we also found significantly higher level of systolic and diastolic blood pressure. The same trend for these variables, although not significant for HDL-cholesterol and blood pressure, was seen in diabetic men. In diabetic women, total and LDL-cholesterol were significantly lower in the highest insulin quartile (p < .001). while no significant differences were seen in nondiabetic: women or in men, we also found higher levels of white blood cells in the highest insulin quartile: of diabetic women. Conclusions. These results, apparently in disagreement with earlier reports on the clustering of cardiovasculur disease risk factors in hyperinsulinemic individuals, could be due to the high frequency of chronic inflammation and the high prevalence of urinary infections in older diabetic women. C1 Univ Padua, Ctr Aging, Natl Res Council, Padua, Italy. NIA, Epidemiol Demog & Biometry Program, NIH, Bethesda, MD 20892 USA. Univ Catania, I-95124 Catania, Italy. CNR, Florence, Italy. RP Maggi, S (reprint author), Univ Padua, Med Clin 1, Ctr Aging, MPH,CNR, Via Giustiniani 2, I-35128 Padua, Italy. RI MINICUCI, NADIA/D-5237-2016 OI MINICUCI, NADIA/0000-0002-0970-6531 NR 28 TC 10 Z9 10 U1 2 U2 2 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD APR PY 2001 VL 56 IS 4 BP M236 EP M242 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 421AZ UT WOS:000168041100013 PM 11283197 ER PT J AU Markides, KS Black, SA Ostir, GV Angel, RJ Guralnik, JM Lichtenstein, M AF Markides, KS Black, SA Ostir, GV Angel, RJ Guralnik, JM Lichtenstein, M TI Lower body function and mortality in Mexican American elderly people SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID LOWER-EXTREMITY FUNCTION; SUBSEQUENT DISABILITY; HEALTH-STATUS; OLDER ADULTS AB Background. The purpose of this analysis was to examine the differential impact of performance-based and self-reported lower body measures on 2-year mortality in Mexican American elderly persons. Methods. Data employed are from the Hispanic Established Population for Epidemiological Studies of the Elderly, a probability survey of 3050 community-dwelling Mexican Americans aged 65 and older from the five Southwestern states interviewed in 1993 and 1994. Of the baseline sample with complete data. 198 persons were confirmed deceased 2 years later. A three-task, performance-based. lower body function measure consisting of a short walk, balance. and repeated chair stands tests was used. Self-reported lower body function was measured by a 4-item Activities of Daily Living (ADL) measure involving the lower body. Results. The three-task. lower body function measure was a significant predictor of 2-year mortality. The short walk alone was as predictive as the summary measure. The predictive ability of both measures was minimally reduced by the inclusion of the self-reported ADL measure and life-threatening medical conditions. Finally. the ADL measure was not a significant predictor of mortality with all the other variables in the analysis. Conclusion. Objective measures of lower body function were significant predicators of mortality in Mexican American elderly persons, as found in the general population. Unlike previous studies, the ADL measure was not an independent predictor of mortality after controlling for the objective measure and other risk factors. Additional research is needed to address why objective measures of function are such strong predictors of death. C1 Univ Texas, Med Branch, Dept Prevent Med & Community Hlth, Galveston, TX 77555 USA. Univ Texas, Med Branch, Ctr Aging, Galveston, TX 77555 USA. Univ Texas, Dept Sociol, Austin, TX 78712 USA. NIA, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78284 USA. RP Markides, KS (reprint author), Univ Texas, Med Branch, Dept Prevent Med & Community Hlth, Galveston, TX 77555 USA. FU NIA NIH HHS [AG10939]; PHS HHS [17231] NR 24 TC 48 Z9 51 U1 0 U2 3 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD APR PY 2001 VL 56 IS 4 BP M243 EP M247 PG 5 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 421AZ UT WOS:000168041100014 PM 11283198 ER PT J AU Zhong, Z Connor, HD Yin, M Wheeler, MD Mason, RP Thurman, RG AF Zhong, Z Connor, HD Yin, M Wheeler, MD Mason, RP Thurman, RG TI Viral delivery of superoxide dismutase gene reduces cyclosporine A-induced nephrotoxicity SO KIDNEY INTERNATIONAL LA English DT Article DE immunosuppression; free radicals; adenovirus; oxidative stress; antioxidant enzyme ID VITAMIN-E; LIVER-TRANSPLANTATION; RADICAL GENERATION; REPERFUSION INJURY; LIPID-PEROXIDATION; DIETARY GLYCINE; RAT-HEART; INVIVO; METABOLISM; VASOCONSTRICTION AB Background. Cyclosporine A (CsA) increases Gee radical formation in the kidney. Accordingly, this study investigated whether gene delivery of superoxide dismutase (SOD) reduced radical production and nephrotoxicity caused by CsA. Methods. Rats were given adenovirus (Ad) carrying lacZ or Cu/Zn-SOD genes three days prior to CsA treatment. Histology, glomerular filtration rates (GFRs) and free radical adducts in urine were assessed. Results. SOD activity was increased 2.5-fold three days after viral infection and remained at 2- and 1.6-fold higher 10 and 17 days later. Treatment with CsA for seven days decreased GFR by 70% in rats infected with Ad-lacZ as expected; however, the decrease was diminished significantly in rats receiving Ad-SOD. CsA treatment for two weeks caused a loss of brush border and dilation of proximal tubules, necrosis. and increased leukocyte infiltration into the kidney; these effects were minimized by SOD. Dimethyl sulfoxide (DMSO) was attacked by the hydroxyl radical to produce a methyl radical. Indeed, administration of CsA with C-12-DMSO in rats infected with Ad-lacZ produced a radical adduct with hyperfine coupling constants similar to 4-POBN/methyl radical adduct and another unknown radical adduct. CsA given with C-13-DMSO produced a 12-line spectrum, confirming the involvement of hydroxyl radicals. Free radical adducts detected in urine were increased approximately fivefold by CsA, an effect blocked completely by SOD. Conclusions. CsA increases free radical formation. Gene delivery of SOD blocks formation of free radicals, thereby minimizing nephrotoxicity caused by CsA. C1 Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. Univ N Carolina, Lab Hepatobiol & Toxicol, Chapel Hill, NC 27599 USA. NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Thurman, RG (reprint author), Univ N Carolina, Dept Pharmacol, CB 7365,Mary Ellen Jones Bldg, Chapel Hill, NC 27599 USA. FU NIAAA NIH HHS [AA-09156, AA-11605-1] NR 49 TC 20 Z9 22 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD APR PY 2001 VL 59 IS 4 BP 1397 EP 1404 DI 10.1046/j.1523-1755.2001.0590041397.x PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 415RV UT WOS:000167737200021 PM 11260401 ER PT J AU Kimmel, PL Levy, N Vassalotti, J Christensen, A Friend, R Veis, J Peterson, R Devins, G Lew, SQ Star, R Reiss, D AF Kimmel, PL Levy, N Vassalotti, J Christensen, A Friend, R Veis, J Peterson, R Devins, G Lew, SQ Star, R Reiss, D TI Psychosocial factors in dialysis patients SO KIDNEY INTERNATIONAL LA English DT Article DE end-stage renal disease; stress; depression; social support; illness effects; marriage; family ID STAGE RENAL-DISEASE; LONG-TERM DIALYSIS; QUALITY-OF-LIFE; URBAN HEMODIALYSIS-PATIENTS; MAJOR DEPRESSION; SOCIOECONOMIC-STATUS; BEHAVIORAL COMPLIANCE; ILLNESS INTRUSIVENESS; AFRICAN-AMERICAN; FAMILY SUPPORT C1 NIDDKD, Diabet Nephropathy Program, NIH, Bethesda, MD 20892 USA. George Washington Univ, Med Ctr, Dept Med, Div Renal Dis & Hypertens, Washington, DC 20037 USA. NIDDKD, HIV Programs, NIH, Bethesda, MD 20892 USA. SUNY Hlth Sci Ctr, Brooklyn, NY 11203 USA. Mt Sinai Sch Med, New York, NY USA. Univ Iowa, Iowa City, IA USA. SUNY Stony Brook, Stony Brook, NY 11794 USA. Washington Hosp Ctr, Washington, DC 20010 USA. George Washington Univ, Dept Psychol, Washington, DC 20052 USA. Univ Toronto, Toronto, ON, Canada. RP Kimmel, PL (reprint author), NIDDKD, Diabet Nephropathy Program, NIH, 2 Democracy Plaza,6707 Democracy Blvd, Bethesda, MD 20892 USA. NR 81 TC 197 Z9 209 U1 3 U2 10 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD APR PY 2001 VL 59 IS 4 BP 1599 EP 1613 DI 10.1046/j.1523-1755.2001.0590041599.x PG 15 WC Urology & Nephrology SC Urology & Nephrology GA 415RV UT WOS:000167737200053 PM 11260433 ER PT J AU Said, JW Hoyer, KK French, SW Rosenfelt, L Garcia-Lloret, M Koh, PJ Cheng, TC Sulur, GG Pinkus, GS Kuehl, WM Rawlings, DJ Wall, R Teitell, MA AF Said, JW Hoyer, KK French, SW Rosenfelt, L Garcia-Lloret, M Koh, PJ Cheng, TC Sulur, GG Pinkus, GS Kuehl, WM Rawlings, DJ Wall, R Teitell, MA TI TCL1 oncogene expression in B cell subsets from lymphoid hyperplasia and distinct classes of B cell lymphoma SO LABORATORY INVESTIGATION LA English DT Article ID EPSTEIN-BARR-VIRUS; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; AIDS-RELATED LYMPHOMAS; NON-HODGKINS-LYMPHOMAS; IN-VITRO; ATAXIA TELANGIECTASIA; GENE; MALIGNANCIES; TRANSLOCATION; LEUKEMIA AB Activation of the TCL1 oncogene has been implicated in T cell leukemias/lymphomas and recently was associated with AIDS diffuse large B cell lymphomas (AIDS-DLBCL). Also, in nonmalignant lymphoid tissues, antibody staining has shown that mantle zone B cells expressed abundant Tcl1 protein, whereas germinal center (GC; centrocytes and centroblasts) B cells showed markedly reduced expression. Here, we analyze isolated B cell subsets from hyperplastic tonsil to determine a more precise pattern of Tcl1 expression with development. We also examine multiple B cell lines and B lymphoma patient samples to determine whether different tumor classes retain or alter the developmental pattern of expression. We show that TCL1 expression is not affected by Epstein-Barr virus (EBV) infection and is high in naive B cells, reduced in GC B cells, and absent in memory B cells and plasma cells. Human herpesvirus-8 infected primary effusion lymphomas (PEL) and multiple myelomas are uniformly TCL1 negative, whereas all other transformed B cell lines tested express moderate to abundant TCL1. This observation supports the hypothesis that PEL, like myeloma, usually arise from post-GC stages of B cell development. Tell protein is also detected in most naive/GC-derived B lymphoma patient samples (23 of 27 [85%] positive), whereas most post-GC-derived B lymphomas lack expression (10 of 41 [24%] positive). These data indicate that the pattern of Tell expression is distinct between naive/GC and post-GC-derived B lymphomas (P < 0.001) and that the developmental pattern of expression is largely retained. However, post-GC-derived AIDS-DLBCL express TCL1 at a frequency equivalent to naive/GC-derived B lymphomas in immune-competent individuals (7 of 9 [78%] positive), suggesting that TCL1 down-regulation is adversely affected by severe immune system dysfunction. These findings demonstrate that TCL1 expression in B cell lymphoma usually reflects the stage of B cell development from which they derive, except in AIDS-related lymphomas. C1 Univ Calif Los Angeles, Sch Med, Ctr Hlth Sci, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Dept Pediat, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Microbiol & Immunol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. NCI, Dept Genet, Bethesda, MD 20892 USA. RP Teitell, MA (reprint author), Univ Calif Los Angeles, Sch Med, Ctr Hlth Sci, Dept Pathol & Lab Med, 10833 Le Conte Ave, Los Angeles, CA 90095 USA. FU NCI NIH HHS [CA74929, CA85841]; NIGMS NIH HHS [GM40185] NR 39 TC 63 Z9 67 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD APR PY 2001 VL 81 IS 4 BP 555 EP 564 PG 10 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 423JW UT WOS:000168174000014 PM 11304575 ER PT J AU Aoki, Y Tosato, G AF Aoki, Y Tosato, G TI Vascular endothelial growth factor/vascular permeability factor in the pathogenesis of primary effusion lymphomas SO LEUKEMIA & LYMPHOMA LA English DT Article DE VEGF/VPF; PEL; KSHV/HHV-8; Flt-1; KDR/Flk-1; AIDS ID HERPESVIRUS-ENCODED INTERLEUKIN-6; MOUSE ASCITES TUMORS; EPSTEIN-BARR VIRUS; KAPOSIS-SARCOMA; TYROSINE KINASE; ANGIOGENESIS; EXPRESSION; CELLS; HUMAN-HERPESVIRUS-8; CD138/SYNDECAN-1 AB Primary effusion lymphomas (PEL), rare lymphomas associated with Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) infection, present as malignant lymphomatous effusions in body cavities. We have recently found that PEL effusions contain high levels: of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF). VEGF/VPF, an important regulator of tumor-angiogenesis in vivo, exerts its effects acting through the receptors KDR/Flk-1 and Flt-1 on the endothelial cell membrane. In vitro, the PEL cell lines BC-1, BCP-1 and BCBL-1 produce high levels of VEGF. RT-PCR analysis of RNA from the PEL cell lines amplified the three VEGF/VPF secreted isoforms, VEGF/VPF121, VEGF/VPF145 and VEOF/VPF165. Two of the PEL cell lines express the VEGF/VPF receptor Flt-1. hut VEGF did not stimulate proliferation in these cells. SCID/beige mice inoculated intraperitoneally with BCBL-1 cells developed effusion lymphoma of human cell origin with prominent bloody ascites. In contrast, none of the mice treated with a neutralizing anti-human VEGF/VPF antibody developed ascites and effusion lymphoma. Although the precise mechanisms by which VEGF/VPF can promote vascular permeability are not fully understood. VEGF/VPF stimulation of vascular leakage may be critical to the pathogenesis of PEL. C1 NCI, Med Branch, NIH, Bethesda, MD 20892 USA. RP Aoki, Y (reprint author), NCI, Med Branch, NIH, Bldg 10,Rm 12C207,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 38 TC 30 Z9 32 U1 0 U2 0 PU HARWOOD ACAD PUBL GMBH PI READING PA C/O STBS LTD, PO BOX 90, READING RG1 8JL, BERKS, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD APR PY 2001 VL 41 IS 3-4 BP 229 EP + DI 10.3109/10428190109057978 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA 432AX UT WOS:000168665000001 PM 11378536 ER PT J AU Peters, DC Epstein, FH McVeigh, ER AF Peters, DC Epstein, FH McVeigh, ER TI Myocardial wall tagging with undersampled projection reconstruction SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE tagging; projection reconstruction; myocardial wall motion; undersampling; radial imaging ID COMPUTED-TOMOGRAPHY; SPATIAL MODULATION; INFARCTION; CONTRAST; MAGNETIZATION; RESOLUTION; MRI AB Azimuthally undersampled projection reconstruction (PR) acquisition is investigated for use in myocardial wall tagging with MR using grid tags to provide increased temporal and spatial resolution. PR can provide the high-resolution images required for tagging with very few projections, at the expense of artifact, Insight is provided into the PR undersampling artifact, in the context of measuring myocardial motion with tags. For Fourier transform imaging, at least 112 phase-encodings must be collected to image tagging grids spaced 7 pixels apart. PR requires about 80 projections, a 1.4-fold reduction in scan time. Magn Reson Med 45:562-567, 2001, Published 2001 Wiley-Liss, Inc.dagger. C1 NIH, Cardiac Energet Lab, Bethesda, MD 20892 USA. RP Peters, DC (reprint author), NIH, Cardiac Energet Lab, 10 Ctr Dr,Bldg 10 B1D416, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 HL004608-08] NR 25 TC 26 Z9 26 U1 1 U2 2 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD APR PY 2001 VL 45 IS 4 BP 562 EP 567 DI 10.1002/mrm.1076 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 417DA UT WOS:000167819100005 PM 11283982 ER PT J AU Van de Putte, T Zwijsen, A Lonnoy, O Rybin, V Cozijnsen, M Francis, A Baekelandt, W Kozak, CA Zerial, M Huylebroeck, D AF Van de Putte, T Zwijsen, A Lonnoy, O Rybin, V Cozijnsen, M Francis, A Baekelandt, W Kozak, CA Zerial, M Huylebroeck, D TI Mice with a homozygous gene trap vector insertion in mgcRacGAP die during pre-implantation development SO MECHANISMS OF DEVELOPMENT LA English DT Article DE blastocyst; cytokinesis; gene trapping; pre-implantation development; GTPase-activating protein ID GTPASE-ACTIVATING PROTEIN; MOUSE 8-CELL BLASTOMERES; EMBRYONIC STEM-CELLS; RHO-GTPASES; BRAIN; CDC42; EXPRESSION; BCR; RAC; ELECTROFUSION AB In a phenotypic screen in mice using a gene trap approach in embryonic stem cells, we have identified a recessive loss-of-function mutation in the mgcRacGAP gene. Maternal protein is present in the oocyte. and mgcRacGAP gene transcription starts at the four-cell stage and persists throughout mouse pre-implantation development. Total mgcRacGAP deficiency results in pre-implantation lethality. Such E3.5 embryos display a dramatic reduction in cell number, but undergo compaction and form a blastocoel. At E3.0-3.5, binucleated blastomeres in which the nuclei are partially interconnected are frequently observed, suggesting that mgcRacGAP is required for normal mitosis and cytokinesis in the pre-implantation embryo. All homozygous mutant blastocysts fail to grow out on fibronectin-coated substrates, but a fraction of them can still induce decidual swelling in vivo. The mgcRacGAP mRNA expression pattern in post-implantation embryos and adult mouse brain suggests a role in neuronal cells. Our results indicate that mgcRacGAP is essential for the earliest stages of mouse embryogenesis, and add evidence that CYK-4-like proteins also play a role in microtubule-dependent steps in the cytokinesis of vertebrate cells. In addition, the severe phenotype of null embryos indicates that mgcRacGAP is functionally non-redundant and cannot be substituted by other GAPs during early cleavage of the mammalian embryo. (C) 2001 Elsevier Science ireland Ltd. All rights reserved. C1 Catholic Univ Leuven VIB, Dept Cell Growth Differentiat & Dev VIB07, B-3000 Louvain, Belgium. Katholieke Univ Leuven, Lab Mol Biol CELGEN, B-3000 Louvain, Belgium. Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany. Katholieke Univ Leuven, Lab Expt Neurosurg & Neuroanat, Louvain, Belgium. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Huylebroeck, D (reprint author), Catholic Univ Leuven VIB, Dept Cell Growth Differentiat & Dev VIB07, Herestr 49, B-3000 Louvain, Belgium. EM danny.huylebroeck@med.kuleuven.ac.be NR 54 TC 32 Z9 33 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 EI 1872-6356 J9 MECH DEVELOP JI Mech. Dev. PD APR PY 2001 VL 102 IS 1-2 BP 33 EP 44 DI 10.1016/S0925-4773(01)00279-9 PG 12 WC Developmental Biology SC Developmental Biology GA 430JV UT WOS:000168571500003 PM 11287179 ER PT J AU Yoshino, K Rubin, JS Higinbotham, KG Uren, A Anest, V Plisov, SY Perantoni, AO AF Yoshino, K Rubin, JS Higinbotham, KG Uren, A Anest, V Plisov, SY Perantoni, AO TI Secreted Frizzled-related proteins can regulate metanephric development SO MECHANISMS OF DEVELOPMENT LA English DT Article DE embryonic induction; secreted Frizzled-related proteins; kidney; tubulogenesis; wnt ID KIDNEY DEVELOPMENT; EPITHELIAL TRANSFORMATION; SIGNAL-TRANSDUCTION; SPEMANN ORGANIZER; BETA-CATENIN; WNT FAMILY; EXPRESSION; MESENCHYME; RECEPTORS; DIFFERENTIATION AB Wnt-4 signaling plays a critical role in kidney development and is associated with the epithelial conversion of the metanephric mesenchyme. Furthermore, secreted Frizzled-related proteins (sFRPs) that can bind Wnts are normally expressed in the developing metanephros, and function in other systems as modulators of Wnt signaling. sfrp-1 is distributed throughout the medullary and cortical stroma in the metanephros, but is absent from condensed mesenchyme and primitive tubular epithelia of the developing nephron where wnt-1 is highly expressed. In contrast, sfrp-2 is expressed in primitive tubules. To determine their role in kidney development, recombinant sFRP-1, sFRP-2 or combinations of both were applied to cultures of 13-dpc rat metanephroi. Both tubule formation and bud branching were markedly inhibited by sFRP-1, but concurrent sFRP-2 treatment restored some tubular differentiation and bud branching, sFRP-2 itself showed no effect on cultures of metanephroi. In cultures of isolated, induced rat metanephric mesenchymes, sFRP-1 blocked events associated with epithelial conversion (tubulogenesis and expression of lim-1, sfrp-2 and E-cadherin); however, it had no demonstrable effect on early events (compaction of mesenchyme and expression of wt1). As shown herein, sFRP-1 binds Wnt-4 with considerable avidity and inhibits the DNA-binding activity of TCF, an effector of Wnt signaling, while sFRP 2 had no effect on TCF activation. These observations suggest that sFRP-1 and sFRP-2 compete locally to regulate Wnt signaling during renal organogenesis. The antagonistic effect of sFRP-1 may be important either in preventing inappropriate development within differentiated areas of the medulla or in maintaining a population of cortical blastemal cells to facilitate further renal expansion. On the other hand, sFRP-2 might promote tubule formation by permitting Wnt-4 signaling in the presence of sFRP-1. Published by Elsevier Science Ireland Ltd. C1 NCI, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. RP Yoshino, K (reprint author), NCI, Comparat Carcinogenesis Lab, Bldg 538,Room 205E, Frederick, MD 21702 USA. NR 43 TC 74 Z9 77 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD APR PY 2001 VL 102 IS 1-2 BP 45 EP 55 DI 10.1016/S0925-4773(01)00282-9 PG 11 WC Developmental Biology SC Developmental Biology GA 430JV UT WOS:000168571500004 PM 11287180 ER PT J AU Itoh, M Chitnis, AB AF Itoh, M Chitnis, AB TI Expression of proneural and neurogenic genes in the zebrafish lateral line primordium correlates with selection of hair cell fate in neuromasts SO MECHANISMS OF DEVELOPMENT LA English DT Article DE proneural; neurogenic; lateral inhibition; atonal; Notch; Delta; lateral line; neuromasts ID BRAIN; EMBRYOS AB Expression of a mouse atonal homologue, math1, defines: cells with the potential to become sensory hair cells in the mouse inner ear (Science 284 (1999) 1837) and Notch signaling limits the number of cells that are permitted to adopt this fate (Nat. Genet. 21 (1999) 289; J. Neurocytol. 28 (1999) 809). Failure of lateral inhibition mediated by Notch signaling is associated with an overproduction of ear hair cells in the zebrafish mind bomb (mib) and deltaA mutants (Development 125 (1998a) 4637; Development 126 (1999) 5669), suggesting a similar role for these genes in limiting the number of hair cells in the zebrafish ear. This study extends the analysis of proneural and neurogenic gene expression to the lateral line system, which detects movement via clusters of related sensory hair cells in specialized structures called neuromasts. We have compared the expression of a zebrafish atonal homologue, zath1, and neurogenic genes, deltaA, deltaB and notch3, in neuromasts and the posterior lateral line primordium (PLLP) of wild-type and mib mutant embryos. We describe progressive restriction of proneural and neurogenic gene expression in the migrating PLLP that appears to correlate with selection of hair cell fate in maturing neuromasts. In mib mutants there is a failure to restrict expression of zath1 and Delta homologues in the neuromasts revealing similarities with the phenotype previously described in the ear. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 NICHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. RP Chitnis, AB (reprint author), NICHD, Genet Mol Lab, NIH, Bldg 6B,Room 3B315, Bethesda, MD 20892 USA. NR 14 TC 87 Z9 89 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD APR PY 2001 VL 102 IS 1-2 BP 263 EP 266 DI 10.1016/S0925-4773(01)00308-2 PG 4 WC Developmental Biology SC Developmental Biology GA 430JV UT WOS:000168571500031 PM 11287207 ER PT J AU Daniels, N Sabin, JE AF Daniels, N Sabin, JE TI What are fairness and consistency in a national pharmacy benefit? SO MEDICAL CARE LA English DT Editorial Material ID ACCOUNTABILITY; ETHICS; CARE C1 Tufts Univ, Dept Philosophy, Medford, MA 02155 USA. NIH, Clin Bioeth Ctr, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Boston, MA USA. Harvard Pilgrim Hlth Care, Wellesley, MA USA. RP Daniels, N (reprint author), Tufts Univ, Dept Philosophy, Miner Hall, Medford, MA 02155 USA. NR 7 TC 4 Z9 4 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD APR PY 2001 VL 39 IS 4 BP 312 EP 314 DI 10.1097/00005650-200104000-00002 PG 3 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 419RD UT WOS:000167961700002 PM 11329518 ER PT J AU Lemmer, JT Ivey, FM Ryan, AS Martel, GF Hurlbut, DE Metter, JE Fozard, JL Fleg, JL Hurley, BF AF Lemmer, JT Ivey, FM Ryan, AS Martel, GF Hurlbut, DE Metter, JE Fozard, JL Fleg, JL Hurley, BF TI Effect of strength training on resting metabolic rate and physical activity: age and gender comparisons SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE resistance training; weight training; metabolic effects ID FAT-FREE MASS; ENERGY-EXPENDITURE; BODY-COMPOSITION; OLDER MEN; ADIPOSE-TISSUE; SUBSTRATE UTILIZATION; MUSCLE HYPERTROPHY; SKELETAL-MUSCLE; WEIGHT-LOSS; WOMEN AB Purpose: The purpose of this study was to compare age and gender effects of strength training (ST) on testing metabolic rate (RMR), energy expenditure of physical activity (EEPA), and body composition. Methods: RMR and EEPA were measured before and after 24 wk of ST in IO young men (20-30 yr), 9 young women (20-30 yr), ii older men (65-75 yr), and IO older women (65-75 yr). Results: When all subjects were pooled together, absolute RMR significantly increased by 7% (5928 +/- 1225 vs 6328 +/- 1336 kJ.d(-1), P < 0.001). Furthermore, ST increased absolute RMR by 78 in both young (6302 1458 vs 6719 +/- 1617 kJ.d(-1), P < 0.01) and older (5614 916 vs 5999 +/- 973 kJ.d(-1), P < 0.05) subjects, with no significant interaction between the two age groups. In contrast, there was a significant gender X time interaction (P < 0.05) for absolute RMR with men increasing RMR by 9% (6645 +/- 1073 vs 7237 +/- 1150 kJ.d(-1), P < 0.001), whereas women showed no significant increase (5170 884 vs 5366 +/- 692 kJ.d(-1), P = 0.108). When RMR was adjusted for fat-free mass (FFM) using ANCOVA, with all subjects pooled together, there was still a significant increase in RMR with ST. Additionally, there was still a gender effect (P < 0.05) and no significant age effect (P = NS), with only the men still showing a significant elevation in RMR. Moreover, EEPA and TEE estimated with a Tritrac accelerometer and TEE estimated by the Stanford Seven-Day physical Activity Recall: Questionnaire did not change in response to ST for any group. Conclusions: In conclusion changes in absolute and relative RMR in response to ST are influenced by gender but not age. In contrast to what has been suggested previously, changes in body composition in response to ST are not due to changes in physical activity outside of training. C1 Univ Maryland, Dept Kinesiol, Coll Hlth & Human Performance, College Pk, MD 20742 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Univ Maryland Eastern Shore, Dept Phys Therapy, Princess Anne, MD 21853 USA. Univ Maryland, Dept Med, Div Gerontol, Baltimore, MD 21201 USA. Morton Plant Mease Hlth Care, Florida Geriatr Res Program, Clearwater, FL 33756 USA. RP Hurley, BF (reprint author), Univ Maryland, Dept Kinesiol, Coll Hlth & Human Performance, College Pk, MD 20742 USA. RI Fozard, James Leonard/B-3660-2009 FU NIA NIH HHS [2T32AG00219, 1AG42148] NR 36 TC 83 Z9 85 U1 1 U2 21 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD APR PY 2001 VL 33 IS 4 BP 532 EP 541 PG 10 WC Sport Sciences SC Sport Sciences GA 419UN UT WOS:000167967200005 PM 11283427 ER PT J AU El-Hage, N Babb, K Carroll, JA Lindstrom, N Fischer, ER Miller, JC Gilmore, RD Mbow, ML Stevenson, B AF El-Hage, N Babb, K Carroll, JA Lindstrom, N Fischer, ER Miller, JC Gilmore, RD Mbow, ML Stevenson, B TI Surface exposure and protease insensitivity of Borrelia burgdorferi Erp (OspEF-related) lipoproteins SO MICROBIOLOGY-UK LA English DT Article DE spirochaete; immunofluourescence; Erp proteins; bacterial surface proteins; protease resistance; Lyme disease ID LYME-DISEASE SPIROCHETE; 32-KILOBASE CIRCULAR PLASMIDS; UPSTREAM HOMOLOGY BOX; OUTER-MEMBRANE; MONOCLONAL-ANTIBODY; IN-VIVO; IMMUNOLOGICAL CHARACTERIZATION; CONFORMATIONAL NATURE; TREPONEMA-PALLIDUM; MAMMALIAN HOST AB Borrelia burgdorferi can encode numerous lipoproteins of the Erp family. Although initially described as outer surface proteins, the technique used in that earlier study has since been demonstrated to disrupt bacterial membranes and allow labelling of subsurface proteins. Data are now presented from additional analyses indicating that Erp proteins are indeed surface exposed in the outer membrane. Surface localization of these infection-associated proteins indicates the potential for interactions of Erp proteins with vertebrate tissues, Some Erp proteins were resistant to in situ digestion by certain proteases, suggesting that those proteins fold in manners which hide protease cleavage sites, or that they interact with other protective membrane components. Additionally, cultivation of B. burgdorferi in the presence of antibodies directed against Erp proteins inhibited bacterial growth. C1 Univ Kentucky, Albert B Chandler Med Ctr, Coll Med, Dept Microbiol & Immunol, Lexington, KY 40536 USA. NIAID, Rocky Mt Labs, Microscopy Branch, NIH, Hamilton, MT 59840 USA. Ctr Dis Control & Prevent, Div Vector Borne Infect Dis, Natl Ctr Infect Dis, Ft Collins, CO 80522 USA. Colorado State Univ, Coll Vet Med & Biomed Sci, Dept Pathol, Ft Collins, CO 80523 USA. RP Stevenson, B (reprint author), Univ Kentucky, Albert B Chandler Med Ctr, Coll Med, Dept Microbiol & Immunol, MS 415, Lexington, KY 40536 USA. FU NIAID NIH HHS [R01-AI44254] NR 68 TC 53 Z9 53 U1 0 U2 0 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AE, BERKS, ENGLAND SN 1350-0872 J9 MICROBIOL-UK JI Microbiology-(UK) PD APR PY 2001 VL 147 BP 821 EP 830 PN 4 PG 10 WC Microbiology SC Microbiology GA 422EF UT WOS:000168105000006 PM 11283278 ER PT J AU Debrabant, A Bastien, P Dwyer, DM AF Debrabant, A Bastien, P Dwyer, DM TI A unique surface membrane anchored purine-salvage enzyme is conserved among a group of primitive eukaryotic human pathogens SO MOLECULAR AND CELLULAR BIOCHEMISTRY LA English DT Article DE human pathogen; protozoan parasite; class-I nuclease; pulsed field gel electrophoresis; genome; chromosome ID LEISHMANIA-DONOVANI PROMASTIGOTES; 3'-NUCLEOTIDASE NUCLEASE ACTIVITY; CLASS-I NUCLEASE; CRITHIDIA-LUCILIAE; TRYPANOSOMA-BRUCEI; LOCALIZATION; EXPRESSION; 5'-NUCLEOTIDASE; PURIFICATION; AMASTIGOTES AB Previously, we isolated and characterized the gene encoding the 3'-Nucleotidase/Nuclease (Ld3'NT/NU) from the human pathogen, Leishmania donovani. This unique cell surface enzyme has been shown to be involved in the salvage of host-derived purines, which are essential for the survival of this important protozoan parasite. In this report, we assessed whether the 3'-Nucleotidase/Nuclease was conserved amongst other pathogenic Leishmania and related trypanosomatid parasites. Results of pulsed field gel electrophoresis and Southern blotting showed that a Ld3'NT/NU gene homolog was present in each of the visceral and cutaneous Leishmania species tested (i.e. isolates of L. donovani, L. infantum, L. tropica, L. major and L. mexicana, respectively). Further, results of colorimetric assays using 3'-adenosine monophosphate as substrate demonstrated that each of these organisms also expressed significant levels of 3'-nucleotidase enzyme activity. In addition, we showed that a Ld3'NT/NU gene homolog was expressed in each of these Leishmania species as a > 40 kDa 3'-nucleotidase enzyme activity. A Ld3'NT/NU gene homolog was also identified in two Crithidia species (C. fasciculata and C. luciliae) and Leptomonas seymouri but was only marginally detectable in Trypanosoma brucei, Trypanosoma cruzi and Phytomonas serpens. Cumulatively, results of this study showed that an Ld3'NT/NU homolog was conserved amongst pathogenic Leishmania sp. which suggests that this enzyme must play an critical role in purine salvage for all members of this group of human pathogens. C1 NIAID, Cell Biol Sect, Parasit Dis Lab, Div Intramural Res,NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Div Emerging & Transfus Transmitted Dis, Bethesda, MD USA. Fac Med, Parasitol Lab, CNRS, UMR 5093, Montpellier, France. RP Dwyer, DM (reprint author), NIAID, Cell Biol Sect, Parasit Dis Lab, Div Intramural Res,NIH, Bldg 4,Room 126,4 Ctr Dr MSC 0425, Bethesda, MD 20892 USA. RI Bastien, Patrick/F-5904-2013 NR 30 TC 13 Z9 14 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0300-8177 J9 MOL CELL BIOCHEM JI Mol. Cell. Biochem. PD APR PY 2001 VL 220 IS 1-2 BP 109 EP 116 DI 10.1023/A:1010809420104 PG 8 WC Cell Biology SC Cell Biology GA 429WQ UT WOS:000168541300014 PM 11451370 ER PT J AU Park, JM Gim, BS Kim, JM Yoon, JH Kim, HS Kang, JG Kim, YJ AF Park, JM Gim, BS Kim, JM Yoon, JH Kim, HS Kang, JG Kim, YJ TI Drosophila mediator complex is broadly utilized by diverse gene-specific transcription factors at different types of core promoters SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RNA-POLYMERASE-II; TATA-BINDING PROTEIN; IN-VIVO; REPRESSES TRANSCRIPTION; PREINITIATION COMPLEX; COFACTOR COMPLEX; LACKING TAF(II)S; ACTIVATION; HOLOENZYME; YEAST AB To decipher the mechanistic roles of Mediator proteins in regulating developmental specific gene expression and compare them to those of TATA-binding protein (TBP)-associated factors (TAFs), we isolated and analyzed a multiprotein complex containing Drosophila Mediator (dMediator) homologs. dMediator interacts with several sequence-specific transcription factors and basal transcription machinery and is critical for activated transcription in response to diverse transcriptional activators. The requirement for dMediator did not depend on a specific core promoter organization. By contrast, TAFs are preferentially utilized by promoters having a specific core element organization. Therefore, Mediator proteins are suggested to act as a pivotal coactivator that integrates promoter-specific activation signals to the basal transcription machinery. C1 Sungkyunkwan Univ, Sch Med, Sansung Biomed Res Inst, Natl Creat Res Initiat Ctr Genome Regulat, Suwon 440746, Kyunggido, South Korea. Digital Genom Inc, Seoul 120749, South Korea. NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kim, YJ (reprint author), Sungkyunkwan Univ, Sch Med, Sansung Biomed Res Inst, Natl Creat Res Initiat Ctr Genome Regulat, Chunchundong 300,Jangan Ku, Suwon 440746, Kyunggido, South Korea. EM yjk321@netian.com RI Marion-Poll, Frederic/D-8882-2011 OI Marion-Poll, Frederic/0000-0001-6824-0180 NR 42 TC 49 Z9 58 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD APR PY 2001 VL 21 IS 7 BP 2312 EP 2323 DI 10.1128/MCB.21.7.2312-2323.2001 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 410QW UT WOS:000167451500007 PM 11259581 ER PT J AU Buschmann, T Potapova, O Bar-Shira, A Ivanov, VN Fuchs, SY Henderson, S Fried, VA Minamoto, T Alarcon-Vargas, D Pincus, MR Gaarde, WA Holbrook, NJ Shiloh, Y Ronai, Z AF Buschmann, T Potapova, O Bar-Shira, A Ivanov, VN Fuchs, SY Henderson, S Fried, VA Minamoto, T Alarcon-Vargas, D Pincus, MR Gaarde, WA Holbrook, NJ Shiloh, Y Ronai, Z TI Jun NH2-terminal kinase phosphorylation of p53 on Thr-81 is important for p53 stabilization and transcriptional activities in response to stress SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID DNA-BINDING FUNCTION; ACTIVATED KINASES; WILD-TYPE; IN-VITRO; PROTEIN; DAMAGE; APOPTOSIS; UBIQUITINATION; DEGRADATION; STABILITY AB The p53 tumor suppressor protein plays a key role in the regulation of stress-mediated growth arrest and apoptosis. Stress-induced phosphorylation of p53 tightly regulates its stability and transcriptional activities. Mass spectrometry analysis of p53 phosphorylated in 293T cells by active Jun NH2-terminal kinase (JNK) identified T81 as the JNK phosphorylation site. JNK phosphorylated p53 at T81 in response to DNA damage and stress-inducing agents, as determined by phospho-specific antibodies to T81. Unlike wild-type p53, in response to JNK stimuli p53 mutated on T81 (T81A) did not exhibit increased expression or concomitant activation of transcriptional activity, growth inhibition, acid apoptosis, Forced expression of MKP5, a JNK phosphatase, in JNK kinase-expressinig cells decreased T81 phosphorylation while reducing p53 transcriptional activity and p53-mediated apoptosis. Similarly transfection of antisense JNK 1 and -2 decreased T81 phosphorylation in response to UV irradiation. More than 180 human tumors have been reported to contain p53 with mutations within the region that encompasses T81 and the JNK binding site (amino acids 81 to 116). Our studies identify an additional mechanism for the regulation of p53 stability and functional activities in response to stress. C1 CUNY Mt Sinai Sch Med, Ruttenberg Canc Ctr, New York, NY 10029 USA. CUNY Mt Sinai Sch Med, Dept Cell Biol, New York, NY 10029 USA. New York Med Coll, Dept Cell Biol & Anat, Valhalla, NY 10595 USA. SUNY Hlth Sci Ctr, Dept Pathol & Lab Med, Brooklyn, NY 11203 USA. NIA, Cell Stress & Aging Sect, Biol Chem Lab, NIH, Baltimore, MD 21224 USA. Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. Kanazawa Univ, Canc Res Inst, Kanazawa, Ishikawa 920, Japan. ISIS Pharmaceut, Carlsbad, CA 92008 USA. RP Ronai, Z (reprint author), CUNY Mt Sinai Sch Med, Ruttenberg Canc Ctr, 1 Gustave L Levy Pl,Box 1130, New York, NY 10029 USA. RI Ivanov, Vladimir/A-3081-2008; OI Ivanov, Vladimir/0000-0002-2933-6339; RONAI, ZEEV/0000-0002-3859-0400 FU NCI NIH HHS [CA78419, R01 CA078419]; NCRR NIH HHS [1 S10 RR0 9145-01] NR 61 TC 201 Z9 204 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD APR PY 2001 VL 21 IS 8 BP 2743 EP 2754 DI 10.1128/MCB.21.8.2743-2754.2001 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 416BN UT WOS:000167760000013 PM 11283254 ER PT J AU Zelko, I Sueyoshi, T Kawamoto, T Moore, R Negishi, M AF Zelko, I Sueyoshi, T Kawamoto, T Moore, R Negishi, M TI The peptide near the C terminus regulates receptor CAR nuclear translocation induced by xenochemicals in mouse liver SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID LIGAND-BINDING DOMAINS; PHENOBARBITAL RESPONSIVENESS; CRYSTAL-STRUCTURE; CYP2B GENE; HORMONE; EXPORT; TRANSACTIVATION; IDENTIFICATION; HETERODIMER; ACTIVATION AB In response to phenobarbital (PB) and other PR-type inducers, the nuclear receptor CAR translocates to the mouse liver nucleus (T. Kawamoto et at., Mel. Cell. Biol. 19:6318-6322, 1999). To define the translocation mechanism, fluorescent protein-tagged human CAR (hCAR) was expressed in the mouse livers using the in situ DNA injection and gene delivery systems. As in the wild-type hCAR, the truncated receptor lacking the C-terminal 10 residues (i.e., AF2 domain) translocated to the nucleus, indicating that the PB-inducible translocation is AF2 independent. Deletion of the 30 C-terminal residues abolished the receptor translocation, and subsequent site-directed mutagenesis delineated the PR-inducible translocation activity of the receptor to the peptide L(313)GLL(316)AEL(319). Ala mutations of Leu313, Leu316, or Leu319 abrogated the translocation of CAR in the livers, while those of Leu312 or Leu315 did not affect the nuclear translocation. The leucine-rich peptide dictates the nuclear translocation of hCAR in response to various PB-type inducers and appears to be conserved in the mouse and rat receptors. C1 NIH, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIEHS, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), NIH, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIEHS, Res Triangle Pk, NC 27709 USA. RI Zelko, Igor/L-2673-2013; Kawamoto, Takeshi/D-7938-2015 OI Zelko, Igor/0000-0003-3976-3884; Kawamoto, Takeshi/0000-0003-3337-1775 NR 25 TC 117 Z9 121 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD APR PY 2001 VL 21 IS 8 BP 2838 EP 2846 DI 10.1128/MCB.21.8.2838-2846.2001 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 416BN UT WOS:000167760000021 PM 11283262 ER PT J AU Angeloni, D Duh, FM Wei, MH Johnson, BE Lerman, MI AF Angeloni, D Duh, FM Wei, MH Johnson, BE Lerman, MI TI A C-to-A single nucleotide polymorphism in intron 2 of the human CACNA2D2 gene that maps at 3p21.3 SO MOLECULAR AND CELLULAR PROBES LA English DT Article DE CACNA2D2; loss of heterozygosity (LOH); lung cancer; single nucleotide polymorphism (SNP) C1 NCI, Frederick Canc Res & Dev Ctr, Immunobiol Lab, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC, Intramural Res Support Program, Frederick, MD 21702 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Angeloni, D (reprint author), NCI, Frederick Canc Res & Dev Ctr, Immunobiol Lab, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 3 TC 5 Z9 5 U1 0 U2 2 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0890-8508 J9 MOL CELL PROBE JI Mol. Cell. Probes PD APR PY 2001 VL 15 IS 2 BP 125 EP 127 DI 10.1006/mcpr.2000.0341 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology GA 422AL UT WOS:000168095700010 PM 11292331 ER PT J AU Lu, ZM Joseph, D Bugnard, E Zaal, KJM Ralston, E AF Lu, ZM Joseph, D Bugnard, E Zaal, KJM Ralston, E TI Golgi complex reorganization during muscle differentiation: Visualization in living cells and mechanism SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID MICROTUBULE-ORGANIZING CENTERS; ENDOPLASMIC-RETICULUM; RETROGRADE TRANSPORT; BREFELDIN-A; EXIT SITES; ER; APPARATUS; COPII; MYOGENESIS; PROTEINS AB During skeletal muscle differentiation, the Golgi complex (GC) undergoes a dramatic reorganization. We have now visualized the differentiation and fusion of living myoblasts of the mouse muscle cell line C2, permanently expressing a mannosidase-green fluorescent protein (GFP) construct. These experiments reveal that the reorganization of the GC is progressive (1-2 h) and is completed before the cells start fusing. Fluorescence recovery after photobleaching (FRAP), immunofluorescence, and immunogold electron microscopy demonstrate that the GC is fragmented into elements localized near the endoplasmic reticulum (ER) exit sites. FRAP analysis and the ER relocation of endogenous GC proteins by phospholipase A2 inhibitors demonstrate that Golgi-ER cycling of resident GC proteins takes place in both myoblasts and myotubes. All results support a model in which the GC reorganization in muscle reflects changes in the Golgi-ER cycling. The mechanism is similar to that leading to the dispersal of the GC caused, in all mammalian cells, by microtubule-disrupting drugs. We propose that the trigger for the dispersal results, in muscle, from combined changes in microtubule nucleation and ER exit site localization, which place the ER exit sites near microtubule minus ends. Thus, changes in GC organization that initially appear specific to muscle cells, iri fact use pathways common to all mammalian cells. C1 NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Ralston, E (reprint author), NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. NR 53 TC 54 Z9 58 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD APR PY 2001 VL 12 IS 4 BP 795 EP 808 PG 14 WC Cell Biology SC Cell Biology GA 461DQ UT WOS:000170350000004 PM 11294887 ER PT J AU Wang, XQ Zamore, PD Hall, TMT AF Wang, XQ Zamore, PD Hall, TMT TI Crystal structure of a Pumilio homology domain SO MOLECULAR CELL LA English DT Article ID SEGMENTATION GENE HUNCHBACK; RNA-BINDING DOMAIN; DROSOPHILA EMBRYOS; MESSENGER-RNA; DIFFERENTIAL REGULATION; PROTEIN-STRUCTURE; C-ELEGANS; NANOS; LOCALIZATION; CRYSTALLOGRAPHY AB Puf proteins regulate translation and mRNA stability by binding sequences in their target RNAs through the Pumilio homology domain (PUM-HD), which is characterized by eight tandem copies of a 36 amino acid motif, the PUM repeat. We have solved the structure of the PUM-HD from human Pumilio1 at 1.9 Angstrom resolution. The structure reveals that the eight PUM repeats correspond to eight copies of a single, repeated structural motif. The PUM repeats pack together to form a right-handed superhelix that approximates a half doughnut. The distribution of side chains on the inner and outer faces of this half doughnut suggests that the inner face of the PUM-HD binds RNA while the outer face interacts with proteins such as Nanos, Brain Tumor, and cytoplasmic polyadenylation element binding protein. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Massachusetts, Sch Med, Dept Biochem & Mol Pharmacol, Worcester, MA 01655 USA. RP Hall, TMT (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Zamore, Phillip/A-8941-2013 NR 51 TC 137 Z9 143 U1 3 U2 12 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD APR PY 2001 VL 7 IS 4 BP 855 EP 865 DI 10.1016/S1097-2765(01)00229-5 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 428LH UT WOS:000168462800015 PM 11336708 ER PT J AU Baumann, CT Ma, H Wolford, R Reyes, JC Maruvada, P Lim, C Yen, PM Stallcup, MR Hager, GL AF Baumann, CT Ma, H Wolford, R Reyes, JC Maruvada, P Lim, C Yen, PM Stallcup, MR Hager, GL TI The glucocorticoid receptor interacting protein 1 (GRIP1) localizes in discrete nuclear foci that associate with ND10 bodies and are enriched in components of the 26S proteasome SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID UBIQUITIN-MEDIATED PROTEOLYSIS; LIGAND-DEPENDENT ACTIVATION; HUMAN ESTROGEN-RECEPTOR; CELL-CYCLE; TRANSCRIPTIONAL COACTIVATOR; INTRACELLULAR-LOCALIZATION; HISTONE ACETYLTRANSFERASE; PROGESTERONE RECEPTORS; LIVING CELLS; RAR-ALPHA AB The glucocorticoid receptor interacting protein-1 (GRIP1) is a member of the steroid receptor coactivator (SRC) family of transcriptional regulators. Green fluorescent protein (GFP) fusions were made to full-length GRIP1, and a series of GRIP1 mutants lacking the defined regulatory regions and the intracellular distribution of these proteins was studied in HeLa cells. The distribution of GRIP1 was complex, ranging from diffuse nucleoplasmic to discrete intranuclear foci. Formation of these foci was dependent on the C-terminal region of GRIP1,which contains the two characterized transcriptional activation domains, AD1 and AD2. A subpopulation of GRIP1 foci associate with ND10s, small nuclear bodies that contain several proteins including PML, SP100, DAXX, and CREB-binding protein (CBP). Association with the ND10s is dependent on the AD1 of GRIP1, a region of the protein previously described as a CBP-interacting domain. The GRIP1 foci are enriched in components of the 26S proteasome, including the core 20S proteasome, PA28 alpha, and ubiquitin. In addition, the irreversible proteasome inhibitor lactacystin induced an increase in the total fluorescence intensity of the GFP-GRIP1 expressing cells, demonstrating that GRIP1 is degraded by the proteasome. These findings suggest the intriguing possibility that degradation of GRIP1 by the 26S proteasome may be a key component of its regulation. C1 NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. NIDDKD, Mol Regulat & Neuroendocrinol Sect, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Univ So Calif, Dept Pathol, Los Angeles, CA 90033 USA. RP Hager, GL (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bldg 41,Room B602, Bethesda, MD 20892 USA. RI Reyes, Jose/K-3699-2014 OI Reyes, Jose/0000-0002-8042-5142 NR 83 TC 82 Z9 82 U1 0 U2 0 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD APR PY 2001 VL 15 IS 4 BP 485 EP 500 DI 10.1210/me.15.4.485 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 417BH UT WOS:000167815100001 PM 11266502 ER PT J AU Cabral, WA Chernoff, EJ Marini, JC AF Cabral, WA Chernoff, EJ Marini, JC TI G76E substitution in type I collagen is the first nonlethal glutamic acid substitution in the alpha 1(I) chain and alters folding of the N-terminal end of the helix SO MOLECULAR GENETICS AND METABOLISM LA English DT Article ID MILD OSTEOGENESIS IMPERFECTA; GLYCINE SUBSTITUTIONS; TRIPLE-HELIX; PRO-ALPHA-1(I) CHAIN; MUTATION-DATABASE; CYSTEINE; DOMAINS; HETEROGENEITY; PROCOLLAGEN; DIGESTION AB The majority of osteogenesis imperfecta (OI) is caused by substitutions for glycine residues in the two ar chains of type I collagen. Since only 4% of possible nucleotide changes in type I collagen glycine codons would result in a glutamic acid substitution, these are predicted to be infrequent. Only one glutamic acid substitution in type I collagen has been fully reported. We describe here the clinical, biochemical, and molecular characterization of a girl with severe type III OI caused by a G76E substitution in COL1A1, This is the first delineation of a glutamic acid substitution in the alpha1(I) chain causing nonlethal osteogenesis imperfecta, The proband's fibroblast type I collagen chains and cyanogen bromide peptides were electrophoretically normal, while osteoblast collagen was slightly overmodified. This suggested a mutation near the N-terminal end of the collagen helix. A mismatch was detected by RNA:DNA hybrid analysis in cDNA coding for 106 amino acids at the N-terminal end of the helical region, Subclones of both alleles were sequenced and revealed a G --> A (c.761G > A) mutation causing an alpha1(I) G76E substitution in one allele, The presence of the mutation in the proband's leukocyte gDNA and its absence in parental gDNA, was confirmed by Tsp509I digestion, The glutamic acid substitution alters the folding of the mutant collagen helices, Pericellular processing of type I collagen by the proband's fibroblasts yielded an earlier appearance of the pC-alpha1(I)(I) form and of mature alpha chains as compared to control cell processing. Also, the presence of the glutamic acid substitution apparently exposes the adjacent Arg75 residue in the alpha1 chain. Trypsin digestion of proband fibroblast collagen resulted in shortened alpha1 chains, as confirmed by CNBr analysis. In addition, the Tm for mutant helices from fibroblasts and osteoblasts was decreased 2-4 degrees C versus controls, demonstrating a decrease in helix stability, These findings increase our understanding of the disruptive effect of glutamic acid substitutions in collagen. (C) 2001 Academic Press. C1 NICHHD, Heritbale Disorders Branch, Sect Connect Tissue Disorders, NIH, Bethesda, MD 20892 USA. RP Marini, JC (reprint author), NICHD, Heritable Disorders Branch, Bldg 10,Room 9S241,9000 Rockville Pike, Bethesda, MD 20892 USA. EM oidoc@helix.nih.gov NR 31 TC 5 Z9 6 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD APR PY 2001 VL 72 IS 4 BP 326 EP 335 DI 10.1006/mgme.2001.3155 PG 10 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 422AH UT WOS:000168095400008 PM 11286507 ER PT J AU Thameem, F Wolford, JK Bogardus, C Prochazka, M AF Thameem, F Wolford, JK Bogardus, C Prochazka, M TI Analysis of SLC19A2, on 1q23.3 encoding a thiamine transporter as a candidate gene for type 2 diabetes mellitus in Pima Indians SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE SLC19A2; TRMA; type 2 diabetes mellitus; single nucleotide polymorphism; candidate gene; association analysis; Pima Indians ID MEGALOBLASTIC-ANEMIA SYNDROME; SUSCEPTIBILITY GENES; MUTATIONS; DEAFNESS; FAMILY; SEARCH AB Mutations in the SLC19A2 gene cause thiamine-responsive megaloblastic anemia (TRMA) frequently combined with diabetes mellitus and deafness. Type 2 diabetes mellitus is heritable and a region on 1q21-q23 encompassing SLC19A2 was linked with the disease in Pima Indians and Caucasians. We therefore investigated this candidate gene in selected diabetic and nondiabetic Pimas and found no variants. We conclude that mutations in SLC19A2 do not contribute to type 2 diabetes in this population. (C) 2001 Academic Press. C1 NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. RP Thameem, F (reprint author), NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, NIH, 4212 N 16Th St, Phoenix, AZ 85016 USA. NR 17 TC 8 Z9 8 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD APR PY 2001 VL 72 IS 4 BP 360 EP 363 DI 10.1006/mgme.2001.3154 PG 4 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 422AH UT WOS:000168095400013 PM 11286512 ER PT J AU Siren, AL McCarron, R Wang, L Garcia-Pinto, P Ruetzler, C Martin, D Hallenbeck, JM AF Siren, AL McCarron, R Wang, L Garcia-Pinto, P Ruetzler, C Martin, D Hallenbeck, JM TI Proinflammatory cytokine expression contributes to brain injury provoked by chronic monocyte activation SO MOLECULAR MEDICINE LA English DT Article ID TUMOR-NECROSIS-FACTOR; BACILLUS-CALMETTE-GUERIN; FOCAL CEREBRAL-ISCHEMIA; INTERLEUKIN-1-BETA MESSENGER-RNA; BLADDER-CANCER PATIENTS; FACTOR-ALPHA; PERIPHERAL-CIRCULATION; RISK-FACTORS; RAT-BRAIN; AGED RATS AB Background: We have proposed that an increased interaction between monocyte/macrophages and blood vessel endothelium predisposes subjects to strokes. The effect of chronic monocyte activation on the development of cerebral infarcts was thus studied in rats after provocation of a modified local Swartzman reaction, in brain vasculature. Materials and Methods: Two weeks after an IV bolus of bacillus Calmette-Guerin (BCG), we studied spontaneous superoxide production, integrin expression, endothelial adhesion of monocytes' and the neurological symptoms, brain histology, and cytokine immunoreactivity after a provocative dose of LPS (30-300 mug/rat i.c.v.). Results: Monocyte migration into the brain was stimulated by BCG priming. The incidence of paralysis and death in response to LPS was markedly increased in BCG-primed rats. Histological evaluation of the brains of neurologically impaired and moribund animals revealed intravascular thrombosis and pale and hemorrhagic infarcts. Infiltrates of leukocytes expressing immunoreactive IL-1 beta, IL-6, and TNF-alpha were found around blood vessels, cerebral ventricles, and meninges, and were accompanied by a profound microglial expression of IL1 beta, endothelial expression of IL-6, and expression of TNF-alpha and TNF-R1 in glia and neurons of cortex and hippocampus. Treatment (2 x 100 mug/10 mul, i.c.v.) with recombinant human (rh-)TNF 55kDa receptor completely prevented, and treatment with rh-IL-l receptor antagonist significantly decreased the incidence of paralysis and death in response to BCG + LPS. The improvement of neurological symptoms was accompanied by reduced histological damage and supppression of IL-1 beta expression in the brain tissue. Conclusions: The data demonstrate that chronic monocyte activation predisposes subjects to thrombosis and hemorrhage via an exaggerated release of proinflammatory cytokines. C1 Max Planck Inst Expt Med, D-37075 Gottingen, Germany. Uniformed Serv Univ Hlth Sci, Dept Neurol, Bethesda, MD 20814 USA. NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. Univ Gottingen, Dept Psychiat, D-37075 Gottingen, Germany. Univ Gottingen, Dept Neurol, D-37075 Gottingen, Germany. USN, Inst Med, Bethesda, MD 20889 USA. Amgen Inc, Dept Pharmacol, Thousand Oaks, CA 91320 USA. RP Siren, AL (reprint author), Max Planck Inst Expt Med, Hermann Rein Str 3, D-37075 Gottingen, Germany. OI Siren, Anna-Leena/0000-0002-2217-0081 FU NINDS NIH HHS [NS-28225] NR 40 TC 25 Z9 26 U1 0 U2 0 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4319 USA SN 1076-1551 J9 MOL MED JI Mol. Med. PD APR PY 2001 VL 7 IS 4 BP 219 EP 229 PG 11 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 432UM UT WOS:000168714100001 PM 11471566 ER PT J AU Rusyn, I Kadiiska, MB Dikalova, A Kono, H Yin, M Tsuchiya, K Mason, RP Peters, JM Gonzalez, FJ Segal, BH Holland, SM Thurman, RG AF Rusyn, I Kadiiska, MB Dikalova, A Kono, H Yin, M Tsuchiya, K Mason, RP Peters, JM Gonzalez, FJ Segal, BH Holland, SM Thurman, RG TI Phthalates rapidly increase production of reactive oxygen species in vivo: Role of Kupffer cells SO MOLECULAR PHARMACOLOGY LA English DT Article ID PEROXISOME PROLIFERATOR WY-14,643; ACTIVATED RECEPTOR-ALPHA; IN-VIVO; HEPATOCYTE PROLIFERATION; LIPID-PEROXIDATION; RAT-LIVER; MECHANISM; OXIDASE; IRON; SYSTEMS AB The role of oxidants in the mechanism of tumor promotion by peroxisome proliferators remains controversial. The idea that induction of acyl-coenzyme A oxidase leads to increased production of H2O2, which damages DNA, seems unlikely; still, free radicals might be important in signaling in specialized cell types such as Kupffer cells, which produce mitogens. Because hard evidence for increased oxidant production in vivo after treatment with peroxisome proliferators is lacking, the spin-trapping technique and electron spin resonance spectroscopy were used. Rats were given di(2-ethylhexyl)phthalate (DEHP) acutely. The spin trapping agent alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone was also given and bile samples were collected for 4 h. Under these conditions, the intensity of the six-line radical adduct signal increased to a maximum value of 2.5-fold 2 h after administration of DEHP, before peroxisomal oxidases were induced. Furthermore, DEHP given with [C-13(2)]dimethyl sulfoxide produced a 12-line electron spin resonance spectrum, providing evidence that DEHP stimulates (OH)-O-. radical formation in vivo. Furthermore, when rats were pretreated with dietary glycine, which inactivates Kupffer cells, DEHP did not increase radical signals. Moreover, similar treatments were performed in knockout mice deficient in NADPH oxidase (p47(phox) subunit). Importantly, DEHP increased oxidant production in wild-type but not in NADPH oxidase-deficient mice. These data provide evidence for the hypothesis that the molecular source of free radicals induced by peroxisome proliferators is NADPH oxidase in Kupffer cells. On the contrary, radical adduct formation was not affected in peroxisome proliferator-activated receptor alpha knockout mice. These observations represent the first direct, in vivo evidence that phthalates increase free radicals in liver before peroxisomal oxidases are induced. C1 Univ N Carolina, Dept Pharmacol, Hepatobiol & Toxicol Lab, Chapel Hill, NC 27599 USA. Univ N Carolina, Curriculum Toxicol, Chapel Hill, NC USA. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Rusyn, I (reprint author), Univ N Carolina, Dept Pharmacol, Hepatobiol & Toxicol Lab, 1124 ME Jones Bldg,CB 7365, Chapel Hill, NC 27599 USA. RI Peters, Jeffrey/D-8847-2011; Rusyn, Ivan/S-2426-2016 FU NIEHS NIH HHS [ES04325, ES07126] NR 43 TC 60 Z9 62 U1 1 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD APR PY 2001 VL 59 IS 4 BP 744 EP 750 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 414MK UT WOS:000167670300011 PM 11259618 ER PT J AU Wang, HQ Kim, MP Tiano, HF Langenbach, R Smart, RC AF Wang, HQ Kim, MP Tiano, HF Langenbach, R Smart, RC TI Protein kinase C-alpha coordinately regulates cytosolic phospholipase A(2) activity and the expression of cyclooxygenase-2 through different mechanisms in mouse keratinocytes SO MOLECULAR PHARMACOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; CCAAT/ENHANCER-BINDING-PROTEINS; SYNTHASE-2 GENE-EXPRESSION; ARACHIDONIC-ACID RELEASE; SQUAMOUS CARCINOMA-CELLS; SMOOTH-MUSCLE CELLS; FACTOR KAPPA-B; TRANSCRIPTIONAL REGULATION; GROWTH-FACTOR AB Transgenic mice (K5-PKC alpha) in which the keratin 5 promoter directs the expression of protein kinase C-alpha (PKC alpha) to epidermal keratinocytes display a 10-fold increase in PKC alpha protein in their epidermis and alterations in phorbol ester-induced cutaneous inflammation [J Cell Science 1999;112:3497-3506]. In the current study, we have used these K5-PKC alpha mice to examine the role of PKC alpha in keratinocyte phospholipid metabolism/eicosanoid production and cutaneous inflammation. Primary keratinocytes from wild-type and transgenic mice were prelabeled in culture with [H-3]arachidonic acid (AA) and subsequently treated with TPA. Compared with wild-type keratinocytes, K5-PKC alpha keratinocytes displayed a 2-fold increase in AA release. TPA treatment resulted in the phosphorylation of cPLA(2). PKC inhibitors GF-109203X or H7, but not mitogen-activated protein/extracellular signal-regulated protein kinase (MEK) inhibitor PD 98059, could inhibit phosphorylation and AA release. Topical 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment of K5-PKC alpha mice resulted in a 5-fold increase in epidermal COX-2 induction and a 2- to 3-fold increase in prostaglandin (PG) E-2 levels above that observed in TPA-treated wild-type mice. PD 98059, GF-109203X, or H7 could block cyclooxygenase-2 (COX-2) induction by TPA. Because C/EBP beta, a basic leucine zipper transcription factor, can be activated via a PKC alpha /mitogen-activated protein kinase pathway and can influence COX-2 expression, we examined whether C/EBP beta is involved in TPA-induced epidermal COX-2 expression. TPA-induced COX-2 expression was similar in C/EBP beta nullizygous and wild-type mice. In summary, our results indicate that epidermal PKC alpha coordinately regulates cPLA(2) activity and COX-2 expression resulting in increased levels of AA and PGE(2). Furthermore, PKC alpha -induced AA release and cPLA(2) phosphorylation are independent of MEK, whereas PKC alpha -induced COX-2 expression and PGE(2) production are MEK-dependent and C/EBP beta -independent events. C1 N Carolina State Univ, Dept Environm & Mol Toxicol, Cell Signaling & Canc Grp, Raleigh, NC 27695 USA. NIEHS, Lab Expt Carcinogenesis & Mutagenesis, Res Triangle Pk, NC 27709 USA. RP Smart, RC (reprint author), N Carolina State Univ, Dept Environm & Mol Toxicol, Cell Signaling & Canc Grp, Raleigh, NC 27695 USA. FU NCI NIH HHS [CA46637] NR 47 TC 42 Z9 45 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD APR PY 2001 VL 59 IS 4 BP 860 EP 866 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 414MK UT WOS:000167670300024 PM 11259631 ER PT J AU Baek, SJ Kim, KS Nixon, JB Wilson, LC Eling, TE AF Baek, SJ Kim, KS Nixon, JB Wilson, LC Eling, TE TI Cyclooxygenase inhibitors regulate the expression of a TGF-beta superfamily member that has proapoptotic and antitumorigenic activities SO MOLECULAR PHARMACOLOGY LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; COLON-CANCER CELLS; MORPHOGENETIC PROTEIN; CARCINOMA-CELLS; APOPTOSIS; GROWTH; PROLIFERATION; SULINDAC; P53; TUMORIGENESIS AB The antitumorigenic activity of nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase (COX) inhibitors, is well established, but responsible molecular mechanisms are not fully understood. NSAIDs stimulate apoptosis by COX dependent and independent mechanisms in colorectal cells in culture. Identification of genes regulated by COX inhibitors could lead to a better understanding of their proapoptotic and anti-neoplastic activities. Using subtractive hybridization, a cDNA which was designated as NSAID activated gene (NAG-1) was identified from NSAID-treated HCT-116, human colorectal cells. NAG-1 has an identical sequence with a novel member of the TGF-beta superfamily that has 5 different names. In the HCT-116 cells, NAG-1 expression is increased and apoptosis is induced by treatment with some NSAIDs in a concentration and time-dependent manner. NAG-1 transfected cells exhibited increased basal apoptosis, increased response to NSAIDs and reduced soft agar cloning efficiency. Furthermore, transplantable tumors derived from NAG-1 transfected HCT-116 cells showed reduced tumorigenicity in athymic nude mice compared with vector-transfected HCT-116 cells. The increased NAG-1 expression by NSAIDs provides a suitable explanation for COX-independent apoptotic effects of NSAIDs in cultured cells. These data demonstrate that NAG-1 is an antitumorigenic and proapoptotic protein, and its regulation by COX inhibitors may provide new clues for explaining their proapoptotic and antitumorigenic activities. C1 NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Eling, TE (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. OI Baek, Seung/0000-0001-7866-7778 NR 33 TC 269 Z9 286 U1 1 U2 5 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD APR PY 2001 VL 59 IS 4 BP 901 EP 908 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 414MK UT WOS:000167670300029 PM 11259636 ER PT J AU Mendoza, GJA Seidel, NE Otsu, M Anderson, SM Simon-Stoos, K Herrera, A Hoogstraten-Miller, S Malech, HL Candotti, F Puck, JM Bodine, DM AF Mendoza, GJA Seidel, NE Otsu, M Anderson, SM Simon-Stoos, K Herrera, A Hoogstraten-Miller, S Malech, HL Candotti, F Puck, JM Bodine, DM TI Comparison of five retrovirus vectors containing the human IL-2 receptor gamma chain gene for their ability to restore T and B lymphocytes in the X-linked severe combined immunodeficiency mouse model SO MOLECULAR THERAPY LA English DT Article DE human X severe combined immunodeficiency (XSCID); hematopoietic stem cell gene therapy; human IL2 receptor gamma chain; ex vivo gene therapy; retroviral vector; MFG-S-hIL2RG; murine XSCID; in vivo selection ID HEMATOPOIETIC STEM-CELLS; BONE-MARROW TRANSPLANTATION; LONG TERMINAL REPEAT; ADENOSINE-DEAMINASE; MOLECULAR-BASIS; SINGLE-CENTER; MURINE MODEL; EXPRESSION; INTERLEUKIN-2; THERAPY AB X-linked severe combined immunodeficiency (XSCID) is caused by mutations in the IL-2 receptor gamma chain (IL2RC) gene, resulting in absent T lymphocytes and nonfunctional B lymphocytes. Recently T lymphocyte production and B lymphocyte function were restored in XSCID patients infused with autologous stem cells transduced with a retrovirus containing the human IL2RC cDNA. To optimize the expression of human IL2RC for future clinical trials, we compared five retroviral vectors expressing human IL2RC from different LTR enhancer-promoter elements in a mouse model. Northern and Southern blot analysis of hematopoietic tissues from repopulated mice revealed that the retroviral vector with the highest expression per copy number was MFG-S-hIL2RC, followed by MND-hlL2RG, All five vectors were capable of restoring lymphopoiesis in irradiated XSCID mice transplanted with transduced IL2RG-deficient hematopoietic stem cells. Transduction of IL2RG-deficient hematopoietic stem cells with all five vectors restored T lymphopoiesis in transplanted stem cell-deficient W/W-v mouse recipients. However, only XSCID stem cells transduced with the MFG-S-hIL2RG vector generated B lymphocytes in W/W-v mice. We conclude that the MFG-S-hIL2RG vector provides the best opportunity for in vivo selection and development of B and T lymphocytes for human XSCID gene therapy. C1 Natl Human Genome Res Inst, Hematopoiesis Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Immunol Genet Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Clin Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Off Lab Anim Med, NIH, Bethesda, MD 20892 USA. NIAID, Host Def Lab, Bethesda, MD 20892 USA. RP Bodine, DM (reprint author), Natl Human Genome Res Inst, Hematopoiesis Sect, Genet & Mol Biol Branch, NIH, 49 Convent Dr,Room 3A14,MSC 4442, Bethesda, MD 20892 USA. OI Malech, Harry/0000-0001-5874-5775 NR 52 TC 16 Z9 16 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD APR PY 2001 VL 3 IS 4 BP 565 EP 573 DI 10.1006/mthe.2001.0292 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 426UV UT WOS:000168367500021 ER PT J AU Chheda, MG Ashery, U Thakur, P Rettig, J Sheng, ZH AF Chheda, MG Ashery, U Thakur, P Rettig, J Sheng, ZH TI Phosphorylation of Snapin by PKA modulates its interaction with the SNARE complex SO NATURE CELL BIOLOGY LA English DT Article ID LONG-TERM POTENTIATION; PROTEIN-PROTEIN INTERACTIONS; NEUROTRANSMITTER RELEASE; SYNAPTIC TRANSMISSION; TRANSMITTER RELEASE; MEMBRANE-FUSION; HIPPOCAMPAL-NEURONS; SECRETORY MACHINERY; CHROMAFFIN CELLS; CALCIUM CHANNELS AB cAMP-dependent protein kinase A (PKA) can modulate synaptic transmission by acting directly on unknown targets in the neurotransmitter secretory machinery. Here we identify Snapin, a protein of relative molecular mass 15,000 that is implicated in neurotransmission by binding to SNAP-25, as a possible target. Deletion mutation and site-directed mutagenetic experiments pinpoint the phosphorylation site to serine 50. PKA-phosphorylation of Snapin significantly increases its binding to synaptosomal-associated protein-25 (SNAP-25). Mutation of Snapin serine 50 to aspartic acid (S50D) mimics this effect of PKA phosphorylation and enhances the association of synaptotagmin with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. Furthermore, treatment of rat hippocampal slices with nonhydrolysable cAMP analogue induces in vivo phosphorylation of Snapin and enhances the interaction of both Snapin and synaptotagmin with the SNARE complex. In adrenal chromaffin cells, overexpression of the Snapin S50D mutant leads to an increase in the number of release-competent vesicles. Our results indicate that Snapin may be a PKA target for modulating transmitter release through the cAMP-dependent signal-transduction pathway. C1 Natl Inst Neurol Disorders & Stroke, Synapt Funct Unit, NIH, Bethesda, MD 20892 USA. Max Planck Inst Biophys Chem, Dept Membrane Biophys, D-37077 Gottingen, Germany. RP Sheng, ZH (reprint author), Natl Inst Neurol Disorders & Stroke, Synapt Funct Unit, NIH, 36 Convent Dr, Bethesda, MD 20892 USA. RI Rettig, Jens/K-5103-2013 OI Rettig, Jens/0000-0001-6160-3954 NR 49 TC 111 Z9 121 U1 0 U2 6 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD APR PY 2001 VL 3 IS 4 BP 331 EP 338 DI 10.1038/35070000 PG 8 WC Cell Biology SC Cell Biology GA 421CE UT WOS:000168043900010 PM 11283605 ER PT J AU Wilson, KL Benavente, R Burke, B Craigie, R Foisner, R Furukawa, K Gerace, L Goldman, RD Gruenbaum, Y Harris, C Hutchison, CJ Krohne, G Morris, GE Otto, H Simon, AJ Worman, HJ AF Wilson, KL Benavente, R Burke, B Craigie, R Foisner, R Furukawa, K Gerace, L Goldman, RD Gruenbaum, Y Harris, C Hutchison, CJ Krohne, G Morris, GE Otto, H Simon, AJ Worman, HJ TI Problems with LAP nomenclature SO NATURE CELL BIOLOGY LA English DT Letter ID MUSCULAR-DYSTROPHY; NUCLEAR-ENVELOPE; PROTEINS; GENE C1 Johns Hopkins Sch Med, Baltimore, MD USA. Univ Wurzburg, D-97070 Wurzburg, Germany. Univ Calgary, Calgary, AB T2N 1N4, Canada. NIH, Bethesda, MD 20892 USA. Univ Vienna, A-1010 Vienna, Austria. Niigata Univ, Niigata 95021, Japan. Scripps Res Inst, La Jolla, CA 92037 USA. Northwestern Univ, Sch Med, Chicago, IL USA. Hebrew Univ Jerusalem, IL-91905 Jerusalem, Israel. RW Johnson Pharmaceut Res Inst, San Diego, CA 92121 USA. Univ Durham, Durham DH1 3HP, England. Free Univ Berlin, D-1000 Berlin, Germany. Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel. Columbia Univ, New York, NY USA. RP Wilson, KL (reprint author), Johns Hopkins Sch Med, Baltimore, MD USA. NR 5 TC 1 Z9 1 U1 0 U2 1 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD APR PY 2001 VL 3 IS 4 BP E90 EP E90 DI 10.1038/35070147 PG 1 WC Cell Biology SC Cell Biology GA 421CE UT WOS:000168043900002 PM 11283624 ER PT J AU Shih, DQ Bussen, M Sehayek, E Ananthanarayanan, M Shneider, BL Suchy, FJ Shefer, S Bollileni, JS Gonzalez, FJ Breslow, JL Stoffel, M AF Shih, DQ Bussen, M Sehayek, E Ananthanarayanan, M Shneider, BL Suchy, FJ Shefer, S Bollileni, JS Gonzalez, FJ Breslow, JL Stoffel, M TI Hepatocyte nuclear factor-1 alpha is an essential regulator of bile acid and plasma cholesterol metabolism SO NATURE GENETICS LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; RECEPTOR LXR-ALPHA; TRANSCRIPTION FACTOR; TRANSGENIC MICE; GENE; EXPRESSION; ATHEROSCLEROSIS; LIVER; PROTEIN; PATHWAY AB Maturity-onset diabetes of the young type 3 (MODY3) is caused by haploinsufficiency of hepatocyte nuclear factor-let (encoded by TCF1). Tcf1(-/-) mice have type 2 diabetes, dwarfism, renal Fanconi syndrome, hepatic dysfunction and hypercholestrolemia. Here we explore the molecular basis for the hypercholesterolemia using oligonucleotide microchip expression analysis. We demonstrate that Tcf1(-/-) mice have a defect in bile acid transport, increased bile acid and liver cholesterol synthesis, and impaired HDL metabolism. Tcf1(-/-) liver has decreased expression of the basolateral membrane bile acid transporters Slc10a1, Slc21a3 and Slc21a5, leading to impaired portal bile acid uptake and elevated plasma bile acid concentrations. In intestine and kidneys, Tcf1(-/-) mice lack expression of the ileal bile acid transporter (Slc10a2), resulting in increased fecal and urinary bile acid excretion. The Tcf1 protein (also known as HNF-1 alpha) also regulates transcription of the gene ((Nr1h4) encoding the farnesoid X receptor-1 (Fxr-1), thereby leading to reduced expression of small heterodimer partner-1 (Shp-1) and repression of Cyp7a1, the rate-limiting enzyme in the classic bile acid biosynthesis pathway. In addition, hepatocyte bile acid storage protein is absent from Tcf1(-/-) mice. Increased plasma cholesterol of Tcf1(-/-) mice resides predominantly in large, buoyant, high-density lipoprotein (HDL) particles. This is most likely due to reduced activity of the HDL-catabolic enzyme hepatic lipase (Lipc) and increased expression of HDL-cholesterol esterifying enzyme lecithin:cholesterol acyl transferase (Lcat). Our studies demonstrate that Tcf1, in addition to being an important regulator of insulin secretion, is an essential transcriptional regulator of bile acid and HDL-cholesterol metabolism. C1 Rockefeller Univ, Lab Metab Dis, New York, NY 10021 USA. Rockefeller Univ, Biochem Genet & Metab Lab, New York, NY 10021 USA. Mt Sinai Sch Med, Dept Pediat, New York, NY USA. Univ Med & Dent New Jersey, Dept Med, Piscataway, NJ 08854 USA. NCI, Bethesda, MD 20892 USA. RP Stoffel, M (reprint author), Rockefeller Univ, Lab Metab Dis, 1230 York Ave, New York, NY 10021 USA. RI Breslow, Jan/B-7544-2008 FU NICHD NIH HHS [HD20632]; NIDDK NIH HHS [DK02076, R01DK55033-01, DK26756]; NIGMS NIH HHS [GM07739] NR 43 TC 269 Z9 279 U1 2 U2 10 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD APR PY 2001 VL 27 IS 4 BP 375 EP 382 DI 10.1038/86871 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 416ZU UT WOS:000167811200011 PM 11279518 ER PT J AU Kuehl, P Zhang, J Lin, Y Lamba, J Assem, M Schuetz, J Watkins, PB Daly, A Wrighton, SA Hall, SD Maurel, P Relling, M Brimer, C Yasuda, K Venkataramanan, R Strom, S Thummel, K Boguski, MS Schuetz, E AF Kuehl, P Zhang, J Lin, Y Lamba, J Assem, M Schuetz, J Watkins, PB Daly, A Wrighton, SA Hall, SD Maurel, P Relling, M Brimer, C Yasuda, K Venkataramanan, R Strom, S Thummel, K Boguski, MS Schuetz, E TI Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression SO NATURE GENETICS LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISMS; HUMAN CYTOCHROME-P450 ENZYMES; ADULT HUMAN-LIVER; CLINICAL PRESENTATION; DRUG-METABOLISM; ALLELIC VARIANT; 3A; SUBSTITUTIONS; ASSOCIATION; MUTATIONS AB Variation in the CYP3A enzymes, which act in drug metabolism, influences circulating steroid levels and responses to half of all oxidatively metabolized drugs. CYP3A activity is the sum activity of the family of CYP3A genes, including CYP3A5, which is polymorphically expressed at high levels in a minority of Americans of European descent and Europeans thereafter collectively referred to as 'Caucasians'). Only people with at least one CYP3A5*1 allele express large amounts of CYP3A5. Our findings show that single-nucleotide polymorphisms (SNPs) in CYP3A5*3 and CYP3A5*6 that cause alternative splicing and protein truncation result in the absence of CYP3A5 from tissues of some people. CYP3A5 was more frequently expressed in livers of African Americans (60%) than in those of Caucasians (33%). Because CYP3A5 represents at least 50% of the total hepatic CYP3A content in people polymorphically expressing CYP3A5, CYP3A5 may be the most important genetic contributor to interindividual and interracial differences in CYP3A-dependent drug clearance and in responses to many medicines. C1 St Jude Childrens Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. Univ Maryland, Dept Mol & Cell Biol, Baltimore, MD 21201 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Johns Hopkins Univ, KcKusick Nathans Inst Geriatr Med, Baltimore, MD USA. Univ Washington, Dept Pharmaceut, Seattle, WA 98195 USA. Univ N Carolina, Chapel Hill, NC USA. Newcastle Univ, Dept Pharmacol Sci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. Eli Lilly & Co, Dept Drug Metab, Indianapolis, IN 46285 USA. Indiana Univ, Dept Clin Pharmacol, Indianapolis, IN 46204 USA. INSERM, Montpellier, France. Univ Pittsburgh, Dept Pharm, Pittsburgh, PA USA. Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA. RP Schuetz, E (reprint author), St Jude Childrens Hosp, Dept Pharmaceut Sci, 332 N Lauderdale St, Memphis, TN 38105 USA. EM erin.schuetz@stjude.org RI Strom, Stephen/A-6501-2008; Daly, Ann/H-3144-2011; Cline, Cynthia/F-7065-2012 OI Daly, Ann/0000-0002-7321-0629; FU NCI NIH HHS [CA51001, P30 CA21765]; NIEHS NIH HHS [ES08658]; NIGMS NIH HHS [GM32165, GM60346, U01GM61374, U01GM61393] NR 44 TC 1295 Z9 1419 U1 4 U2 35 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD APR PY 2001 VL 27 IS 4 BP 383 EP 391 DI 10.1038/86882 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 416ZU UT WOS:000167811200012 PM 11279519 ER PT J AU Zenklusen, JC Conti, CJ Green, ED AF Zenklusen, JC Conti, CJ Green, ED TI Mutational and functional analyses reveal that ST7 is a highly conserved tumor-suppressor gene on human chromosome 7q31 SO NATURE GENETICS LA English DT Article ID PRIMARY BREAST-CANCER; COMMONLY DELETED REGION; LONG ARM; PHYSICAL MAP; OVARIAN-CANCER; SQUAMOUS-CELL; FREQUENT LOSS; HETEROZYGOSITY; HUMAN-CHROMOSOME-7; CARCINOMAS AB Loss of heterozygosity (LOH) of markers on human chromosome 7q31 is frequently encountered in a variety of human neoplasias, indicating the presence of a tumor-suppressor gene (TSC). By a combination of microcell-fusion and deletion-mapping studies, we previously established that this TSG resides within a critical region flanked by the genetic markers D7S522 and D7S677. Using a positional cloning strategy and aided by the availability of near-complete sequence of this genomic interval, we have identified a TSG within 7q31, named ST7 (for suppression of tumorigenicity 7; this same gene was recently reported in another context and called RAY1). ST7 is ubiquitously expressed in human tissues. Analysis of a series of cell lines derived from breast tumors and primary colon carcinomas revealed the presence of mutations in ST7. Introduction of the ST7 cDNA into the prostate-cancer-derived cell line PC3 had no effect on the in vitro proliferation of the cells, but abrogated their in vivo tumorigenicity. Our data indicate that ST7 is a TSG within chromosome 7q31 and may have an important role in the development of some types of human cancer. C1 NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Carcinogenesis, Smithville, TX USA. RP Zenklusen, JC (reprint author), NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NR 50 TC 74 Z9 81 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD APR PY 2001 VL 27 IS 4 BP 392 EP 398 DI 10.1038/86891 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 416ZU UT WOS:000167811200013 PM 11279520 ER PT J AU Arikawa-Hirasawa, E Wilcox, WR Le, AH Silverman, N Govindraj, P Hassell, JR Yamada, Y AF Arikawa-Hirasawa, E Wilcox, WR Le, AH Silverman, N Govindraj, P Hassell, JR Yamada, Y TI Dyssegmental dysplasia, Silverman-Handmaker type, is caused by functional null mutations of the perlecan gene SO NATURE GENETICS LA English DT Article ID HEPARAN-SULFATE PROTEOGLYCAN; DENSITY-LIPOPROTEIN-RECEPTOR; ATELOSTEOGENESIS TYPE-II; BASEMENT-MEMBRANES; SPLICING DEFECTS; TRANSPORTER GENE; GROWTH-FACTOR; CORE PROTEIN; CARTILAGE; EXPRESSION AB Perlecan is a large heparan sulfate (HS) proteoglycan present in all basement membranes and in some other tissues such as cartilage(1,2), and is implicated in cell growth and differentiation(3-5). Mice lacking the perlecan gene(6,7) (Hspg2) have a severe chondrodysplasia with dyssegmental ossification of the spine and show radiographic, clinical and chondro-osseous morphology similar to a lethal autosomal recessive disorder in humans termed dyssegmental dysplasia, Silverman-Handmaker type (DDSH; MIM 224410). Here we report. a homozygous, 89-bp duplication in exon 34 of HSPG2 in a pair of siblings with DDSH born to consanguineous parents, and heterozygous point mutations in the 5' donor site of intron 52 and in the middle of exon 73 in a third, unrelated patient, causing skipping of the entire exons 52 and 73 of the HSPG2 transcript, respectively. These mutations are predicted to cause a frameshift, resulting in a truncated protein core. The cartilage matrix from these patients stained poorly with antibody specific for perlecan, but there was staining of intracellular inclusion bodies. Biochemically, truncated perlecan was not secreted by the patient fibroblasts, but was degraded to smaller fragments within the cells. Thus, DDSH is caused by a functional null mutation of HSPG2. Our findings demonstrate the critical role of perlecan in cartilage development. C1 Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Sch Med,Cedars Sinai Burns & Allen Res Inst, Ctr Med Genet Birth Defects, Steven Spielberg Pediat Res Ctr, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Cedars Sinai Med Ctr, Dept Obstet & Gynecol,Div Maternal Fetal Med, Los Angeles, CA USA. Shriners Hosp Children, Tampa, FL USA. RP Yamada, Y (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. FU NICHD NIH HHS [5P01 HD22657] NR 29 TC 130 Z9 134 U1 0 U2 1 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD APR PY 2001 VL 27 IS 4 BP 431 EP 434 DI 10.1038/86941 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 416ZU UT WOS:000167811200020 PM 11279527 ER PT J AU Feske, S Giltnane, J Dolmetsch, R Staudt, LM Rao, A AF Feske, S Giltnane, J Dolmetsch, R Staudt, LM Rao, A TI Gene regulation mediated by calcium signals in T lymphocytes SO NATURE IMMUNOLOGY LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; RESONANCE ENERGY-TRANSFER; STORE DEPLETION; INOSITOL TRISPHOSPHATE; INTRACELLULAR CALCIUM; TRANSCRIPTION FACTORS; PLASMA-MEMBRANE; CA2+ ENTRY; NF-AT; CELLS AB Modulation of many signaling pathways in antigen-stimulated T and B cells results in global changes in gene expression. Here we investigate the contribution of calcium signaling to gene expression in T cells using cell lines from two severe-combined immunodeficiency patients with several cytokine deficiencies and diminished activation of the transcription factor NFAT nuclear factor of activated T cells. These T cells show a strong defect in transmembrane calcium influx that is also apparent in their B cells and fibroblasts. DNA microarray analysis of calcium entry-deficient and control T cells shows that Ca2+ signals both activate and repress gene expression and are largely transduced through the phosphatase calcineurin. We demonstrate an elaborate network of signaling pathways downstream of the T cell receptor, explaining the complexity of changes in gene expression during T cell activation. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. NCI, Metab Branch, Div Clin Sci, Bethesda, MD 20892 USA. RP Rao, A (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. RI Giltnane, Jennifer/D-2584-2013; OI Feske, Stefan/0000-0001-5431-8178 FU NCI NIH HHS [CA42471]; NIAID NIH HHS [AI40127] NR 50 TC 387 Z9 403 U1 1 U2 9 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD APR PY 2001 VL 2 IS 4 BP 316 EP 324 DI 10.1038/86318 PG 9 WC Immunology SC Immunology GA 420AZ UT WOS:000167982900012 PM 11276202 ER PT J AU Aoki, K Kurooka, M Chen, JJ Petryniak, J Nabel, EG Nabel, GJ AF Aoki, K Kurooka, M Chen, JJ Petryniak, J Nabel, EG Nabel, GJ TI Extracellular matrix interacts with soluble CD95L: Retention and enhancement of cytotoxicity SO NATURE IMMUNOLOGY LA English DT Article ID PLASMINOGEN-ACTIVATOR INHIBITOR-1; HUMAN FAS LIGAND; INDUCED APOPTOSIS; DOWN-REGULATION; VITRONECTIN; EXPRESSION; MICE; FORM; PURIFICATION; REJECTION AB Fas ligand (CD95L) is synthesized both on the cell surface membrane and in a soluble form. Although CD95L contributes to immune privilege in the cornea and testis, the functions of these alternatively processed proteins are not well understood. Some reports suggest that the cytotoxicity of soluble CD95L is insignificant, whereas others show potent responses in vivo, including hepatocyte apoptosis that causes liver failure. We show here that extracellular matrix proteins interact with soluble CD95L and potentiate its pro-apoptotic activity. The cytotoxicity of supernatants from CD95L-expressing cells was increased by incubation on tissue culture plates coated with these matrix proteins; this effect was mediated by trimeric soluble CD95L. With the use of immunoprecipitation, it was found that CD95L binds directly to fibronectin. In addition, immunohistochemical analysis of the cornea revealed that soluble CD95L binds primarily to extracellular matrix. The retention of soluble CD95L on extracellular matrices is likely to play an important role in the development of peripheral tolerance in immune-privileged sites. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr, Bethesda, MD 20892 USA. NR 32 TC 71 Z9 71 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD APR PY 2001 VL 2 IS 4 BP 333 EP 337 DI 10.1038/86336 PG 5 WC Immunology SC Immunology GA 420AZ UT WOS:000167982900014 PM 11276204 ER PT J AU Zhang, ZJ Butler, JD Levin, SW Wisniewski, KE Brooks, SS Mukherjee, AB AF Zhang, ZJ Butler, JD Levin, SW Wisniewski, KE Brooks, SS Mukherjee, AB TI Lysosomal ceroid depletion by drugs: Therapeutic implications for a hereditary neurodegenerative disease of childhood SO NATURE MEDICINE LA English DT Article ID PALMITOYL-PROTEIN THIOESTERASE; NEUROBLASTOMA-CELLS; LIPID MODIFICATIONS; MOLECULAR-GENETICS; FATTY ACYLATION; RAT-BRAIN; LIPOFUSCINOSIS; EXPRESSION; IDENTIFICATION; ENZYME AB Neuronal ceroid lipofuscinoses (NCLs) are the most common hereditary neurodegenerative diseases of childhood. The infantile form, INCL, is caused by lysosomal palmitoyl-protein thioesterase (PPT) deficiency, which impairs the cleavage of thioester linkages in palmitoylated proteins, preventing their hydrolysis by lysosomal proteinases. Consequent accumulation of these lipid-modified proteins (constituents of ceroid) in lysosomes leads to INCL. Because thioester linkages are susceptible to nucleophilic attack, drugs with this property may have therapeutic potential for INCL. We report here that two such drugs, phosphocysteamine and N-acetylcystelne, disrupt thioester linkages in a model thioester compound, [C-14]palmitoyl-CoA. Most importantly, in lymphoblasts derived from INCL patients, phosphocysteamine, a known lysosomotrophic drug, mediates the depletion of lysosomal ceroids, prevents their re-accumulation and inhibits apoptosis. Our results define a novel pharmacological approach to lysosomal ceroid depletion and raise the possibility that nucleophilic drugs such as phosphocysteamine hold therapeutic potential for INCL. C1 NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. Inst Basic Res Dev Disabilities, Staten Isl, NY USA. New York State Inst Basic Res Dev Disabil, Dept Pathol Neurobiol, Staten Isl, NY 10314 USA. RP Mukherjee, AB (reprint author), NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. FU NINDS NIH HHS [R01 NS389 88-01] NR 47 TC 52 Z9 53 U1 0 U2 7 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD APR PY 2001 VL 7 IS 4 BP 478 EP 484 DI 10.1038/86554 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 419QQ UT WOS:000167960500044 PM 11283676 ER PT J AU Phelps, EA O'Connor, KJ Gatenby, JC Gore, JC Grillon, C Davis, M AF Phelps, EA O'Connor, KJ Gatenby, JC Gore, JC Grillon, C Davis, M TI Activation of the left amygdala to a cognitive representation of fear SO NATURE NEUROSCIENCE LA English DT Article ID POTENTIATED STARTLE; NEURONS; HUMANS; BRAIN; ANTICIPATION; RESPONSES; REFLEX; STRESS; CORTEX; FMRI AB We examined the neural substrates involved when subjects encountered an event linked verbally, but not experientially, to an aversive outcome. This instructed fear task models a primary way humans learn about the emotional nature of events. Subjects were told that one stimulus (threat) represents an aversive event (a shock may be given), whereas another (safe) represents safety (no shock will be given). Using functional magnetic resonance imaging (fMRI), activation of the left amygdala was observed in response to threat versus safe conditions, which correlated with the expression of the fear response as measured by skin conductance. Additional activation observed in the insular cortex is proposed to be involved in conveying a cortical representation of fear to the amygdala. These results suggest that the neural substrates that support conditioned fear across species have a similar but somewhat different role in more abstract representations of fear in humans. C1 NYU, Dept Psychol, New York, NY 10003 USA. MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. Yale Univ, Sch Med, Dept Radiol, New Haven, CT 06520 USA. NIMH, Bethesda, MD 20892 USA. Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. RP Phelps, EA (reprint author), NYU, Dept Psychol, 6 Washington Pl,8th Floor, New York, NY 10003 USA. FU NIMH NIH HHS [MH50812]; NINDS NIH HHS [NS33332] NR 28 TC 519 Z9 526 U1 3 U2 31 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD APR PY 2001 VL 4 IS 4 BP 437 EP 441 DI 10.1038/86110 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 433MB UT WOS:000168762200026 PM 11276236 ER PT J AU Mittmann, C Schuler, C Chung, CH Hoppner, G Nose, M Kehrl, JH Wieland, T AF Mittmann, C Schuler, C Chung, CH Hoppner, G Nose, M Kehrl, JH Wieland, T TI Evidence for a short form of RGS3 preferentially expressed in the human heart SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Article DE RGS protein; G protein; human heart ID PROTEIN ALPHA-SUBUNITS; SACCHAROMYCES-CEREVISIAE; ADENYLATE-CYCLASE; DILATED CARDIOMYOPATHY; FACTOR PHEROMONES; PHOSPHOLIPASE-C; G1 ARREST; A-FACTOR; REGULATORS; MEMBRANE AB RGS proteins (regulators of G protein signalling) negatively regulate G protein function as GTPase-activating proteins (GAP) for G protein alpha -subunits. The existence of mRNAs of different size for some of the RGS proteins, e.g. RGS3, suggests that these proteins may exist in isoforms due to alternative splicing. We therefore investigated RGS3 mRNA and protein expression in different human tissues. Ribonuclease protection assays and Northern blot analysis showed two specific mRNAs for RGS3 (RGS3L, RGS3S) in human myocardium, suggesting an additional, N-terminally truncated form of approximately 168 aa. When expressed as a recombinant protein RGS3S was recognized at similar to 23 kDa by an antipeptide antiserum originally raised against an RGS2 sequence. In membranes of human tissues this antiserum detected specific signals for RGS3L (similar to 70 kDa), RGS2 (similar to 30 kDa) and a 25-kDa protein, most likely RGS3S. Both RGS3S mRNA and the 25 kDa protein were abundant in human heart, whereas expression in liver, brain and myometrium was much weaker. To characterize RGS3S functionally, single turnover GTPase, adenylyl cyclase (AC) and phospholipase C (PLC) activities were determined. Both recombinant RGS3S and RGS16 increased P-i release from G(alpha i1) by about 150% and increased GTP- and GTP plus isoprenaline-stimulated AC activity by 20-30% in human left ventricular myocardial membranes. Additionally, both RGS proteins reduced basal and endothelin-stimulated PLC activity in these membranes by about 40%. We conclude that an additional truncated form of RGS3 is expressed in the human heart. As described for the full-length protein, RGS3S negatively regulates the activity of G(i/o)- and G(q)-, but not G(s)-subfamily members. C1 Univ Hamburg, Klinikum Eppendorf, Abt Pharmakol, Inst Expt & Klin Pharmakol & Toxikol, D-20246 Hamburg, Germany. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Mittmann, C (reprint author), Univ Hamburg, Klinikum Eppendorf, Abt Pharmakol, Inst Expt & Klin Pharmakol & Toxikol, Martinistr 52, D-20246 Hamburg, Germany. RI Wieland, Thomas/G-1772-2012; OI Kehrl, John/0000-0002-6526-159X NR 29 TC 18 Z9 18 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD APR PY 2001 VL 363 IS 4 BP 456 EP 463 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 413XD UT WOS:000167636100012 PM 11330340 ER PT J AU Bauer, B Nobmann, S Miller, D Fricker, G AF Bauer, B Nobmann, S Miller, D Fricker, G TI Transport of Paclitaxel in isolated functionally intact brain microvessels and cultured brain capillary endothelial cells. SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract C1 Inst Pharmazeut Technol & Biopharm, D-69120 Heidelberg, Germany. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD APR PY 2001 VL 363 IS 4 SU S MA 17 BP R8 EP R8 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 414TK UT WOS:000167682100028 ER PT J AU Culmsee, C Kruman, II Yu, Q Zhu, X Camandola, S Chan, SL Guo, Z Junker, V Krieglstein, J Greig, N Mattson, MP AF Culmsee, C Kruman, II Yu, Q Zhu, X Camandola, S Chan, SL Guo, Z Junker, V Krieglstein, J Greig, N Mattson, MP TI Evidence for the emerging role of DNA-damage and activation of p53 in neuron cell death SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract C1 Univ Marburg, Inst Pharmakol & Toxikol, D-35037 Marburg, Germany. NIA, Neurosci Lab, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD APR PY 2001 VL 363 IS 4 SU S MA 350 BP R91 EP R91 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 414TK UT WOS:000167682100361 ER PT J AU Hoffmann, C Soltysiak, K West, P Barak, D Jacobson, KA AF Hoffmann, C Soltysiak, K West, P Barak, D Jacobson, KA TI Identification of uracil recognition domains in the rat P2Y(6) receptor: A P2Y(1/6) chimeric receptor approach SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract C1 NIH, NIDDK, Mol Recognit Sect, LBC, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD APR PY 2001 VL 363 IS 4 SU S MA 60 BP R18 EP R18 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 414TK UT WOS:000167682100071 ER PT J AU von Kugelgen, I Jacobson, KA AF von Kugelgen, I Jacobson, KA TI Blockade of P2Y6-receptors by diisothiocyanatostilbene-disulfonic acid (DIDS) and analogues SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract C1 Univ Bonn, Dept Pharmacol, D-53113 Bonn, Germany. NIDDK, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD APR PY 2001 VL 363 IS 4 SU S MA 122 BP R34 EP R34 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 414TK UT WOS:000167682100133 ER PT J AU Wolter, S Mushinsky, F Resch, K Kracht, M AF Wolter, S Mushinsky, F Resch, K Kracht, M TI Analysis of cellular function of MAP kinase kinase 7 SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract C1 Hannover Med Sch, Inst Pharmacol, D-30625 Hannover, Germany. NCI, Genet Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD APR PY 2001 VL 363 IS 4 SU S MA 245 BP R65 EP R65 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 414TK UT WOS:000167682100256 ER PT J AU Zhou, H Trendelenburg, AU Wess, J Gomeza, J Klebroff, W Starke, K AF Zhou, H Trendelenburg, AU Wess, J Gomeza, J Klebroff, W Starke, K TI Presynaptic muscarinic receptors on noradrenergic axons studied with M-2- and M-4-receptor-deficient mice SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract C1 Univ Freiburg, Inst Pharmakol, D-7800 Freiburg, Germany. NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD APR PY 2001 VL 363 IS 4 SU S MA 92 BP R26 EP R26 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 414TK UT WOS:000167682100103 ER PT J AU Lu, CB Fu, WM Mattson, MP AF Lu, CB Fu, WM Mattson, MP TI Caspase-mediated suppression of glutamate (AMPA) receptor channel activity in hippocampal neurons in response to DNA damage promotes apoptosis and prevents necrosis: Implications for neurological side effects of cancer therapy and neurodegenerative disorders SO NEUROBIOLOGY OF DISEASE LA English DT Article ID MEMBRANE LIPID-PEROXIDATION; FOCAL CEREBRAL-ISCHEMIA; CELL-DEATH; ALZHEIMERS-DISEASE; CORTICAL-NEURONS; TOPOISOMERASE-I; INTERLEUKIN-1-BETA-CONVERTING ENZYME; MITOCHONDRIAL-FUNCTION; EXCITOTOXIC NECROSIS; SYNAPTIC PLASTICITY AB DNA damage in neurons is implicated in the pathogenesis of several neurodegenerative disordersand may also contribute to the often severe neurological complications in cancer patients treated with chemotherapeutic agents. DNA damage can trigger apoptosis, a form of controlled cell death that involves activation of cysteine proteases called caspases. The excitatory neurotransmitter glutamate plays central roles in the activation of neurons and in processes such as learning and memory, but overactivation of ionotropic glutamate receptors can induce either apoptosis or necrosis. Glutamate receptors of the AMPA (Phi -amino-3-hydroxy-5-methylisoxazole-4-propionate) type mediate such physiological and pathological processes in most neurons. We now report that DNA damage can alter glutamate receptor channel activity by a mechanism involving activation of caspases. Whole-cell patch clamp analyses revealed a marked decrease in AMPA-induced currents after exposure of neurons to camptothecin, a topoisomerase inhibitor that induces DNA damage; N-methyr-D-aspartate (NMDA)-induced currents were unaffected by camptothecin. The decrease in AMPA-induced current was accompanied by a decreased calcium response to AMPA. pharmacological inhibition of caspases abolished the effects of camptothecin on AMPA-induced current and calcium responses, and promoted excitotoxic necrosis. Combined treatment with glutamate receptor antagonists and a caspase inhibitor prevented camptothecin-induced neuronal death. Caspase-mediated suppression of AMPA currents may allow neurons with damaged DNA to withdraw their participation in excitatory circuits and undergo apoptosis, thereby avoiding widespread necrosis. These findings have important implications for treatment of patients with cancer and neurodegenerative disorders. (C) 2001 Academic press. C1 NIA, Neurosci Lab, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Lu, CB (reprint author), NIA, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 67 TC 20 Z9 21 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD APR PY 2001 VL 8 IS 2 BP 194 EP 206 DI 10.1006/nbdi.2000.0377 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 425JA UT WOS:000168286400002 PM 11300717 ER PT J AU Woods, A Zangen, A AF Woods, A Zangen, A TI A direct chemical interaction between dynorphin and excitatory amino acids SO NEUROCHEMICAL RESEARCH LA English DT Article DE aspartatic acid; dynorphin; glutamic acid; matrix-assisted laser desorption ionization (MALDI) mass-spectrometry ID NMDA RECEPTOR; RAT; ASPARTATE; INVOLVEMENT; MECHANISMS; PEPTIDES; BINDING; BRAIN; MOTOR AB The endogenous opioid peptide dynorphin A elicits non-opioid receptor-mediated neurotoxic effects. These effects are blocked by pretreatment with N-methyl-D-aspartate (NMDA) receptor antagonists. Herein, the mechanism for the non-opioid effects of dynorphin and related peptides was studied by matrix-assisted laser desorption ionization (MALDI) mass-spectrometry. We observed that both glutamate or aspartate bind non-covalently to dynorphin A and dynorphin 2-17. However, when dynorphin A or dynorphin 2-17 were added to an equimolar mixture of Glutamate and Aspartate, they both complexed preferentially with glutamate. These data may explain the non-opioid physiological effects of dynorphin A and related peptides and indicate that the direct chemical interaction between neurotransmitters should be monitored when studying interactions between different neurochemical systems. C1 NIDA, NIH, Baltimore, MD 21224 USA. RP Woods, A (reprint author), NIDA, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 26 TC 12 Z9 13 U1 0 U2 1 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD APR PY 2001 VL 26 IS 4 BP 395 EP 400 DI 10.1023/A:1010903215566 PG 6 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 458BP UT WOS:000170173600008 PM 11495350 ER PT J AU Balijepalli, S Kenchappa, RS Boyd, MR Ravindranath, V AF Balijepalli, S Kenchappa, RS Boyd, MR Ravindranath, V TI Protein thiol oxidation by haloperidol results in inhibition of mitochondrial complex I in brain regions: comparison with atypical antipsychotics SO NEUROCHEMISTRY INTERNATIONAL LA English DT Article DE antipsychotic; haloperidol; brain; complex I; mitochondria; oxidative stress ID ELECTRON-TRANSPORT CHAIN; LIPOIC ACID; PARKINSONS-DISEASE; CEREBRAL-ISCHEMIA; GLUTATHIONE; DOPAMINE; STRESS; RATS; REPERFUSION; RECEPTORS AB Usage of 'typical' but not 'atypical' antipsychotic drugs is associated with severe side effects involving extrapyramidal tract (EPT). Single dose of haloperidol caused selective inhibition of complex I in frontal cortex, striatum and midbrain (41 and 26%, respectively) which was abolished by pretreatment of mice with thiol antioxidants, alpha -lipoic acid and glutathione isopropyl ester: and reversed, in vitro, by disulfide reductant, dithiothreitol. Prolonged administration of haloperidol to mice resulted in complex I loss in frontal cortex, hippocampus, striatum and midbrain, while chronic dosing with clozapine affected only hippocampus and frontal cortex. Risperidone caused complex I loss in frontal cortex, hippocampus and striatum but not in midbrain from which extrapyramidal tract emanates. Inhibition of the electron transport chain component, complex I by haloperidol is mediated through oxidation of essential thiol groups to disulfides, in vivo. Further, loss of complex I in extrapyramidal brain regions by anti-psychotics correlated with their known propensity to generate side-effects involving extra-pyramidal tract. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Natl Inst Mental Hlth & Neurosci, Dept Neurochem, Bangalore 560029, Karnataka, India. NCI, Frederick Canc Res & Dev Ctr, Dev Therapeut Program, Lab Drug Discovery Res & Dev, Frederick, MD 21702 USA. Natl Brain Res Ctr, New Delhi 110067, India. RP Natl Inst Mental Hlth & Neurosci, Dept Neurochem, Hosur Rd, Bangalore 560029, Karnataka, India. EM vijir@vsnl.com NR 37 TC 58 Z9 59 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0197-0186 EI 1872-9754 J9 NEUROCHEM INT JI Neurochem. Int. PD APR PY 2001 VL 38 IS 5 BP 425 EP 435 DI 10.1016/S0197-0186(00)00108-X PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 412BL UT WOS:000167534100008 PM 11222923 ER PT J AU Mulert, C Gallinat, J Pascual-Marqui, R Dorn, H Frick, K Schlattmann, P Mientus, S Herrmann, WM Winterer, G AF Mulert, C Gallinat, J Pascual-Marqui, R Dorn, H Frick, K Schlattmann, P Mientus, S Herrmann, WM Winterer, G TI Reduced event-related current density in the anterior cingulate cortex in schizophrenia SO NEUROIMAGE LA English DT Article DE schizophrenia; anterior cingulate cortex; event-related potentials; reaction time; LORETA ID RESOLUTION ELECTROMAGNETIC TOMOGRAPHY; AUDITORY-EVOKED POTENTIALS; MISMATCH NEGATIVITY MMN; CEREBRAL BLOOD-FLOW; SELECTIVE ATTENTION; FIRST-EPISODE; EXECUTIVE PROCESSES; NORMAL VOLUNTEERS; HESCHL GYRUS; BRAIN AB There is good evidence from neuroanatomic postmortem and functional imaging studies that dysfunction of the anterior cingulate cortex plays a prominent role in the pathophysiology of schizophrenia. So far, no electrophysiological localization study has been performed to investigate this deficit. We investigated 18 drug-free schizophrenic patients and 25 normal subjects with an auditory choice reaction task and measured event-related activity with 19 electrodes. Estimation of the current source density distribution in Talairach space was performed with low-resolution electromagnetic tomography (LORETA). In normals, we could differentiate between an early event-related potential peak of the N1 (90-100 ms) and a later N1 peak (120-130 ms). Subsequent current-density LORETA analysis in Talairach space showed increased activity in the auditory cortex area during the first N1 peak and increased activity in the anterior cingulate gyrus during the second N1 peak. No activation difference was observed in the auditory cortex between normals and patients with schizophrenia. However, schizophrenics showed significantly less anterior cingulate gyrus activation and slowed reaction times. Our results confirm previous findings of an electrical source in the anterior cingulate and an anterior cingulate dysfunction in schizophrenics. Our data also suggest that anterior cingulate function in schizophrenics is disturbed at a relatively early time point in the information-processing stream (100-140 ms poststimulus). (C) 2001 Academic Press. C1 Humboldt Univ, Dept Neurol, Charite, D-10098 Berlin, Germany. Free Univ Berlin, Dept Psychiat, Lab Clin Psychophysiol, Berlin, Germany. Univ Zurich Hosp, Dept Psychiat, KEY Inst Brain Mind Res, CH-8091 Zurich, Switzerland. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Mulert, C (reprint author), Humboldt Univ, Dept Neurol, Charite, Schumannstr 20-21, D-10098 Berlin, Germany. RI Schlattmann, Peter/B-5289-2008; Mulert, Christoph/F-2576-2012; Pascual-Marqui, Roberto/A-2012-2008 OI Pascual-Marqui, Roberto/0000-0002-5029-4065 NR 77 TC 125 Z9 128 U1 2 U2 7 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD APR PY 2001 VL 13 IS 4 BP 589 EP 600 DI 10.1006/nimg.2000.0727 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 413TR UT WOS:000167628500004 PM 11305888 ER PT J AU Elliot, EE White, JM AF Elliot, EE White, JM TI The acute effects of zolpidem compared to diazepam and lorazepam using radiotelemetry SO NEUROPHARMACOLOGY LA English DT Article DE zolpidem; lorazepam; diazepam; radiotelemetry; muscle relaxation ID BENZODIAZEPINE RECEPTORS; RAT-BRAIN; SUBTYPES; PHARMACOLOGY; TEMPERATURE; SUBUNITS; PROFILES; NEURONS; SITES AB The present study used a radiotelemetric method to compare the muscle relaxant, hypothermic and locomotor depressant actions of the imidazopyridine zolpidem, with those of the benzodiazepines lorazepam and diazepam. Rats, n = 7 per group, were divided into 3 dose-dependent treatment groups (highest, middle, and lowest). Each rat within a treatment group received a single dose of diazepam, lorazepam, zolpidem and vehicle. All three drugs induced dose-dependent decreases in body temperature, locomotor activity and electromyographic (EMO) activity. Administration of zolpidem (5 and 10 mg/kg) resulted in maximal decrements in locomotor activity that were comparable to those elicited by both diazepam (10 and 20 mg/kg) and lorazepam (12.5 and 25 mg/kg). Zolpidem (10 mg/kg) decreased EMG activity levels to approximately 45% of vehicle treated controls; a value similar to that induced by diazepam (2.5 mg/kg). These data suggest that the imidazopyridine zolpidem has a similar profile of acute effects in comparison to the benzodiazepines diazepam and lorazepam. However, the relative magnitude of the effects differed, with zolpidem producing less hypothermia and muscle relaxation than the two benzodiazepines. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Univ Adelaide, Dept Clin & Expt Pharmacol, Adelaide, SA 5005, Australia. RP Elliot, EE (reprint author), NIDA, NIH, Psychobiol Sect, Baltimore, MD 21224 USA. RI White, Jason /A-2795-2011 OI White, Jason /0000-0001-6750-1078 NR 20 TC 21 Z9 22 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD APR PY 2001 VL 40 IS 5 BP 717 EP 721 DI 10.1016/S0028-3908(00)00196-9 PG 5 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 431MW UT WOS:000168636000010 PM 11311900 ER PT J AU Schenk, S Partridge, B Shippenberg, TS AF Schenk, S Partridge, B Shippenberg, TS TI Effects of the kappa-opioid receptor agonist, U69593, on the development of sensitization and on the maintenance of cocaine self-administration SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE cocaine sensitization; self-administration; kappa-opioids; U69593 ID INDUCED BEHAVIORAL SENSITIZATION; CONDITIONED PLACE PREFERENCE; LIMBIC-STRIATAL INTERACTIONS; REWARD-RELATED PROCESSES; EXCITOTOXIC LESIONS; 2ND-ORDER SCHEDULE; SEEKING BEHAVIOR; RHESUS-MONKEYS; D-AMPHETAMINE; DRUG-SEEKING AB Previous studies showed that prior administration of kappa-opioid agonists decreased the development of sensitization to some of the behavioral effects of cocaine. The present study sought to determine whether the development of sensitization to cocaine's reinforcing effects was also sensitive to antagonism by kappa-opioid agonists. During a pretreatment phase, the kappa-opioid agonist, U69593 (0.0 ou 0.32 mg/kg) was administered prior to (1) 2 daily injections of cocaine (0.0 or 20.0 mg/kg), or (2) cocaine or saline administered via a yoking procedure. Cocaine pretreatment decreased the latency to acquisition of cocaine self-administration. However, prior administration of U69593 during the pretreatment phase failed to attenuate the development of this sensitized response to cocaine's reinforcing effect. In other groups, the effect of acute U69593 pretreatment on the maintenance of cocaine self-administration was examined during a 10 hr session. During training and testing, a stimulus was associated with each self-administered cocaine infusion for one group whereas responding of another group was reinforced by a cocaine infusion alone. On the test day, pretreatment with U69593 (0.32 mg/kg) decreased responding during each hour of the 10 hr session for the group that was reinforced with cocaine plus the cocaine-associated stimulus. U69593 failed to produce a long-lasting disruption of cocaine self-administration for vats that were trained and tested without the cocaine-associated stimulus. These data suggest that the acquisition and maintenance of cocaine self-administration ave differentially sensitive to manipulations of kappa-opioid systems. Futher, the disruption of cocaine selfadministration by U69593 may be due to interactions with mechanisms that underlie facilitative effects of stimuli that have been associated with self-administered cocaine infusions. (C) 2001 American College of Neuropsychopharmacology. Published by Elsevier Science Inc. C1 Texas A&M Univ, Dept Psychol, College Stn, TX 77843 USA. NIDA, Integrat Neurosci Unit, Baltimore, MD USA. RP Schenk, S (reprint author), Texas A&M Univ, Dept Psychol, 230 Psychol Bldg, College Stn, TX 77843 USA. FU NIDA NIH HHS [DA 10084] NR 48 TC 21 Z9 21 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD APR PY 2001 VL 24 IS 4 BP 441 EP 450 DI 10.1016/S0893-133X(00)00190-1 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 413UC UT WOS:000167629400011 PM 11182539 ER PT J AU Pluta, RM Rak, R Wink, DA Woodward, JJ Khaldi, A Oldfield, EH Watson, JC AF Pluta, RM Rak, R Wink, DA Woodward, JJ Khaldi, A Oldfield, EH Watson, JC TI Effects of nitric oxide on reactive oxygen species production and infarction size after brain reperfusion injury SO NEUROSURGERY LA English DT Article DE anoxia; nitric oxide; oxygen free radicals; reperfusion injury; stroke ID TISSUE-PLASMINOGEN-ACTIVATOR; FOCAL CEREBRAL-ISCHEMIA; HYDROXYL RADICAL GENERATION; SUBARACHNOID HEMORRHAGE; INTRACRANIAL MICRODIALYSIS; THROMBOEMBOLIC STROKE; THROMBOLYTIC THERAPY; SYNTHASE INHIBITION; ARTERY OCCLUSION; EMBOLIC STROKE AB OBJECTIVE: Deleterious effects of strokes may be ameliorated when thrombolysis (i.e., with recombinant tissue plasminogen activator) restores circulation. However, reperfusion injury, mediated by oxygen free radicals (reactive oxygen species [ROS]), may limit the benefits of recombinant tissue plasminogen activator treatment. We hypothesized that, during reperfusion, exogenous nitric oxide (NO) would reduce stroke size by quenching ROS. METHODS: To investigate this hypothesis, we used two in vive ischemia-reperfusion models, i.e., autologous cerebral embolism in rabbits and filament middle cerebral artery occlusion in rats. Using these models, we measured ROS levels (rabbit model) and stroke volumes (rat model) in response to transient ischemia, with and without intracarotid administration of ultrafast NO donor proline NO (proliNO). RESULTS: In the rabbit cerebral embolism model, intracarotid administration of proliNO (10(-6) mol/L) (n = 6) during reperfusion decreased free radical levels from 538 +/- 86 nmol/L in the vehicle-treated group (n = 7) to 186 +/- 31 nmol/L (2,3(1)-dihydroxybenzoic acid; P < 0.001) and from 521 86 nmol/L (n = 7) to 201 +/- 39 nmol/L (2,5(1)-dihydroxybenzoic acid; P < 0.002). In the rat middle cerebral artery occlusion model, intracarotid administration of proliNO (10(-5) mol/L (n = 10) during reperfusion reduced the brain infarction volume from 256 48 mm(3) in the vehicle-treated group (n = 8) to 187 +/- 41 mm(3) (P < 0.005). In both experimental groups, intracarotid infusion of proliNO did not affect regional cerebral blood flow, mean arterial blood pressure, or brain and body temperatures. CONCLUSION: The beneficial effects of early restoration of cerebral circulation after cerebral ischemia were enhanced by intracarotid infusion of proliNO, most likely because of ROS scavenging by NO. These findings suggest the possibility of preventive treatment of reperfusion injury using NO donors. C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NCI, Radiat Biol Branch, NIH, Bethesda, MD USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. RP Pluta, RM (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,Room 5D37, Bethesda, MD 20892 USA. FU NIAAA NIH HHS [R01 AA009986] NR 57 TC 46 Z9 54 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD APR PY 2001 VL 48 IS 4 BP 884 EP 892 DI 10.1097/00006123-200104000-00039 PG 9 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 416YN UT WOS:000167808200088 PM 11322449 ER PT J AU Emmert, S Schneider, TD Khan, SG Kraemer, KH AF Emmert, S Schneider, TD Khan, SG Kraemer, KH TI The human XPG gene: gene architecture, alternative splicing and single nucleotide polymorphisms SO NUCLEIC ACIDS RESEARCH LA English DT Article ID PIGMENTOSUM GROUP-G; DNA-REPAIR GENE; TRANSCRIPTION-COUPLED REPAIR; CYCLOBUTANE PYRIMIDINE DIMERS; COCKAYNE-SYNDROME PATIENTS; XERODERMA-PIGMENTOSUM; EXCISION-REPAIR; SKIN-CANCER; SCHIZOSACCHAROMYCES-POMBE; LUNG-CANCER AB Defects in the XPG DNA repair endonuclease gene can result in the cancer-prone disorders xeroderma pigmentosum (XP) or the XP-Cockayne syndrome complex. While the XPG cDNA sequence was known, determination of the genomic sequence was required to understand its different functions. In cells from normal donors, we found that the genomic sequence of the human XPG gene spans 30 kb, contains 15 exons that range from 61 to 1074 bp and 14 introns that range from 250 to 5763 bp, Analysis of the splice donor and acceptor sites using an information theory-based approach revealed three splice sites with low information content, which are components of the minor (U12) spliceosome, We identified six alternatively spliced XPG mRNA isoforms in cells from normal donors and from XPG patients: partial deletion of exon 8, partial retention of intron 8, two with alternative exons tin introns 1 and 6) and two that retained complete introns (introns 3 and 9), The amount of alternatively spliced XPG mRNA isoforms varied in different tissues. Most alternative splice donor and acceptor sites had a relatively high information content, but one has the U12 spliceosome sequence. A single nucleotide polymorphism has allele frequencies of 0.74 for 3507G and 0.26 for 3507C in 91 donors. The human XPG gene contains multiple splice sites with low information content in association with multiple alternatively spliced isoforms of XPG mRNA. C1 NCI, Basic Res Lab, NIH, Bethesda, MD 20892 USA. NCI, Lab Expt & Computat Biol, Frederick, MD 21701 USA. RP Kraemer, KH (reprint author), Univ Gottingen, Dept Dermatol, D-3400 Gottingen, Germany. OI Schneider, Thomas/0000-0002-9841-1531 FU Intramural NIH HHS [Z01 BC004517-31] NR 67 TC 47 Z9 51 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD APR 1 PY 2001 VL 29 IS 7 BP 1443 EP 1452 DI 10.1093/nar/29.7.1443 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 419VW UT WOS:000167970300006 PM 11266544 ER PT J AU Trimble, EL AF Trimble, EL TI A guest editorial: Update on diethylstilbestrol SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material ID ADENOCARCINOMA; CANCER; WOMEN; RISK; VAGINA C1 Johns Hopkins Univ, Sch Med, Baltimore, MD USA. NCI, Bethesda, MD USA. RP Trimble, EL (reprint author), 6130 Execut Blvd,Suite 741,MSC 7436, Bethesda, MD 20892 USA. NR 11 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD APR PY 2001 VL 56 IS 4 BP 187 EP 189 DI 10.1097/00006254-200104000-00001 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 424ZR UT WOS:000168264300001 PM 11285433 ER PT J AU Yancey, MK Zhang, J Schweitzer, DL Schwarz, J Klebanoff, MA AF Yancey, MK Zhang, J Schweitzer, DL Schwarz, J Klebanoff, MA TI Epidural analgesia and fetal head malposition at vaginal delivery SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID CESAREAN DELIVERY; 2ND STAGE; NULLIPAROUS WOMEN; RANDOMIZED TRIAL; LABOR; ASSOCIATION; INFUSION; PROGRESS; RATES AB Objective: To determine if nulliparas who delivered with on-demand epidural analgesia are more likely to have malpositioning of the fetal vertex at delivery than women delivered during a period of restricted epidural use. Methods: A retrospective cohort of nulliparous women with spontaneous labor delivered during a 12-month period immediately before the availability of on-demand labor epidural analgesia was compared with a similar group of nulliparas delivered after labor epidural analgesia was available on request. The primary outcome variable was a non-occiput anterior position or malpositioned fetal head at vaginal delivery. Results: The frequency of epidural use increased from 0.9% before epidural analgesia became available on demand to 82.9% afterward. Fetal head malpositioning at vaginal delivery occurred in 26 of 434 (6.0%) women delivered in the before period compared with 29 of 511 (5.7%) in the after period (relative risk 0.95, 95% confidence interval 0.6, 1.6). No statistically significant difference in the incidence of fetal head malpositioning was present after patients were stratified by mode of delivery (Mantel-Haenszel weighted relative risk 0.94, 95% confidence interval 0.6, 1.4). The study sample size provided 85% power to detect a two-fold increase in the incidence of fetal malpositioning from a baseline rate of 6% associated with on-demand epidural use. Conclusion: Providing on-request labor epidural analgesia to nulliparas in spontaneous labor did not result in a clinically significant increase in the frequency of fetal head malpositioning at vaginal delivery. C1 Tripler Army Med Ctr, Dept Obstet & Gynecol, Honolulu, HI 96859 USA. NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. RP Yancey, MK (reprint author), Tripler Army Med Ctr, Dept Obstet & Gynecol, MCHK OB, 1 Jarrett White Rd, TAMC, HI 96859 USA. FU NICHD NIH HHS [Y1-HD-8290] NR 22 TC 19 Z9 20 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD APR PY 2001 VL 97 IS 4 BP 608 EP 612 DI 10.1016/S0029-7844(00)01230-8 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 416ZP UT WOS:000167810800023 PM 11275036 ER PT J AU Biggar, RJ AF Biggar, RJ TI AIDS-related cancers in the era of highly active antiretroviral therapy SO ONCOLOGY-NEW YORK LA English DT Article ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; KAPOSIS-SARCOMA; HOMOSEXUAL MEN; VIRUS TYPE-1; RISK-FACTORS; HIV; INFECTION; REGRESSION; COHORT; HAART AB Highly active antiretroviral therapy (HAART) has shown great efficacy in reducing human immunodeficiency virus levels, increasing immunity, and prolonging the survival of persons with acquired immunodeficiency syndrome (AIDS). The risk of life-threatening infections has been greatly reduced. However, the impact of HAART on the incidence of malignancy has been less clear. Published studies generally show that the risk of developing Kaposi's sarcoma declined by about two-thirds between 1994 and 1995 and from 1996 onward (considered the HAART era). Even before 1994, the risk of Kaposi's sarcoma in persons with AIDS had declined considerably and this cancer has now become relatively uncommon. The mechanism by which this decline in incidence was achieved appears to involve improved immunity. Data on the reduction in the risk for non-Hodgkin's lymphoma, although the most recent data (from 1997 to 1999) show a 42% decrease in risk. Even with a one-third reduction, the risk for non-Hodgkin's lymphoma remains considerably elevated. This high risk may be related to the fact that HAART therapy does not restore the immune system to normalcy. The increased lymphocyte turnover, with its accompanying risk of genetic errors, may increase the risk of developing non-Hodgkin's lymphoma. Most reports have insufficient data to analyze the impact of HAART therapy on incidence of central nervous system lymphomas, but recent data (from 1997 to 1999) showed a significant reduction in that risk. The mechanism by which this might occur is unclear because the central nervous system is an immunologic sanctuary. The relatively low incidence of other cancers in persons with AIDS makes it difficult to gauge the effect of HAART on their incidence, but to date, no significant trends have been reported for specific tumor types or for the overall risk on non-AIDS-related cancers. C1 NCI, Viral Epidemiol Branch, Bethesda, MD 20892 USA. RP Biggar, RJ (reprint author), EPS-8014,6120 Execut Blvd, Bethesda, MD 20852 USA. NR 41 TC 33 Z9 35 U1 0 U2 1 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD APR PY 2001 VL 15 IS 4 BP 439 EP + PG 9 WC Oncology SC Oncology GA 426DF UT WOS:000168334000011 PM 11346932 ER PT J AU Trimble, EL Rowland, J Varricchio, C Gore-Langton, RE AF Trimble, EL Rowland, J Varricchio, C Gore-Langton, RE TI Clinical trials - Referral resource SO ONCOLOGY-NEW YORK LA English DT Article C1 NCI, Bethesda, MD 20892 USA. RP Trimble, EL (reprint author), NCI, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD APR PY 2001 VL 15 IS 4 BP 456 EP 456 PG 1 WC Oncology SC Oncology GA 426DF UT WOS:000168334000013 PM 11346933 ER PT J AU Trimble, EL Rowland, J Varricchio, C Gore-Langton, RE AF Trimble, EL Rowland, J Varricchio, C Gore-Langton, RE TI Health-related quality of life in cancer clinical trials SO ONCOLOGY-NEW YORK LA English DT Article C1 NCI, Bethesda, MD 20892 USA. RP Trimble, EL (reprint author), NCI, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD APR PY 2001 VL 15 IS 4 BP 456 EP + PG 8 WC Oncology SC Oncology GA 426DF UT WOS:000168334000014 PM 11346933 ER PT J AU Murthy, GVS Gupta, S Ellwein, LB Munoz, SR Bachani, D Dada, VK AF Murthy, GVS Gupta, S Ellwein, LB Munoz, SR Bachani, D Dada, VK TI A population-based eye survey of older adults in a rural district of Rajasthan I. Central vision impairment, blindness, and cataract surgery SO OPHTHALMOLOGY LA English DT Article ID QUALITY-OF-LIFE; VISUAL-ACUITY; DOUMEN COUNTY; SHUNYI COUNTY; CHINA; PREVALENCE; OUTCOMES; NEPAL AB Purpose: To assess the prevalence of central vision blindness and cataract surgery in older adults in rural northwest India. Design: Population-based, cross-sectional study. Participants: A total of 4284 examined persons 50 years of age or older. Methods: A random selection of village-based clusters was used to identify a population sample in the predominantly rural Bharatpur district of Rajasthan. Eligible subjects in the 25 selected clusters were enumerated through a door-to-door household survey and invited to village sites for visual acuity testing and eye examination early in 1999. The principal cause of reduced central vision was identified for eyes that had visual acuity worse than 6/18. Independent replicate testing for quality assurance monitoring took place in participants with reduced vision and in a sample of those with normal vision in five of the study clusters. Main Outcome Measures: Presenting and best-corrected visual acuity and lens status. Results: A total of 4728 eligible persons in 2821 households were enumerated, and 4284 (90.6%) were examined. The prevalence of presenting and best-corrected visual acuity worse than 6/60 in both eyes was 11.9% (95% confidence interval: 10.0%-13.9%) and 6.1% (95% CI: 4.7%-7.4%), respectively. Presenting blindness was associated with increasing age, female gender, lack of schooling, and rural residence. Cataract was the principal cause of blindness in one or both eyes in 67.5% of blind persons, with uncorrected aphakia and other refractive error affecting 18.4% in at least one eye. The prevalence of cataract surgery was 12.8% (95% CI, 11.6%-14.0%), with an estimated 65.7% of the cataract blind operated on; low surgical coverage was associated with lack of schooling. Conclusions: Blindness, particularly blindness because of cataract, continues to be a significant problem among the elderly living in remote areas of rural northwest India. increased attention should be given to reaching women and the illiterate. (C) 2001 by the American Academy of Ophthalmology. C1 NEI, NIH, Bethesda, MD 20892 USA. All India Inst Med Sci, Dr Rajendra Prasad Ctr Ophthalm Sci, New Delhi 110029, India. Univ La Frontera, Unidad Epidemiol Clin, Temuco, Chile. Govt India, Minist Hlth, Natl Programme Control Blindness, New Delhi, India. RP Ellwein, LB (reprint author), NEI, NIH, Bethesda, MD 20892 USA. NR 13 TC 74 Z9 78 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD APR PY 2001 VL 108 IS 4 BP 679 EP 685 DI 10.1016/S0161-6420(00)00579-0 PG 7 WC Ophthalmology SC Ophthalmology GA 415XT UT WOS:000167749400026 PM 11297483 ER PT J AU Murthy, GVS Ellwein, LB Gupta, S Tanikachalam, K Ray, M AF Murthy, GVS Ellwein, LB Gupta, S Tanikachalam, K Ray, M TI A population-based eye survey of older adults in a rural district of Rajasthan II. Outcomes of cataract surgery SO OPHTHALMOLOGY LA English DT Article ID QUALITY-OF-LIFE; VISUAL-ACUITY; DOUMEN COUNTY; SHUNYI COUNTY; BLINDNESS; CHINA; INDIA; NEPAL; PREVALENCE AB Purpose: To assess the outcomes of cataract surgery in rural northwest India. Design: Population-based, cross-sectional study. Participants: A total of 549 cataract-operated persons (723 operated eyes). Methods: Cluster sampling was used in randomly selecting a cross-sectional sample of persons 50 years of age or older for visual acuity measurement, refraction, and slit-lamp and direct ophthalmoscope examination early in 1999. Those operated on for cataract were queried as to the date and place of surgery. The principal cause of reduced vision was identified for all examined eyes with presenting visual acuity worse than 6/18. Main Outcome Measures: Presenting and best-corrected visual acuity and cause of vision loss. Results: Presenting visual acuity was less than 6/60 in the better eye in 33.7% of cataract-operated persons and greater than or equal to 6/18 in both eyes in 8.2%; 31.7% were bilaterally operated on. Of cataract-operated eyes, 44.1% initially had visual acuity less than 6/60 and 31.5% greater than or equal to 6/18; with best correction, the corresponding percentages were 14.0% and 61.5%. Intracapsular cataract extraction was used in 92% of cases, and 66% had been operated on in surgery camps. Surgical complications were common and a major cause of vision impairment. In multiple logistic regression modeling, female gender and residence in a rural area were associated negatively with both presenting and best-corrected visual acuity outcomes, and surgery conducted before 1990 was associated negatively with best-corrected visual acuity. Place of surgery and subject schooling were not associated with vision outcomes. Conclusions: Cataract surgery subjects in rural areas of India that are without adequately equipped facilities and skilled surgeons, and lack of availability of intraocular lenses, are not realizing the full sight-restoring potential of modern-day surgery. Emphasis on the quality of cataract surgery outcomes must be increased to keep pace with that being given to increasing surgical volume. (C) 2001 by the American Academy of Ophthalmology. C1 NEI, NIH, Bethesda, MD 20892 USA. All India Inst Med Sci, Dr Rajendra Prasad Ctr Ophthalm Sci, New Delhi 110029, India. RP Ellwein, LB (reprint author), NEI, NIH, Bethesda, MD 20892 USA. NR 18 TC 43 Z9 47 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD APR PY 2001 VL 108 IS 4 BP 686 EP 692 DI 10.1016/S0161-6420(00)00578-9 PG 7 WC Ophthalmology SC Ophthalmology GA 415XT UT WOS:000167749400027 PM 11297484 ER PT J AU Domanski, MJ Zipes, DP Benditt, DG Camm, AJ Exner, DV Ezekowitz, MD Greene, HL Lesh, MD Miller, JM Pratt, CM Saksena, S Scheinman, MM Singh, BN Tracy, CM Waldo, AL AF Domanski, MJ Zipes, DP Benditt, DG Camm, AJ Exner, DV Ezekowitz, MD Greene, HL Lesh, MD Miller, JM Pratt, CM Saksena, S Scheinman, MM Singh, BN Tracy, CM Waldo, AL TI Central clinical research issues in electrophysiology: Report of the NASPE Committee SO PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY LA English DT Article DE electrophysiology; arrhythmias; syncope; research ID ACUTE MYOCARDIAL-INFARCTION; CONGESTIVE-HEART-FAILURE; SUDDEN CARDIAC DEATH; OBSTRUCTIVE HYPERTROPHIC CARDIOMYOPATHY; SIGNAL-AVERAGED ELECTROCARDIOGRAPHY; RADIOFREQUENCY CATHETER ABLATION; RECURRENT UNEXPLAINED SYNCOPE; LEFT-VENTRICULAR DYSFUNCTION; QT DISPERSION; DILATED CARDIOMYOPATHY AB This article contains the results of an attempt by appointed members of the North American Society of Pacing and Electrophysiology to define the research frontier in electrophysiology and suggest areas of study as an aid in setting the research agenda. C1 NHLBI, Clin Trials Grp, Bethesda, MD 20892 USA. Indiana Univ, Sch Med, Div Cardiol, Indianapolis, IN 46204 USA. Indiana Univ, Sch Med, Krannert Inst Cardiol, Indianapolis, IN 46202 USA. Univ Minnesota, Sch Med, Cardiac Arrhythmia Ctr, Minneapolis, MN 55455 USA. Univ London, St Georges Med Sch, London, England. NHLBI, Div Cardiol, Bethesda, MD 20892 USA. Yale Univ, Sch Med, New Haven, CT USA. Univ Washington, Seattle, WA 98195 USA. Univ Calif San Francisco, Med Ctr, San Francisco, CA 94143 USA. Krannert Inst Cardiol, Indianapolis, IN USA. Baylor Coll Med, Houston, TX 77030 USA. Robert Wood Johnson Med Sch, New Brunswick, NJ USA. Univ Calif San Francisco, Sch Med, San Francisco, CA USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. Georgetown Univ, Washington, DC USA. Case Western Reserve Univ, Sch Med, Cleveland, OH 44106 USA. RP Domanski, MJ (reprint author), NASPE, 6 Strathmore Rd, Natick, MA 01760 USA. OI Zipes, Douglas/0000-0001-7141-6829 NR 65 TC 5 Z9 5 U1 0 U2 1 PU FUTURA PUBL CO PI ARMONK PA 135 BEDFORD RD, PO BOX 418, ARMONK, NY 10504-0418 USA SN 0147-8389 J9 PACE JI PACE-Pacing Clin. Electrophysiol. PD APR PY 2001 VL 24 IS 4 BP 526 EP 534 DI 10.1046/j.1460-9592.2001.00526.x PN 1 PG 9 WC Cardiac & Cardiovascular Systems; Engineering, Biomedical SC Cardiovascular System & Cardiology; Engineering GA 426HD UT WOS:000168343000023 PM 11341097 ER PT J AU Monaghan, SC Little, RE Hulchiy, O Strassner, H Gladen, BC AF Monaghan, SC Little, RE Hulchiy, O Strassner, H Gladen, BC TI Risk factors for spontaneous preterm birth in two urban areas of Ukraine SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article ID SOCIAL VARIATION; WEIGHT-GAIN; DELIVERY; PREGNANCY; ASSOCIATION; OUTCOMES; INFANT; INDEX AB The economic, social and health problems faced by former eastern bloc countries after the demise of the Soviet Union are unique in the recent history of Europe. We conducted a study in two urban areas of Ukraine, asking if the traditional predictors of preterm delivery continue to be associated with risk under those conditions. Subjects were pregnant women with last menstrual period (LMP) between 25 December 1992 and 23 July 1994. Self-completed questionnaires and the medical record provided data. We compared 137 spontaneous preterm deliveries with 2886 full-term births, using all established risk factors fur which we had data. Maternal age was the variable most strongly related to preterm birth. Being 18 or less had an odds ratio (OR) of 3.7; being 30+ had an OR of 2.5 relative to the reference group of age 25-29. Placental complications and pre-existing hypertension had ORs of 2.7 and 2.3, respectively, but the confidence interval included 1.0. Low net pregnancy weight gain (less than 10 kg) was significantly associated with preterm birth, but the rate of net weight gain was not. Marital status and educational category were only weakly related. We conclude that although Ukraine faced serious difficulties during its transition to a market Economy, these problems did not generally alter the outcome of pregnancy in our sample when the classic risk factors for preterm delivery were present. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Univ Illinois, Sch Publ Hlth, Chicago, IL USA. Rush Med Ctr, Dept Maternal Fetal Med, Chicago, IL USA. Natl Med Univ, Kyiv, Ukraine. RP Little, RE (reprint author), NIEHS, A3-05,Box 12233, Res Triangle Pk, NC 27709 USA. NR 35 TC 14 Z9 14 U1 1 U2 2 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD APR PY 2001 VL 15 IS 2 BP 123 EP 130 DI 10.1046/j.1365-3016.2001.00327.x PG 8 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 437FN UT WOS:000168980500005 PM 11383576 ER PT J AU Klebanoff, MA Levine, RJ Morris, CD Hauth, JC Sibai, BM Curet, LB Catalano, P Wilkins, DG AF Klebanoff, MA Levine, RJ Morris, CD Hauth, JC Sibai, BM Curet, LB Catalano, P Wilkins, DG TI Accuracy of self-reported cigarette smoking among pregnant women in the 1990s SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article ID SERUM COTININE LEVELS; BIRTH-WEIGHT; EXPOSURE; RISK; PREECLAMPSIA; CESSATION; SMOKERS AB In large, prospective studies of pregnancy conducted in the 1960s, women reported very accurately whether or not they smoked. However, in the 1990s, pregnant women who smoke are often pressured to reduce or quit smoking, and the incentive to misreport may be greater than in the past To assess the accuracy of reported smoking, the authors compared self-reported smoking with cotinine in the serum and/or urine of 105 women who participated in the Calcium for Pre-eclampsia Prevention pilot study in 1992. Cotinine confirmed the report of 84.6% of women who reported smoking and 94.5% of women who denied smoking. Those fractions are virtually identical to those obtained in a pregnancy cohort from the 1960s. nh authors conclude that in the setting of two obstetrical research studies not specifically focused on smoking, the accuracy of self-reported cigarette smoking did not change substantially from the 1960s to the 1990s. C1 NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. Oregon Hlth Sci Univ, Div Med Informat & Outcomes Res, Portland, OR 97201 USA. Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. Univ Tennessee, Dept Obstet & Gynecol, Memphis, TN 38103 USA. Univ New Mexico, Dept Obstet & Gynecol, Albuquerque, NM 87131 USA. Case Western Reserve Univ, Metrohlth Med Ctr, Dept Reprod Biol, Cleveland, OH USA. Univ Utah, Ctr Human Toxicol, Salt Lake City, UT USA. RP Klebanoff, MA (reprint author), NICHD, DESPR, NIH, 6100 Bldg,Room 7B05, Bethesda, MD 20892 USA. FU NICHD NIH HHS [N01-HD-1-3121, N01-HD-1-3122, N01-HD-1-3123] NR 17 TC 114 Z9 114 U1 0 U2 4 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD APR PY 2001 VL 15 IS 2 BP 140 EP 143 DI 10.1046/j.1365-3016.2001.00321.x PG 4 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 437FN UT WOS:000168980500008 PM 11383579 ER PT J AU Kattan, M Platzker, A Mellins, RB Schluchter, MD Chen, XC Peavy, H Steinbach, S Wohl, ME Hiatt, P Hunter, J Colin, AA AF Kattan, M Platzker, A Mellins, RB Schluchter, MD Chen, XC Peavy, H Steinbach, S Wohl, ME Hiatt, P Hunter, J Colin, AA TI Respiratory diseases in the first year of life in children born to HIV-1-infected women SO PEDIATRIC PULMONOLOGY LA English DT Article DE HIV-1 infection; pneumonia; Pneumocystis carinii pneumonia; bronchiolitis; CD4 lymphocytes; infants; radiology ID HUMAN-IMMUNODEFICIENCY-VIRUS; PNEUMOCYSTIS-CARINII PNEUMONIA; INFANTS BORN; UNITED-STATES; CYTOMEGALOVIRUS-INFECTION; HIV-INFECTION; PROGRESSION; MORTALITY; TYPE-1; PROPHYLAXIS AB Our objective was to describe the respiratory complications, clinical findings, and chest radiographic changes in the first year of life in infected and uninfected children born to HIV-1-infected women. We prospectively followed a cohort of 600 infants born to HIV-l-infected women from birth to 12 months in a multicenter study. Of these, 93 infants (15.5%) were HIV-1 infected, 463 were uninfected, and 44 were of unknown status prior to death or loss to follow-up. The cumulative incidence (+/- SE) of an initial pneumonia episode at 12 months was 24.1 +/- 4.7% in HIV-1-infected children compared to 1.4 +/- 0.6% in HIV-1-uninfected children (P < 0.001). The rate of Pneumocystis carinii pneumonia (PCP) was 9.5 per 100 child-years. The HIV-1 RNA load was not higher in the group that developed pneumonia in the first year vs. those who did not. Children who developed lower respiratory tract infections or PCP had increased rates of decline of CD4 cell counts during the first 6 months of life. Lower maternal CD4 cell counts were associated with higher rates of pneumonia, and upper and lower respiratory tract infections, The rates of upper respiratory tract infection and bronchiolitis/reactive airway disease in infected children were not significantly different than in uninfected children. At 12 months, significantly more HIV-1-infected than uninfected children had tachypnea and chest radiographs with nodular and reticular densities. There was no relationship between cytomegalo virus infection in the first year of life and radiographic changes or occurrences of pneumonia. In conclusion, despite a low incidence of PCP, rates of pneumonia remain high in HIV-infected children in the first year of life. The incidence of pneumonia in uninfected infants born to HIV-1-infected mothers is low. Chest X-ray abnormalities and tachypnea suggest that subacute disease is present in infected infants. Further follow-up is warranted to determine its nature. <(c)> 2001 Wiley-Liss. Inc. C1 Mt Sinai Sch Med, Dept Pediat, New York, NY 10029 USA. Univ Calif Los Angeles, Univ So Calif, Dept Pediat, Los Angeles, CA USA. Columbia Univ, Dept Pediat, New York, NY 10027 USA. Cleveland Clin Fdn, Dept Biostat & Epidemiol, Cleveland, OH 44195 USA. NHLBI, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Harvard Univ, Childrens Hosp, Sch Med, Boston, MA 02115 USA. Baylor Coll Med, Houston, TX 77030 USA. RP Kattan, M (reprint author), Mt Sinai Sch Med, Dept Pediat, Box 1202-B,1 Gustave L Levy Pl, New York, NY 10029 USA. NR 41 TC 13 Z9 15 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 8755-6863 J9 PEDIATR PULM JI Pediatr. Pulmonol. PD APR PY 2001 VL 31 IS 4 BP 267 EP 276 DI 10.1002/ppul.1038 PG 10 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA 419EC UT WOS:000167935500001 PM 11288208 ER PT J AU Stein, MT Zentall, S Shaywitz, SE Shaywitz, BA AF Stein, MT Zentall, S Shaywitz, SE Shaywitz, BA TI A school-aged child with delayed reading skills SO PEDIATRICS LA English DT Article DE dyslexia; phonetic code; learning disabilities C1 Univ Calif San Diego, San Diego, CA 92103 USA. Purdue Univ, W Lafayette, IN 47907 USA. Yale Univ, Sch Med, NICHD Yale Ctr Study Learning & Attent, New Haven, CT USA. RP Stein, MT (reprint author), Univ Calif San Diego, San Diego, CA 92103 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD APR PY 2001 VL 107 IS 4 SU S BP 916 EP 920 PG 5 WC Pediatrics SC Pediatrics GA 422QD UT WOS:000168130000022 ER PT J AU Fieschi, C Dupuis, S Picard, C Smith, CIE Holland, SM Casanova, JL AF Fieschi, C Dupuis, S Picard, C Smith, CIE Holland, SM Casanova, JL TI High levels of interferon gamma in the plasma of children with complete interferon gamma receptor deficiency SO PEDIATRICS LA English DT Article DE interferon gamma; mycobacteria; genetic susceptibility; immunodeficiency; plasma ID BACILLE CALMETTE-GUERIN; MYCOBACTERIAL INFECTION; IFN-GAMMA; INTERLEUKIN-12; SUSCEPTIBILITY; MUTATION; PATHWAY; DEFECTS; CHAIN AB We have found that children with complete interferon gamma (IFN gamma) receptor deficiency, unlike patients with other genetic defects predisposing them to mycobacterial diseases, have very high levels of IFN gamma in their plasma. This unexpected observation provides a simple and accurate diagnostic method for complete IFN gamma receptor deficiency in children with clinical disease caused by bacille Calmette-Guerin vaccines or environmental nontuberculous mycobacteria. C1 Necker Enfants Malad Med Sch, Lab Human Genet Infect Dis, F-75015 Paris, France. Karolinska Inst, Huddinge, Sweden. NIH, Host Def Lab, Bethesda, MD 20892 USA. Necker Enfants Malad Med Sch, Pediat Immunol Unit, F-75015 Paris, France. RP Casanova, JL (reprint author), Necker Enfants Malad Med Sch, Lab Human Genet Infect Dis, 153 Rue Vaugirad, F-75015 Paris, France. NR 15 TC 37 Z9 38 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD APR PY 2001 VL 107 IS 4 BP art. no. EP e48 DI 10.1542/peds.107.4.e48 PG 3 WC Pediatrics SC Pediatrics GA 422KC UT WOS:000168116200005 PM 11335769 ER PT J AU Kinney, JW Scruggs, B Avery, DD AF Kinney, JW Scruggs, B Avery, DD TI Peripheral administration of urocortin suppresses operant responding for food reward SO PEPTIDES LA English DT Article DE urocortin; corticotropin-releasing factor; satiety; operant responding ID CORTICOTROPIN-RELEASING-FACTOR; INGESTIVE BEHAVIOR; FEEDING-BEHAVIOR; BOMBESIN; NEUROPEPTIDE; RATS; CHOLECYSTOKININ AB The effects of peripheral systemic administration of urocortin on operant responding to obtain food were investigated using three separate concentrations. The drug was administered intraparitoneally at a concentration of 10 mug/ml/Kg, 5 mug/ml/Kg, and 0 mug/ml/Kg suspended in saline at a volume of 1 ml/Kg to Sprague-Dawley rats fifteen minutes prior to being exposed to an operant bar press task. Eleven subjects were used, each receiving a single injection of each concentration on separate days with the order of treatment counterbalanced. The results indicated that the administration of urocortin in a dose dependent manner reduced responding of food deprived subjects for a food reward in a thirty minute session. These data indicated that the peripheral administration of urocortin reduced the motivation of food deprived subjects to respond, (C) 2001 Elsevier Science Inc. All rights reserved. C1 NIMH, Sect Behav Neuropharmacol, Bethesda, MD 20892 USA. Colorado State Univ, Dept Psychol, Ft Collins, CO 80523 USA. RP Kinney, JW (reprint author), NIMH, Sect Behav Neuropharmacol, Bethesda, MD 20892 USA. NR 23 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD APR PY 2001 VL 22 IS 4 BP 583 EP 587 DI 10.1016/S0196-9781(01)00367-9 PG 5 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 426GD UT WOS:000168340700004 PM 11311727 ER PT J AU Lee, YM Jeong, HJ Na, HJ Ku, JY Kim, DK Goo-Moon Chae, HJ Kim, HR Baek, SH Kim, HM AF Lee, YM Jeong, HJ Na, HJ Ku, JY Kim, DK Goo-Moon Chae, HJ Kim, HR Baek, SH Kim, HM TI Inhibition of immunologic and nonimmunologic stimulation-mediated anaphylactic reactions by water extract of white eggplant (Solanum melongena) SO PHARMACOLOGICAL RESEARCH LA English DT Article DE Solanum melongena; anaphylactic reactions; mast cells; histamine; tumor necrosis factor-alpha ID PERITONEAL MAST-CELLS; TUMOR-NECROSIS-FACTOR; HISTAMINE-RELEASE; HIGH-AFFINITY; SUBSTANCE-P; RECEPTOR; IGE; RAT; COMPOUND-48/80; RECRUITMENT AB We investigated the effect of water extract of Solanum melongena (SMWE) on immunologic and nonimmunologic stimulation-mediated anaphylactic reactions. Nonimmunologic anaphylactic reaction was induced by compound 48/80 injection. Oral administration of SMWE (I g kg(-1)) completely inhibited compound 48/80-induced anaphylactic reaction. Immunologic anaphylactic reaction was generated by sensitizing the skin with anti-dinitrophenyl (DNP) IgE followed 48 h later with an injection of antigen, Oral administration of SMWE (0.01-1 g kg(-1)) significantly inhibited passive cutaneous anaphylactic reaction activated by anti-DNP IgE to between 83.10 +/- 1.67% and 70.17 +/- 2.17%. SMWE (0.01-1 mg ml(-1)) also inhibited histamine release activated by compound 48/80 to between 93 +/- 2.65 and 70 +/- 1.50%. Moreover, SMWE (0.01-1 mg ml(-1)) had a significant inhibitory effect on IgE-induced tumor necrosis factor (TNF)-alpha, secretion from rat peritoneal mast cells. These results indicate that SMWE inhibits immunologic and nonimmunologic stimulation-mediated anaphylactic reactions and TNF-alpha secretion from mast cells. (C) 2001 Academic Press. C1 Wonkwang Univ, Coll Pharm, Dept Oriental Pharm, Iksan 570749, Chonbuk, South Korea. Wonkwang Univ, Ctr Oriental Med Sci, Iksan 570749, Chonbuk, South Korea. NIAID, Lab Allerg Dis, NIH, Rockville, MD 20852 USA. Wonkwang Univ, Coll Oriental Med, Iksan 570749, Chonbuk, South Korea. Wonkwang Univ, Sch Dent, Dept Dent Pharmacol, Iksan 570749, Chonbuk, South Korea. Wonkwang Univ, Profess Grad Sch Oriental Med, Dept Nat Prod, Iksan 570749, Chonbuk, South Korea. RP Kim, HM (reprint author), Wonkwang Univ, Coll Pharm, Dept Oriental Pharm, Iksan 570749, Chonbuk, South Korea. NR 24 TC 5 Z9 7 U1 1 U2 3 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-6618 J9 PHARMACOL RES JI Pharmacol. Res. PD APR PY 2001 VL 43 IS 4 BP 405 EP 409 DI 10.1006/phrs.2001.0807 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 422AY UT WOS:000168096800014 PM 11352546 ER PT J AU Knapp, CM Foye, MM Cottam, N Ciraulo, DA Kornetsky, C AF Knapp, CM Foye, MM Cottam, N Ciraulo, DA Kornetsky, C TI Adenosine agonists CGS 21680 and NECA inhibit the initiation of cocaine self-administration SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article; Proceedings Paper CT 9th Meeting of the International-Behavioral-Neuroscience-Society CY APR 06-09, 2000 CL DENVER, COLORADO SP Int Behav Neurosci Soc DE cocaine; self-administration; adenosine receptors ID RAT-BRAIN; RECEPTOR AGONIST; AUTORADIOGRAPHIC LOCALIZATION; SEEKING BEHAVIOR; TAKING BEHAVIOR; CAFFEINE; REINSTATEMENT; CYCLOHEXYLADENOSINE; ANTAGONISTS; WITHDRAWAL AB Administration of the adenosine antagonist caffeine will facilitate the reinstatement of cocaine self-administration responding. This suggests that adenosine receptors may play a role in the motivational systems that regulate cocaine-seeking behaviors. If so then adenosine agonists may act to block cocaine self-administration To test this hypothesis, the effects of the nonselective adenosine agonist NECA and of the A(2A) selective agonist, CGS 21680 on the self-administration of cocaine were determined. In these experiments, rats were allowed to obtain intravenous cocaine infusions (0.6 mg/kg/infusion) delivered under a Fixed Ratio 5 schedule. Treatment with either NECA or CGS 21680 in comparison to vehicle administration reduced the number of infusions received per session. This, primarily, was due to a marked increase in the latency for delivery of the first cocaine infusion. Responding after drug-induced delays tended to be at control levels. Adenosine agonists are known to have sedative effects and these actions might play a role in NECA and CGS 21680-induced increases in latencies for cocaine delivery. These results indicate that the administration of adenosine agonists may inhibit cocaine-seeking behaviors. The degree to which these actions are on motivational systems as opposed to involving less specific effects remains to be fully elucidated. (C) 2001 Elsevier Science Inc. All rights reserved. C1 Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. NIDA, Medicat Dev Res Unit, Boston Vet Affairs, Boston, MA USA. Boston Univ, Sch Med, Dept Pharmacol, Boston, MA 02118 USA. RP Knapp, CM (reprint author), Boston Univ, Sch Med, Dept Psychiat, 715 Albany St,L-602, Boston, MA 02118 USA. FU NIDA NIH HHS [KO5-DA00099, DA-02326, 1 Y01 DA-50038] NR 37 TC 55 Z9 56 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD APR PY 2001 VL 68 IS 4 BP 797 EP 803 DI 10.1016/S0091-3057(01)00486-5 PG 7 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 432KJ UT WOS:000168690500022 PM 11526979 ER PT J AU Roberts, RL Jenkins, KT Lawler, T Wegner, FH Norcross, JL Bernhards, DE Newman, JD AF Roberts, RL Jenkins, KT Lawler, T Wegner, FH Norcross, JL Bernhards, DE Newman, JD TI Prolactin levels are elevated after infant carrying in parentally inexperienced common marmosets SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE Callithrix jacchus; marmoset; prolactin; parental behavior; alloparental behavior; cooperative breeding ID NEW-WORLD PRIMATE; CALLITHRIX-JACCHUS; HELPING-BEHAVIOR; SAGUINUS-OEDIPUS; RECEPTOR; MECHANISMS; RESISTANCE; TAMARINS; STRESS; RATS AB Alloparental behavior (parental behavior directed to nondescendant young) is pervasive among human cultures but rare among other mammals. New World primates of the family Callitrichidae, including common marmosets (Callithrix jacchus jacchus), dwell in large families and many family members carry and/or provision infants. This study experimentally characterized alloparenting in common marmosets by measuring infant retrieval and carrying outside of the context of the family group. Prolactin was measured in samples collected before and after infant exposure to determine whether elevated prolactin levels were predictive of alloparental responsiveness. Seventeen nonbreeding, parentally inexperienced, singly or peer-housed common marmosets (10 females, 7 males, 6-66 months of age) were tested repeatedly in an infant retrieval paradigm. Infant retrieval was shown by 5 out of 17 monkeys (29%) in their first teal. The rate of retrieval increased to 10 monkeys (59%) by the fourth test. No significant differences in age, sex, or housing condition existed between monkeys that retrieved infants and those not retrieving. Prolactin concentrations were significantly elevated in serum obtained after testing only in monkeys that retrieved infants. Prolactin levels after infant exposure were positively related to carrying duration. A separate experiment verified that neither prolactin nor cortisol was significantly elevated in response to prolonged handling. Cortisol levels were inversely proportional to handling time. Prolactin levels were not significantly related to handling time. Our results indicate that alloparental behavior is expressed at high rates after minimal infant experience, and prolactin levels rise concomitantly with the expression of alloparental behavior in this species. (C) 2001 Elsevier Science Inc. All rights reserved. C1 NICHHD, Unit Dev Neuroethol, Comparat Ethol Lab, NIH Anim Ctr, Poolesville, MD 20837 USA. Univ Wisconsin, Wisconsin Reg Primate Res Ctr, Madison, WI 53715 USA. RP Roberts, RL (reprint author), NICHHD, Unit Dev Neuroethol, Comparat Ethol Lab, NIH Anim Ctr, POB 529, Poolesville, MD 20837 USA. FU NCRR NIH HHS [RR00167] NR 27 TC 28 Z9 28 U1 1 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD APR PY 2001 VL 72 IS 5 BP 713 EP 720 DI 10.1016/S0031-9384(01)00430-9 PG 8 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 431FY UT WOS:000168622200011 PM 11337003 ER PT J AU Shih, CYT Wu, JL Jia, SF Khan, AA Ting, KLH Shih, DS AF Shih, CYT Wu, JL Jia, SF Khan, AA Ting, KLH Shih, DS TI Purification of an osmotin-like protein from the seeds of Benincasa hispida and cloning of the gene encoding this protein SO PLANT SCIENCE LA English DT Article DE osmotin-like protein; Benincasa hispida; pathogenesis-related proteins; thaumatin-like proteins ID PATHOGENESIS-RELATED PROTEINS; THAUMATIN-LIKE PROTEINS; CRYSTAL-STRUCTURE; ANGSTROM RESOLUTION; ANTIFUNGAL PROTEIN; PR-5 PROTEIN; CDNA CLONE; VIRUS AB A pathogenesis-related (PR) protein was purified from the seeds of Benincasa hispida, which is a medicinal plant and a member of the Cucurbitaceae family. Purification was achieved by using a procedure consisting of an acid treatment step followed by two chromatography steps. The protein is a basic protein with molecular mass of similar to 28 kDa. The sequences of the N-terminal 30 amino acids and four peptides generated from protease digestion were determined. These sequences indicated that the protein is an osmotin-like protein (OLP). Osmotin and OLPs are members of the thaumatin-like, PR-5 family of the PR proteins. A genomic clone of the gene encoding the protein was isolated and sequenced. The predicted protein has a signal peptide of 18 amino acids, and the mature protein has a molecular mass of 24.8 kDa with an isoelectric point of 7.67. The protein has 17 cysteine residues, of which 16 appear in the same positions as those appear in the sweet-tasting protein thaumatin and several other thaumatin-like proteins. Southern hybridization analysis indicated that the gene encoding the protein is a single copy gene. A computer-generated, three-dimensional model of the protein is presented. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 So Univ, Hlth Res Ctr, RCMI Program, Baton Rouge, LA 70813 USA. So Univ, Dept Biol, Baton Rouge, LA 70813 USA. Louisiana State Univ, Dept Biol Sci, Baton Rouge, LA 70803 USA. Louisiana State Univ, Ctr Agr, Baton Rouge, LA 70803 USA. NCI, Lab Expt & Computat Biol, NIH, Bethesda, MD 20892 USA. RP Shih, CYT (reprint author), So Univ, Hlth Res Ctr, RCMI Program, Baton Rouge, LA 70813 USA. NR 26 TC 14 Z9 16 U1 1 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0168-9452 J9 PLANT SCI JI Plant Sci. PD APR PY 2001 VL 160 IS 5 BP 817 EP 826 DI 10.1016/S0168-9452(00)00450-7 PG 10 WC Biochemistry & Molecular Biology; Plant Sciences SC Biochemistry & Molecular Biology; Plant Sciences GA 425VL UT WOS:000168312300005 ER PT J AU Banks, MK Besheer, J Szypczak, J Goodpaster, LL Phipps, EJ Garraghty, PE AF Banks, MK Besheer, J Szypczak, J Goodpaster, LL Phipps, EJ Garraghty, PE TI The effects of carbamazepine on an appetitive-to-aversive transfer task: Comparison to untreated and phenytoin SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Review DE antiepileptic; carbamazepine; learning; memory; phenytoin ID LONG-TERM POTENTIATION; ANTIEPILEPTIC DRUGS; COGNITIVE FUNCTION; EPILEPTIC CHILDREN; NORMAL VOLUNTEERS; ANTICONVULSANT DRUGS; SEIZURE TYPE; MONOTHERAPY; VALPROATE; PERFORMANCE AB 1. Concerns over negative consequences resulting from chronic maintenance with antiepileptic medications have led to increased research regarding such impairments, often with disparate results. The authors have previously reported that phenytoin profoundly impairs the ability of adult rats, in comparison to controls, to learn a tone-signaled active avoidance response after learning a tone-signaled appetitive response (Banks et al., 1995; Banks et al., 1999). Such results lend further support to the suggestion that pharmacological treatment itself can produce cognitive difficulties that are comparable to those experienced by epileptic patients (Meador, 1994; Smith et al., 19X7). 2. In the present experiments, the authors have continued their investigation of antiepileptic compounds by treating rats with carbamazepine, another commonly prescribed "first-line defense" antiepileptic medication. In comparison to intact animals, carbamazepine-treated rats demonstrate variable deficiencies in the acquisition of the secondarily acquired avoidance response. 3. This result is in agreement with the finding for phenytoin-treated animals, albeit to a lesser degree. Continuing experiments are needed to investigate the relative nature of the deficits produced by such antiepileptic medications, as well as the underlying neurobiological mechanism(s). C1 Indiana Univ, Dept Psychol, Bloomington, IN USA. Indiana Univ, Program Neural Sci, Bloomington, IN USA. RP Banks, MK (reprint author), NINDS, NIGMS, NIH, ERB, 10 Ctr Dr,MSC 1408, Bethesda, MD 20892 USA. FU NIMH NIH HHS [MH55548] NR 39 TC 6 Z9 6 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD APR PY 2001 VL 25 IS 3 BP 551 EP 572 DI 10.1016/S0278-5846(00)00175-5 PG 22 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 424RJ UT WOS:000168245000006 PM 11370997 ER PT J AU Tella, SR Goldberg, SR AF Tella, SR Goldberg, SR TI Subtle differences in the discriminative stimulus effects of cocaine and GBR-12909 SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Review DE cocaine; discriminative stimulus; dopamine transporter; sodium channels ID A 20-ALPHA-BENZOATE BINDING; MONOAMINE UPTAKE INHIBITORS; DOPAMINE RECEPTOR SUBTYPES; TRANSPORTER KNOCKOUT MICE; RHESUS-MONKEYS; INTRAVENOUS COCAINE; LOCAL-ANESTHETICS; PHARMACOLOGICAL CHARACTERIZATION; SODIUM-CHANNELS; D-AMPHETAMINE AB 1. In addition to inhibiting the dopamine transporter, cocaine affects a variety of other neurotransmitter systems. In the present study, the involvement of both dopaminergic and the nondopaminergic systems in the behavioral effects of cocaine was studied using an intravenous drug discrimination procedure. 2. One group (Group 1) of rats were trained to discriminate cocaine (1 mg/kg, i.v.) from saline, while a second group (Group 2) of rats were trained to discriminate the same dose of cocaine from both GBR-12909 (1 mg/kg i.v.), a dopamine-selective uptake inhibitor, and saline. 3. Following training, substitution tests with different doses of cocaine and several drugs pharmacologically related to cocaine were conducted. When cocaine dose was varied, there was a dose-dependent generalization to the cocaine-training stimulus in both groups of rats. Conversely, GBR-12909 and GBR-12935, another dopamine-selective uptake inhibitor, generalized to the cocaine-training stimulus in Group 1, but there was minimal or no generalization in Group 2. 4. The norepinephrine-selective uptake inhibitors, desipramine and nisoxetine, and the serotonin-selective uptake inhibitor, zimeldine, produced little or no generalization to the cocaine-training stimulus in either group of rats. The sodium channel blocker, dimethocaine which has a relatively high affinity for the dopamine transporter fully generalized to the cocaine stimulus in both groups of rats, while procaine which has a low affinity for the dopamine transporters only partially generalized to the cocaine-training stimulus in both groups of rats. 5. Finally, lidocaine, which has negligible affinity for the dopamine transporter, did not generalize to the cocaine-training stimulus in either group of rats. The findings suggest similarities as well as subtle, but important, differences between the discriminative stimulus effects of cocaine and the dopamine uptake inhibitors, GBR-12909 and GBR12935. C1 Georgetown Univ, Med Ctr, Dept Pharmacol, Washington, DC 20007 USA. NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, Intramural Res Program,NIH, Baltimore, MD USA. RP Tella, SR (reprint author), Georgetown Univ, Med Ctr, Dept Pharmacol, C405,Med Dent Bldg,3900 Reservoir Rd NW, Washington, DC 20007 USA. FU NIDA NIH HHS [DA08830] NR 90 TC 7 Z9 7 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD APR PY 2001 VL 25 IS 3 BP 639 EP 656 DI 10.1016/S0278-5846(00)00180-9 PG 18 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 424RJ UT WOS:000168245000011 PM 11371002 ER PT J AU Hsi, LC Kamitani, H Cornicelli, JA Eling, TE AF Hsi, LC Kamitani, H Cornicelli, JA Eling, TE TI Evaluation of the activity and localization of 15-lipoxygenase-1 after introduction into human colorectal carcinoma Caco-2 cells SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article ID MAMMALIAN LIPOXYGENASES; RETICULOCYTE 15-LIPOXYGENASE; DEFICIENT MICE; PPAR-GAMMA; OXYGENATION; EXPRESSION; PHOSPHATIDYLCHOLINE; 12/15-LIPOXYGENASE; ATHEROSCLEROSIS; ATHEROGENESIS AB In human colorectal carcinoma Caco-2 cells, sodium butyrate (NaBT) induces the expression of the reticulocyte, 15-lipoxygenase-1 (15-LO-1) and causes these cells to undergo differentiation and apoptosis.15-LO-1 is also expressed in human colorectal epithelium with a significant higher expression observed in colorectal tumors. In this study, we have prepared stable Caco-2 cells that expressed 15-LO-1 under control of an inducible promoter. These cells provide a model system to study regulation of 15-LO-1 activity in colorectal cells without the interfering presence of NaBT and are useful to study the biological function of 15-LO-1. The expressed 15-LO-1 was highly active as measured in cell lysates, but we were unable to detect metabolism in intact cells. The addition of calcium to the media for the Caco-2 cells was required for 15-LO-1 to translocate from the cytosol to the membrane which is frequently a requirement for lipoxygenase activity. Despite the addition of calcium and translocation, little lipoxygenase activity was detected with intact cells. However, after removal of phenol red, a common constituent of cell culture media, we were able to detect 15-LO-1 activity in the transfected Caco-2 cultured cells. Thus the presence of calcium and the absence of antioxidants present in commonly used culture media are required for expressed 15-LO-1 to be catalytically active and to permit an examination of its biological effects. (C) 2001 Harcourt Publishers Ltd. C1 NIEHS, Eicosanoid Biochem Sect, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. Pfizer Inc, Global Res & Dev, Ann Arbor Labs, Ann Arbor, MI 48105 USA. RP Eling, TE (reprint author), NIEHS, Eicosanoid Biochem Sect, Mol Carcinogenesis Lab, POB 12233, Res Triangle Pk, NC 27709 USA. NR 30 TC 2 Z9 2 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0952-3278 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD APR-MAY PY 2001 VL 64 IS 4-5 BP 217 EP 225 DI 10.1054/plef.2001.0263 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 450LQ UT WOS:000169744700002 PM 11418015 ER PT J AU Webber, MM Quader, STA Kleinman, HK Bello-DeOcampo, D Storto, PD Bice, G DeMendonca-Calaca, W Williams, DE AF Webber, MM Quader, STA Kleinman, HK Bello-DeOcampo, D Storto, PD Bice, G DeMendonca-Calaca, W Williams, DE TI Human cell lines as an in vitro/in vivo model for prostate carcinogenesis and progression SO PROSTATE LA English DT Article DE carcinogenesis; human cell lines; prostate cancer; tumor progression ID ANCHORAGE-INDEPENDENT GROWTH; METHYL-N-NITROSOUREA; EPITHELIAL-CELLS; INTRAEPITHELIAL NEOPLASIA; EARLY EVENT; CANCER; CARCINOMA; MICE; N-(4-HYDROXYPHENYL)RETINAMIDE; CHEMOPREVENTION AB BACKGROUND. The study of prostate carcinogenesis and tumor progression is made difficult by the lack of appropriate in vitro and in vivo models. High prevalence of prostatic intra-epithelial neoplasia and latent prostatic carcinoma, representing multiple steps in carcinogenesis to invasive carcinoma, are relevant targets for cancer prevention. From the RWPE-1, immortalized, non-tumorigenic, human prostate epithelial cell line, we have derived four tumorigenic cell lines with progressive malignant characteristics. METHODS. Cell lines were derived by exposure of RWPE-1 to N-methyl-N-nitrosourea (MNU), selected and cloned in vivo and in vitro, and characterized by prostatic epithelial and differentiation markers, karyotype analysis, anchorage-independent growth, invasiveness, tumorigenicity, and pathology of the derived tumors. RESULTS. Cytokeratins 8 and 18, androgen receptor, and prostate-specific antigen expression in response to androgen, confirm prostatic epithelial origin. RWPE-1 cells do not grow in agar and are not tumorigenic in mice, but the growth, tumorigenicity, and tumor pathology of the MNU cell lines correlate with their invasive ability. The WPE1-NA22 (least malignant) form small, well-differentiated, and WPE1-NB26 cells (most malignant) form large, poorly differentiated, invasive tumors. Overall, loss of heterozygosity for chromosomes 7q, 13q, 18q, and 22, and gain of 5, 9q, 11q, and 20, was observed. The MNU cell lines, in order of increasing malignancy are; WPE1-NA22, WPE1-NB14, WPE1-NB11, and WPEI-NB26. CONCLUSIONS. This family of cell lines with a common lineage represents a unique and relevant model which mimics stages in prostatic intra-epithelial neoplasia (PIN) and progression to invasive cancer, and can be used to study carcinogenesis, progression, intervention, and chemoprevention. Prostate 47:1-13, 2001. (C) 2001 Wiley-Liss, Inc. C1 Michigan State Univ, Dept Zool & Med, E Lansing, MI 48824 USA. Natl Inst Dent & Carniofacial Res, Cell Biol Sect, NIH, Bethesda, MD USA. Michigan State Univ, Cytogenet Lab, Dept Pediat & Human Dev, E Lansing, MI 48824 USA. Sparrow Reg Canc Ctr, Dept Pathol, Lansing, MI USA. RP Webber, MM (reprint author), Michigan State Univ, Dept Zool & Med, S-350 Plant Biol Bldg, E Lansing, MI 48824 USA. NR 43 TC 64 Z9 68 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 0270-4137 J9 PROSTATE JI Prostate PD APR 1 PY 2001 VL 47 IS 1 BP 1 EP 13 PG 13 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 415YF UT WOS:000167750600001 PM 11304724 ER PT J AU Tanskanen, A Hibbeln, JR Tuomilehto, J Uutela, A Haukkala, A Viinamaki, H Lehtonen, J Vartiainen, E AF Tanskanen, A Hibbeln, JR Tuomilehto, J Uutela, A Haukkala, A Viinamaki, H Lehtonen, J Vartiainen, E TI Fish consumption and depressive symptoms in the general population in Finland SO PSYCHIATRIC SERVICES LA English DT Article ID POLYUNSATURATED FATTY-ACIDS; OMEGA-3-FATTY-ACIDS AB Fish contains high concentrations of omega-3 polyunsaturared fatty acids. Several studies have reported depletions of omega-3 fats among depressed patients, and a cross-national comparison has revealed a significant inverse con elation between annual prevalence of major depression and fish consumption. In a sample of 3,204 Finnish adults, depressive symptoms were estimated with tire Beck Depression Inventory. A frequency question was used to measure fish consumption. Multiple logistic regression analysis was conducted to assess the association between depression and fish consumption. After the analysis adjusted for potential confounders, the likelihood of having depressive symptoms was significantly higher among infrequent fish consumers than among frequent consumers. C1 Univ Kuopio, Dept Psychiat, Res & Dev Unit, Kuopio 70211, Finland. Natl Inst Alcohol Abuse & Alcoholism, Rockville, MD USA. Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Helsinki, Finland. RP Tanskanen, A (reprint author), Univ Kuopio, Dept Psychiat, Res & Dev Unit, POB 1777, Kuopio 70211, Finland. OI Haukkala, Ari/0000-0001-8567-1548 NR 10 TC 214 Z9 226 U1 1 U2 12 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 1075-2730 J9 PSYCHIATR SERV JI Psychiatr. Serv. PD APR PY 2001 VL 52 IS 4 BP 529 EP 531 DI 10.1176/appi.ps.52.4.529 PG 3 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 418EC UT WOS:000167877100019 PM 11274502 ER PT J AU Redwine, LS Altemus, M Leong, YM Carter, CS AF Redwine, LS Altemus, M Leong, YM Carter, CS TI Lymphocyte responses to stress in postpartum women: relationship to vagal tone SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE immune; stress; lactation; postpartum; human; autonomic ID ACUTE PSYCHOLOGICAL STRESSOR; PITUITARY-ADRENAL AXIS; CARDIOVASCULAR REACTIVITY; RHEUMATOID-ARTHRITIS; IMMUNE; NEUROENDOCRINE; CATECHOLAMINE; PROLIFERATION; PREGNANCY; PROLACTIN AB Although women spend their lives in various phases of the reproductive cycle, including menstrual, pregnancy, postpartum, lactation and menopause, few studies have examined immune responses to stress in women as a function of events associated with reproduction. The objective of this study was to evaluate differential effects of breastfeeding (n=16), bottlefeeding (n=10) and non-postpartum (n=10) status on lymphocyte responses to stressful tasks (public speaking and mental arithmetic). To measure cellular immune responses, lymphocyte proliferation to plant lectins. poke weed mitogen (PWM) and phytohemagglutinin (PHA) were used. The autonomic measures, heart rate, vagal tent, blood pressure and the hormones of the HPA axis, ACTH and cortisol, were measured and their possible roles in mediating lymphocyte proliferation responses were examined. Recently parturient women who were breastfeeding or bottlefeeding had attenuated stress-induced change in lymphocyte responses to PWM compared with non-postpartum women, tested in the follicular phase of their cycle (P<0.05). Also, lymphocyte responses to PHA were higher in the breastfeeding group compared with non-postpartum controls (P<0.05). Regression analyses revealed that an index of cardiac vagal tone, but not other autonomic or endocrine measures, was positively predictive of lymphocyte proliferation to PWM, To summarize, these findings suggest that lactation and parturition can influence lymphocyte proliferation and that activity in the vagal system may influence lymphocyte responses to stress. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Univ Calif San Diego, Dept Psychiat, San Diego, CA 92161 USA. Cornell Univ, Weill Med Coll, New York, NY 10021 USA. NIMH, NIH, Bethesda, MD 20892 USA. Univ Maryland, Dept Biol, College Pk, MD 20742 USA. RP Redwine, LS (reprint author), Univ Calif San Diego, Dept Psychiat, San Diego, CA 92161 USA. OI Redwine, Laura/0000-0001-7633-2034 FU NIMH NIH HHS [K05-MH 01050]; PHS HHS [T32 18399] NR 34 TC 22 Z9 22 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD APR PY 2001 VL 26 IS 3 BP 241 EP 251 DI 10.1016/S0306-4530(00)00049-4 PG 11 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA 409WJ UT WOS:000167408400002 PM 11166487 ER PT J AU Burgdorf, J Knutson, B Panksepp, J Shippenberg, TS AF Burgdorf, J Knutson, B Panksepp, J Shippenberg, TS TI Evaluation of rat ultrasonic vocalizations as predictors of the conditioned aversive effects of drugs SO PSYCHOPHARMACOLOGY LA English DT Article DE naloxone; lithium chloride; morphine; ultrasonic vocalization; conditioned place aversion; rat ID AGGRESSIVE ENCOUNTERS; BODY-TEMPERATURE; SOCIAL STRESS; MORPHINE; WITHDRAWAL; REWARD; ANTICIPATION; ANXIOLYTICS; INVOLVEMENT; NORVEGICUS AB Rationale: Since cues that predict aversive outcomes can elicit both avoidance and 20 kHz ultrasonic vocalizations (USVs) in adult rats, 20 kHz USVs may also index the conditioned aversive effects of drugs. Objective: We evaluated whether exposure to compartments associated with drugs With aversive effects would selectively increase 20 but not 50 kHz USVs in rats. Method: Rats were injected with naloxone (NAL) or lithium chloride (LiCl) and placed in one compartment or with Saline (VEH) and placed in another compartment for three 50-min conditioning sessions. 20 kHz USVs, 50 kHz USVs, and time spent in each chamber were recorded during subsequent 15-min testing sessions during which rats had access to both compartments (expt 1) or were confined to the drug- or VEH-paired compartment (expt 2). Results: In expt 1, animals conditioned either with NAL (0.3 and 3.0 mg/kg) or LiCl (10 and 30 mg/kg) emitted increased 20 1;Hz USVs in the drug-paired compartment, relative to VEH-conditioned controls. Conditioning with high doses of both drugs also increased conditioned place aversion and decreased emission of 50 kHz USVs, In expt 2, restriction of animals to the compartment paired with high doses of NAL and LiCl also increased emission of 20 kHz USVs and decreased 50 kHz USVs, relative to VEH-conditioned controls. Conclusions: In rats, cues associated with drugs with aversive effects increase 20 kHz USVs and decrease 50 kHz USVs, suggesting that USVs may provide a useful model for predicting the conditioned aversive effects of drugs. C1 NIAAA, Clin Studies Lab, Sect Brain Imaging & electrophysiol, Intramural Res Program,NIH, Bethesda, MD 20892 USA. NIDA, Integrat Neurosci Unit, Behav Neurosci Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. Bowling Green State Univ, Dept Psychol, Bowling Green, OH 43402 USA. RP Knutson, B (reprint author), NIAAA, Clin Studies Lab, Sect Brain Imaging & electrophysiol, Intramural Res Program,NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. OI Knutson, Brian/0000-0002-7669-426X NR 32 TC 71 Z9 73 U1 0 U2 3 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD APR PY 2001 VL 155 IS 1 BP 35 EP 42 DI 10.1007/s002130100685 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 429MX UT WOS:000168522200005 PM 11374334 ER PT J AU Chausmer, AL Katz, JL AF Chausmer, AL Katz, JL TI The role of D-2-like dopamine receptors in the locomotor stimulant effects of cocaine in mice SO PSYCHOPHARMACOLOGY LA English DT Article DE cocaine; locomotor activity; D-2-like; eticlopride; haloperidol; raclopride; spiperone; sulpiride ID RAT NUCLEUS-ACCUMBENS; ROTATIONAL BEHAVIOR; EXTRACELLULAR DOPAMINE; SUBSTANTIA-NIGRA; D1 RECEPTOR; ANTAGONISTS; AMPHETAMINE; LESIONS; AGONISTS; 6-HYDROXYDOPAMINE AB Rationale: Previous studies indicate antagonism of cocaine-stimulated locomotor activity by dopamine D-2-like receptor antagonists, but only at doses of the antagonists that by themselves attenuate locomotor activity, raising questions of the specificity of the interaction and whether it might be due solely to a summation of opposing effects. Objectives: The interactions of cocaine and several D-2-like dopamine antagonists and non-dopamine "physiological antagonists" were compared across a full range of doses in order to fully characterize the interaction and assess the specificity of the effects of dopamine antagonists and cocaine. Methods: Swiss Webster mice were treated with either vehicle, a D-2-like antagonist (haloperidol, spiperone, raclopride, spiperone, (+) or (-) eticlopride), or a "physiological" antagonist (chlordiazepoxide, clonidine, or R(-) N6-(2-phenylisopropyl)adenosine) and cocaine (5-80 mg/kg) prior to a 30-min locomotor activity test. Results: All test drugs decreased locomotor activity when given alone. All test drugs attenuated cocaine-induced locomotion and decreased peak responding to cocaine. In general, the D-2-like antagonists also decreased maximal responding to cocaine and decreased the slope of the ascending limb of the cocaine dose-effect curve, effects not obtained with physiological antagonists. Conclusions: Blockade of D-2-like receptors resulted in an interaction with cocaine that was fundamentally different from that produced through non-dopaminergic mechanisms and appears to be more than a summation of opposing effects. The present data suggest that D-2-like receptors are involved in the mechanisms underlying the induction of locomotor activity by cocaine. C1 NIDA, Medicat Discovery Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Katz, JL (reprint author), NIDA, Medicat Discovery Res Branch, Intramural Res Program, NIH, POB 5180, Baltimore, MD 21224 USA. NR 41 TC 46 Z9 46 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD APR PY 2001 VL 155 IS 1 BP 69 EP 77 DI 10.1007/s002130000668 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 429MX UT WOS:000168522200009 PM 11374338 ER PT J AU Sudakov, SK Medvedeva, OF Rusakova, IV Terebilina, NN Goldberg, SR AF Sudakov, SK Medvedeva, OF Rusakova, IV Terebilina, NN Goldberg, SR TI Differences in genetic predisposition to high anxiety in two inbred rat strains: role of substance P, diazepam binding inhibitor fragment and neuropeptide Y SO PSYCHOPHARMACOLOGY LA English DT Article DE anxiety; substance P; diazepam binding inhibitor; neuropeptide Y; rat ID RECEPTOR ANTAGONIST; CONFLICT TEST; PLUS-MAZE; BRAIN; CHOLECYSTOKININ; BEHAVIORS; AGONISTS; MODELS; MICE; NPY AB Rationale: Regulatory neuropeptide systems appear to modulate anxiety and emotionality, since anxiety in rats can be increased by intracerebroventricular (ICV) administration of diazepam-binding-inhibitor fragment (DBI) and decreased by ICV administration of neuropeptide Y (NPY) or substance P (SP). Objective: Involvement of these three neuropeptides in genetic predisposition to anxiety was studied in two inbred rat strains. Methods: Levels of anxiety to novel environments were first measured in Fischer-344 (F-344/N) and Wistar Albino Glare (WAG/G) rats using open-field conflict, hole-board, black and white box, elevated-plus maze and Vogel lick suppression procedures. Levels of SP, DBI and NPY in the hippocampus, midbrain and hypothalamus of F-344/N and WAG/G rats were then measured without stress (basal levels) or after stress induced by shuttle-box, shock-avoidance testing. Finally, effects of ICV injection of SP or NPY rats were measured in F-344/N and WAG/G rats using the hole-board test. Results: F-344/N rats had elevated level of anxiety compare to WAG/G rats with all five procedures. Levels of SP in the hippocampus, midbrain and hypothalamus of F-344/N rats were significantly lower than in WAG/G rats and levels of SP decreased in WAG/G, but not F-344/N, rats after stress. Levels of DBI in the hippocampus and midbrain of F-344/N rats were also lower than in WAG/G rats, but they increased in F-344/N rats after stress. In contrast, levels of NPY were higher in the midbrain of F-344/N rats than in WAG/G rats, especially after stress. ICV injection of SP or NPY decreased anxiety in the black and white box in both F-344/N and WAG/G rats, but F-344/N rats were more sensitive. Conclusions: These findings support the hypothesis that decreased levels of SP in certain brain regions may contribute to high levels of anxiety in rats. Decreased levels of DBI and increased levels of NPY in high-anxiety animals may act as compensatory mechanisms. C1 Res Inst Addict, Moscow, Russia. NIDA, Preclin Pharmacol Sect, NIH, Baltimore, MD USA. RP Sudakov, SK (reprint author), Res Inst Addict, Malyi Mogiltzevskij Per 3, Moscow, Russia. OI Sudakov, Sergey/0000-0002-9485-3439 NR 39 TC 24 Z9 25 U1 0 U2 3 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD APR PY 2001 VL 154 IS 4 BP 327 EP 335 DI 10.1007/s002130000651 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 422GQ UT WOS:000168110500001 PM 11349384 ER PT J AU Katz, JL Agoston, GE Alling, KL Kline, RH Forster, MJ Woolverton, WL Kopajtic, TA Newman, AH AF Katz, JL Agoston, GE Alling, KL Kline, RH Forster, MJ Woolverton, WL Kopajtic, TA Newman, AH TI Dopamine transporter binding without cocaine-like behavioral effects: synthesis and evaluation of benztropine analogs alone and in combination with cocaine in rodents SO PSYCHOPHARMACOLOGY LA English DT Article DE cocaine; dopamine transporter; stimulant effect; benztropine analogs; discriminative stimulus effect ID UPTAKE INHIBITORS; 3-ALPHA-(DIPHENYLMETHOXY)TROPANE ANALOGS; ANTAGONISTS; RECEPTORS; PROFILES; LIGAND; POTENT AB Rationale: Previous SAR studies demonstrated that small halogen substitutions on the diphenylether system of benztropine (BZT), such as a para-Cl group, retained high affinity at the cocaine binding site on the dopamine transporter Despite this high affinity, the compounds generally had behavioral effects different from those of cocaine. However, compounds with meta-Cl substitutions had effects more similar to those of cocaine. Objectives: A series of phenyl-ring analogs of benztropine (BZT) substituted with 3'-, 4'-, 3',4 "- and 4',4 " -position CI-groups were synthesized and their pharmacology was evaluated in order to assess more fully the contributions to pharmacological activity of substituents in these positions. Methods: Compounds were synthesized and their pharmacological activity was assessed by examining radioligand binding and behavioral techniques. Results: All of the compounds displaced [H-3]WIN 35,428 binding with affinities ranging from 20 to 32.5 nM. Affinities at norepinephrine ([H-3]nisoxetine) and serotonin ([H-3]citalopram) transporters, respectively ranged from 259 to 5120 and 451 to 2980 nM. Each of the compounds also inhibited [H-3]pirenzepine binding to muscarinic M-1 receptors, with affinities ranging from 0.98 to 47.9 nM. Cocaine and the BZT analogs produced dose-related increases in locomotor activity in mice. However, maximal effects of the BZT analogs were uniformly less than those produced by cocaine, and were obtained 2-3 h after injection compared to the relatively rapid onset (within 30 min) of cocaine effects. In rats trained to discriminate IP saline from 29 mu mol/kg cocaine (10 mg/kg), cocaine produced a dose-related increase in responding on the cocaine lever, reaching 100% at the training dose; however, none of the BZT analogs fully substituted for cocaine, with maximum cocaine responding from 20 to 69%. Despite their reduced efficacy compared to cocaine in cocaine discrimination, none of the analogs antagonized the effects of cocaine. As has been reported previously for 4'-Cl-BZT, the cocaine discriminative-stimulus effects were shifted leftward by co-administration of the present BZT analogs. Conclusions: The present results indicate that although the BZT analogs bind with relatively high affinity and selectivity at the dopamine transporter, their behavioral profile is distinct from that of cocaine. The present results suggest that analogs of BZT may be useful as treatments for cocaine abuse in situations in which an agonist treatment is indicated. These compounds possess features such as reduced efficacy compared to cocaine and a long duration of action that may render them particularly useful leads for the development of therapeutics for cocaine abusers. C1 NIDA, Psychobiol Sect, Medicat Discovery Res Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. NIDA, Med Chem Sect, Medicat Discovery Res Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. Univ Mississippi, Dept Psychiat, Jackson, MS 39216 USA. Univ N Texas, Hlth Sci Ctr, Dept Pharmacol, Ft Worth, TX USA. RP Katz, JL (reprint author), NIDA, Psychobiol Sect, Medicat Discovery Res Branch, Intramural Res Program,NIH, POB 5180, Baltimore, MD 21224 USA. OI Katz, Jonathan/0000-0002-1068-1159 NR 24 TC 31 Z9 32 U1 0 U2 3 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD APR PY 2001 VL 154 IS 4 BP 362 EP 374 DI 10.1007/s002130000667 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 422GQ UT WOS:000168110500006 PM 11349389 ER PT J AU Woolverton, WL Hecht, GS Agoston, GE Katz, JL Newman, AH AF Woolverton, WL Hecht, GS Agoston, GE Katz, JL Newman, AH TI Further studies of the reinforcing effects of benztropine analogs in rhesus monkeys SO PSYCHOPHARMACOLOGY LA English DT Article DE monkey; reinforcement; benztropine; dopamine uptake inhibitor ID DOPAMINE UPTAKE INHIBITORS; PROGRESSIVE-RATIO SCHEDULE; 3-ALPHA-(DIPHENYLMETHOXY)TROPANE ANALOGS; COCAINE; TRANSPORTER; GBR-12909; PHARMACOLOGY; BEHAVIOR; LIGANDS; BINDING AB Rationale: Several halogenated analogs of benztropine (BZT) have previously been characterized as potent DA uptake inhibitors with behavioral profiles that indicate diminished psychomotor stimulant effects relative to cocaine. In a previous study using a fixed-ratio 10 schedule, two chloro-analogs (3'-C1-BZT and -4'-Cl-BZT) maintained IV self-administration in monkeys but appeared to be weak positive reinforcers. Objectives: The present experiments were designed to test the hypothesis that 3'-C1-BZT and 4'-Cl-BZT are relatively weak reinforcers by evaluating reinforcing effects under increased response requirements. To examine further the effect of this halogen substitution on self-administration, 3',4 " -diCl-BZT was also evaluated for reinforcing effects. Methods: Four rhesus monkeys self-administered cocaine (0.03 mg/kg per injection, IV) under a fixed-ratio 25 (FR25) schedule until stable responding was established. Saline, various doses of cocaine (0.003-0.2 mg/kg per injection), the BZT analogs (0.012-0.2 mg/kg per injection), GBR 12909 (0.012-0.2 mg/kg per injection), and compounds with known reinforcing effects (d-amphetamine, morphine, pentobarbital, ketamine) were then made available for self-administration. Various doses (0.01-0.3 mg/kg per injection) of the compounds that maintained self-administration under the FR schedule were then substituted for cocaine (0:1 mg/kg per injection) under progressive-ratio (PR) schedules. Results: Reinforcing effects were evident under the FR schedule for 3'-C1-BZT, 4'-Cl-BZT, GBR 12909, and the control compounds, but not by 3',4 " -diCl-BZT. Results with the PR suggested that the rank order of these compounds for their effectiveness as reinforcers was cocaine>GBR 12909>3'-C1-BZT=4'-Cl-BZT>>3',4 " -diCl-BZT. Conclusions: This study confirms and extends previous results suggesting that compounds with high DAT affinity can have strong, moderate, weak, or no effectiveness as reinforcers. The mechanisms that may underlie this variation in reinforcing effectiveness of these DAT ligands remain to be established. C1 Univ Mississippi, Med Ctr, Dept Psychiat & Human Behav, Jackson, MS 39216 USA. NIDA, Psychobiol Sect, Div Intramural Res, NIH, Baltimore, MD 21224 USA. RP Woolverton, WL (reprint author), Univ Mississippi, Med Ctr, Dept Psychiat & Human Behav, 2500 N State St, Jackson, MS 39216 USA. OI Katz, Jonathan/0000-0002-1068-1159 FU NIDA NIH HHS [DA-10352, K02-DA-00161] NR 29 TC 46 Z9 46 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD APR PY 2001 VL 154 IS 4 BP 375 EP 382 DI 10.1007/s002130000616 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 422GQ UT WOS:000168110500007 PM 11349390 ER PT J AU Li, ZK Xia, LQ Lee, LM Khaletskiy, A Wang, JY Wong, JYC Li, JJ AF Li, ZK Xia, LQ Lee, LM Khaletskiy, A Wang, JY Wong, JYC Li, JJ TI Effector genes altered in MCF-7 human breast cancer cells after exposure to fractionated ionizing radiation SO RADIATION RESEARCH LA English DT Article ID NF-KAPPA-B; INDUCED APOPTOSIS; GENOTOXIC STRESS; CYCLIN B1; INDUCED RADIORESISTANCE; P53-INDUCED APOPTOSIS; MAMMALIAN-CELLS; DNA-DAMAGE; HELA-CELLS; S-PHASE AB Understanding the molecular mechanisms involved in the response of tumors to fractionated exposures to ionizing radiation is important for improving radiotherapy and/or radiochemotherapy. In the present study, we examined the expression of stress-related genes in an MCF-7 cell population (MCF-IR20) that has been derived through treatment with fractionated irradiation (2 Gy per fraction with a total dose of 40 Gy). MCF-IR20 cells showed a 1.6-fold increase in sensitization with dose at 10% isosurvival in a clonogenic assay, and a reduced growth delay (similar to 15 h compared to similar to 27 h), compared to the parental MCF-7 cells treated with a single dose of 5 Gy. To determine which effector genes were altered in the MCF-IR20 cells, the expression of stress-related effector genes was measured using a filter with 588 genes (Clontech) that included major elements involved in cell cycle control, DNA repair, and apoptosis. Compared to MCF-7 cells that were not exposed to fractionated radiation, 19 genes were upregulated (2.2-5.1-fold) and 4 were down-regulated (2.7-3.4-fold) in the MCF-IR20 cells. In agreement with the array results, 6 up-regulated genes tested by RT-PCR showed elevated expression. Also, activities of the stress-related transcription factors NFKB, TP53 and AP1 showed a 1.2-4.5-fold increase after a single dose of 5 Gy in MCF-IR20 cells compared with parental MCF-7 cells. However, when the radioresistant MCF-IR20 cell were cultured for more than 12 passages after fractionated irradiation (MCF-RV), radioresistance was lost, with the radiosensitivity being the same as the parental MCF-7 cells. Interestingly, expression levels of CCNB1, CD9 and CDKN1A in MCF-RV cells returned to levels expressed by the parental cells, whereas the expression levels of three other genes, MSH2, MSH6 and RPA remained elevated. To determine if any of the changes in gene expression could be responsible for the induced radioresistance, CCNB1 and CDKN1A, both of which were up-regulated in MCF-IR20 cells and down-regulated in MCF-RV cells, were studied further by transfection with antisense oligonucleotides. Antisense of CCNB1 significantly reduced the clonogenic survival of MCF-IR20 cells at doses of 5 and 10 Gy, from 42% to 26% and from 5.7% to 1.0%, respectively. Antisense of CDKN1A, however, had no effect on radiation survival of MCF-IR20 cells. In summary, these results suggest that stress-related effector genes are altered in cells after treatment with fractionated irradiation, and that up-regulation of CCNB1 is responsible, at least in part, for radioresistance after fractionated irradiation. (C) 2001 by Radiation Research Society. C1 City Hope Natl Med Ctr, Beckman Res Inst, Dept Radiat Res, Duarte, CA 91010 USA. NCI, Frederick Canc Res & Dev Ctr, Recombinant DNA Lab, Frederick, MD 21702 USA. RP Li, JJ (reprint author), City Hope Natl Med Ctr, Beckman Res Inst, Dept Radiat Res, 1500 E Duarte Rd,Halper S Bldg, Duarte, CA 91010 USA. NR 59 TC 70 Z9 73 U1 0 U2 3 PU RADIATION RESEARCH SOC PI OAK BROOK PA 820 JORIE BOULEVARD, OAK BROOK, IL 60523 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD APR PY 2001 VL 155 IS 4 BP 543 EP 553 DI 10.1667/0033-7587(2001)155[0543:EGAIMH]2.0.CO;2 PG 11 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 418GB UT WOS:000167881600004 PM 11260656 ER PT J AU Summers, RM Johnson, CD Pusanik, LM Malley, JD Youssef, AM Reed, JE AF Summers, RM Johnson, CD Pusanik, LM Malley, JD Youssef, AM Reed, JE TI Automated polyp detection at CT colonography: Feasibility assessment in a human population SO RADIOLOGY LA English DT Article DE colon, CT; colon neoplasms, diagnosis; computed tomography (CT), computer programs; computed tomography (CT), image processing; computed tomography (CT), three-dimensional ID VIRTUAL COLONOSCOPY; COLORECTAL POLYPS; BRONCHOSCOPY; NEOPLASMS; DISPLAY; CANCER AB PURPOSE: To test the feasibility of and improve a computer algorithm to automatically detect colonic polyps in real human computed tomographic (Ci) colonographic data sets. MATERIALS AND METHODS: Twenty patients with known polyps underwent CT colonography in the supine position. CT colonographic data were processed by using a shape-based algorithm that depicts masses that protrude into the lumen. We studied nine shape criteria and three isosurface threshold settings. Results were compared with those of conventional colonoscopy performed the same day. RESULTS: There were 50 polyps (28 were greater than or equal to 10 mm in size; 12, 5-9 mm; 10, <5 mm). The sensitivity with optimal settings for detecting polyps 10 mm or greater was 64% (18 of 28). Sensitivity improved to 71% (10 of 14) for polyps 10 mm or greater in well-distended colonic segments. Performance decreased for polyps less than 10 mm, poorly distended colonic segments, and other shape algorithms. There was a mean of six false-positive lesion sites per colon. These sites were reduced 39% to 3.5 per colon by sampling CT attenuation at the lesion site and discarding sites having attenuation less than a threshold. CONCLUSION: Automated detection of colonic polyps, especially clinically important large polyps, is feasible. Colonic distention is an important determinant of sensitivity. Further increases in sensitivity may be achieved by adding prone CT colonography. C1 NIH, Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. Mayo Clin, Dept Radiol, Rochester, MN USA. RP Summers, RM (reprint author), NIH, Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, Bldg 10,Rm 1C660,10 Ctr Dr,MSC 1182, Bethesda, MD 20892 USA. EM rms@nih.gov NR 25 TC 201 Z9 205 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD APR PY 2001 VL 219 IS 1 BP 51 EP 59 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 414LD UT WOS:000167667400008 PM 11274534 ER PT J AU Faith, M Thayer, JF AF Faith, M Thayer, JF TI A dynamical systems interpretation of a dimensional model of emotion SO SCANDINAVIAN JOURNAL OF PSYCHOLOGY LA English DT Article DE a dynamical system; emotion; circumplex; induced emotion; valence; arousal ID BRAIN ELECTRICAL-ACTIVITY; STARTLE REFLEX; INDIVIDUAL-DIFFERENCES; CIRCUMPLEX MODEL; BASIC EMOTIONS; SINGLE-SUBJECT; FACIAL SIGNS; P-TECHNIQUE; MOOD; MULTIVARIATE AB The dimensional structure of emotion was investigated using self reports of induced mood and idiographic and nomothetic analyses. Subjects attended four experimental sessions during which an array of affective states was induced via auditory, visual, and imaginal channels. For each of 118 stimulus events, subjects self-rated their response. Factor analysis yielded the predicted bipolar factors of valence and arousal: these were obtained in group-aggregated analysis and subsequently confirmed as change dimensions at the intraindividual level. Controversy over the fundamental dimensions of affective space was considered with respect to methodological issues such as factor rotation and sampling of data space. Valence and arousal are discussed as motivational, driving parameters of affective experience and a dynamical systems conceptualization of emotion is proposed. C1 NIA, Gerontol Res Ctr, LPC, NIH, Baltimore, MD 21224 USA. RP Thayer, JF (reprint author), NIA, Gerontol Res Ctr, LPC, NIH, Room 2C13,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 84 TC 24 Z9 25 U1 5 U2 16 PU BLACKWELL PUBL LTD PI OXFORD PA 108 COWLEY RD, OXFORD OX4 1JF, OXON, ENGLAND SN 0036-5564 J9 SCAND J PSYCHOL JI Scand. J. Psychol. PD APR PY 2001 VL 42 IS 2 BP 121 EP 133 DI 10.1111/1467-9450.00221 PG 13 WC Psychology, Multidisciplinary SC Psychology GA 420EX UT WOS:000167992500005 PM 11321635 ER PT J AU Yang, X Sun, YX Zhou, J Huang, PT Huang, CF Xu, XL Li, CL Gotay, J Chen, L Deng, CX AF Yang, X Sun, YX Zhou, J Huang, PT Huang, CF Xu, XL Li, CL Gotay, J Chen, L Deng, CX TI Establishment of murine Smad5 double knockout ES cells and the studies on their properties SO SCIENCE IN CHINA SERIES C-LIFE SCIENCES LA English DT Article DE Smad5; double knockout; ES cells; Cre-LoxP ID TUMOR-SUPPRESSOR; TGF-BETA; TARGETED DISRUPTION; MESODERM INDUCTION; MOUSE EMBRYOS; MICE; DEFECTS; PROTEINS; LACKING AB Smad5 is an intracellular transducer of TGF-P signals. Targeted disruption of murine Smad5 gene resulted in embryonic lethal. To study the function of Smad5 in organgenesis, we generated Smad5 double knockout ES cells by homologous recombination. We deleted the neo gene of the Smad5 targeted ES cells using Cre-LoxP system. Smad5 double knockout ES cells were obtained by transfecting the targeted ES cells using the same targeting construct. The results of chimeric study showed that Smad5 might play an important role during the development of heart and neural tube. Smad5 double knockout ES cells formed teratoma when injected subcutaneously into nude mice. They differentiated into several types of cells, including neural cells, muscle cells, chondrocytes, endothelial cells and glandaceous cells. Smad5 double knockout ES cells are useful for studying the function of Smad5 mediated TGF- beta during the organgenesis and the in vitro differentiation of ES cells. C1 Inst Biotechnol, Beijing 100071, Peoples R China. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Yang, X (reprint author), Inst Biotechnol, Beijing 100071, Peoples R China. RI deng, chuxia/N-6713-2016 NR 21 TC 2 Z9 2 U1 0 U2 4 PU SCIENCE PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1006-9305 J9 SCI CHINA SER C JI Sci. China Ser. C-Life Sci. PD APR PY 2001 VL 44 IS 2 BP 121 EP 129 DI 10.1007/BF02879316 PG 9 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 429HP UT WOS:000168510900002 PM 18726428 ER PT J AU Stetler-Stevenson, WG Yu, AE AF Stetler-Stevenson, WG Yu, AE TI Proteases in invasion: matrix metalloproteinases SO SEMINARS IN CANCER BIOLOGY LA English DT Article DE matrix metalloproteinases; cancer; cellular invasion; angiogenesis ID EXTRACELLULAR-MATRIX; TISSUE INHIBITOR; CELL-MIGRATION; TUMOR-GROWTH; IN-VITRO; METASTASIS; ANGIOGENESIS; CANCER; MATRILYSIN; CYTOSKELETON AB The role of proteases in general, and the matrix metalloproteinases in particular, in tumor invasion and metastasis is well established. However, the classic view that these enzymes simply provide a mechanism for the breakdown of connective tissue barriers has been challenged. This overview summarizes recent evidence to support the changing view of the role of matrix metalloproteinases in cancer progression. First we briefly review the central role of cell invasion in cancer progression and also the matrix metalloproteinase family members. We then focus on the emerging roles for these enzymes in cancer progression, including the role of matrix metalloproteinases in cell proliferation and release of growth factors, cell migration and in modification of the extracellular matrix to reveal cryptic sites that alter cell behaviour. C1 NCI, Pathol Lab, Div Clin Sci, NIH, Bethesda, MD 20892 USA. Human Genome Sci, Rockville, MD 20850 USA. RP Stetler-Stevenson, WG (reprint author), NCI, Pathol Lab, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RI Stetler-Stevenson, William/H-6956-2012 OI Stetler-Stevenson, William/0000-0002-5500-5808 NR 55 TC 283 Z9 297 U1 1 U2 17 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-579X J9 SEMIN CANCER BIOL JI Semin. Cancer Biol. PD APR PY 2001 VL 11 IS 2 BP 143 EP 152 DI 10.1006/scbi.2000.0365 PG 10 WC Oncology SC Oncology GA 429HY UT WOS:000168511800006 PM 11322833 ER PT J AU Marti, GE Stetler-Stevenson, N Bleesing, JJH Fleisher, TA AF Marti, GE Stetler-Stevenson, N Bleesing, JJH Fleisher, TA TI Introduction to flow cytometry SO SEMINARS IN HEMATOLOGY LA English DT Editorial Material ID WHOLE-BLOOD LYSIS; LYMPHOCYTE SUBSETS; FLUORESCENCE SENSITIVITY; PERIPHERAL-BLOOD; REFERENCE RANGES; CELL SUBSETS; LIGHT; ENUMERATION; CAUCASIANS; POPULATION C1 US FDA, Flow & Image Cytometry Sect, Lab Med & Mol Genet, Div Cell & Gene Therapies,CBER, Bethesda, MD 20892 USA. NCI, Hematopathol Sect, Pathol Lab, Bethesda, MD 20892 USA. NIH, Dept Lab Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Marti, GE (reprint author), US FDA, Flow & Image Cytometry Sect, Lab Med & Mol Genet, Div Cell & Gene Therapies,CBER, Bldg 29B,Room 2NN08,8800 Rockville Pike, Bethesda, MD 20892 USA. NR 36 TC 15 Z9 15 U1 2 U2 14 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD APR PY 2001 VL 38 IS 2 BP 93 EP 99 DI 10.1053/shem.2001.21921 PG 7 WC Hematology SC Hematology GA 423NM UT WOS:000168182400001 PM 11309691 ER PT J AU Bleesing, JJH Fleisher, TA AF Bleesing, JJH Fleisher, TA TI Immunophenotyping SO SEMINARS IN HEMATOLOGY LA English DT Article ID BONE-MARROW TRANSPLANTATION; STEM-CELL TRANSPLANTATION; WISKOTT-ALDRICH-SYNDROME; CD8(+) T-CELLS; AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; SEVERE COMBINED IMMUNODEFICIENCY; ACTIVE ANTIRETROVIRAL THERAPY; PERIPHERAL-BLOOD LYMPHOCYTES; FLOW CYTOMETRIC ANALYSIS; HYPER-IGM SYNDROME C1 NIH, Dept Lab Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Bleesing, JJH (reprint author), NIH, Dept Lab Med, Warren G Magnuson Clin Ctr, Bldg 10,Room 2C410,10 Ctr Dr,MCS 1508, Bethesda, MD 20892 USA. NR 78 TC 19 Z9 19 U1 1 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD APR PY 2001 VL 38 IS 2 BP 100 EP 110 DI 10.1053/shem.2001.21922 PG 11 WC Hematology SC Hematology GA 423NM UT WOS:000168182400002 PM 11309692 ER PT J AU Stetler-Stevenson, M Braylan, RC AF Stetler-Stevenson, M Braylan, RC TI Flow cytometric analysis of lymphomas and lymphoproliferative disorders SO SEMINARS IN HEMATOLOGY LA English DT Article ID NON-HODGKINS-LYMPHOMA; CHRONIC LYMPHOCYTIC-LEUKEMIA; S-PHASE FRACTION; CANADIAN CONSENSUS RECOMMENDATIONS; CELL PROLIFERATIVE DISORDERS; POLYMERASE-CHAIN-REACTION; MARROW PLASMA-CELLS; MULTIPLE-MYELOMA; BONE-MARROW; IMMUNOPHENOTYPIC ANALYSIS C1 NCI, Flow Cytometry Unit, Pathol Lab, DCS,NIH, Bethesda, MD 20892 USA. Univ Florida, Coll Med, Dept Pathol, Gainesville, FL USA. RP Stetler-Stevenson, M (reprint author), NCI, Flow Cytometry Unit, Pathol Lab, DCS,NIH, Bldg 10,Room 2N-108, Bethesda, MD 20892 USA. NR 53 TC 36 Z9 43 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD APR PY 2001 VL 38 IS 2 BP 111 EP 123 DI 10.1053/shem.2001.21923 PG 13 WC Hematology SC Hematology GA 423NM UT WOS:000168182400003 PM 11309693 ER PT J AU Bleesing, JJH Fleisher, TA AF Bleesing, JJH Fleisher, TA TI Cell function-based flow cytometry SO SEMINARS IN HEMATOLOGY LA English DT Article ID CD8(+) T-CELLS; CHRONIC GRANULOMATOUS-DISEASE; BLOOD MONONUCLEAR-CELLS; PEPTIDE-MHC TETRAMERS; PERIPHERAL-BLOOD; PROTEIN-PHOSPHORYLATION; INTRACELLULAR CYTOKINES; MELANOMA PATIENTS; TH1/TH2 PARADIGM; CD1D TETRAMERS C1 NIH, Dept Lab Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Bleesing, JJH (reprint author), NIH, Dept Lab Med, Warren G Magnuson Clin Ctr, Bldg 10,Room 2C410,10 Ctr Dr,MCS 1508, Bethesda, MD 20892 USA. NR 60 TC 7 Z9 7 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD APR PY 2001 VL 38 IS 2 BP 169 EP 178 DI 10.1053/shem.2001.21928 PG 10 WC Hematology SC Hematology GA 423NM UT WOS:000168182400008 PM 11309698 ER PT J AU Cheng, PC Cherukuri, A Dykstra, M Malapati, S Sproul, T Chen, MR Pierce, SK AF Cheng, PC Cherukuri, A Dykstra, M Malapati, S Sproul, T Chen, MR Pierce, SK TI Floating the raft hypothesis: the roles of lipid rafts in B cell antigen receptor function SO SEMINARS IN IMMUNOLOGY LA English DT Review DE antigen processing; B cell development; CD19/CD21 coreceptor; Epstein-Barr Virus; signal transduction ID COMPLEX; LYMPHOCYTES; THRESHOLDS; IMMUNITY; SIGNALS; ENTRY AB The initiation of antibody responses to foreign antigens requires that B cells receive and integrate a variety of signals through an array of cell surface receptors including the B cell antigen receptor (BCR) as well as a number of essential coreceptors. Recent evidence indicates that cholesterol-rich plasma membrane microdomains, referred to here as lipid rafts, serve as platforms for BCR signaling and trafficking in B cells. The existence of rafts suggests a previously unappreciated level of organization at the B cell surface that may explain, at least in part, how BCR signaling is coordinated. Here the current evidence that lipid rafts play a key role in B cell responses is reviewed. C1 NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. Northwestern Univ, Dept Biochem Mol Biol & Cell Biol, Evanston, IL 60208 USA. RP Pierce, SK (reprint author), NIAID, Immunogenet Lab, NIH, Twinbrook 2,12441 Parklawn Dr,Room 200B,MSC 8180, Rockville, MD 20852 USA. NR 24 TC 55 Z9 55 U1 0 U2 1 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD APR PY 2001 VL 13 IS 2 BP 107 EP 114 DI 10.1006/smim.2000.0302 PG 8 WC Immunology SC Immunology GA 424EE UT WOS:000168218500004 PM 11308294 ER PT J AU Porcalla, AR Rodriguez, WJ AF Porcalla, AR Rodriguez, WJ TI Soft tissue and cartilage infection by Salmonella oranienburg in a healthy girl SO SOUTHERN MEDICAL JOURNAL LA English DT Article ID PATIENT AB Focal extraintestinal infections from nontyphoid salmonellae have increased in incidence during the past decade, Typically, they are manifested as either osteomyelitis or meningitis as a complication of either bacteremia or enteric fever. Isolated salmonellal soft tissue infections, however, are rare and occur mostly in adults with chronic underlying conditions such as human immunodeficiency virus (HIV) infection, diabetes mellitus, and cell-mediated immunity defects. We report a case of an otherwise healthy adolescent who was exposed to a guinea pig with a skin mass. She subsequently had an isolated soft tissue infection with cartilaginous involvement of the anterior chest wall due to Salmonella enterica serogroup C-1 (bioserotype oranienburg). C1 Natl Inst Dent & Craniofacial Res, NIH, Oral Infect & Immun Branch, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Dept Infect Dis, Washington, DC 20010 USA. RP Porcalla, AR (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Oral Infect & Immun Branch, Bldg 30,Room 334, Bethesda, MD 20892 USA. NR 12 TC 14 Z9 14 U1 0 U2 2 PU SOUTHERN MEDICAL ASSN PI BIRMINGHAM PA 35 LAKESHORE DR PO BOX 190088, BIRMINGHAM, AL 35219 USA SN 0038-4348 J9 SOUTHERN MED J JI South.Med.J. PD APR PY 2001 VL 94 IS 4 BP 435 EP 437 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 425WJ UT WOS:000168314400017 PM 11332914 ER PT J AU LaBiche, R Koziol, D Quinn, TC Gaydos, C Azhar, S Ketron, G Sood, S DeGraba, TJ AF LaBiche, R Koziol, D Quinn, TC Gaydos, C Azhar, S Ketron, G Sood, S DeGraba, TJ TI Presence of Chlamydia pneumoniae in human symptomatic and asymptomatic carotid atherosclerotic plaque SO STROKE LA English DT Article DE atherosclerosis; carotid arteries; chlamydia; immunoglobulin; symptoms ID INFECTION; DISEASE; ARTERY; ENDARTERECTOMY; LESIONS; STROKE; RISK AB Background-Chlamydia pneumoniae has been identified in atherosclerotic plaques of patients with cerebrovascular and cardiovascular disease. However, the direct causative effect of C pneumoniae infection in the activation of atherosclerotic plaque to a prothrombotic state remains to be established. The aim of the present study is to examine the correlation between intraplaque presence of chlamydiae and symptomatic carotid disease in humans. Methods-Plaques from 37 symptomatic and 57 asymptomatic consenting patients undergoing carotid endarterectomy were snap-frozen, and the tissue was prepared for polymerase chain reaction analysis for Chlamydia pneumoniae per Institutional Review Board-approved protocol. Blood was drawn from each patient at the time of surgery for serological analysis. Results-The overall rate of plaques positive for C pneumoniae was 14.82%, with 5 of 37 (13.5%) plaques from symptomatic patients and 9 of 57 (15.8%) from asymptomatic patients, which revealed a definitive presence of the organism. No association existed between C pneumoniae presence and symptomatic disease (P=1.0), Also, no association existed between presence of C pneumoniae and severity of stenosis. Finally, seropositivity for antichlamydial IgG, IgA, and IgM anti-chlamydial antibodies did not correlate with identification of C pneumoniae in the plaques. However, high-serum anti-chlamydial IgA levels (greater than or equal to1:128) were associated with occurrence of symptomatic disease (P=0.03; odds ratio, 2.86; 95% CI, 1.12 to 7.28). Conclusions-Presence of C pneumoniae as a single factor does not appear to be sufficient to explain the occurrence of cerebrovascular symptoms. Low sensitivity of seropositivity for IgG, IgA, or IgM associated with PCR-identified C pneumoniae presence in the plaque makes it unlikely to be Valuable as the single determining factor for actively infected plaque. Association of high-level anti-chlamydial IgA with symptomatic disease suggests that chronic or acute chlamydial infection anywhere in the body could play a role in atherosclerotic plaque activation and be used as a marker to target populations in future stroke prevention trials. C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Biostat & Clin Epidemiol Serv, Bethesda, MD 20892 USA. Johns Hopkins Univ, Div Infect Dis, Baltimore, MD 21218 USA. Natl Naval Med Ctr, Bethesda, MD USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP DeGraba, TJ (reprint author), NINDS, Stroke Branch, NIH, 36 Room 4A-03,36 Convent Dr,MSC 4128, Bethesda, MD 20892 USA. RI Gaydos, Charlotte/E-9937-2010 NR 35 TC 63 Z9 67 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2001 VL 32 IS 4 BP 855 EP 860 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 419LV UT WOS:000167951300008 PM 11283382 ER PT J AU Perera, L Darden, TA Pedersen, LG AF Perera, L Darden, TA Pedersen, LG TI Modeling human zymogen factor IX SO THROMBOSIS AND HAEMOSTASIS LA English DT Review DE factor IX; molecular dynamics simulations; serine protease; calcium binding ID PARTICLE MESH EWALD; MOLECULAR-DYNAMICS SIMULATION; COAGULATION-FACTOR VIIA; FACTOR-LIKE DOMAINS; X-RAY STRUCTURE; BLOOD-COAGULATION; PROTEIN-C; CRYSTAL-STRUCTURE; TISSUE FACTOR; ACTIVE-SITE AB Modern theoretical techniques are employed to provide complete three dimensional structure for the zymogen and activated forms of human coagulation factors IX and IXa. These structures are fully calcium bound and equilibrated in an electrically neutral aqueous environment. The relationship of structure to mutational data is examined. We find that a substantial relative orientational change of the catalytic domain occurs on activation. Also, we find that the electrostatistically dipolar nature of the catalytic domain is substantially modified upon activation, with cleavage of the negatively charged activation peptide leaving behind a largely hydrophobic face in factor IXa. While the backbone atoms of the catalytic residues have little relative movement, nearby loops are found that do move. The presence or absence of these changes likely defines specificity. C1 Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Pedersen, LG (reprint author), Univ N Carolina, Dept Chem, CB 3290, Chapel Hill, NC 27599 USA. RI perera, Lalith/B-6879-2012; Pedersen, Lee/E-3405-2013 OI perera, Lalith/0000-0003-0823-1631; Pedersen, Lee/0000-0003-1262-9861 FU NHLBI NIH HHS [HL-06350] NR 50 TC 16 Z9 16 U1 0 U2 3 PU F K SCHATTAUER VERLAG GMBH PI STUTTGART PA P O BOX 10 45 43, LENZHALDE 3, D-70040 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD APR PY 2001 VL 85 IS 4 BP 596 EP 603 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 422EG UT WOS:000168105100005 PM 11341491 ER PT J AU Saito, J Kohn, AD Roth, RA Noguchi, Y Tatsumo, I Hirai, A Suzuki, K Kohn, LD Saji, M Ringel, MD AF Saito, J Kohn, AD Roth, RA Noguchi, Y Tatsumo, I Hirai, A Suzuki, K Kohn, LD Saji, M Ringel, MD TI Regulation of FRTL-5 thyroid cell growth by phosphatidylinositol (OH) 3 kinase-dependent Akt-mediated signaling SO THYROID LA English DT Article ID THREONINE PROTEIN-KINASE; COENZYME-A REDUCTASE; FACTOR-I; GERMLINE MUTATIONS; DOWN-REGULATION; DNA-SYNTHESIS; S-PHASE; INSULIN; THYROTROPIN; EXPRESSION AB Thyrotropin (TSH)-initiated cell cycle progression from G(1) to S phase in FRTL-5 thyroid cells requires serum, insulin, or insulin-like growth factor 1 (IGF-1) and involves activation of 3-hydroxSr-3-methylglutaryl-CoA reductase, geranylgeranylation of RhoA, p27(Kip1) degradation, and activation of cyclin-dependent kinase (cdk) 2. In the present report, we show that the serine-threonine kinase Akt is an important mediator of insulin/ IGF-1/serum effects on cell cycle progression in FRTL-5 thyroid cells. The phosphoinositol (OH) 3 kinase inhibitors, Wortmannin (WM) and Ly294002 (LY), block the ability of insulin/IGF-1 to reduce p27 expression, to induce expression of cyclins E, D1, and A as well as cdk 2 and 4, and to phosphorylate retinoblastoma protein. They also inhibit insulin/IGF-1-increased DNA synthesis and cell cycle entrance (S+G(2)/M). Insulin/IGF-1 rapidly induced activation of Akt1 in a PI3 kinase-dependent manner, and increased Akt1 RNA levels. Most importantly, FRTL-5 cells transfected with a constitutively active form of Akt1 have higher basal rates of DNA synthesis and no longer require exogenous insulin/IGF-1 or serum for TSH-induced growth. In sum, Akt1 appears to have an important role in insulin/IGF-1 regulation of FRTL-5 thyroid cell growth and cell cycle progression. C1 Washington Hosp Ctr, Medstar Res Inst, Endocrinol Sect, Mol Endocrinol Lab, Washington, DC 20010 USA. NIH, Bethesda, MD 20892 USA. Chiba Univ, Dept Internal Med 2, Chuou Ku, Chiba, Japan. Stanford Univ, Sch Med, Dept Mol Pharmacol, Palo Alto, CA 94304 USA. Uniformed Serv Univ Hlth Sci, Dept Med, Bethesda, MD 20814 USA. RP Ringel, MD (reprint author), Washington Hosp Ctr, Medstar Res Inst, Endocrinol Sect, Mol Endocrinol Lab, 110 Irving St,NW Room 2A-46B, Washington, DC 20010 USA. RI Saji, Motoyasu/E-4007-2011 NR 56 TC 55 Z9 56 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1050-7256 J9 THYROID JI Thyroid PD APR PY 2001 VL 11 IS 4 BP 339 EP 351 DI 10.1089/10507250152039073 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 429GH UT WOS:000168507400006 PM 11349832 ER PT J AU Fain, MA Zhao, T Kindt, TJ AF Fain, MA Zhao, T Kindt, TJ TI Improved typing procedure for the polymorphic single-copy RLA-DQA gene of the rabbit reveals a new allele SO TISSUE ANTIGENS LA English DT Article DE heteroduplex analysis; MHC; RLA; segregation analysis; single-stranded conformation; polymorphism ID CLASS-II GENES; MAJOR HISTOCOMPATIBILITY COMPLEX; NUCLEOTIDE-SEQUENCE; MHC; EVOLUTION; ALPHA; PATTERNS; HOMOLOGY; REGION; DNA AB The DQA gene of the rabbit major histocompatibility complex (MHC, RLA) is highly polymorphic and, in contrast to those reported for other mammalian species, is present as a single copy. These properties allow use of this gene in a method to type the class II locus of RLA by a combination of single-stranded conformational polymorphism (SSCP) and heteroduplex (I-ID) analysis. Familial segregation of RLA-DQA was shown and RLA class II types for rabbits of unknown pedigree were determined using migration patterns of amplified genomic DNA. Typing results were confirmed in experiments where unknown samples were mixed with products from rabbits of RLA types defined by sequence analysis. These analyses detected an RLA-DQA allele in addition to the five previously described; this new allele is designated RLA-DQA-F. C1 NIAID, Mol & Cellular Immunogenet Sect, NIH, Bethesda, MD 20892 USA. RP Fain, MA (reprint author), NIAID, Mol & Cellular Immunogenet Sect, NIH, Bldg 10,Room 4A31,10 Ctr Dr MSC 1356, Bethesda, MD 20892 USA. NR 21 TC 9 Z9 9 U1 0 U2 2 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD APR PY 2001 VL 57 IS 4 BP 332 EP 338 DI 10.1034/j.1399-0039.2001.057004332.x PG 7 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 440RG UT WOS:000169187600006 PM 11380942 ER PT J AU Hulla, JE French, JE Dunnick, JK AF Hulla, JE French, JE Dunnick, JK TI Chromosome 11 loss from thymic lymphomas induced in heterozygous Trp53 mice by phenolphthalein SO TOXICOLOGICAL SCIENCES LA English DT Article DE allelotype; simple sequence length polymorphism; SSLP; carcinogenesis; thymus; lymphoma; phenolphthalein; recombination; LOH; chromosome loss ID MICRONUCLEATED ERYTHROCYTES; P53-DEFICIENT MICE; P53 GENE; MOUSE; INDUCTION; 1,2-DIMETHYLHYDRAZINE; PROMOTER; BINDING; REGION; TUMORS AB C57BL/6 p53 (+/-) N5 mice heterozygous for a null p53 allele were given phenolphthalein to learn more about mechanisms of carcinogenesis and to evaluate the p53-deficient mouse as a tool for identifying potential human carcinogens. DNA samples isolated from 10 phenolphthalein-induced thymic lymphomas were analyzed for loss of heterozygosity (LOH) at the Trp53 locus and simple sequence length polymorphic (SSLP) loci. The initial screening revealed remarkable results from only chromosome 11. Allelotyping at approximately five centiMorgan intervals, we found SSLP heterozygosity for C57BL/6 and 129Sv over much of chromosome Il. In the tumors, treatment-related LOH was apparent on chromosome 11 at each of the 28 informative loci examined. The strain-specific polymorphism lost from individual tumors allowed us to deduce the distribution of alleles along the length of the maternal and paternal chromosomes 11. The allelic patterns indicate that mitotic homologous recombination occurred during embryogenesis if breeding protocols were carried out as described. The mitotic recombination observed may be attributable to p53 haploinsufficiency for normal suppression of mitotic recombination. C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. Univ N Dakota, Sch Med, Grand Forks, ND 58202 USA. RP Hulla, JE (reprint author), NIEHS, NIH, 111 TW Alexander Dr,Box 12233,F1-05, Res Triangle Pk, NC 27709 USA. FU NCRR NIH HHS [5-P20RR11817-03]; NIEHS NIH HHS [ES21207-05] NR 36 TC 4 Z9 4 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD APR PY 2001 VL 60 IS 2 BP 264 EP 270 DI 10.1093/toxsci/60.2.264 PG 7 WC Toxicology SC Toxicology GA 414KU UT WOS:000167666400009 PM 11248138 ER PT J AU O'Brien, ML Twaroski, TP Cunningham, ML Glauert, HP Spear, BT AF O'Brien, ML Twaroski, TP Cunningham, ML Glauert, HP Spear, BT TI Effects of peroxisome proliferators on antioxidant enzymes and antioxidant vitamins in rats and hamsters SO TOXICOLOGICAL SCIENCES LA English DT Article DE Wy-14,643; dibutyl phthalate; gemfibrozil; superoxide dismutase; DT-diaphorase; alpha-tocopherol; ascorbic acid; peroxisome proliferator (PP); Sprague-Dawley rat; Syrian hamster ID S-TRANSFERASE ISOENZYMES; OXIDATIVE STRESS; SUPEROXIDE-DISMUTASE; DT-DIAPHORASE; SPECIES-DIFFERENCES; LIPID-PEROXIDATION; GLUTATHIONE-PEROXIDASE; ACTIVATED RECEPTORS; HYDROGEN-PEROXIDE; CELL REPLICATION AB Peroxisome proliferators (PPs) cause hepatomegaly, peroxisome proliferation, and hepatocarcinogenesis in rats and mice, whereas hamsters are less responsive to PPs. PPs increase the activities of enzymes involved in peroxisomal P-oxidation and omega -hydroxylation of fatty acids, which has been hypothesized to result in oxidative stress. The hypothesis of this study was that differential modulation of antioxidant enzymes and vitamins might account for differences in species susceptibility to PPs. Accordingly, we measured the activities of DT-diaphorase and superoxide dismutase (SOD) and the hepatic content of ascorbic acid and cu-tocopherol in male Sprague-Dawley rats and Syrian hamsters fed 2 doses of 3 known peroxisome proliferators (dibutyl phthalate [DBP], gemfibrozil, and [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14,643) for 6, 34, or 90 days. In untreated animals, the activity of DT-diaphorase was much higher in hamsters than in rats, but the control levels of SOD, ascorbic acid and alpha -tocopherol were similar. In rats and hamsters treated with Wy-14,643, we observed decreases in alpha -tocopherol content and total SOD activity. DT-diaphorase was decreased in activity following Wy-14,643 treatment in rats at all time points and doses, but only sporadically affected in hamsters. Rats and hamsters treated with DBP demonstrated increased SOD activity at 6 days; however, in the rat, DBP decreased SOD activity at 90 days and cu-tocopherol content was decreased throughout. In gemfibrozil treated rats and hamsters, a decrease in cu-tocopherol content and an increase in DT-diaphorase activity were observed. In either species, no consistent trend was observed in total ascorbic acid content after treatment with any of the PPs. In conclusion, these data suggest that both rats and hamsters are compromised in anti-; oxidant capabilities following PP treatment and additional hypotheses for species susceptibility should be considered. C1 Univ Kentucky, Grad Ctr Toxicol, Lexington, KY 40536 USA. NIEHS, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. Univ Kentucky, Grad Sch Nutrit Sci, Lexington, KY 40536 USA. Univ Kentucky, Dept Microbiol & Immunol, Lexington, KY 40536 USA. Univ Kentucky, Dept Pathol & Lab Med, Lexington, KY 40536 USA. RP Spear, BT (reprint author), Microbiol & Immunol, MS433A Med Sci Bldg,800 Rose St, Lexington, KY 40536 USA. OI Spear, Brett/0000-0002-4343-9393 FU NIEHS NIH HHS [T32 ES07266, ES09771] NR 69 TC 31 Z9 32 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD APR PY 2001 VL 60 IS 2 BP 271 EP 278 DI 10.1093/toxsci/60.2.271 PG 8 WC Toxicology SC Toxicology GA 414KU UT WOS:000167666400010 PM 11248139 ER PT J AU Moser, VC Shafer, TJ Ward, TR Meacham, CA Harris, MW Chapin, RE AF Moser, VC Shafer, TJ Ward, TR Meacham, CA Harris, MW Chapin, RE TI Neurotoxicological outcomes of perinatal heptachlor exposure in the rat SO TOXICOLOGICAL SCIENCES LA English DT Article DE heptachlor; developmental neurotoxicity; Morris water maze; pesticide exposure ID NEUROBEHAVIORAL SCREENING BATTERY; BRAIN-STEM; PRENATAL EXPOSURE; CHLORIDE TRANSPORT; PESTICIDE DIELDRIN; GABA(A) RECEPTORS; MONOAMINE NEURONS; IN-VITRO; LINDANE; INSECTICIDES AB The developing nervous system has been identified as a potential target of pesticide exposure. Heptachlor is a cyclodiene pesticide that was widely used for many years, and for which inadvertent exposure to children and fetuses took place in the early 1980s; yet little is known regarding the developmental neurotoxicity of it and other cyclodienes. The aim of this study was to determine whether perinatal heptachlor exposure results in persistent alterations in nervous system function, Pregnant Sprague-Dawley dams were dosed from gestational day (GD) 12 to postnatal day (PND) 7, whereupon the rat pups were dosed directly until PND 21 (group A) or PND 42 (group B), Dose levels were 0, 0.03, 0,3, or 3 mg/kg/day, po, There were no dose-related effects on maternal weight, litter size, or pup growth. GABA, receptor binding (using [S-35] tert-butylbicyclophosphotothionate; TBPS) and GABA-stimulated Cl- flux were evaluated in control and high-dose brain tissues taken on PND 7, 21, and 43, The B-max values for [S-35]-TBPS binding in brainstem, but not cortex, were decreased in female rats across all ages tested. There were no such changes in male rats, nor were K-D values altered in either tissue or gender. GABA-stimulated Cl- flux was decreased in female cortex synaptoneurosomes only on PND 21, The ontogeny of the righting response (PND 2-5) was delayed in the high-dose females. All subsequent testing took place a week to months after dosing ceased. The functional observational battery (FOB) showed treatment-related, but not necessarily dose-related, changes in different aspects of the rat's reactivity and activity levels. Group-A rats also showed altered within-session habituation of motor activity. There were no heptachlor-related differences in motor activity following challenge with a range of chlordiazepoxide doses. Cognitive assessments were conducted in both groups of rats. There were no statistically significant differences among treatment groups in a one-trial passive avoidance test, although there was a trend toward less learning. In group B, rats (both sexes), heptachlor altered spatial learning in the Morris water maze during two weeks of daily training (2 trials/day). On probe trials, heptachlor-treated rats did not show significant preference for the correct quadrant tall dose groups in males, high dose in females). These rats did not show alterations on subsequent working-memory training (where the platform position was relearned each day). Thus, perinatal exposure to heptachlor produced neurochemical and persistent neurobehavioral changes, including alterations in spatial learning and memory, C1 US EPA, NTD MD74B, Div Neurotoxicol,Off Res & Dev, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. NIEHS, Reprod Toxicol Grp, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Moser, VC (reprint author), US EPA, NTD MD74B, Div Neurotoxicol,Off Res & Dev, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. EM moser.ginger@epa.gov RI Shafer, Timothy/D-6243-2013; OI Chapin, Robert/0000-0002-5997-1261; Shafer, Timothy/0000-0002-8069-9987 NR 47 TC 27 Z9 28 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD APR PY 2001 VL 60 IS 2 BP 315 EP 326 DI 10.1093/toxsci/60.2.315 PG 12 WC Toxicology SC Toxicology GA 414KU UT WOS:000167666400015 PM 11248144 ER PT J AU Rier, SE Coe, CL Lemieux, AM Martin, DC Morris, R Lucier, GW Clark, GC AF Rier, SE Coe, CL Lemieux, AM Martin, DC Morris, R Lucier, GW Clark, GC TI Increased tumor necrosis factor-alpha production by peripheral blood leukocytes from TCDD-exposed rhesus monkeys SO TOXICOLOGICAL SCIENCES LA English DT Article DE endometriosis; rhesus; environmental toxicants; dioxin; TCDD; PCBs (polychlorinated biphenyls); dioxin-like chemicals ID ENDOMETRIAL STROMAL CELLS; ACUTE INFLAMMATORY RESPONSE; NATURAL-KILLER ACTIVITY; PERITONEAL-FLUID; TNF-ALPHA; AH LOCUS; 2,3,7,8-TETRACHLORODIBENZO-PARA-DIOXIN TCDD; LYMPHOCYTE SUBPOPULATIONS; REPRODUCTIVE TOXICITY; MACACA-MULATTA AB Previous work has shown that exposure to 2,3,7,8-tetrachrorodibenzo-p-dioxin (TCDD) is associated with a dose-dependent increase in the incidence and severity of endometriosis in the rhesus monkey, Studies also suggest that immune mechanisms participate in TCDD-mediated toxicity and the pathogenesis of endometriosis, Thirteen years after TCDD treatment was terminated, we characterized the phenotypic distribution of peripheral blood mononuclear cells (PBMC) from TCDD-exposed and -unexposed rhesus monkeys and determined the ability of these cells to produce cytokines and exert cytolytic activity against NK and T-cell-sensitive cell lines. We also determined whether elevated serum levels of TCDD, dioxin-like PHAH congeners, and triglycerides correlated with changes in PBMC phenotype or function. For all animals, TCDD exposure correlated with increased PBMC tumor necrosis factor-alpha (TNF-alpha) secretion in response to stimulation by T-cell mitogen and decreased cytolytic activity against NK-sensitive target cells. Furthermore, increased production of this cytokine by PHA-stimulated leukocytes was associated with elevated serum triglyceride levels. Leukocyte TNF-alpha secretion in response to viral antigen and PBMC production of interferon gamma (IFN gamma), IL-6, and IL-10 following exposure to mitogen or antigen were unaffected by previous TCDD treatment. Although TCDD exposure was not associated with changes in PBMC surface antigen expression, elevated serum concentrations of TCDD, 1,2,3,6,7,8-hexachlorodibenzofuran and 3,3',4,4',5-pentachlorobiphenyl correlated with increased numbers of CD3+/ CD25- and CD3-/CD25f leukocytes and enhanced secretion of TNF-alpha by mitogen-stimulated PBMC. These findings indicate that TCDD-exposed rhesus monkeys with endometriosis exhibit long-term alterations in systemic immunity associated with elevated serum levels of specific PHAH congeners. C1 Dartmouth Med Sch, Dept Physiol, Lebanon, NH 03756 USA. Univ Wisconsin, Harlow Ctr Biol Psychol, Madison, WI 53715 USA. Univ Tennessee, Dept Obstet & Gynecol, Memphis, TN 38103 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Rier, SE (reprint author), Vanderbilt Univ, Med Ctr, Dept Obstet & Gynecol, B-1100 Med Ctr N, Nashville, TN 37232 USA. FU NIEHS NIH HHS [ES08545-01] NR 61 TC 23 Z9 27 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD APR PY 2001 VL 60 IS 2 BP 327 EP 337 DI 10.1093/toxsci/60.2.327 PG 11 WC Toxicology SC Toxicology GA 414KU UT WOS:000167666400016 PM 11248145 ER PT J AU Brown, P AF Brown, P TI Transfusion medicine and spongiform encephalopathy SO TRANSFUSION LA English DT Editorial Material ID CREUTZFELDT-JAKOB-DISEASE; PRION PROTEIN; BLOOD-TRANSFUSION; SURVEILLANCE; INFECTIVITY; COMPONENTS; BSE C1 NIH, Bethesda, MD 20892 USA. RP Brown, P (reprint author), NIH, Bldg 36,Room 4A05,36 Convent Dr,MSC-4122, Bethesda, MD 20892 USA. NR 27 TC 19 Z9 19 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD APR PY 2001 VL 41 IS 4 BP 433 EP 436 DI 10.1046/j.1537-2995.2001.41040433.x PG 4 WC Hematology SC Hematology GA 425NF UT WOS:000168296800001 PM 11316889 ER PT J AU Pistillo, MP Tazzari, PL Gaudiano, C Cilla, V Kato, T Matsui, T Nishioka, K Capanni, P Conte, R Ferrara, GB AF Pistillo, MP Tazzari, PL Gaudiano, C Cilla, V Kato, T Matsui, T Nishioka, K Capanni, P Conte, R Ferrara, GB TI Patients with neoplastic and nonneoplastic hematologic diseases acquire CTLA-4 antibodies after blood transfusion SO TRANSFUSION LA English DT Article ID EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; B-CELL ACTIVATION; NEGATIVE REGULATOR; AUTOIMMUNE-DISEASE; AUTOANTIBODIES; CARCINOMA; BLOCKADE; RESPONSES; APOPTOSIS; PROTEIN AB BACKGROUND: The presence of antibodies to CTLA-4, a negative regulator of T-cell activation, was investigated in multiply transfused patients with malignant and nonmalignant hematologic diseases. A previous study showed that, in multiply transfused patients, an immune response against nuclear matrix proteins can be induced by WBCs undergoing apoptosis during RBC unit storage. This study evaluated whether the same phenomenon could be involved in the induction of CTLA-4 antibodies in the patients analyzed. STUDY DESIGN AND METHODS: Patient sera were tested for binding to the recombinant full-length CTLA-4 P-galactosidase fusion protein by an ELISA. Immunofluorescence stainings were performed to analyze the CTLA-4 epitopes recognized by the antibodies and to detect such epitopes in the apoptotic cells present in the RBC units. RESULTS: CTLA-4 antibodies were found in multiply transfused patients with P-thalassemia (40%) and with other hemolytic diseases (33%) including leukemias (42%). A higher incidence of CTLA-4 antibodies was found in patients receiving non-WBC-reduced blood (88%) than in those receiving WBC-reduced blood (26%). Immunofluorescence staining showed that WBCs undergoing apoptosis in the RBC unit expressed CTLA-4 epitopes. CONCLUSIONS: The apoptotic WBCs present in the RBC units, after cold storage, express CTLA-4 epitopes. These epitopes can be released and induce formation of CTLA-4 antibodies with profound implications in the development of autoimmune disorders and in facilitating tumor dissemination and metastasis. C1 Natl Canc Inst, Immunogenet Lab, Genoa, Italy. Policlin S Orsola Malpighi, Serv Transfus Med, Bologna, Italy. Matera Hosp, Microcytem Unit, Matera, Italy. St Marianna Univ, Sch Med, Rheumatol Immunol & Genet Program, Inst Med Sci, Kawasaki, Kanagawa, Japan. Thalassem Day Hosp, Microcytem Unit, Matera, Italy. Ctr Biotechnol Avanzate, Serv Immunogenet, Dept Oncol Biol & Genet, I-16132 Genoa, Italy. RP Pistillo, MP (reprint author), Ctr Biotechnol Avanzate, Serv Immunogenet, Dept Oncol Biol & Genet, Largo Rosanna Benzi 10, I-16132 Genoa, Italy. NR 31 TC 7 Z9 8 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD APR PY 2001 VL 41 IS 4 BP 462 EP 469 DI 10.1046/j.1537-2995.2001.41040462.x PG 8 WC Hematology SC Hematology GA 425NF UT WOS:000168296800007 PM 11316895 ER PT J AU Klein, HG AF Klein, HG TI Will blood transfusion ever be safe enough? SO TRANSFUSION MEDICINE LA English DT Article; Proceedings Paper CT Millennium Festival of Medicine Conference CY NOV 06-10, 2000 CL LONDON, ENGLAND ID RED-CELL SUBSTITUTES; HEPATITIS-C VIRUS; TRANSMISSION; HIV-1; TESTS; RISK C1 NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Klein, HG (reprint author), NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NR 21 TC 11 Z9 12 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0958-7578 J9 TRANSFUSION MED JI Transfus. Med. PD APR PY 2001 VL 11 IS 2 BP 122 EP 124 DI 10.1046/j.1365-3148.2001.00295-2.x PG 3 WC Hematology SC Hematology GA 425DW UT WOS:000168273900011 PM 11372636 ER PT J AU Conry-Cantilena, C AF Conry-Cantilena, C TI Phlebotomy, blood donation, and hereditary hemochromatosis SO TRANSFUSION MEDICINE REVIEWS LA English DT Review ID IRON OVERLOAD; MYOCARDIAL-INFARCTION; UNITED-STATES; RISK; DISEASE; SYMPTOMS; DONORS; GENE C1 NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20894 USA. RP Conry-Cantilena, C (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bldg 10,Room 1C 711, Bethesda, MD 20894 USA. NR 33 TC 6 Z9 7 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 0887-7963 J9 TRANSFUS MED REV JI Transf. Med. Rev. PD APR PY 2001 VL 15 IS 2 BP 136 EP 143 DI 10.1053/tm.2001.22616 PG 8 WC Hematology SC Hematology GA 420XG UT WOS:000168030100002 PM 11309733 ER PT J AU Aravind, L Koonin, EV AF Aravind, L Koonin, EV TI THUMP - a predicted RNA-binding domain shared by 4-thiouridine, pseudouridine synthases and RNA methylases SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Article ID ESCHERICHIA-COLI; RIBOSOMAL-RNA; BIOSYNTHESIS; PROTEIN; THIAMIN; THII; IDENTIFICATION; GENERATION; ENZYMES; ISCS AB Sequence profile searches were used to identify an ancient domain in Thil-like thiouridine synthases, conserved RNA methylases, archaeal pseudouridine synthases and several uncharacterized proteins. We predict that this domain is an RNA-binding domain that adopts an alpha/beta fold similar to that found in the C-terminal domain of translation initiation factor 3 and ribosomal protein S8. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20894 USA. NR 21 TC 54 Z9 54 U1 2 U2 5 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD APR PY 2001 VL 26 IS 4 BP 215 EP 217 DI 10.1016/S0968-0004(01)01826-6 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 432WZ UT WOS:000168719900005 PM 11295541 ER PT J AU Randazzo, PA Miura, K Nie, ZZ Orr, A Theibert, AB Kearns, BG AF Randazzo, PA Miura, K Nie, ZZ Orr, A Theibert, AB Kearns, BG TI Cytohesins and centaurins: mediators of PI 3-kinase regulated Arf signaling SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Letter ID PLECKSTRIN HOMOLOGY DOMAINS; GTPASE-ACTIVATING PROTEINS; STRUCTURAL BASIS C1 NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. Univ Alabama, Dept Neurobiol, Birmingham, AL 35294 USA. RP Randazzo, PA (reprint author), NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. NR 6 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD APR PY 2001 VL 26 IS 4 BP 220 EP 221 DI 10.1016/S0968-0004(01)01806-0 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 432WZ UT WOS:000168719900007 PM 11295547 ER PT J AU Caughey, B AF Caughey, B TI Interactions between prion protein isoforms: the kiss of death? SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review ID TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES; SPECIES BARRIERS; RESISTANT STATE; AMYLOID PLAQUES; SCRAPIE; CONVERSION; PRP; INHIBITION; DISEASES; BINDING AB Direct interactions between the normal and aberrant forms of prion protein appear to be crucial in the transmission and pathogenesis of transmissible spongiform encephalopathies (TSEs) or prion diseases. Recent studies of such interactions in vitro have provided mechanistic insight into how TSE-associated prion protein might promote its own propagation in a man ner that is specific enough to account, at least in part, for TSE strains and species barriers. C1 NIH, Persistent Viral Dis Lab, Rocky Mt Labs, NIAID, Hamilton, MT 59840 USA. RP Caughey, B (reprint author), NIH, Persistent Viral Dis Lab, Rocky Mt Labs, NIAID, 903 S 4th St, Hamilton, MT 59840 USA. NR 42 TC 101 Z9 104 U1 0 U2 7 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD APR PY 2001 VL 26 IS 4 BP 235 EP 242 DI 10.1016/S0968-0004(01)01792-3 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 432WZ UT WOS:000168719900011 PM 11295556 ER PT J AU Fields, RD Stevens, B AF Fields, RD Stevens, B TI Response: glia-neuronal culture models - do we need to change the paradigms? SO TRENDS IN NEUROSCIENCES LA English DT Letter ID IN-SITU; ASTROCYTES; CALCIUM; ATP C1 NICHD, NIH, Bethesda, MD 20892 USA. RP Fields, RD (reprint author), NICHD, NIH, Bldg 49,Room 5A38, Bethesda, MD 20892 USA. NR 6 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD APR PY 2001 VL 24 IS 4 BP 205 EP 206 DI 10.1016/S0166-2236(00)01774-4 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 433NH UT WOS:000168766000010 ER PT J AU Lieberman, R Nelson, WG AF Lieberman, R Nelson, WG TI New clinical trial strategies for prostate cancer prevention - Introduction SO UROLOGY LA English DT Editorial Material C1 NCI, Prostate & Urol Canc Res Grp, Div Canc Prevent, Rockville, MD 20852 USA. Johns Hopkins Univ, Baltimore, MD USA. RP Lieberman, R (reprint author), NCI, Prostate & Urol Canc Res Grp, Div Canc Prevent, 5130 Execut Blvd,EPN 2015, Rockville, MD 20852 USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD APR PY 2001 VL 57 IS 4A SU S BP 1 EP 3 DI 10.1016/S0090-4295(01)00932-3 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 423HT UT WOS:000168170400002 PM 11295589 ER PT J AU Lieberman, R Nelson, WG Sakr, WA Meysken, FL Klein, EA Wilding, G Partin, AW Lee, JJ Lippman, SM AF Lieberman, R Nelson, WG Sakr, WA Meysken, FL Klein, EA Wilding, G Partin, AW Lee, JJ Lippman, SM TI Executive summary of the National Cancer Institute Workshop: Highlights and recommendations SO UROLOGY LA English DT Article; Proceedings Paper CT National-Cancer-Institute Workshop CY 1999 CL ROCKVILLE, MARYLAND SP NCI AB Prostate cancer chemoprevention represents a relatively new and promising strategy for reducing the immense public health burden of this devastating cancer of men in the United States and Western societies, Chemoprevention is defined as the administration of agents (drugs, biologics, and natural products) that modulate (inhibit) one or more steps in the multistage carcinogenesis process culminating in invasive adenocarcinoma of the prostate. In 2000, there were an estimated 170,000 new cases of prostate cancer and 31,000 deaths in the United States. During the past decade, the National Cancer Institute (NCI) organized the chemoprevention research program and began testing the first generation of promising agents leg, 4-(hydroxy)-fenretinide [4-HPR], difluoromethylornithine [DFMO], antiandrogens in high-risk cohorts and launched the first-large scale US phase 3 primary prevention trial, known as Prostate Cancer Prevention Trial (PCPT-1), in 18,000 average-risk men (age more than 55 years and prostate-specific antigen [PSA] less than 3 ng/mL) treated for 7 years with finasteride or placebo. In the summer of 1998, the NCI Prostate Cancer Progress Review Group, (PRC) Report to the director of NCI was published in response to the leadership of the prostate cancer advocacy community in conjunction with Congress. To further elucidate and address critical issues identified in this report and to develop a research agenda for the newly created Prostate and Urologic Cancer Research Group in the Division of Cancer Prevention at NCI. the NCI organized the workshop "New Clinical Trial Strategies for Prostate Cancer Chemoprevention." The major objectives were to promote understanding and cooperation among the NCI, US Food and Drug Administration (FDA), academia, pharmaceutical industry, and the public regarding new opportunities for clinical prevention trials for prostate cancer. The workshop was divided into three concurrent breakout panels and a fourth joint integrative panel. The workshop addressed multiple key areas identified in the PRC report in the following panels: (1) Molecular Targets and Promising Agents in Clinical Development; (2) Intermediate Endpoint Biomarkers for Prevention Trials; (3) High-Risk Study Populations for Prevention Trials, and (4) Preventive Clinical Trial Designs and Regulatory Issues. Expert panelists were drawn from leading academic, pharmaceutical, and government scientists in basic research and clinical investigation. Key pharmaceutical, biotechnology, academic, and National Institutes of Health scientists presented overviews of their new agents and products in clinical development (representing the next generation of promising agents). Senior FDA physicians from the Center for Drugs and Center for Biologics presented on current standards for new drug and biologic approval for chemoprevention efficacy. Some of the key topics included recent advances in the state of knowledge of promising agents in the clinic based on molecular targets as well as bottlenecks in drug development for pharmaceutical sponsors; strategic modulable biomarkers that call serve as primary endpoints in phase 1/2 trials to assess preventive efficacy; high-risk cohorts with precancer (high-grade prostatic intraepithelial neoplasia) and representative clinical trial designs that are ready for immediate translation into efficient prevention trials, such as Bayesian sequential monitoring for early assessment of biologic activity and factorial designs for assessment of multiagent combinations. Finally, each expert panel generated recommendations for areas of future research emphasizing opportunities and infrastructure needs. (C) 2001, Elsevier Science Inc. C1 NCI, Prostate & Urol Canc Res Grp, Div Canc Prevent, Rockville, MD 20852 USA. Johns Hopkins Univ, Baltimore, MD USA. Wayne State Univ, Detroit, MI USA. Univ Calif Irvine, Irvine, CA USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Univ Wisconsin, Madison, WI USA. Univ Texas, Houston, TX USA. RP Lieberman, R (reprint author), NCI, Prostate & Urol Canc Res Grp, Div Canc Prevent, 5130 Execut Blvd,EPN 2105, Rockville, MD 20852 USA. EM rl39r@nih.gov NR 10 TC 16 Z9 17 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD APR PY 2001 VL 57 IS 4A SU S BP 4 EP 27 DI 10.1016/S0090-4295(00)00931-6 PG 24 WC Urology & Nephrology SC Urology & Nephrology GA 423HT UT WOS:000168170400003 PM 11295590 ER PT J AU Kelloff, GJ Lieberman, R Seele, VE Boone, CM Lubet, RA Kopelovich, L Malone, WA Crowell, JA Higley, HR Sigman, CC AF Kelloff, GJ Lieberman, R Seele, VE Boone, CM Lubet, RA Kopelovich, L Malone, WA Crowell, JA Higley, HR Sigman, CC TI Acents, biomarkers, and cohorts for chemopreventive agent development in prostate cancer SO UROLOGY LA English DT Article; Proceedings Paper CT National-Cancer-Institute Workshop CY 1999 CL ROCKVILLE, MARYLAND SP NCI ID PREVENTION TRIAL; LNCAP CELLS; SUPPLEMENTATION; EXPRESSION; INHIBITOR; MODEL; RAT AB Chemoprevention is the use of agents to slow progression of, reverse, or inhibit carcinogenesis thereby lowering the risk of developing invasive or clinically significant disease, With its long latency, high incidence and significant morbidity and mortality, prostate cancer is a relevant target for chemoprevention. Developing rational chemopreventive strategies for prostate cancer requires well-characterized agents, suitable cohorts, and reliable intermediate biomarkers of cancer. Chemopreventive agent requirements are experimental or epidemiologic data showing efficacy, safety on chronic administration, and a mechanistic rationale for activity. Current promising agents include antiandrogens and antiestrogens; steroid aromatase inhibitors; retinoids and their modulators: 5 alpha -reductase inhibitors: vitamins D, E, and analogs; selenium compounds; carotenoids; soy isoflavones; dehydroepiandrostenedione and analogs; 2-difluoromethylornithine; lipoxygenase inhibitors: apoptosis inducers; and nonsteroidal anti-inflammatory drugs, Identifying biomarkers and validating them as surrogate endpoints for cancer incidence are critical for prostate chemoprevention trials. Potentially useful biomarkers for prostate chemoprevention are associated with histologic, proliferative, differentiation-related, biochemical, and genetic/regulatory features of prostatic disease. In that the prostate is not easily visualized, critical issues also include adequacy and consistency of tissue sampling. Various drugs for the chemoprevention of prostate cancer are now under evaluation in phase 1, 2, and 3 clinical trials. Cohort selection should he based on various patient characteristics (stage of the disease, previous cancers or premalignant lesions, or high risk factors) and should be conducted within the context of standard treatment. (C) 2001, Elsevier Science Inc. C1 CCS Associates, Mt View, CA USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Kelloff, GJ (reprint author), Execut Plaza N,EPN306,5130 Execut Blvd, Rockville, MD 20852 USA. NR 29 TC 41 Z9 42 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD APR PY 2001 VL 57 IS 4A SU S BP 46 EP 51 DI 10.1016/S0090-4295(00)00940-7 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 423HT UT WOS:000168170400007 PM 11295594 ER PT J AU Boone, CW Lieberman, R Mairinger, T Palcic, B Bacus, J Bartels, P AF Boone, CW Lieberman, R Mairinger, T Palcic, B Bacus, J Bartels, P TI Computer-assisted image analysis-derived intermediate endpoints SO UROLOGY LA English DT Article; Proceedings Paper CT National-Cancer-Institute Workshop CY 1999 CL ROCKVILLE, MD SP NCI ID PROSTATIC INTRAEPITHELIAL NEOPLASIA; NUCLEAR CHROMATIN TEXTURE; CANCER; LESIONS; PIN; CHEMOPREVENTION; ADENOCARCINOMA; PROGRESSION AB The development of prostatic lesions undergoes a slow progression. To establish efficacy of chemopreventive intervention it is therefore necessary to define surrogate endpoint biomarkers. Such biomarkers should be sensitive in their ability to indicate response. They should be objective, ie, the result of measurement, and numerically defined so that a statistical validation of response is possible. They should be able to indicate not only a halt of progression of a lesion, but also a reversal of progression. The spatial and statistical distribution of nuclear chromatin in the secretory and luminal cells in prostatic intraepithelial neoplastic lesions has been shown to be well defined. It can be represented by a set of features. These have been used to define a progression curve along which progression or regression of a lesion can be assessed. One could define a fixed endpoint, or one might choose to accept a statistically significant regression along the progression curve as criterion for chemopreventive efficacy. Expected difficulties could arise from lesion heterogeneity, as it would affect the sampling, and from multifocal lesions of differing progressions. Lesion heterogeneity thus limits the precision with which regression could be detected. These problems might be partially overcome by observations taken in histologically normal appearing regions of the prostate. The nuclear chromatin pattern of secretory cell nuclei measured in such tissue regions from prostates harboring intraepithelial or malignant lesions has been shown to exhibit distinctive changes from the chromatin pattern seen in secretory cell nuclei from prostates free from any such lesions. These changes appear to be expressed in the tissue up to a substantial distance from a lesion. The expression of changes in the nuclear chromatin suggests the existence of an intraepithelial preneoplastic lesion that can be detected by biomarkers, but which is not apparent from visual microscopic inspection. Since chemoprevention might be expected to be most effective at the earliest stages of lesion development, the assessment of such early alterations is seen as highly relevant to efforts to validate the efficacy of chemopreventive intervention. (C) 2001, Elsevier Science Inc. C1 Univ Arizona, Tucson, AZ 85721 USA. Bacus Labs Inc, Lombard, IL USA. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. Univ Innsbruck, A-6020 Innsbruck, Austria. NCI, Bethesda, MD 20892 USA. RP Bartels, P (reprint author), Univ Arizona, 1630 E Univ Blvd, Tucson, AZ 85721 USA. NR 14 TC 9 Z9 9 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD APR PY 2001 VL 57 IS 4A SU S BP 129 EP 131 DI 10.1016/S0090-4295(00)00956-0 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 423HT UT WOS:000168170400023 PM 11295610 ER PT J AU DeWeese, TL Hruszkewycz, AM Marnett, LJ AF DeWeese, TL Hruszkewycz, AM Marnett, LJ TI Oxidative stress in chemoprevention trials SO UROLOGY LA English DT Article; Proceedings Paper CT National-Cancer-Institute Workshop CY 1999 CL ROCKVILLE, MARYLAND SP NCI ID CHROMATOGRAPHY-MASS-SPECTROMETRY; DNA-DAMAGE; LIPID-PEROXIDATION; PROSTATE-CANCER; SULINDAC; MALONDIALDEHYDE; CARCINOGENESIS; METHYLATION; POLYPOSIS; ADDUCTS AB Prostate cancer continues to be the most frequently diagnosed cancer in men in the United States. Despite aggressive intervention, a significant number of men with prostate cancer will not be cured of their disease and will face the possibility of metastatic disease. Thus, development of potent prevention strategies to diminish or eliminate this threat is in order. Cellular exposure to chronic oxidative stress may be 1 possible etiologic factor in the development of many cancers, including prostate cancer. Oxygen radicals can attack DNA directly and result in the accumulation of potentially promutagenic oxidized DNA bases such as 8-hydroxydeoxyguanosine. In addition, chronic oxidant stress may also result in lipid peroxidation and the subsequent generation of a range of reactive products that can damage DNA. Disruption of certain genes may result in cellular tolerance to oxidative genomic injury. GSTP1 is an enzyme that helps catalyze the conjugation reaction between potentially damaging electrophiles and glutathione. inactivation of GSTP1 has been documented to occur in nearly 100% of human prostate cancers; it is also frequently inactivated in prostatic intraepithelial neoplasia lesions. This inactivation may leave the cell vulnerable to oxidative DNA damage and/or tolerant to accumulation of oxidized DNA base adducts, These base adducts can be measured by several quantitative methods, such as gas chromatography-mass spectrometry with selected ion monitoring. These sophisticated methods can be readily integrated into prostate cancer chemoprevention studies of new and developing prevention agents by providing quantitative assessment of oxidative DNA damage before and after administration of these candidate chemopreventive drugs. The combination of genetic information, state-of-the-art assessment tools, and novel agents will allow rational. directed prostate cancer chemoprevention studies to be performed and, together, will help determine the role of chronic oxidative stress in the carcinogenic process of prostate cancer. (C) 2001, Elsevier Science Inc. C1 Johns Hopkins Univ, Sch Med, Radiat Biol Program, Dept Radiat Oncol, Baltimore, MD 21231 USA. Johns Hopkins Univ, Sch Med, Dept Urol, Baltimore, MD 21231 USA. Johns Hopkins Univ, Sch Med, Dept Expt Therapeut, Baltimore, MD 21231 USA. Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37212 USA. Vanderbilt Univ, Sch Med, Dept Chem, Nashville, TN 37212 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP DeWeese, TL (reprint author), Johns Hopkins Univ, Sch Med, Radiat Biol Program, Dept Radiat Oncol, 1650 Orleans St,Room 1-144, Baltimore, MD 21231 USA. NR 35 TC 34 Z9 37 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD APR PY 2001 VL 57 IS 4A SU S BP 137 EP 140 DI 10.1016/S0090-4295(00)00959-6 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 423HT UT WOS:000168170400025 PM 11295612 ER PT J AU Ali, IU Senger, DR Smith, LEH AF Ali, IU Senger, DR Smith, LEH TI Angiogenesis as a potential biomarker in prostate cancer chemoprevention trials SO UROLOGY LA English DT Article; Proceedings Paper CT National-Cancer-Institute Workshop CY 1999 CL ROCKVILLE, MARYLAND SP NCI ID ENDOTHELIAL GROWTH-FACTOR; MICROVESSEL DENSITY; TUMOR ANGIOGENESIS; RADICAL PROSTATECTOMY; PROGNOSTIC MARKER; MOLECULAR-BIOLOGY; FACTOR RECEPTORS; FACTOR ANTIBODY; IN-VIVO; EXPRESSION AB Prostate cancer is a multistep process in which progression rather than initiation may be the rate-limiting step. A strong possibility is that prostatic intraepithelial neoplasia lesions that switch to angiogenic phenotype eventually progress to cancer. However, it is a challenging task to quantitate angiogenesis in preneoplastic lesions. A promising approach to measuring angiogenesis involves real-time TaqMan polymerase chain reaction to quantitate mRNAs encoding a panel of angiogenesis markers. This highly sensitive molecular technique has potential for quantitating angiogenesis in clinical settings and can be used as a high-throughput screening procedure in prostate cancer clinical trials. C1 NCI, Div Canc Prevent, NIH, Rockville, MD 20852 USA. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. Harvard Univ, Childrens Hosp, Sch Med, Boston, MA USA. RP Ali, IU (reprint author), NCI, Div Canc Prevent, NIH, EPN 2109,6130 Execut Blvd, Rockville, MD 20852 USA. NR 49 TC 20 Z9 20 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD APR PY 2001 VL 57 IS 4A SU S BP 143 EP 147 DI 10.1016/S0090-4295(00)00961-4 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 423HT UT WOS:000168170400027 PM 11295614 ER PT J AU Kim, NW Hruszkewycz, AM AF Kim, NW Hruszkewycz, AM TI Telomerase activity modulation in the prevention of prostate cancer SO UROLOGY LA English DT Article; Proceedings Paper CT National-Cancer-Institute Workshop CY 1999 CL ROCKVILLE, MARYLAND SP NCI ID AMPLIFICATION PROTOCOL TRAP; INTRAEPITHELIAL NEOPLASIA; HUMAN FIBROBLASTS; RNA COMPONENT; NEEDLE-BIOPSY; CELLS; EXPRESSION; BENIGN; EPITHELIUM; CARCINOMA AB Telomerase is a ribonucleoprotein that stabilizes chromosomes by maintaining their telomeric ends. Although telomerase is normally expressed in reproductive tissues, it is virtually absent in most normal somatic tissues. During carcinogenesis, cells activate telomerase to protect chromosomal ends from the telomere erosion that occurs with replication. Prevention of telomere loss by activation of telomerase allows for the cellular immortalization that is a characteristic of cancer cells, Recent studies have shown that genetic instability arising from critical telomere shortening is a mechanism through which cancer cells attain multiple genetic aberrations that characterize a malignant clone. Thus, the timing of telomerase activation during carcinogenesis is likely to play an important role in modulating the genetic instability that determines the malignant phenotype. Earlier activation of telomerase should minimize genetic aberrations in neoplastic cells and lead to less aggressive tumors, or may prevent carcinogenesis, in this article, we discuss recent data on telomerase expression in prostate cancer, propose a model that relates the dynamics of telomerase activation to the evolution of different prostatic malignancies, and discuss the potential application of telomerase activation as a strategy for the prevention of prostate cancer. C1 Geron Corp, Menlo Park, CA 94025 USA. NCI, Div Canc Prevent, NIH, Rockville, MD USA. RP Kim, NW (reprint author), Geron Corp, 230 Constitut Dr, Menlo Park, CA 94025 USA. NR 50 TC 10 Z9 11 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD APR PY 2001 VL 57 IS 4A SU S BP 148 EP 153 DI 10.1016/S0090-4295(00)00962-6 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 423HT UT WOS:000168170400028 PM 11295615 ER PT J AU Grouse, LH Munson, PJ Nelson, PS AF Grouse, LH Munson, PJ Nelson, PS TI Sequence databases and microarrays as tools for identifying prostate cancer biomarkers SO UROLOGY LA English DT Article; Proceedings Paper CT National-Cancer-Institute Workshop CY 1999 CL ROCKVILLE, MARYLAND SP NCI ID GENE-EXPRESSION; PEDB AB Identification, acquisition, and assessment of molecular markers that could be adopted as surrogate endpoints for evaluating a response to prostate cancer intervention strategies is highly desirable. Recent advances in the fields of genomics and biotechnology have dramatically increased the quantity and accessibility of molecular information that is relevant to the study of prostate carcinogenesis. One major advance involves the construction of comprehensive databases that archive gene sequences and gene expression data. This information is in a format suitable for virtual queries designed to distinguish the molecular differences between normal and cancer cells. A second major advance uses robotic tools to construct microarrays comprising thousands of distinct genes expressed in pi-estate tissues. Such arrays offer a powerful approach for monitoring the expression of thousands of genes simultaneously and provide access for techniques designed to assess patterns or "fingerprints" of gene expression that may ultimately be used as signatures of response to therapeutic intervention. C1 NCI, Off Canc Genom, NIH, Bethesda, MD 20892 USA. NIH, Ctr Informat Technol, Math & Stat Comp Lab, Bethesda, MD USA. Fred Hutchinson Canc Res Ctr, Program Genom, Div Human Biol, Seattle, WA 98104 USA. RP Grouse, LH (reprint author), NCI, Off Canc Genom, NIH, 31 Ctr Dr,MSC 2590,Bldg 31,Room 11A03, Bethesda, MD 20892 USA. NR 11 TC 13 Z9 16 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD APR PY 2001 VL 57 IS 4A SU S BP 154 EP 159 DI 10.1016/S0090-4295(00)00963-8 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 423HT UT WOS:000168170400029 PM 11295616 ER PT J AU Paweletz, CP Liotta, LA Petricoin, EF AF Paweletz, CP Liotta, LA Petricoin, EF TI New technologies for biomarker analysis of prostate cancer progression: Laser capture microdissection and tissue proteomics SO UROLOGY LA English DT Article; Proceedings Paper CT National-Cancer-Institute Workshop CY 1999 CL ROCKVILLE, MARYLAND SP NCI ID ANTIGEN; ASSAY AB The widespread use of serum markers during cancer screenings has led to the belief that there may be tumor markers yet to be discovered that offer better specificity and sensitivity than prostate-specific antigen (PSA). Proteomics, the analysis and characterization of global protein modifications, will add to our understanding of gene function and aid in biomarker and/or therapeutic target discovery. in the past, most proteomic studies were either performed using turner cell lines or homogenized bulk tissue. Unfortunately, these approaches may not accurately reflect molecular events that take place in the actual ductal epithelium that change as a consequence of the malignant process. This report describes alternative proteomic-based approaches aimed at the identification of protein markers in the actual premalignant and frankly malignant epithelium. C1 US FDA, Ctr Biol Evaluat & Res, Div Therapeut Prot, Tissue Proteom Unit, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Dept Chem, Washington, DC 20057 USA. RP Petricoin, EF (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Therapeut Prot, Tissue Proteom Unit, Bldg 29A,Room 2B02,8800 Rockville Pike, Bethesda, MD 20892 USA. NR 17 TC 90 Z9 106 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD APR PY 2001 VL 57 IS 4A SU S BP 160 EP 163 DI 10.1016/S0090-4295(00)00964-X PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 423HT UT WOS:000168170400030 PM 11295617 ER PT J AU Lopacznski, W Hruszkewycz, AM Lieberman, R AF Lopacznski, W Hruszkewycz, AM Lieberman, R TI Preprostatectomy: A clinical model to study stromal-epithelial interactions SO UROLOGY LA English DT Article; Proceedings Paper CT National-Cancer-Institute Workshop CY 1999 CL ROCKVILLE, MARYLAND SP NCI ID NERVE GROWTH-FACTOR; PROSTATE-SPECIFIC ANTIGEN; FACTOR RECEPTOR; CELL-LINE; CANCER GROWTH; HUMAN BENIGN; CARCINOGENESIS; EXPRESSION; DIFFERENTIATION; FIBROBLASTS AB The preprostatectomy setting serves as a valuable clinical model for early developmental clinical trials for evaluating promising agents for chemoprevention. In the preprostatectomy model, study agents are administered between the diagnostic biopsy for prostate cancer and definitive therapy. The prostatic tissue that is available after prostatectomy allows for biomarker evaluation of all the components of the prostate, including the glandular epithelium, blood vessels, and the stroma. This provides an opportunity to study the reciprocal interactions between the stroma and the epithelium. Morphologic studies suggest that prostatic stromal cells play a critical role in affecting the growth and maturation of prostatic epithelium. Experimental studies in tissue culture show that carcinoma-associated stromal cells can promote prostatic carcinogenesis, and normal stromal cells may be able to inhibit prostatic carcinogenesis by inducing differentiation and decreasing the proliferation of the epithelium. Although the complex molecular mechanisms through which stroma modulates the epithelial cell phenotype remain to be elucidated, there are several well-characterized signaling pathways, such as for growth factors and steroid hormones, that are likely to contribute to the modulation of transformed epithelial cells. There is evidence of an association between increased serum levels of ICF-I and an increased risk of prostate cancer. The IGF system appears to play an important role in the development of prostate cancer by modulation of paracrine pathways, and also by modulation of the concentrations of different stromal and epithelial IGFBP, which are differentially expressed in the epithelium and stroma. Nerve growth factor is capable of stimulating a proliferative response via a high affinity Trk receptor present in normal and malignant prostate epithelia, and alternatively can mediate apoptosis via the low affinity p75NTR receptor that is progressively lost from the malignant prostate. As the role of each stromal element involved in carcinogenesis becomes further defined, these elements offer promising targets for new chemopreventive strategies. C1 NCI, Div Canc Prevent, Prostate & Urol Canc Res Grp, Rockville, MD 20852 USA. Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. RP Lopacznski, W (reprint author), NCI, Div Canc Prevent, Prostate & Urol Canc Res Grp, 6130 Execut Blvd EPN 2105, Rockville, MD 20852 USA. NR 42 TC 14 Z9 15 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD APR PY 2001 VL 57 IS 4A SU S BP 194 EP 199 DI 10.1016/S0090-4295(00)00973-0 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 423HT UT WOS:000168170400039 PM 11295626 ER PT J AU Lee, JD Lieberman, R Sloan, JA Piantadosi, S Lippman, SM AF Lee, JD Lieberman, R Sloan, JA Piantadosi, S Lippman, SM TI Design considerations for efficient prostate cancer chemoprevention trials SO UROLOGY LA English DT Article; Proceedings Paper CT National-Cancer-Institute Workshop CY 1999 CL ROCKVILLE, MARYLAND SP NCI ID QUALITY-OF-LIFE; SURGICAL-ADJUVANT-BREAST; CLINICAL-TRIALS; PREVENTION TRIAL; BOWEL-PROJECT; BETA-CAROTENE; END-POINTS; HEALTH; MEN; ANTIGEN AB Prostate cancer, even with its substantial public health impact of 180,400 new cases and 31,900 deaths estimated for 2000, still has a very low annual incidence (0.27% for men 34.4 years and older), which makes designing and conducting efficient prostate cancer prevention trials a challenge. Definitive prevention trials with cancer endpoints, such as the Breast Cancer Prevention Trial (BCPT), Prostate Cancer Prevention Trial (PCPT), and Selenium and Vitamin E Cancer Prevention Trial (SELECT), require long trial duration (up to 12 years) and large sample size (up to 32,400 subjects) to accomplish their objectives. This article discusses design concepts for potential prostate cancer prevention trials that require fewer years, subjects, and resources to complete. Design elements, such as high-risk populations, randomization, surrogate endpoints, including quality-of-life endpoints, masking/blinding, and various clinical/statistical designs (including 1-way layout, all-versus-none, factorial, and adaptive designs), are discussed, along with the ultimate goal of gaining US Food and Drug Administration approval for prostate-cancer preventive agents that can improve ea public health by reducing prostate cancer incidence and mortality. C1 Univ Texas, MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Clin Can Prevent, Houston, TX 77030 USA. Johns Hopkins Oncol Ctr, Baltimore, MD USA. Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. NCI, Div Canc Prevent, Rockville, MD USA. RP Lee, JD (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Biostat, Box 447,1515 Holcombe Blvd, Houston, TX 77030 USA. FU NCI NIH HHS [CA16672] NR 45 TC 15 Z9 16 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD APR PY 2001 VL 57 IS 4A SU S BP 205 EP 212 DI 10.1016/S0090-4295(00)00976-6 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 423HT UT WOS:000168170400042 PM 11295629 ER PT J AU Weiss, HL Urban, DA Grizzle, WE Cronin, KA Freedman, LS Kelloff, GJ Lieberman, R AF Weiss, HL Urban, DA Grizzle, WE Cronin, KA Freedman, LS Kelloff, GJ Lieberman, R TI Bayesian monitoring of a phase 2 chemoprevention trial in high-risk cohorts for prostate cancer SO UROLOGY LA English DT Article; Proceedings Paper CT National-Cancer-Institute Workshop CY 1999 CL ROCKVILLE, MARYLAND SP NCI ID CLINICAL-TRIALS AB The objective of phase 2 cancer chemoprevention trials is to evaluate whether a chemopreventive agent will cause significant modulation of intermediate endpoint biomarkers (IEB) in patients at high risk for the disease. A phase 2 chemoprevention trial of 4-hydroxyphenyl retinamide (4-HPR) Versus placebo was conducted in men with a histologic diagnosis of early prostate cancer and scheduled to have radical prostatectomy. A Bayesian monitoring method was used to sequentially monitor this trial for evidence of biological activity or ineffectiveness based on a single IEB variable. Different prior distributions were used and posterior distributions were obtained to calculate the probability that treatment differences are greater than or less than a predetermined clinically significant effect. The interim analysis of transforming growth factor-st expression indicated a high probability of insufficient biological activity of 4-HPR on this IEB, This study demonstrates the potential utility of Bayesian methods in the decision-making process in the conduct of phase 2 chemoprevention trials. C1 Univ Alabama, Ctr Comprehens Canc, Biostat Unit, Birmingham, AL 35294 USA. Univ Alabama, Dept Urol, Birmingham, AL 35294 USA. Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. NCI, Bethesda, MD 20892 USA. Bar Ilan Univ, Ramat Gan, Israel. RP Weiss, HL (reprint author), Univ Alabama, Ctr Comprehens Canc, Biostat Unit, WTI 153,1824 6th Ave S, Birmingham, AL 35294 USA. NR 6 TC 7 Z9 7 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD APR PY 2001 VL 57 IS 4A SU S BP 220 EP 223 DI 10.1016/S0090-4295(00)00979-1 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 423HT UT WOS:000168170400045 PM 11295632 ER PT J AU Lieberman, R AF Lieberman, R TI Prostate cancer chemoprevention: Strategies for designing efficient clinical trials SO UROLOGY LA English DT Article; Proceedings Paper CT National-Cancer-Institute Workshop CY 1999 CL ROCKVILLE, MARYLAND SP NCI ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; NUCLEAR CHROMATIN TEXTURE; RADICAL PROSTATECTOMY; DISEASE RECURRENCE; SUPPLEMENTATION; PROGRESSION; PREVENTION; ANTIGEN; MEN AB A chemoprevention (CP) strategy has evolved for conducting efficient clinical trials for prostate cancer (PCa) prevention. It integrates five key components, including agents, biomarkers, cohorts, designs, and endpoints. The rationale for the CP strategy relates to the natural history of prostate cancer. There is a wide array of natural and synthetic agents that hold promise for inhibiting, reversing, or modulating the transition from normal to precancer and from precancer to cancer. These agent classes include antiandrogens, antiestrogens, phytoestrogens, antioxidants, anti-inflammatory (proapoptotic) agents, antiproliferation/antidifferentiation agents, signal transduction modulators of receptor tyrosine kinase and ras farnesylation, antiangiogenesis agents, insulinlike growth factor (IGF)-1, peroxisome proliferator-activator receptor modulators (-gamma and -delta), and gene-based interventions. Biomarkers and endpoints are guided by the level of evidence required leg, phase 1, 2, 3). Two candidate surrogate endpoints (SE) based on histology are high-grade prostatic intraepithelial neoplasia (HGPIN) and computer-assisted image analysis of dysplastic lesions. Phase 1 trials use standard endpoints of safety, pharmacokinetics and limited pharmacodynamics. Phase 2 trials use endpoints of modulation of biomarkers and correlation with histology. Phase 3 trials use endpoints of clinical benefit, such as cancer incidence reduction and quality of life, Validation of a biomarker as a SE involves correlation of the biomarker with clinical benefit. Cohorts (target populations) for phase 2/3 trials include the general population of men over age 50 with a normal prostate-specific antigen (PSA), subjects with a strong family history of PCa, subjects with elevated PSA/negative biopsy, and subjects with HGPIN/negative biopsy. These at-risk populations reflect key individual risk factors (age, race, serum PSA [free/total]; serum IGF-1/IGF binding protein (IGFBP)-3; 1, 25(OH)(2) D3; family history of PCa; carriers of PCa susceptibility genes [ELAC2, CYP3A4, SRD5A2, etc.]; and histology such as atypia and HGPIN) that could be combined into a multivariate risk model for PCa. The probability of cancer risk (recurrence) is a key factor that impacts on the clinical trial design (power, sample size, and primary endpoint). Multivariate predictive mathematical models for biochemical recurrence after radical prostatectomy by decreasing sample size and time to clinical outcomes maximize trial efficiency and identify the patients most likely to benefit from secondary prevention. The two large primary prevention trials, Prostate Cancer Prevention Trial/Seleninium and Vitamin E Chemoprevention Trial (PCPT/ SELECT), in low- and average-risk subjects have sample sizes of 18,000 to 32,000, with a treatment duration of 7 years to detect a 25% reduction in biopsy-proven PCa. Subjects with HGPIN have the highest known cancer risk (approximately 50% at 3 years), and thus require a small sample size (n = 450) to detect a 33% reduction in cancer incidence. A schema involving three sequential trials for agent registration is described. in summary, a CP strategy that incorporates well-defined agents, clinical and validated SE, and high-risk cohorts defined by genetic at-id acquired risk factors in a series of well-designed randomized controlled trials provides an efficient pathway for evaluating and approving new agents for PCa prevention. C1 NCI, Div Canc Prevent, Rockville, MD 20852 USA. RP Lieberman, R (reprint author), NCI, Div Canc Prevent, 6130 Execut Blvd,EPN 210, Rockville, MD 20852 USA. NR 23 TC 16 Z9 16 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD APR PY 2001 VL 57 IS 4A SU S BP 224 EP 229 DI 10.1016/S0090-4295(00)00981-X PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 423HT UT WOS:000168170400046 PM 11295633 ER PT J AU Sloan, JA Varricchio, C AF Sloan, JA Varricchio, C TI Quality of life endpoints in prostate chemoprevention trials SO UROLOGY LA English DT Article; Proceedings Paper CT National-Cancer-Institute Workshop CY 1999 CL ROCKVILLE, MARYLAND SP NCI ID OF-LIFE; CANCER-PATIENTS; INSTRUMENT PROSQOLI; ANALOGOUS SCALES; CLINICAL-TRIAL; EORTC QLQ-C30; MEN; THERAPY; EXPERIENCE; SURVIVAL AB Although the ultimate goal of any chemoprevention study is to extend life by preventing cancer, it is also important that in doing so, the quality of life is not reduced. Hence, quality of life (QOL) endpoints are secondary only in importance to survival as an endpoint for prostate chemoprevention trials. One can conceptualize QOL endpoints as just another surrogate endpoint biomarker. QOL can be administered and collected in a valid and reliable fashion from cancer patients as demonstrated by numerous clinical trials. To date more than 25 prostate cancer QOL tools have been developed with over 700 different items. However, patients may be asymptomatic, leaving the sensitivity and specificity of the QOL instrumentation in question. Judicious use of a global QOL measure supplemented by protocol-specific or disease-specific instruments is an efficient approach for prostate chemoprevention trials. Clinical significance and missing data considerations need to be elucidated a priori in definitive terms so that results are directly interpretable from the data obtained. The effect of chemopreventive agents on QOL needs to be sufficiently modest to be practical to justify administration in a healthy population. As such, great care needs to be given to a priori determination of the QOL constructs that are most likely to change. C1 Mayo Clin, Ctr Comprehens Canc, Rochester, MN 55905 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Sloan, JA (reprint author), Mayo Clin, Ctr Comprehens Canc, Charlton 6-129,200 1st St SW, Rochester, MN 55905 USA. NR 41 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD APR PY 2001 VL 57 IS 4A SU S BP 235 EP 240 DI 10.1016/S0090-4295(00)00982-1 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 423HT UT WOS:000168170400048 PM 11295635 ER PT J AU Hahn, SH Yoo, OJ Gahl, WA AF Hahn, SH Yoo, OJ Gahl, WA TI Effect of metal ions on the stability of metallothionein in the degradation by cellular fractions in vitro SO EXPERIMENTAL AND MOLECULAR MEDICINE LA English DT Article DE metallothionein; lysosome; degradation; copper; zinc ID INDIAN CHILDHOOD CIRRHOSIS; MILK MUTANT MOUSE; CADMIUM-METALLOTHIONEIN; DEOXYRIBONUCLEIC-ACID; PROTECTIVE ROLE; APOPTOSIS; ZINC; MICE; FIBROBLASTS; INDUCTION AB Metallothioneins (MT), small molecular weight metal binding proteins are known to play an important protective role against heavy metal toxicity, either as antioxidants or pre-oxidants. However, the mode of metabolic fate of MTs in various metal complexes is not clearly understood. This study was carried out to better understand the mode of selective turnover rate of various form of MT in complexes with different metals. The degradation of in vitro translated mouse S-35-cysteine-MT was examined in lysosomal or cytosolic fractions from mouse liver by gel electrophoresis and autoradiography. Overnight incubations of MT showed extensive proteolysis in the lysosomal fraction but not in cytosolic fractions. However, Cu2+-MT was found to be stable under the same experimental condition. In contrast, Zn did not interfere with NIT degradation. These results suggest that lysosomes are chiefly responsible for MT removal and appears to be selective on the metals involved in the MT complex. In vitro, translated, radiolabeled MT provides a suitable substrate for investigating the characteristics of MT degradation. C1 Ajou Univ, Sch Med, Dept Pediat, Suwon 441749, South Korea. Korea Adv Inst Sci & Technol, Ctr Biomed, Dept Biol Sci, Taejon 305701, South Korea. NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD USA. RI Yoo, Ook Joon/C-1860-2011 NR 28 TC 9 Z9 12 U1 0 U2 2 PU KOREAN SOC MED BIOCHEMISTRY MOLECULAR BIOLOGY PI SEOUL PA #812 KOFST, 635-4 YOKSAM-DONG KANGNAM-GU, SEOUL 135-703, SOUTH KOREA SN 1226-3613 J9 EXP MOL MED JI Exp. Mol. Med. PD MAR 31 PY 2001 VL 33 IS 1 BP 32 EP 36 PG 5 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 421MD UT WOS:000168067400007 PM 11322484 ER PT J AU Sills, RC French, JE Cunningham, ML AF Sills, RC French, JE Cunningham, ML TI New models for assessing carcinogenesis: An ongoing process SO TOXICOLOGY LETTERS LA English DT Article; Proceedings Paper CT 38th European Congress of Toxicology (Eurotox 2000) CY SEP 17-20, 2000 CL LONDON, ENGLAND DE chemical carcinogenesis; lacI model; mouse models; p53 deficient model; transgenic mice ID TUMOR-SUPPRESSOR GENE; T BASE-PAIRS; TRANSGENIC MICE; CHEMICAL CARCINOGENESIS; VINYL-CHLORIDE; B6C3F1 MICE; IN-VIVO; HETEROZYGOUS P53-DEFICIENT; MULTISTAGE CARCINOGENESIS; THYMIC LYMPHOMAS AB Traditionally, the use of rodent models in assessing the carcinogenic potential of chemicals has been expensive and lengthy, and the relevance of the carcinogenic effect to humans is often not fully understood. Today, however, with the rapid advances in molecular biology, genetically altered mice containing genes relevant to humans (e.g. oncogenes, tumor suppressor genes) and reporter genes (e.g. lacI) provide powerful tools for examining specific chemical-gene interactions thereby allowing a better understanding of the mechanisms of carcinogenesis in a shorter period of time. This paper will cover an overview of ongoing validation efforts, followed by examples of studies using several genetically engineered models including the p53(def) mouse model and the Big Blue((R)) transgenic mouse model. Specifically. examples when transgenic models were integrated into the testing program based on specific hypotheses dealing with genetic alterations in cancer genes and reporter genes will be discussed. The examples will highlight possible ways genetically altered mice may be integrated into a comprehensive research and testing strategy and thereby provide an improved estimation of human health risks. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Environm Carcinogenesis & Mutagenesis, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Sills, RC (reprint author), NIEHS, Lab Expt Pathol, POB 12233,MD B3-08, Res Triangle Pk, NC 27709 USA. EM sills@niehs.nih.gov NR 51 TC 18 Z9 20 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD MAR 31 PY 2001 VL 120 IS 1-3 BP 187 EP 198 DI 10.1016/S0378-4274(01)00293-4 PG 12 WC Toxicology SC Toxicology GA 426EK UT WOS:000168336700023 PM 11323177 ER PT J AU Gonzalez, FJ AF Gonzalez, FJ TI The use of gene knockout mice to unravel the mechanisms of toxicity and chemical carcinogenesis SO TOXICOLOGY LETTERS LA English DT Article; Proceedings Paper CT 38th European Congress of Toxicology CY SEP 17-20, 2000 CL LONDON, ENGLAND DE xenobiotic; cytochrome p450; gene knockout; carcinogenesis; peroxisome proliferators ID CAFFEINE URINARY METABOLITES; ACETAMINOPHEN TOXICITY; AH RECEPTOR; C-OXIDATION; ETHANOL; CYP1A2; CYTOCHROME-P450; CYP2A6; CANCER; HEPATOTOXICITY AB Metabolism of toxins and carcinogens is carried out by large groups of xenobiotic-metabolizing enzymes. These enzymes are generally considered to be required for elimination of xenobiotics such as drugs, dietary chemicals and environmental pollutants, and to be required for chemical toxicity and carcinogenicity. An important role for these enzymes in metabolism of endogenous chemicals has not been established. Mouse lines in which the genes encoding several xenobiotic-metabolizing enzymes were knocked out were produced and are being used to determine the role of metabolism in carcinogenesis, and acute and chronic toxicities in vivo. Mouse lines lacking the P450s CYP1A1, CYP1A2, CYP1B1 and CYP2E1. microsomal epoxide hydrolase (mEH), NADPH:quinone oxidoreductase and the glutathione S-transferase P1 have no deleterious phenotypes, indicating that these enzymes are not required for mammalian development and physiological homeostasis. However, when challenged with toxins and carcinogens, they respond differently from their wild-type (WT) counterparts. For example, mice lacking CYP1A2 and CYP2E1 are totally resistant to acetaminophen-induced hepatotoxicity. Mice lacking CYP1B1 or mEH are less responsive to tumorigenesis by 7,12-dimethybenz[a]anthracene. However, CYP1A2-null mice do not significantly differ from WT mice in their response to the hepatocarcinogen 4-aminobiphenyl. These and other studies indicate that the xenobiotic-metabolism null mice are of great value in the study of the mechanisms of chemical injury. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 NCI, Dept Basic Sci, Bethesda, MD 20892 USA. RP Gonzalez, FJ (reprint author), NCI, Dept Basic Sci, Bldg 37,Room 3E-24, Bethesda, MD 20892 USA. NR 44 TC 47 Z9 48 U1 0 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD MAR 31 PY 2001 VL 120 IS 1-3 BP 199 EP 208 DI 10.1016/S0378-4274(01)00296-X PG 10 WC Toxicology SC Toxicology GA 426EK UT WOS:000168336700024 PM 11323178 ER PT J AU Miller, MC Mohrenweiser, HW Bell, DA AF Miller, MC Mohrenweiser, HW Bell, DA TI Genetic variability in susceptibility and response to toxicants SO TOXICOLOGY LETTERS LA English DT Article; Proceedings Paper CT 38th European Congress of Toxicology CY SEP 17-20, 2000 CL LONDON, ENGLAND DE xenobiotics; variability; polymorphisms; DNA adducts; DNA repair; genetic risk ID GLUTATHIONE-S-TRANSFERASE; ARYLAMINE N-ACETYLTRANSFERASE; NUCLEOTIDE EXCISION-REPAIR; BLADDER-CANCER RISK; AMYOTROPHIC-LATERAL-SCLEROSIS; SQUAMOUS-CELL CARCINOMA; GSTM1 NULL GENOTYPE; DNA-REPAIR; ACETYLATOR PHENOTYPE; COLORECTAL-CANCER AB Everyone has a unique combination of polymorphic traits that modify susceptibility and response to drugs, chemicals and carcinogenic exposures. The metabolism of exogenous and endogenous chemical toxins may be modified by inherited and induced variation in CYP (P450), acetyltransferase (NAT) and glutathione S-transferase (GST) genes. We observe that specific 'at risk' genotypes for GSTM1 and NAT1/2 increase risk for bladder cancer among smokers. Genotypic and phenotypic variation in DNA repair may affect risk of somatic mutation and cancer. Variants of base excision and nucleotide excision repair genes (XRCC1 and XPD) appear to modify exposure-induced damage from cigarette smoke and radiation. We are currently engaged in discovering genetic variation in environmental response genes and determining if this variation has any effect on gene function or if it is associated with disease risk. These and other results are discussed in the context of evaluating inherited or acquired susceptibility risk factors for environmentally caused disease. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Univ Calif Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, Livermore, CA USA. RP Bell, DA (reprint author), NIEHS, POB 12233,111 Alexander Dr,Bldg 101,Room B323, Res Triangle Pk, NC 27709 USA. FU NIEHS NIH HHS [Y1-ES-8054-05] NR 95 TC 110 Z9 115 U1 1 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD MAR 31 PY 2001 VL 120 IS 1-3 BP 269 EP 280 DI 10.1016/S0378-4274(01)00279-X PG 12 WC Toxicology SC Toxicology GA 426EK UT WOS:000168336700031 PM 11323185 ER PT J AU Jacobson, JM Hafner, R Remington, J Farthing, C Holden-Wiltse, J Bosler, EM Harris, C Jayaweera, DT Roque, C Luft, BJ AF Jacobson, JM Hafner, R Remington, J Farthing, C Holden-Wiltse, J Bosler, EM Harris, C Jayaweera, DT Roque, C Luft, BJ CA ACTG 156 Study Team TI Dose-escalation, phase I/II study of azithromycin and pyrimethamine for the treatment of toxoplasmic encephalitis in AIDS SO AIDS LA English DT Article DE AIDS; azithromycin; HIV; pyrimethamine; toxoplasmic encephalitis ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; CENTRAL-NERVOUS-SYSTEM; IMMUNE-DEFICIENCY SYNDROME; MACROLIDE ANTIBIOTICS; MAINTENANCE THERAPY; DRUG-INTERACTIONS; GONDII; SULFADIAZINE; EFFICACY; PHARMACOKINETICS AB Objective: To assess the safety, tolerance and activity of increasing doses of azithromycin in combination with pyrimethamine for the treatment of toxoplasmic encephalitis (TE) in patients with AIDS. Design: A phase I/II dose-escalation study of oral azithromycin in combination with pyrimethamine. Setting: Eight clinical sites in the United States. Patients: Forty-two adult HIV-infected patients with confirmed or presumed acute TE. Methods: Patients were enrolled into three successive cohorts receiving azithromycin 900, 1200 and 1500 mg a day with pyrimethamine as induction therapy. The induction period was 6 weeks followed by 24 weeks of maintenance therapy. Main outcome measures: Patient response was evaluated clinically and radiologically. Results: Of the 30 evaluable patients, 20 (67%) responded to therapy during the induction period. Ten experienced disease progression. Of the 15 patients who received maintenance therapy, seven (47%) relapsed. Six patients discontinued treatment during the induction period as a result of reversible toxicities. Treatment-terminating adverse events occurred most frequently among the patients receiving the 1500 mg dose. Conclusion: The combination of azithromycin (900-1200 mg a day) and pyrimethamine may be useful as an alternative therapy for TE among patients intolerant of sulfonamides and clindamycin, but maintenance therapy with this combination was associated with a high relapse rate. The combination was safe, but low-grade adverse events were common. (C) 2001 Lippincott Williams & Wilkins. C1 Mt Sinai Med Ctr, AIDS Ctr, Dept Med, New York, NY 10029 USA. NIAID, Div Aids, Bethesda, MD 20892 USA. Palo Alto Med Fdn, Palo Alto, CA USA. Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. NYU, Med Ctr, New York, NY 10016 USA. Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. Univ Miami, Dept Med, Miami, FL USA. SUNY Stony Brook, Dept Med, Stony Brook, NY 11794 USA. SUNY Stony Brook, Dept Radiol, Stony Brook, NY 11794 USA. RP Jacobson, JM (reprint author), Mt Sinai Med Ctr, AIDS Ctr, Dept Med, 1 Gustave Levy Pl,Box 1009, New York, NY 10029 USA. FU PHS HHS [A125831, A125893, A125903, A127667, A13885, A138857, U01A125831] NR 22 TC 20 Z9 22 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAR 30 PY 2001 VL 15 IS 5 BP 583 EP 589 DI 10.1097/00002030-200103300-00007 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 419GV UT WOS:000167941700006 PM 11316995 ER PT J AU Valdez, H Metcalf, JA Gripshover, BM Jacobson, JM Mitsuyasu, R Lederman, MM AF Valdez, H Metcalf, JA Gripshover, BM Jacobson, JM Mitsuyasu, R Lederman, MM TI Effect of IL-2 therapy on plasma hepatitis C virus-RNA levels in HIV/hepatitis C virus co-infected patients SO AIDS LA English DT Letter ID HUMAN-IMMUNODEFICIENCY-VIRUS; RECOMBINANT INTERLEUKIN-2; CONTROLLED TRIAL; T-CELL C1 Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Mt Sinai Med Ctr, New York, NY 10029 USA. Univ Calif Los Angeles, Los Angeles, CA USA. RP Valdez, H (reprint author), Case Western Reserve Univ, Cleveland, OH 44106 USA. NR 10 TC 8 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAR 30 PY 2001 VL 15 IS 5 BP 661 EP 662 DI 10.1097/00002030-200103300-00023 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 419GV UT WOS:000167941700022 PM 11317011 ER PT J AU Lieberman, AP Friedlich, DL Harmison, G Howell, BW Jordan, CL Breedlove, SM Fischbeck, KH AF Lieberman, AP Friedlich, DL Harmison, G Howell, BW Jordan, CL Breedlove, SM Fischbeck, KH TI Androgens regulate the mammalian homologues of invertebrate sex determination genes tra-2 and fox-1 SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE androgen receptor; motor neuron; RNA-binding proteins; sex determination ID PRE-MESSENGER-RNA; SPLICING FACTORS; PROTEIN-KINASES; SR PROTEINS; DROSOPHILA-MELANOGASTER; CAENORHABDITIS-ELEGANS; MUSCULAR-ATROPHY; X-CHROMOSOME; CELL-DEATH; RECEPTOR AB Androgens, like other steroid hormones, exert profound effects on cell growth and survival by modulating the expression of target genes. in vertebrates, androgens play a critical role downstream of the testis determination pathway, influencing the expression of sexually dimorphic traits, Among cells of the nervous system, motor neurons respond to trophic effects of androgen stimulation, with a subpopulation of spinal motor neurons exhibiting sexually dimorphic survival. To study the mechanisms of androgen action in these cells, we performed a subtractive screen for genes upregulated by androgen in a motor neuron cell line. We show androgen-inducible expression of two RNA-binding proteins that are the mammalian homologues of invertebrate sex determination genes. Androgens upregulate the expression of tra-2 alpha, an enhancer of RNA splicing homologous to Drosophila tra-2, and promote redistribution of the protein from a diffuse to a speckled pattern within the nucleus, Similarly, androgens upregulate the expression of a novel gene homologous to Caenorhabditis elegans fox-1. These data indicate that androgens exert their effects, in part, by modulating the expression and function of genes involved in RNA processing, and identify homologues of invertebrate sex determination genes as androgen-responsive genes in mammals. (C) 2001 Academic Press. C1 NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. Univ Calif Berkeley, Dept Psychol, Berkeley, CA 94720 USA. RP Lieberman, AP (reprint author), NINDS, Neurogenet Branch, NIH, Bldg 10,Room 3B14,MSC1250, Bethesda, MD 20892 USA. EM lieberma@ninds.nih.gov OI Howell, Brian/0000-0002-0204-0773 NR 49 TC 24 Z9 25 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 30 PY 2001 VL 282 IS 2 BP 499 EP 506 DI 10.1006/bbrc.2001.4617 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 416UL UT WOS:000167798500021 PM 11401487 ER PT J AU Myers, CS Contreras, MA Chang, MCJ Rapoport, SI Appel, NM AF Myers, CS Contreras, MA Chang, MCJ Rapoport, SI Appel, NM TI Haloperidol downregulates phospholipase A(2) signaling in rat basal ganglia circuits SO BRAIN RESEARCH LA English DT Article DE haloperidol; phospholipase; arachidonic acid; dopamine; schizophrenia; autoradiography ID MAGNETIC-RESONANCE SPECTROSCOPY; FATTY-ACID INCORPORATION; DOPAMINE-RECEPTORS; BRAIN INCORPORATION; PREFRONTAL CORTEX; SIGMA-RECEPTOR; DRUG-TREATMENT; D-2 RECEPTORS; SCHIZOPHRENIA; STRIATUM AB Our laboratory has developed an in vivo method to quantitatively evaluate phospholipase A(2) (PLA(2))-mediated signal transduction in brain regions of rodents. In this method, quantitative autoradiography is used to identify brain uptake of intravenously injected, radiolabeled arachidonic acid ([H-3]AA). Dopamine D-2 receptors are coupled to G-proteins that activate PLA(2), releasing AA from the stereospecifically numbered (sn) 2 position of phospholipids, and regional [H-3]AA uptake is proportional to the rate of release. In the present experiment, the D, antagonist haloperidol (1.0 mg/kg i.p.) or the drug vehicle was administered to male adult rats for 21 days. Rats were infused 3 days later with 1.75 mCi/kg [H-3]AA (i.v.), anesthetized and decapitated 20 min after infusion onset, and brains were processed for quantitative autoradiography. Chronic haloperidol significantly decreased [H-3]AA incorporation in two primary dopaminergic basal ganglia-frontal cortex circuits, the mesocorticolimbic and nigrostriatal systems, while insignificant changes in AA incorporation were noted in other brain regions. These results suggest that one mechanism by which haloperidol exerts its effect is by downregulating D-2-mediated PLA(2) signaling involving AA release in basal ganglia-frontal cortex circuitry. Published by Elsevier Science B.V. C1 NIA, Sect Brain Physiol & Metab, NIH, Bethesda, MD USA. US FDA, Ctr Drug Evaluat & Res, Off Testing & Res, Div Appl Pharmacol Res, Laurel, MD USA. RP Myers, CS (reprint author), Univ Maryland, Maryland Psychiat Res Ctr, POB 21247, Baltimore, MD 21228 USA. NR 44 TC 11 Z9 12 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 MAR 30 PY 2001 VL 896 IS 1-2 BP 96 EP 101 DI 10.1016/S0006-8993(01)02014-5 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 419KL UT WOS:000167947900012 PM 11277978 ER PT J AU Kusiak, JW Lee, LL Zhao, BY AF Kusiak, JW Lee, LL Zhao, BY TI Expression of mutant amyloid precursor proteins decreases adhesion and delays differentiation of Hep-1 cells SO BRAIN RESEARCH LA English DT Article DE endothelial cells; differentiation; Matrigel; amyloid precursor protein processing; blood-brain barrier; vasculature ID BLOOD-BRAIN-BARRIER; ALZHEIMERS-DISEASE; BETA-PROTEIN; SECRETION; BINDING; SURFACE; DYSFUNCTION; ASTROCYTES; PATHOLOGY; COLLAGEN AB The amyloid precursor protein (APP) is a type I integral membrane protein and is processed to generate several intra-cellular and secreted fragments. The physiological role of APP and its processed fragments is unclear. Several mutations have been discovered in APP, which are causative of early-onset, familial, neurological disease, including Alzheimer's disease (FAD). These mutations alter the processing of APP and lead to excess production and extra-cellular deposition of A-beta peptide (A beta). We have examined the role of APP in a cell culture model of endothelial cell function. The endothelial cell lint, Hep-1, was stably transfected with wild-type (wt) and FAD mutant forms of APP (mAPP). Secretion of sAPP alpha was reduced in cell lines over-expressing mAPP when these cells were grown on several different substrates. Levels of secreted AP were increased as measured by ELISA in the mutant cell lines. Cell adhesion to laminin-, fibronectin-, collagen I-, and collagen IV-coated culture flasks was reduced in all mAPP-expressing cell lines, while in lines over-expressing wt-APP, adhesiveness was slightly increased. Cell lines over-expressing mAPP differentiated more slowly into capillary network-like structures on Matrigel((TM)) than those expressing wt-APP. No differences were detected among all cell lines in a migration/invasion assay. The results suggest that APP may have a role in cell adhesiveness and maturation of endothelial cells into capillary-like networks. The reduction in adhesion and differentiation in mutant cell lines may be due to reduced amounts of sAPPa released into the culture media or toxic effects of increased extracellular A beta. Published by Elsevier Science B.V. C1 NIA, Mol Neurobiol Unit, Lab Cellular & Mol Biol, Intramural Res Program,Gerontol Res Ctr,NIH, Baltimore, MD 21224 USA. RP Kusiak, JW (reprint author), NIA, Mol Neurobiol Unit, Lab Cellular & Mol Biol, Intramural Res Program,Gerontol Res Ctr,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 36 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAR 30 PY 2001 VL 896 IS 1-2 BP 146 EP 152 DI 10.1016/S0006-8993(01)02153-9 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 419KL UT WOS:000167947900017 PM 11277983 ER PT J AU Schuck, P Taraporewala, Z McPhie, P Patton, JT AF Schuck, P Taraporewala, Z McPhie, P Patton, JT TI Rotavirus nonstructural protein NSP2 self-assembles into octamers that undergo ligand-induced conformational changes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SINGLE-STRANDED-DNA; BINDING-PROTEIN; ESCHERICHIA-COLI; ANALYTICAL ULTRACENTRIFUGATION; IN-VIVO; SEDIMENTATION ANALYSIS; CRYSTAL-STRUCTURE; RNA; REPLICATION; PHOSPHORYLATION AB The nonstructural protein NSP2 is a component of the rotavirus replication machinery and binds single-stranded RNA cooperatively, with high affinity, and independent of sequence, Recently, NSP2 has been shown to form multimers and to possess an NTPase activity, but its precise function remains unclear. In the present study, we have characterized the solution structure of recombinant NSPS by velocity and equilibrium ultracentrifugation, dynamic light scattering, and circular dichroism spectroscopy. We found that NSP2 exists as an octamer, which is functional in the binding of RNA and ADP, In the presence of magnesium, a partial dissociation of the octamer into smaller oligomers was observed, This was reversed by binding of ADP and RNA. We observed an increased sedimentation rate in the presence of ADP and a nonhydrolyzable ATP analogue, which suggests a change toward a significantly more compact octameric conformation, The secondary structure of NSP2 showed a high fraction of P-sheet, with small changes induced by magnesium that were reversed in the presence of RNA. That NSP2 can exist in different conformations lends support to the previously proposed hypothesis (Taraporewala, Z,, Chen, D,, and Patton, J, T, (1999) J, Virol, 73, 9934-9943) of its function as a molecular motor involved in the packaging of viral mRNA. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. NIH, OD, ORS, Div Bioengn & Phys Sci, Bethesda, MD 20892 USA. RP Patton, JT (reprint author), NIAID, Infect Dis Lab, NIH, 7 Ctr Dr,MSC 0720,Rm 117, Bethesda, MD 20892 USA. EM jpatton@niaid.nih.gov OI Schuck, Peter/0000-0002-8859-6966 NR 49 TC 59 Z9 61 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 MAR 30 PY 2001 VL 276 IS 13 BP 9679 EP 9687 DI 10.1074/jbc.M009398200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 420GC UT WOS:000167996400015 PM 11121414 ER PT J AU Roberson, MS Meermann, S Morasso, MI Mulvaney-Musa, JM Zhang, T AF Roberson, MS Meermann, S Morasso, MI Mulvaney-Musa, JM Zhang, T TI A role for the homeobox protein distal-less 3 in the activation of the glycoprotein hormone alpha subunit gene in choriocarcinoma cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MEDIATE TRANSCRIPTIONAL RESPONSES; GONADOTROPIN-RELEASING-HORMONE; PITUITARY-SPECIFIC EXPRESSION; HUMAN CHORIONIC-GONADOTROPIN; IN-SITU HYBRIDIZATION; CHROMOSOME 17Q21.3-Q22; REGULATORY ELEMENTS; DLX HOMEOPROTEINS; HUMAN PLACENTA; PIT-1 AB Synthesis and secretion of chorionic gonadotropin in trophoblast cells of the placenta is required for establishment of early pregnancy in primates. Chorionic gonadotropin is a heterodimeric glycoprotein hormone consisting of alpha and beta subunits, Regulation of the a subunit gene within the placenta requires an array of cia elements within the 5'-flanking region of the promoter. Within this array of elements, the junctional regulatory element (JRE) putatively binds a placental-specific transcription factor. The aim of our studies was to determine the identity and role of the transcriptional regulator that binds to the JRE in choriocarcinoma cells (JEG3 cells). Mutations within the JRE resulted in reduction in basal expression of an a subunit reporter gene, suggesting that the JRE binding factor was necessary for full basal activity. Using electrophoretic mobility shift assays, we determined that the JRE was capable of serving as a homeobox factor-binding site. The homeobox factor, Distal-less 3 (Dlx 3) was found to be expressed in JEG3 cells and in the trophoblast layer of human chorionic villus but not in a gonadotrope cell line that also expresses the a subunit gene. Electrophoretic mobility shift assays revealed that recombinant Dlx 3 could bind specifically to the JRE and endogenous Dlx 3 was present in JRE/JEG3 nuclear protein complexes. Overexpression of Dlx 3 resulted in activation of an alpha subunit reporter gene. A JRE mutation resulted in attenuated activation of the a subunit reporter via an adjacent cis element, suggesting that JRE/ Dlx 3 interactions may facilitate regulation of the a subunit gene at sites immediately upstream of the JRE. Our studies support the conclusion that Dlx 3 is a placental-specific transcriptional regulator that binds to the JRE and contributes to expression of the alpha subunit gene in cells of trophoblast origin. C1 Cornell Univ, Dept Biomed Sci, Ithaca, NY 14853 USA. NIAMS, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. RP Roberson, MS (reprint author), Cornell Univ, Dept Biomed Sci, T6-008A VRT, Ithaca, NY 14853 USA. FU NICHD NIH HHS [HD 34722] NR 56 TC 35 Z9 36 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 30 PY 2001 VL 276 IS 13 BP 10016 EP 10024 DI 10.1074/jbc.M007481200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 420GC UT WOS:000167996400060 PM 11113121 ER PT J AU Akiyoshi, Y Clayton, J Phan, L Yamamoto, M Hinnebusch, AG Watanabe, Y Asano, K AF Akiyoshi, Y Clayton, J Phan, L Yamamoto, M Hinnebusch, AG Watanabe, Y Asano, K TI Fission yeast homolog of murine int-6 protein, encoded by mouse mammary tumor virus integration site, is associated with the conserved core subunits of eukaryotic translation initiation factor 3 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID WD-REPEAT PROTEIN; SACCHAROMYCES-CEREVISIAE; SCHIZOSACCHAROMYCES-POMBE; FACTOR EIF-3; RNA-BINDING; CELL-PROLIFERATION; COMPLEX-FORMATION; NUCLEAR-BODIES; WHEAT-GERM; GENE AB The murine int-6 locus, identified as a frequent integration site of mouse mammary tumor viruses, encodes the 48-kDa eIF3e subunit of translation initiation factor eIF3, Previous studies indicated that the catalytically active core of budding yeast eIF3 consists of five subunits, all conserved in eukaryotes, but does not contain a protein closely related to eIF3e/Int-6, Whereas the budding yeast genome does not encode a protein closely related to murine Int-6, fission yeast does encode an Int-6 ortholog, designated here Int6, We found that fission yeast Int6/eIF3e is a cytoplasmic protein associated with 40 S ribosomes, FLAG epitope-tagged Tif35,a putative core eIF3g subunit, copurified with Int6 and all five orthologs of core eIF3 subunits, An int6 deletion (int6 Delta) mutant was viable but grew slowly in minimal medium. This slow growth phenotype was accompanied by a reduction in the amount of polyribosomes engaged in translation and was complemented by expression of human Int-6 protein. These findings support the idea that human and Schizosaccharomyces pombe Int-6 homologs are involved in translation. Interestingly, haploid int6 Delta cells showed unequal nuclear partitioning, possibly because of a defect in tubulin function, and diploid int6 Delta cells formed abnormal spores. We propose that Int6 is not an essential subunit of eIF3 but might be involved in regulating the activity of eIF3 for translation of specific mRNAs in S. pombe. C1 Univ Tokyo, Grad Sch Sci, Dept Biophys & Biochem, Tokyo 1130033, Japan. NICHD, Lab Eukaryot Gene Regulat, NIH, Bethesda, MD 20892 USA. Japan Sci & Technol Corp, PRESTO, Kawaguchi, Saitama 3320012, Japan. RP Watanabe, Y (reprint author), Univ Tokyo, Grad Sch Sci, Dept Biophys & Biochem, Tokyo 1130033, Japan. NR 43 TC 38 Z9 45 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 30 PY 2001 VL 276 IS 13 BP 10056 EP 10062 DI 10.1074/jbc.M010188200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 420GC UT WOS:000167996400065 PM 11134033 ER PT J AU Yun, CW Bauler, M Moore, RE Klebba, PE Philpott, CC AF Yun, CW Bauler, M Moore, RE Klebba, PE Philpott, CC TI The role of the FRE family of plasma membrane reductases in the uptake of siderophore-iron in Saccharomyces cerevisiae SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MAJOR FACILITATOR SUPERFAMILY; MOLECULAR CHARACTERIZATION; TRANSPORT PROTEIN; FERRIC REDUCTASE; COPPER UPTAKE; GENE ENCODES; FET3 GENE; YEAST; OXIDASE; IDENTIFICATION AB Saccharomyces cerevisiae takes up siderophore-bound iron through two distinct systems, one that requires siderophore transporters of the ARN family and one that requires the high affinity ferrous iron transporter on the plasma membrane. Uptake through the plasma membrane ferrous iron transporter requires that the iron first must dissociate from the siderophore and undergo reduction to the ferrous form. FRE1 and FRE2 encode cell surface metalloreductases that are required for reduction and uptake of free ferric iron. The yeast genome contains five additional FRE1 and FRE2 homologues, four of which are regulated by iron and the major iron-dependent transcription factor, Aft1p, but whose function remains unknown. Fre3p was required for the reduction and uptake of ferrioxamine B-iron and for growth on ferrioxamine B, ferrichrome, triacetyl-fusarinine C, and rhodotorulic acid in the absence of Fre1p and Fre2p, By indirect immunofluorescence, Fre3p was expressed on the plasma membrane in a pattern similar to that of Fet3p, a component of the high affinity ferrous transporter. Enterobactin, a catecholate siderophore, was not a substrate for Fre3p, and reductive uptake required either Fre1p or Fre2p, Fre4p could facilitate utilization of rhodotorulic acid-iron when the siderophore was present in higher concentrations. We propose that Fre3p and Fre4p are siderophore-iron reductases and that the apparent redundancy of the PRE genes confers the capacity to utilize iron from a variety of siderophore sources. C1 NIDDK, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. Univ Oklahoma, Dept Chem & Biochem, Norman, OK 73019 USA. Univ Wisconsin, Dept Chem, Oshkosh, WI 54901 USA. RP NIDDK, Liver Dis Sect, NIH, Bldg 10,Rm 9B16,10 Ctr Dr, Bethesda, MD 20892 USA. EM carolinep@intra.niddk.nih.gov FU NIGMS NIH HHS [GM53836] NR 34 TC 91 Z9 100 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 30 PY 2001 VL 276 IS 13 BP 10218 EP 10223 DI 10.1074/jbc.M010065200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 420GC UT WOS:000167996400085 PM 11120744 ER PT J AU Zhang, JH Barr, VA Mo, YY Rojkova, AM Liu, SH Simonds, WF AF Zhang, JH Barr, VA Mo, YY Rojkova, AM Liu, SH Simonds, WF TI Nuclear localization of G protein beta(5) and regulator of G protein signaling 7 in neurons and brain SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HETEROTRIMERIC G-PROTEINS; ADULT-RAT BRAIN; GAMMA-SUBUNIT; RGS PROTEINS; ALPHA-SUBUNIT; P115 RHOGEF; COMPLEX; G-BETA-5; BINDING; DNA AB The role that G beta (5) regulator of G protein signaling (RGS) complexes play in signal transduction in brain remains unknown. The subcellular localization of G beta (5) and RGS7 was examined in rat PC12 pheochromocytoma cells and mouse brain. Both nuclear and cytosolic localization of G beta (5) and RGS7 was evident in PC12 cells by immunocytochemical staining. Subcellular fractionation of PC12 cells demonstrated G beta (5) immunoreactivity in the membrane, cytosolic, and nuclear fractions. Analysis by limited proteolysis confirmed the identity of G beta (5) in the nuclear fraction, Subcellular fractionation of mouse brain demonstrated G beta (5) and RGS7 but not G gamma (2/3) immunoreactivity in the nuclear fraction. RGS7 and G beta (5) were tightly complexed in the brain nuclear extract as evidenced by their coimmunoprecipitation with anti-RGS7 antibodies. Chimeric protein constructs containing green fluorescent protein fused to wild-type G beta (5) but not green fluorescent fusion proteins with G beta (1) or a mutant G beta (5) impaired in its ability to bind to RGS7 demonstrated nuclear localization in transfected PC12 cells, These findings suggest that G beta (5) undergoes nuclear translocation in neurons via an RGS-dependent mechanism. The novel intracellular distribution of G beta (5). RGS protein complexes suggests a potential role in neurons communicating between classical heterotrimeric G protein subunits and/or their effecters at the plasma membrane and the cell nucleus. C1 NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Diabet Branch, NIH, Bethesda, MD 20892 USA. Univ Illinois, Coll Med, Dept Mol Genet, Chicago, IL 60607 USA. RP Simonds, WF (reprint author), NIDDK, Metab Dis Branch, NIH, Bldg 10,Rm 8C-101,10 Ctr Dr,MSC 1752, Bethesda, MD 20892 USA. RI Mo, Yin-Yuan/B-6141-2011; Rozhkova, Alexandra/E-5607-2014 OI Rozhkova, Alexandra/0000-0003-4901-4705 NR 39 TC 59 Z9 60 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 30 PY 2001 VL 276 IS 13 BP 10284 EP 10289 DI 10.1074/jbc.M009247200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 420GC UT WOS:000167996400093 PM 11152459 ER PT J AU Bebenek, A Dressman, HK Carver, GT Ng, SS Petrov, V Yang, GW Konigsberg, WH Karam, JD Drake, JW AF Bebenek, A Dressman, HK Carver, GT Ng, SS Petrov, V Yang, GW Konigsberg, WH Karam, JD Drake, JW TI Interacting fidelity defects in the replicative DNA polymerase of bacteriophage RB69 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID T-EVEN BACTERIOPHAGES; SPONTANEOUS MUTATION; CRYSTAL-STRUCTURE; BIOCHEMICAL BASIS; ESCHERICHIA-COLI; KLENOW FRAGMENT; MISMATCH REPAIR; MUTANTS; RATES; GENE AB The DNA polymerases (gp43s) of the related bacteriophages T4 and RB69 are B family (polymerase alpha class) enzymes that determine the fidelity of phage DNA replication. A T4 whose gene 43 has been mutationally inactivated can be replicated by a cognate RB69 gp43 encoded by a recombinant plasmid in T l-infected Escherichia coli. We used this phage-plasmid complementation assay to obtain rapid and sensitive measurements of the mutational specificities of mutator derivatives of the RB69 enzyme, RB69 gp43s lacking proofreading function (Exo(-) enzymes) and/or substituted with alanine, serine, or threonine at the conserved polymerase function residue Tyr(567) (Pol(Y567(A/S/T)) enzymes) were examined for their effects on the reversion of specific mutations in the T4 rII gene and on forward mutation in the T4 rI gene. The results reveal that Tyr567 is a key determinant of the fidelity of base selection and that the Pol and fro functions are strongly coupled in this B family enzyme, In vitro assays show that the Pol(Y567A) EXO- enzyme generates mispairs more frequently but extends them less efficiently than does a pol(+) Exo- enzyme. Other replicative DNA polymerases may control fidelity by strategies similar to those used by RB69 gp43. C1 NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. Tulane Univ, Hlth Sci Ctr, Dept Biochem, New Orleans, LA 70112 USA. Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06510 USA. RP Drake, JW (reprint author), NIEHS, Mol Genet Lab, NIH, E3-01,Rm E-344,111 S Alexander Dr, Res Triangle Pk, NC 27709 USA. FU NIDDK NIH HHS [DK09070]; NIGMS NIH HHS [GM18842, GM54627] NR 53 TC 49 Z9 49 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 30 PY 2001 VL 276 IS 13 BP 10387 EP 10397 DI 10.1074/jbc.M007707200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 420GC UT WOS:000167996400105 PM 11133987 ER PT J AU Li, L Yang, FQ Zhang, TY Tu, PF Wu, LJ Ito, YC AF Li, L Yang, FQ Zhang, TY Tu, PF Wu, LJ Ito, YC TI Preparative isolation and purification of acteoside and 2 '-acetyl acteoside from Cistanches salsa (C.A. Mey.) G. Beck by highspeed counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE counter-current chromatography; Cistanches salsa; pharmaceutical analysis; plant materials; preparative chromatography; acteoside; acetylacteoside; phenylethanoids; glycosides AB High-speed counter-current chromatography (HSCCC) was applied to the separation and purification of phenylethanoid glycosides (PhGs) acteoside and 2 ' -acetylacteoside from Cistanches salsa (C.A. Mey) G. Beck with a quaternary two-phase solvent system composed of ethyl acetate-n-butanol-ethanol-water (4:0.6:0.6:5, v/v). HPLC analyses of the CCC fractions revealed that the two main PhGs were over 98% purity. Their chemical structures were identified by LH NMR, C-13 NMR and MS. (C) 2001 Elsevier Science B.V. All rights reserved. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. Peking Univ, Sch Pharmaceut Sci, Beijing 100083, Peoples R China. Beijing Inst New Technol Applicat, Beijing 100035, Peoples R China. Shenyang Pharmaceut Univ, Shenyang 110015, Peoples R China. RP Ito, YC (reprint author), NHLBI, Biophys Chem Lab, NIH, Bldg 10,Rm 7N322,10 Ctr Dr MSC 1676, Bethesda, MD 20892 USA. NR 4 TC 1 Z9 2 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD MAR 30 PY 2001 VL 912 IS 1 BP 181 EP 185 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 413BJ UT WOS:000167589800020 ER PT J AU Horita, DA Ivanova, AV Altieri, AS Klar, AJS Byrd, RA AF Horita, DA Ivanova, AV Altieri, AS Klar, AJS Byrd, RA TI Solution structure, domain features, and structural implications of mutants of the chromo domain from the fission yeast histone methyltransferase Clr4 SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE epigenetic gene regulation; NMR; chromo domain; chromatin; protein structure ID MATING-TYPE REGION; POSITION-EFFECT VARIEGATION; SIDE-CHAIN RESONANCES; SCHIZOSACCHAROMYCES-POMBE; EPIGENETIC INHERITANCE; REPRESS TRANSCRIPTION; C-13 MAGNETIZATION; LARGER PROTEINS; BACKBONE AMIDE; SHADOW DOMAIN AB The encapsulation of otherwise transcribable loci within transcriptionally inactive heterochromatin is rapidly gaining recognition as an important mechanism of epigenetic gene regulation. In the fission yeast Schizosaccharomyces pombe, heterochromatinization of the mat2/mat3 loci silences the mating-type information encoded within these loci. Here, we present the solution structure of the chromo domain from the cryptic loci regulator protein Clr4. Clr4 is known to regulate silencing and switching at the mating-type loci and to affect chromatin structure at centromeres. Clr3 and its human and Drosophila homologs have been identified as histone MS-specific methyltransferases, further implicating this family of proteins in chromatin remodeling. Our structure highlights a conserved surface that may be involved in chrome domain-ligand interactions. We have also analyzed two chrome domain mutants (W31G and W41G) that previously were shown to affect silencing and switching in full-length Clr4. Both mutants are significantly destabilized relative to wild-type. (C) 2001 Academic Press. C1 NCI, Struct Biophys Lab, Frederick, MD 21702 USA. NCI, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. RP Horita, DA (reprint author), Wake Forest Univ, Sch Med, Dept Biochem, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM dhorita@wfubmc.edu; rabyrd@ncifcrf.gov RI Byrd, R. Andrew/F-8042-2015; OI Byrd, R. Andrew/0000-0003-3625-4232; Horita, David/0000-0002-9563-107X NR 61 TC 12 Z9 13 U1 0 U2 5 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 MAR 30 PY 2001 VL 307 IS 3 BP 861 EP 870 DI 10.1006/jmbi.2001.4515 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 419BW UT WOS:000167930300010 PM 11273706 ER PT J AU Whitney, LW Becker, KG AF Whitney, LW Becker, KG TI Radioactive 33-P probes in hybridization to glass cDNA microarrays using neural tissues SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE cDNA microarray; brain; hybridization; radioactive; probe ID GENE-EXPRESSION PATTERNS; SEQUENCE TAGS; BRAIN; SCALE AB cDNA microarrays are becoming widespread tools in the study of complex gene expression patterns with applications using cells lines, animal model systems, and human disease. Class cDNA microarrays using fluorescent labeled cDNA probes require a large amount of input RNA usually not available in man): neuroscience applications. Here we demonstrate a technique for the use of 33-P labeled cDNA probes in hybridizations to the same glass cDNA arrays used for fluorescent applications. This approach allows the use of low quantities of RNA, common phosphoimaging scanners, data acquisition software, and standard DNA and RNA labeling protocols, while being consistent and interchangeable with glass-based cDNA array technology. (C) 2001 Elsevier Science B.V. All rights reserved. C1 NIA, DNA Array Unit, NIH, Gerontol Res Ctr, Baltimore, MD 21224 USA. NINDS, Mol Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Becker, KG (reprint author), NIA, DNA Array Unit, NIH, Gerontol Res Ctr, Room 4-D16,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Becker, Kevin/0000-0002-6794-6656 NR 15 TC 10 Z9 11 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD MAR 30 PY 2001 VL 106 IS 1 BP 9 EP 13 DI 10.1016/S0165-0270(00)00370-8 PG 5 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 419AX UT WOS:000167928100002 PM 11248336 ER PT J AU Wuebben, Y Winterer, G AF Wuebben, Y Winterer, G TI Hypofrontality - a risk-marker related to schizophrenia? SO SCHIZOPHRENIA RESEARCH LA English DT Article DE cortical hypoactivation; EEG activity; hypofrontality; risk-marker ID CEREBRAL BLOOD-FLOW; POSITRON EMISSION TOMOGRAPHY; SCHIZOTYPAL PERSONALITY; DEPRESSED-PATIENTS; SPECTRAL-ANALYSIS; MAJOR DEPRESSION; EEG DIFFERENCES; METABOLIC-RATE; PSYCHIATRY; RELATIVES AB In order to better understand whether cortical hypoactivation and hypofrontality is a possible risk marker for schizophrenia, we investigated resting EEG activity in 39 unmedicated schizophrenics and 21 persons with schizotypal personality. Compared to a normal control group, we found an increased, frontally pronounced delta activity in schizophrenic patients, a result that is in accordance with other studies. Subjects with schizotypal personality, who are believed to have an increased risk for schizophrenia, did not show an increase of delta activity. From this result, we concluded that cortical hypoactivation and hypofrontality - defined as an increase of frontally pronounced delta activity during resting EEG - cannot be interpreted as a risk factor for schizophrenia. However, since it is controversial whether subjects with schizotypal personality are at increased risk for schizophrenia, further studies in unaffected family members of schizophrenic patients are needed. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Free Univ Berlin, Dept Psychiat, D-14050 Berlin, Germany. NIMH, Bethesda, MD 20892 USA. RP Wuebben, Y (reprint author), Free Univ Berlin, Dept Psychiat, Eschenallee 3, D-14050 Berlin, Germany. NR 54 TC 21 Z9 23 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD MAR 30 PY 2001 VL 48 IS 2-3 BP 207 EP 217 DI 10.1016/S0920-9964(00)00047-5 PG 11 WC Psychiatry SC Psychiatry GA 424EZ UT WOS:000168220300006 PM 11295374 ER PT J AU Noga, JT Hyde, TM Bachus, SE Herman, MM Kleinman, JE AF Noga, JT Hyde, TM Bachus, SE Herman, MM Kleinman, JE TI AMPA receptor binding in the dorsolateral prefrontal cortex of schizophrenics and controls SO SCHIZOPHRENIA RESEARCH LA English DT Letter ID GLUTAMATE RECEPTORS; DOPAMINE RELEASE; STRIATUM C1 Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA 30303 USA. NIMH, DIRP, Clin Brain Disorders Branch, Bethesda, MD USA. RP Noga, JT (reprint author), Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA 30303 USA. NR 9 TC 11 Z9 12 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD MAR 30 PY 2001 VL 48 IS 2-3 BP 361 EP 363 DI 10.1016/S0920-9964(00)00121-3 PG 3 WC Psychiatry SC Psychiatry GA 424EZ UT WOS:000168220300020 PM 11295388 ER PT J AU Dunson, DB Weinberg, CR Baird, DD Kesner, JS Wilcox, AJ AF Dunson, DB Weinberg, CR Baird, DD Kesner, JS Wilcox, AJ TI Assessing human fertility using several markers of ovulation SO STATISTICS IN MEDICINE LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRE; TRUE AVERAGE INTAKE; PROGESTERONE METABOLITES; POSTERIOR DISTRIBUTIONS; MEASUREMENT-ERROR; URINARY ESTROGEN; EM ALGORITHM; CONCEPTION; INTERCOURSE; PROBABILITY AB In modelling human fertility one ideally accounts for timing of intercourse relative to ovulation. Measurement error in identifying the day of ovulation can bias estimates of fecundability parameters and attenuate estimates of covariate effects. In the absence of a single perfect marker of ovulation, several error prone markers are sometimes obtained. In this paper we propose a semi-parametric mixture model that uses multiple independent markers of ovulation to account for measurement error. The model assigns each method of assessing ovulation a distinct non-parametric error distribution, and corrects bias in estimates of day-specific fecundability. We use a Monte Carlo EM algorithm for joint estimation of (i) the error distribution for the markers, (ii) the error-corrected fertility parameters, and (iii) the couple-specific random effects. We apply the methods to data from a North Carolina fertility study to assess the magnitude of error in measures of ovulation based on urinary luteinizing hormone and metabolites of ovarian hormones, and estimate the corrected day-specific probabilities of clinical pregnancy. Published in 2001 by John Wiley & Sons, Ltd. C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. NIOSH, Div Biomed & Behav Sci, Expt Toxicol Branch, Bethesda, MD USA. RP Dunson, DB (reprint author), NIEHS, Biostat Branch, MD A3-03,POB 12233, Res Triangle Pk, NC 27709 USA. OI Wilcox, Allen/0000-0002-3376-1311; Baird, Donna/0000-0002-5544-2653 NR 34 TC 35 Z9 35 U1 0 U2 2 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD MAR 30 PY 2001 VL 20 IS 6 BP 965 EP 978 DI 10.1002/sim.716 PG 14 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 414MQ UT WOS:000167670800011 PM 11252016 ER PT J AU Shisler, JL Moss, B AF Shisler, JL Moss, B TI Molluscum contagiosum virus inhibitors of apoptosis: The MC159 v-FLIP protein blocks Fas-induced activation of procaspases and degradation of the related MC160 protein SO VIROLOGY LA English DT Article ID DOMAIN-CONTAINING PROTEIN; DEATH EFFECTOR DOMAINS; CELL-DEATH; POXVIRUS; HOMOLOG; CASPASE-8; INDUCTION; FADD; DOWNSTREAM; INTERACTS AB Molluscum contagiosum virus contains two open reading frames, MC159 and MC160, that encode proteins with death effector domains resembling those of cellular regulators of apoptosis. Previous transfection analyses indicated that the MC159 protein binds to cellular FADD and inhibits Pas-induced cytolysis. For further studies, we inserted the MC159 or MC160 gene into the genome of vaccinia virus that had its own major anti-apoptosis gene deleted. The MC159-expressing virus blocked Pas-induced activation of caspase-3 and -8, degradation of PARP, and cleavage of DNA, whereas the parental vaccinia Virus did not. The MC159 protein bound to procaspase-8, in addition to FADD, and was included in a complex with Fas upon receptor activation. Although the MC160 protein associated with FADD and procaspase-8 in co-immunoprecipitation studies, no protection against morphological or biochemical changes associated with Pas-induced apoptosis were discerned and the MC160 protein it self was degraded. Go-expression of MC159, as well as other caspase inhibitors, protected the MC160 protein from degradation, suggesting a functional relationship between the two viral proteins. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), 4 Ctr Dr,MSC 0445, Bethesda, MD 20892 USA. NR 38 TC 51 Z9 51 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR 30 PY 2001 VL 282 IS 1 BP 14 EP 25 DI 10.1006/viro.2001.0834 PG 12 WC Virology SC Virology GA 416VL UT WOS:000167800800003 PM 11259186 ER PT J AU Boyer, PL Gao, HQ Frank, P Clark, PK Hughes, SH AF Boyer, PL Gao, HQ Frank, P Clark, PK Hughes, SH TI The basic loop of the RNase H domain of MLV RT is important both for RNase H and for polymerase activity SO VIROLOGY LA English DT Article ID VIRUS REVERSE-TRANSCRIPTASE; ESCHERICHIA-COLI; DNA-POLYMERASE; MUTATIONS; REPLICATION; EXPRESSION; TEMPLATE; MUTANTS; BINDING; ENZYME AB Escherichia coli RNase H has a basic extension that is involved in binding nucleic acid substrates. This basic extension is present in the RNase H of Moloney murine leukemia virus reverse transcriptase (MLV RT), but has been deleted from the RNase H of HIV-1 RT. Previous work showed that removing the basic loop from MLV RT (the mutant is called DeltaC) blocked viral replication; however, DeltaC MLV RT retained RNase H activity in an in situ gel assay. We prepared recombinant DeltaC MLV RT and compared its activity to wild-type MLV RT The DeltaC mutant is impaired in both polymerase and RNase H activity; the pattern of defects suggests that the basic loop is involved in the binding of MLV RT to a heteropolymeric template-primer. C1 NCI Frederick, HIV Drug Resistance Program, Frederick, MD 21702 USA. NCI Frederick, SAIC Frederick, Frederick, MD 21702 USA. RP Hughes, SH (reprint author), NCI Frederick, HIV Drug Resistance Program, POB B, Frederick, MD 21702 USA. EM hughes@ncifcrf.gov NR 23 TC 11 Z9 11 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR 30 PY 2001 VL 282 IS 1 BP 206 EP 213 DI 10.1006/viro.2000.0827 PG 8 WC Virology SC Virology GA 416VL UT WOS:000167800800020 PM 11259203 ER PT J AU Huang, Y Hamada, M Patel, J Maraia, RJ AF Huang, Y Hamada, M Patel, J Maraia, RJ TI Construction of FLAG and histidine tagging vectors for Schizosaccharomyces pombe SO YEAST LA English DT Article DE fission yeast; nmt1; tagging; FLAG epitope ID REPRESSIBLE EXPRESSION VECTORS; FISSION YEAST; PURIFICATION; PROTEINS; EFFICIENCY; MUTATIONS; ANTIBODY; COMPLEX; FAMILY; BOX AB Schizosaccharomyces pombe is becoming an increasingly popular model system for investigating important cellular processes. To facilitate detection, purification and functional studies of St. pombe gene products, Ne constructed two tagging expression vectors for use in St. pombe. These vectors allow proteins to be expressed ectopically as fusion proteins with a FLAG epitope and six histidine residue tags attached to their N-terminus or C-terminus. The function and applicability of these vectors were examined and the results are shown using the N-terminal tagging vector encoding Sfc6p, a subunit of the St. pombe RNA polymerase m general transcription factor, TFIIIC. Copyright (C) 2001 John Wiley & Sons, Ltd. C1 NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. RP Huang, Y (reprint author), Bldg 6,Room 3AD3,6 Ctr Dr,MSC 2753, Bethesda, MD 20892 USA. NR 23 TC 8 Z9 10 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0749-503X J9 YEAST JI Yeast PD MAR 30 PY 2001 VL 18 IS 5 BP 463 EP 468 DI 10.1002/yea.692 PG 6 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology GA 419ET UT WOS:000167936900007 PM 11255254 ER PT J AU Wang, SQ Song, LS Lakatta, EG Cheng, HP AF Wang, SQ Song, LS Lakatta, EG Cheng, HP TI Ca2+ signalling between single L-type Ca2+ channels and ryanodine receptors in heart cells SO NATURE LA English DT Article ID FROG SKELETAL-MUSCLE; CARDIAC MYOCYTES; CALCIUM-RELEASE; SARCOPLASMIC-RETICULUM; SPARKS; INACTIVATION AB Ca2+-induced Ca2+ release is a general mechanism that most cells use to amplify Ca2+ signals(1-5). In heart cells, this mechanism is operated between voltage-gated L-type Ca2+ channels (LCCs) in the plasma membrane and Ca2+ release channels, commonly known as ryanodine receptors, in the sarcoplasmic reticulum(3-5) The Ca2+ influx through LCCs traverses a deft of roughly 12 nm formed by the cell surface and the sarcoplasmic reticulum membrane, and activates adjacent ryanodine receptors to release Ca2+ in the form of Ca2+ sparks(6). Here we determine the kinetics, fidelity and stoichiometry of coupling between LCCs and ryanodine receptors. We show that the local Ca2+ signal produced by a single opening of an LCC named a 'Ca2+ sparklet: can trigger about 4-6 ryanodine receptors to generate a Ca2+ spark. The coupling between LCCs and ryanodine receptors is stochastic, as judged by the exponential distribution of the coupling latency. The fraction of sparklets that successfully triggers a spark is less than unity and declines in a use-dependent manner. This optical analysis of single-channel communication affords a powerful means for elucidating Ca2+-signalling mechanisms at the molecular level. C1 NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. Peking Univ, Coll Life Sci, Natl Lab Biomembrane & Membrane Biotechnol, Beijing 100871, Peoples R China. RP Cheng, HP (reprint author), NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RI Song, Long-Sheng/D-5899-2012 NR 29 TC 269 Z9 286 U1 5 U2 34 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 29 PY 2001 VL 410 IS 6828 BP 592 EP 596 DI 10.1038/35069083 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 417WW UT WOS:000167859300050 PM 11279498 ER PT J AU Piscitelli, SC Gallicano, KD AF Piscitelli, SC Gallicano, KD TI Drug therapy: Interactions among drugs for HIV and opportunistic infections SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; PROTEASE INHIBITOR SAQUINAVIR; ST-JOHNS-WORT; P-GLYCOPROTEIN; GRAPEFRUIT JUICE; PHARMACOKINETIC INTERACTION; IN-VITRO; INDINAVIR CONCENTRATIONS; MULTIDRUG TRANSPORTER; FLUCONAZOLE THERAPY C1 NIH, Clin Pharmacokinet Res Lab, Dept Pharm, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Ottawa Hosp, Clin Invest Unit, Ottawa, ON, Canada. Ottawa Hosp, Ottawa Hosp Res Inst, Ottawa, ON, Canada. RP Piscitelli, SC (reprint author), Virco Labs, Johns Hopkins Bayview Campus,Alpha Ctr,3rd Fl,521, Baltimore, MD 21224 USA. NR 117 TC 178 Z9 185 U1 1 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 29 PY 2001 VL 344 IS 13 BP 984 EP 996 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 415HY UT WOS:000167716600007 PM 11274626 ER PT J AU Miller, FG AF Miller, FG TI To protect those who serve SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID CLINICAL RESEARCH C1 NIH, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 29 PY 2001 VL 344 IS 13 BP 1018 EP 1019 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 415HY UT WOS:000167716600018 PM 11280318 ER PT J AU Bressloff, PC Cowan, JD Golubitsky, M Thomas, PJ Wiener, MC AF Bressloff, PC Cowan, JD Golubitsky, M Thomas, PJ Wiener, MC TI Geometric visual hallucinations, Euclidean symmetry and the functional architecture of striate cortex SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES LA English DT Article DE hallucinations; visual imagery; flicker phosphenes; neural modelling; horizontal connections; contours ID HORIZONTAL CONNECTIONS; ORIENTATION SELECTIVITY; INTRINSIC CONNECTIONS; MATHEMATICAL-THEORY; PATTERN; BIFURCATION; POPULATIONS; PERCEPTION; PROJECTION; EQUATIONS AB This paper is concerned with a striking visual experience: that of seeing geometric visual hallucinations. Hallucinatory images were classified by Kluver into four groups called form constants comprising (i) gratings, lattices, fretworks, filigrees, honeycombs and chequer-boards, (ii) cobwebs, (iii) tunnels, funnels, alleys, cones and vessels, and (iv) spirals. This paper describes a mathematical investigation of their origin based on the assumption that the patterns of connection between retina and striate cortex (henceforth referred to as V1) -the retinocortical map-and of neuronal circuits in V1, both local and lateral? determine their geometry. In the first part of the paper we show that form constants, when viewed in V1 coordinates, essentially correspond to combinations of plane waves, the wavelengths of which are integral multiples of the width of a human Hubel-Wiesel hypercolumn, ca. 1.33-2 mm. We next introduce a mathematical description of the large-scale dynamics of V1 in terms of the continuum limit of a lattice of interconnected hypercolumns, each of which itself comprises a number of interconnected iso-orientation columns. We then show that the patterns of interconnection in V1 exhibit a very interesting symmetry i.e. they are invariant rotations, reflections and translations. What is novel is that the lateral connectivity of V1 is such that a new group action is needed to represent its properties: by virtue of its anisotropy it is invariant with respect to certain shifts and twists of the plane. It is this shift-twist invariance that generates new representations of E(2). Assuming that the strength of lateral connections is weak compared with that of local connections, we next calculate the eigenvalues and eigenfunctions of the cortical dynamics, using Rayleigh-Schrodinger perturbation theory The result is that in the absence of lateral connections, the eigenfunctions are degenerate, comprising both even and odd combinations of sinusoids in phi, the cortical label for orientation preference, and plane waves in r, the cortical position coordinate. 'Switching-on' the lateral interactions breaks the degeneracy and either even or else odd eigenfunctions are selected. These results can be shown to follow directly from the Euclidean symmetry we have imposed. In the second part of the paper we study the nature of various even and odd combinations of eigenfunctions or planforms, the symmetries of which are such that they remain invariant under the particular action of E(2) we have imposed. These symmetries correspond to certain subgroups of E(2), the so-called axial subgroups. Axial subgroups are important in that the equivariant branching lemma indicates that when a symmetrical dynamical system becomes unstable, new solutions emerge which have symmetries corresponding to the axial subgroups of the underlying symmetry group. This is precisely the case studied in this paper. Thus we study the various planforms that emerge when our model V1 dynamics become unstable under the presumed action of hallucinogens or flickering lights. We show that the planforms correspond to the axial subgroups of E(2), under the shift-twist action. We then compute what such planforms would look like in the visual field, given an extension of the retinocortical map to include its action on local edges and contours. What is most interesting is that, given our interpretation of the correspondence between V1 planforms and perceived patterns, the set of planforms generates representatives of all the form constants. It is also noteworthy that the planforms derived from our continuum model naturally divide V1 into what are called linear regions, in which the pattern has a near constant orientation, reminiscent of the iso-orientation patches constructed via optical imaging. The boundaries of such regions form fractures whose points of intersection correspond to the well-known 'pinwheels'. To complete the study we then investigate the stability of the planforms, using methods of nonlinear stability analysis, including Liapunov-Schmidt reduction and Poincare-Lindstedt perturbation theory. We find a dose correspondence between stable planforms and form constants. The results are sensitive to the detailed specification of the lateral connectivity and suggest an interesting possibility, that the cortical mechanisms by which geometric visual hallucinations are generated, if sited mainly in V1, are closely related to those involved in the processing of edges and contours. C1 Univ Chicago, Dept Math, Chicago, IL 60637 USA. Univ Utah, Dept Math, Salt Lake City, UT 84112 USA. Univ Houston, Dept Math, Houston, TX 77204 USA. Salk Inst Biol Studies, Computat Neurobiol Lab, San Diego, CA 92186 USA. NIH, Neuropsychol Lab, Bethesda, MD 20892 USA. RP Cowan, JD (reprint author), Univ Chicago, Dept Math, Chicago, IL 60637 USA. FU NIMH NIH HHS [T-32-MH20029] NR 65 TC 171 Z9 172 U1 3 U2 25 PU ROYAL SOC LONDON PI LONDON PA 6 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T ROY SOC B JI Philos. Trans. R. Soc. Lond. Ser. B-Biol. Sci. PD MAR 29 PY 2001 VL 356 IS 1407 BP 299 EP 330 PG 32 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 419WN UT WOS:000167971900003 PM 11316482 ER PT J AU Ishii, Y Yesinowski, JP Tycko, R AF Ishii, Y Yesinowski, JP Tycko, R TI Sensitivity enhancement in solid-state C-13 NMR of synthetic polymers and biopolymers by H-1 NMR detection with high-speed magic angle spinning SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID CORRELATION SPECTROSCOPY; HETERONUCLEAR CORRELATION; ROTATING SOLIDS; CHEMICAL-SHIFT; PROTON; SPECTRA C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. USN, Res Lab, Div Chem, Washington, DC 20375 USA. RP Tycko, R (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. RI Ishii, Yoshitaka/F-4558-2014 OI Ishii, Yoshitaka/0000-0002-7724-6469 NR 21 TC 83 Z9 84 U1 1 U2 26 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 MAR 28 PY 2001 VL 123 IS 12 BP 2921 EP 2922 DI 10.1021/ja015505j PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 416QV UT WOS:000167792400041 PM 11456995 ER PT J AU Ma, K Kan, LS Wang, K AF Ma, K Kan, LS Wang, K TI Polyproline II helix is a key structural motif of the elastic PEVK segment of titin SO BIOCHEMISTRY LA English DT Article ID SECONDARY STRUCTURE; CIRCULAR-DICHROISM; RESIDUAL STRUCTURE; DENATURED STATE; SKELETAL-MUSCLE; SH3 DOMAIN; PROTEIN; NMR; CONFORMATIONS; PEPTIDES AB Titin is a family of giant elastic proteins that constitute an elastic sarcomere matrix in striated muscle. In the I-band region of the sarcomere, where titin extends and develops passive force upon stretch, titin is composed of tandem repeats of similar to 100 residue immunoglobin domains and similar to 28-residue PEVK modules. We have performed 2D NMR and circular dichroism (CD) studies of the conformations of one representative 28-mer PEVK module from human fetal titin (PEPPKEVVPEKKAPVAPPKKPEVPPVKV). NMR data of synthetic peptides of this module as well as three constituent peptides of 9 to 12 residues in aqueous solutions reveal distinguishing features for left-handed three-residue per turn PPII helices: the lack of NOE NN(i, i+1), very large NOE alphaN(i, i+1)/NN(i, i+1), no medium range NOE alphaN(i, i+2), and dihedral angles phi and psi values of -78 and 146, respectively. Structural determinations indicate the presence of three short stretches of PPII helices of 4, 5, and 6 residues that are interposed with an unordered, and presumably flexible, spacer region to give one "polyproline II helix-coil" or "PhC" motif for roughly every 10 residues. These peptides also display the characteristic PPII CD spectra: positive peak or negative shoulder band at 223 nm, negative CD band near 200 nm, and biphasic thermal titration curves that reflect varied stability of these PPII helices. We propose that this PhC motif is a fundamental feature and that the number, length, stability, and distribution of PPII is important in the understanding of the elasticity and protein interactions of the PEVK region of titin. C1 NIAMSD, Phys Biol Lab, NIH, Bethesda, MD 20892 USA. Acad Sinica, Inst Chem, Taipei, Taiwan. RP Wang, K (reprint author), NIAMSD, Phys Biol Lab, NIH, B6,Rm 401, Bethesda, MD 20892 USA. NR 54 TC 111 Z9 112 U1 1 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 27 PY 2001 VL 40 IS 12 BP 3427 EP 3438 DI 10.1021/bi0022792 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 416UJ UT WOS:000167798300003 PM 11297408 ER PT J AU Weber-Ban, E Hur, O Bagwell, C Banik, U Yang, LH Miles, EW Dunn, MF AF Weber-Ban, E Hur, O Bagwell, C Banik, U Yang, LH Miles, EW Dunn, MF TI Investigation of allosteric linkages in the regulation of tryptophan synthase: The roles of salt bridges and monovalent cations probed by site-directed mutation, optical spectroscopy, and kinetics SO BIOCHEMISTRY LA English DT Article ID ULTRAVIOLET-VISIBLE SPECTROSCOPY; ALPHA(2)BETA(2) COMPLEX REVEALS; BIENZYME COMPLEX; ESCHERICHIA-COLI; INTERSUBUNIT COMMUNICATION; ENZYME CATALYSIS; ALPHA-SUBUNIT; L-SERINE; 3-DIMENSIONAL STRUCTURE; SALMONELLA-TYPHIMURIUM AB The tryptophan synthase bienzyme complex is the most extensively documented example of substrate channeling in which the oligomeric unit has been described at near atomic resolution. Transfer of the common metabolite, indole, between the alpha- and the beta -sites occurs by diffusion along a 25-Angstrom -long interconnecting tunnel within each alpha beta -dimeric unit of the alpha (2)beta (2) oligomer. The control of metabolite transfer involves allosteric interactions that trigger the switching of alpha beta -dimeric units between open and closed conformations and between catalytic states of low and high activity. This allosteric signaling is triggered by covalent transformations at the beta -site and ligand binding to the alpha -site. The signals are transmitted between sites via a scaffolding of structural elements that includes a monovalent cation (MVC) binding site and salt bridging interactions of beta Lys 167 with beta Asp 305 or alpha Asp 56. Through the combined strategies of site-directed mutations of these amino acid residues and cation substitutions at the MVC site, this work examines the interrelationship of the MVC site and the alternative salt bridges formed between Lys beta 167 with Asp beta 305 or Asp alpha 56 to the regulation of channeling. These experiments show that both the binding of a MVC and the formation of the Lys beta 167-Asp alpha 56 salt bridge are important to the transmission of allosteric signals between the sites, whereas, the salt bridge between beta K167 and beta D305 appears to be only of minor significance to catalysis and allosteric regulation. The mechanistic implications of these findings both for substrate channeling and for catalysis are discussed. C1 Univ Calif Riverside, Dept Biochem, Riverside, CA 92521 USA. NIH, Bethesda, MD 20892 USA. RP Dunn, MF (reprint author), Univ Calif Riverside, Dept Biochem, Riverside, CA 92521 USA. FU NIGMS NIH HHS [R01 GM55749] NR 44 TC 40 Z9 40 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 27 PY 2001 VL 40 IS 12 BP 3497 EP 3511 DI 10.1021/bi002690p PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 416UJ UT WOS:000167798300011 PM 11297416 ER PT J AU Henry, TR Theodore, WH AF Henry, TR Theodore, WH TI Homocarnosine elevations - A cause or a sign of seizure control? SO NEUROLOGY LA English DT Editorial Material ID BRAIN GABA; INCREASES C1 Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. NIH, Clin Epilepsy Sect, Bethesda, MD USA. RP Henry, TR (reprint author), Emory Univ, Sch Med, Dept Neurol, Woodruff Mem Res Bldg,Suite 6000,1639 Pierce Dr, Atlanta, GA 30322 USA. OI Henry, Thomas/0000-0002-5708-903X NR 10 TC 5 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR 27 PY 2001 VL 56 IS 6 BP 698 EP 699 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 414ZY UT WOS:000167697100002 PM 11274301 ER PT J AU Brown, WE Eliez, S Menon, V Rumsey, JM White, CD Reiss, AL AF Brown, WE Eliez, S Menon, V Rumsey, JM White, CD Reiss, AL TI Preliminary evidence of widespread morphological variations of the brain in dyslexia SO NEUROLOGY LA English DT Article AB The MR images of 16 men with dyslexia and 14 control subjects were compared using a voxel-based analysis. Evidence of decreases in gray matter in dyslexic subjects, most notably in the left temporal lobe and bilaterally in the temporoparietooccipital juncture, but also in the frontal lobe, caudate, thalamus, and cerebellum, was found. Widely distributed morphologic differences affecting several brain regions may contribute to the deficits associated with dyslexia. C1 Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford Psychiat Neuroimaging Lab, Stanford, CA 94305 USA. NIMH, Clin Neurosci Branch, Rockville, MD 20857 USA. RP Reiss, AL (reprint author), Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford Psychiat Neuroimaging Lab, 401 Quarry Rd, Stanford, CA 94305 USA. RI Menon, Vinod/J-6402-2013 OI Menon, Vinod/0000-0003-1622-9857 FU NICHD NIH HHS [HD31715]; NIMH NIH HHS [MH01142] NR 11 TC 120 Z9 120 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR 27 PY 2001 VL 56 IS 6 BP 781 EP 783 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 414ZY UT WOS:000167697100018 PM 11274316 ER PT J AU Bonavita, S Schiffmann, R Moore, DF Frei, K Choi, B Patronas, N Virta, A Boespflug-Tanguy, O Tedeschi, G AF Bonavita, S Schiffmann, R Moore, DF Frei, K Choi, B Patronas, N Virta, A Boespflug-Tanguy, O Tedeschi, G TI Evidence for neuroaxonal injury in patients with proteolipid protein gene mutations SO NEUROLOGY LA English DT Article ID PELIZAEUS-MERZBACHER-DISEASE; PROTON MR SPECTROSCOPY; MYELIN AB The authors used proton MRS to investigate neuropathologic correlates in nine patients with proteolipid protein (PLP) gene mutations who did not show cerebral atrophy on cranial MRI. When compared with 16 age-matched control participants, patients with PLP mutations had significant and widespread decreased brain N-acetyl aspartate, a neuronal marker. The authors conclude that PLP mutations cause neuroaxonal injury, which in turn contributes to the neurologic deficit observed in these patients. C1 NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Neuroimaging Branch, NIH, Bethesda, MD 20892 USA. NINDS, Dept Radiol, Ctr Clin, NIH, Bethesda, MD 20892 USA. Fac Med, INSERM, U384, Clermont Ferrand, France. RP Schiffmann, R (reprint author), NINDS, Dev & Metab Neurol Branch, NIH, Bldg 10,Room 3D03,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 10 TC 27 Z9 30 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR 27 PY 2001 VL 56 IS 6 BP 785 EP 788 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 414ZY UT WOS:000167697100020 PM 11274318 ER PT J AU Hummer, G Szabo, A AF Hummer, G Szabo, A TI Free energy reconstruction from nonequilibrium single-molecule pulling experiments SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DYNAMICS SIMULATIONS; TITIN; ELASTICITY; FORCE; EQUILIBRIUM; MODULES; DNA AB Laser tweezers and atomic force microscopes are increasingly used to probe the interactions and mechanical properties of individual molecules, Unfortunately, using such time-dependent perturbations to force rare molecular events also drives the system away from equilibrium, Nevertheless, we show how equilibrium free energy profiles can be extracted rigorously from repeated nonequilibrium force measurements on the basis of an extension of Jarzynski's remarkable identity between free energies and the irreversible work. C1 NIDDK, LCP, NIH, Bethesda, MD 20892 USA. RP Hummer, G (reprint author), NIDDK, LCP, NIH, Bldg 5,Rm 132, Bethesda, MD 20892 USA. RI Szabo, Attila/H-3867-2012; Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 21 TC 546 Z9 547 U1 4 U2 80 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 MAR 27 PY 2001 VL 98 IS 7 BP 3658 EP 3661 DI 10.1073/pnas.071034098 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 417KG UT WOS:000167833700010 PM 11274384 ER PT J AU Marchetti, F Bishop, JB Lowe, X Generoso, WM Hozier, J Wyrobek, AJ AF Marchetti, F Bishop, JB Lowe, X Generoso, WM Hozier, J Wyrobek, AJ TI Etoposide induces heritable chromosomal aberrations and aneuploidy during male meiosis in the mouse SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID II INHIBITOR ETOPOSIDE; DNA TOPOISOMERASE-II; CHEMICAL-INDUCED ANEUPLOIDY; IN-SITU HYBRIDIZATION; MALE GERM-CELLS; CLEAVABLE COMPLEX; MALE-MICE; INDUCTION; MUTAGENICITY; CHEMOTHERAPY AB Etoposide, a topoisomerase II inhibitor widely used in cancer therapy, is suspected of inducing secondary tumors and affecting the genetic constitution of germ cells. A better understanding of the potential heritable risk of etoposide is needed to provide sound genetic counseling to cancer patients treated with this drug in their reproductive years. We used a mouse model to investigate the effects of clinical doses of etoposide on the induction of chromosomal abnormalities in spermatocytes and their transmission to zygotes by using a combination of chromosome painting and 4 ' ,6-diamidino-2-phenylindole staining. High frequencies of chromosomal aberrations were detected in spermatocytes within 64 h after treatment when over 30% of the metaphases analyzed had structural aberrations (P < 0.01), Significant increases in the percentages of zygotic metaphases with structural aberrations were found only for matings that sampled treated pachytene (28-fold, P < 0.0001) and preleptotene spermatocytes (13-fold, P < 0.001). Etoposide induced mostly acentric fragments and deletions, types of aberrations expected to result in embryonic lethality, because they represent loss of genetic material. Chromosomal exchanges were rare. Etoposide treatment of pachytene cells induced aneuploidy in both spermatocytes (18-fold, P < 0.01) and zygotes (8-fold, P < 0.05). We know of no other report of an agent for which paternal exposure leads to an increased incidence of aneuploidy in the offspring. Thus, we found that therapeutic doses of etoposide affect primarily meiotic germ cells, producing unstable structural aberrations and aneuploidy, effects that are transmitted to the progeny. This finding suggests that individuals who undergo chemotherapy with etoposide may be at a higher risk for abnormal reproductive outcomes especially within the 2 months after chemotherapy. C1 Univ Calif Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, Livermore, CA 94550 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Appl Genet Labs, Melbourne, FL 32901 USA. Oak Ridge Natl Lab, Div Life Sci, Oak Ridge, TN 37831 USA. RP Marchetti, F (reprint author), Univ Calif Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, POB 808,L-448, Livermore, CA 94550 USA. OI Marchetti, Francesco/0000-0002-9435-4867 FU NIEHS NIH HHS [N44ES72003, Y01-ES-10203-00] NR 49 TC 61 Z9 62 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 27 PY 2001 VL 98 IS 7 BP 3952 EP 3957 DI 10.1073/pnas.061404598 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 417KG UT WOS:000167833700063 PM 11274416 ER PT J AU Zeng, G Wang, X Robbins, PF Rosenberg, SA Wang, RF AF Zeng, G Wang, X Robbins, PF Rosenberg, SA Wang, RF TI CD4(+) T cell recognition of MHC class II-restricted epitopes from NY-ESO-1 presented by a prevalent HLA DP4 allele: Association with NY-ESO-1 antibody production SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TUMOR-INFILTRATING LYMPHOCYTES; HUMAN-MELANOMA; IMMUNE-RESPONSE; ANTIGEN; IDENTIFICATION; GENE; TYROSINASE; VITILIGO; CLONING; TRP-2 AB NY-ESO-1 is a tumor-specific shared antigen with distinctive immunogenicity, Both CD8(+) T cells and class-switched Ab responses have been detected from patients with cancer. In this study, a CD4(+) T cell line was generated from peripheral blood mononuclear cells of a melanoma patient and was shown to recognize NY-ESO-1 peptides presented by HLA-DP4, a dominant MHC class II allele expressed in 43-70% of Caucasians. The ESO p157-170 peptide containing the core region of DP4-restricted T cell epitope was present in a number of tumor cell lines tested and found to be recognized by both CD4(+) T cells as well as HLA-AZ-restricted CD8(+) T cells. Thus, the ESO p157-170 epitope represents a potential candidate for cancer vaccines aimed at generating both CD4(+) and CD8(+) T cell responses. More importantly, 16 of 17 melanoma patients who developed Ab against NY-ESO-1 were found to be HLA-DP4-positive. CD4(+) T cells specific for the NY-ESO-1 epitopes were generated from 5 of 6 melanoma patients with NY-ESO-1 Ab, In contrast, no specific DP4-restricted T cells were generated from two patients without detectable NY-ESO-1 Ab, These results suggested that NY-ESO-1-specific DP4-restricted CD4(+) T cells were closely associated with NY-ESO-1 Ab observed in melanoma patients and might play an important role in providing help for activating B cells for NY-ESO-1-specific Ab production. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Wang, RF (reprint author), Baylor Coll Med, ALKEK Bldg,N1120,1 Baylor Plaza, Houston, TX 77030 USA. NR 26 TC 143 Z9 146 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 27 PY 2001 VL 98 IS 7 BP 3964 EP 3969 DI 10.1073/pnas.061507398 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 417KG UT WOS:000167833700065 PM 11259659 ER PT J AU Keenan, DM Licinio, J Veldhuis, JD AF Keenan, DM Licinio, J Veldhuis, JD TI A feedback-controlled ensemble model of the stuess-responsive hypothalamo-pituitary-adrenal axis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CORTICOTROPIN-RELEASING FACTOR; ADRENOCORTICOTROPIN SECRETION; RAT; CORTISOL; HORMONE; SYSTEM; STRESS AB The present work develops and implements a biomathematical statement of how reciprocal connectivity drives stress-adaptive homeostasis in the corticotropic (hypothalamo-pituitary-adrenal) axis. In initial analyses with this interactive construct, we test six specific a priori hypotheses of mechanisms linking circadian (24-h) rhythmicity to pulsatile secretory output. This formulation offers a dynamic framework for later statistical estimation of unobserved in vivo neurohormone secretion and within-axis, dose-responsive interfaces in health and disease. Explication of the core dynamics of the stress-responsive corticotropic axis based on secure physiological precepts should help to unveil new biomedical hypotheses of stressor-specific system failure. C1 Univ Virginia, Hlth Sci Ctr, Div Endocrinol, Dept Internal Med,Gen Clin Res Ctr, Charlottesville, VA 22908 USA. Univ Virginia, Hlth Sci Ctr, Ctr Biomath Technol, Charlottesville, VA 22908 USA. NIMH, Bethesda, MD 20892 USA. Univ Virginia, Dept Stat, Charlottesville, VA 22903 USA. RP Veldhuis, JD (reprint author), Univ Virginia, Hlth Sci Ctr, Div Endocrinol, Dept Internal Med,Gen Clin Res Ctr, POB 800202, Charlottesville, VA 22908 USA. RI Licinio, Julio/L-4244-2013 OI Licinio, Julio/0000-0001-6905-5884 FU NCRR NIH HHS [M01 RR000847, M01 RR00847]; NIA NIH HHS [R01 AG014799, R01 AG14799]; NICHD NIH HHS [P30 HD028934, P50 HD028934, U54 HD028934, U54 HD28934] NR 21 TC 110 Z9 114 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 MAR 27 PY 2001 VL 98 IS 7 BP 4028 EP 4033 DI 10.1073/pnas.051624198 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 417KG UT WOS:000167833700076 PM 11274427 ER PT J AU Duesbery, NS Resau, J Webb, CP Koochekpour, S Koo, HM Leppla, SH Woude, GFV AF Duesbery, NS Resau, J Webb, CP Koochekpour, S Koo, HM Leppla, SH Woude, GFV TI Suppression of ras-mediated transformation and inhibition of tumor growth and angiogenesis by anthrax lethal factor, a proteolytic inhibitor of multiple MEK pathways SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ACTIVATED PROTEIN-KINASE; MICROVASCULAR ENDOTHELIAL-CELLS; BINDING-PROTEIN; FACTOR CLEAVES; IN-VIVO; TYROSINE/THREONINE PHOSPHORYLATION; CULTURED MACROPHAGES; BACILLUS-ANTHRACIS; N-TERMINUS; METASTASIS AB Lethal factor is a protease, one component of Bacillus anthracis exotoxin, which cleaves many of the mitogen-activated protein kinase kinases (MEKs). Given the importance of MEK signaling in tumorigenesis, we assessed the effects of anthrax lethal toxin (LeTx) on tumor cells. LeTx was very effective in inhibiting mitogen-activated protein kinase activation in V12 H-ras-transformed NIH 3T3 cells. In vitro, treatment of transformed cells with LeTx caused them to revert to a nontransformed morphology, and inhibited their abilities to form colonies in soft agar and to invade Matrigel without markedly affecting cell proliferation. In vivo, LeTx inhibited growth of ras-transformed cells implanted in athymic nude mice tin some cases causing tumor regression) at concentrations that caused no apparent animal toxicity. Unexpectedly, LeTx also greatly decreased tumor neovascularization. These results demonstrate that LeTx potently inhibits ras-mediated tumor growth and is a potential antitumor therapeutic. C1 Van Andel Res Inst, Grand Rapids, MI 49503 USA. NCI, Frederick Canc Res & Dev Ctr, Adv Biosci Labs Basic Res Program, NIH, Frederick, MD 21702 USA. Natl Inst Dental Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Duesbery, NS (reprint author), Van Andel Res Inst, 333 Bostwick Ave NE, Grand Rapids, MI 49503 USA. RI Webb, Craig/I-8123-2012; OI DUESBERY, NICK/0000-0002-4258-5655 NR 45 TC 82 Z9 86 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 27 PY 2001 VL 98 IS 7 BP 4089 EP 4094 DI 10.1073/pnas.061031898 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 417KG UT WOS:000167833700087 PM 11259649 ER PT J AU Steiner, RA Hohmann, JG Holmes, A Wrenn, CC Cadd, G Jureust, A Clifton, DK Luo, ML Gutshall, M Ma, SY Mufson, EJ Crawley, JN AF Steiner, RA Hohmann, JG Holmes, A Wrenn, CC Cadd, G Jureust, A Clifton, DK Luo, ML Gutshall, M Ma, SY Mufson, EJ Crawley, JN TI Galanin transgenic mice display cognitive and neurochemical deficits characteristic of Alzheimer's disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID INHIBITS ACETYLCHOLINE-RELEASE; FOREBRAIN CHOLINERGIC NEURONS; DOPAMINE-BETA-HYDROXYLASE; LONG-TERM POTENTIATION; BASAL FOREBRAIN; MUTANT MICE; VENTRAL HIPPOCAMPUS; LOCUS-CERULEUS; NORADRENERGIC NEURONS; BEHAVIORAL PHENOTYPES AB Galanin is a neuropeptide with multiple inhibitory actions on neurotransmission and memory. In Alzheimer's disease (AD), increased galanin-containing fibers hyperinnervate cholinergic neurons within the basal forebrain in association with a decline in cognition. We generated transgenic mice (CAL-tg) that overexpress galanin under the control of the dopamine beta -hydroxylase promoter to study the neurochemical and behavioral sequelae of a mouse model of galanin overexpression in AD. Overexpression of galanin was associated with a reduction in the number of identifiable neurons producing acetylcholine in the horizontal limb of the diagonal band. Behavioral phenotyping indicated that GAL-tgs displayed normal general health and sensory and motor abilities; however, CAL-tg mice showed selective performance deficits on the Morris spatial navigational task and the social transmission of food preference olfactory memory test. These results suggest that elevated expression of galanin contributes to the neurochemical and cognitive impairments characteristic of AD. C1 NIMH, Sect Behav Neuropharmacol, Bethesda, MD 20892 USA. Univ Washington, Dept Physiol & Biophys, Seattle, WA 98195 USA. Univ Washington, Dept Zool, Seattle, WA 98195 USA. Univ Washington, Grad Program Neurobiol & Behav, Seattle, WA 98195 USA. Univ Washington, Dept Obstet & Gynecol, Seattle, WA 98195 USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. RP Crawley, JN (reprint author), NIMH, Sect Behav Neuropharmacol, Bldg 10,Room 4D11, Bethesda, MD 20892 USA. FU NIA NIH HHS [AG05136, AG09466, AG10668, P01 AG009466, P50 AG005136, R01 AG010668]; NICHD NIH HHS [R01 HD027142, U54 HD012629, 3U54-HD12629, HD27142] NR 66 TC 126 Z9 128 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 27 PY 2001 VL 98 IS 7 BP 4184 EP 4189 DI 10.1073/pnas.061445598 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 417KG UT WOS:000167833700103 PM 11259657 ER PT J AU Fernandez-Ruiz, J Wang, J Aigner, TG Mishkin, N AF Fernandez-Ruiz, J Wang, J Aigner, TG Mishkin, N TI Visual habit formation in monkeys with neurotoxic lesions of the ventrocaudal neostriatum SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TEMPORAL AREAS TE; RHESUS-MONKEYS; RHINAL CORTEX; INTERTRIAL INTERVALS; CAUDATE-NUCLEUS; MACAQUE MONKEYS; PARAHIPPOCAMPAL CORTICES; SUBCORTICAL CONNECTIONS; HIPPOCAMPAL-LESIONS; RECOGNITION MEMORY AB Visual habit formation in monkeys, assessed by concurrent visual discrimination learning with 24-h intertrial intervals (ITI), was found earlier to be impaired by removal of the inferior temporal visual area (TE) but not by removal of either the medial temporal lobe or inferior prefrontal convexity, two of TE's major projection targets. To assess the role in this form of learning of another pair of structures to which TE projects, namely the rostral portion of the tail of the caudate nucleus and the overlying ventrocaudal putamen, we injected a neurotoxin into this neostriatal region of several monkeys and tested them on the 24-h ITI task as well as on a test of visual recognition memory. Compared with unoperated monkeys, the experimental animals were unaffected on the recognition test but showed an impairment on the 24-h ITI task that was highly correlated with the extent of their neostriatal damage, The findings suggest that TE and its projection areas in the ventrocaudal neostriatum form part of a circuit that selectively mediates visual habit formation. C1 NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. Natl Autonomous Univ Mexico, Fac Med, Dept Fisiol, Mexico City 04510, DF, Mexico. Neurol & Neurol Associates, Poughkeepsie, NY 12601 USA. NIDA, Ctr Neurosci, Bethesda, MD 20892 USA. RP Mishkin, N (reprint author), NIMH, Neuropsychol Lab, Bldg 9,Room 1880,49 Convent Dr, Bethesda, MD 20892 USA. RI Fernandez-Ruiz, Juan/B-6154-2012 OI Fernandez-Ruiz, Juan/0000-0002-4038-0904 NR 52 TC 91 Z9 92 U1 2 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 27 PY 2001 VL 98 IS 7 BP 4196 EP 4201 DI 10.1073/pnas.061022098 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 417KG UT WOS:000167833700105 PM 11274442 ER PT J AU Royaux, IE Wall, SM Karniski, LP Everett, LA Suzuki, K Knepper, MA Green, ED AF Royaux, IE Wall, SM Karniski, LP Everett, LA Suzuki, K Knepper, MA Green, ED TI Pendrin, encoded by the Pendred syndrome gene, resides in the apical region of renal intercalated cells and mediates bicarbonate secretion SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CORTICAL COLLECTING DUCTS; VACUOLAR H+-ATPASE; RAT-KIDNEY; ANION-EXCHANGER; DISTAL NEPHRON; WATER CHANNEL; PDS GENE; TRANSPORT; EXPRESSION; MUTATIONS AB Pendrin is an anion transporter encoded by the PDS/Pds gene, In humans, mutations in PDS cause the genetic disorder Pendred syndrome, which is associated with deafness and goiter. Previous studies have shown that this gene has a relatively restricted pattern of expression, with PDS/Pds mRNA detected only in the thyroid, inner ear, and kidney. The present study examined the distribution and function of pendrin in the mammalian kidney, Immunolocalization studies were performed using anti-pendrin polyclonal and monoclonal antibodies. Labeling was detected on the apical surface of a subpopulation of cells within the cortical collecting ducts (CCDs) that also express the H+-ATPase but not aquaporin-2, indicating that pendrin is present in intercalated cells of the CCD, Furthermore, pendrin was detected exclusively within the subpopulation of intercalated cells that express the H(-A)(+)TPase but not the anion exchanger 1 (AE1) and that are thought to mediate bicarbonate secretion. The same distribution of pendrin was observed in mouse, rat, and human kidney. However, pendrin was not detected in kidneys from a Pds-knockout mouse, Perfused CCD tubules isolated from alkali-loaded wild-type mice secreted bicarbonate, whereas tubules from alkali-loaded Pds-knockout mice failed to secrete bicarbonate, Together, these studies indicate that pendrin is an apical anion transporter in intercalated cells of CCDs and has an essential role in renal bicarbonate secretion. C1 NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. Univ Texas, Sch Med, Houston, TX 77030 USA. Vet Affairs Med Ctr, Dept Internal Med, Iowa City, IA 52242 USA. Univ Iowa, Iowa City, IA 52240 USA. Washington Hosp Ctr, MedStar Res Inst, Mol Endocrinol Lab, Washington, DC 20010 USA. RP Green, ED (reprint author), NHGRI, Genome Technol Branch, NIH, 49 Convent Dr,Bldg 49,Room 2A08, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999]; NIDDK NIH HHS [DK52935, R01 DK052935, R56 DK052935] NR 45 TC 340 Z9 346 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 27 PY 2001 VL 98 IS 7 BP 4221 EP 4226 DI 10.1073/pnas.071516798 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 417KG UT WOS:000167833700109 PM 11274445 ER PT J AU Goebel, J Forrest, KJ Mikovits, J Emmrich, F Volk, HD Lowry, RP AF Goebel, J Forrest, KJ Mikovits, J Emmrich, F Volk, HD Lowry, RP TI STAT5 pathway: Target of anti-CD4 antibody in attenuation of IL-2 receptor signaling SO TRANSPLANTATION LA English DT Article; Proceedings Paper CT 18th Annual Meeting of the American-Society-of-Transplantation CY MAY 15-19, 1999 CL CHICAGO, ILLINOIS SP Amer Soc Transplantat ID CELL-CYCLE PROGRESSION; T-CELLS; MONOCLONAL-ANTIBODY; ALLOGRAFT SURVIVAL; APOPTOSIS; CD4; PROTECTION; ACTIVATION; MODULATION; TOLERANCE AB Background. Anti-CD4 antibodies induce long-term graft survival by incompletely understood mechanisms, and CD4-ligation with HIV gp120-derivatives attenuates interleukin (IL)-2 receptor signaling. We examined the latter in the context of the CD4-modulating antibody 16H5. Materials and Methods. We performed immunoblots to assess the IL-2-induced phosphorylation of signal transducer and activator of transcription (STAT)S and Akt in the presence or absence of 16H5. Furthermore, we documented the effects of 16H5 on the induction of STATE, activating protein (AP)-1, and myc by IL-2 in DNA-binding assays. H-3-thymidine incorporation of the human lymphoid cell line CMO, which exhibits constitutive activation of the STAT5 pathway and IL 2-independent growth, was also measured during 16H5 treatment. Results. In human T lymphocytes, 16H5 attenuated both the tyrosine phosphorylation of STAT5 by IL-2 and the IL-2-induced DNA-binding of this transcription factor. In contrast, 16H5 had no effect on the serine phosphorylation of Akt by IL-2 or on the IL-2-induced DNA-binding of myc. Signal transduction involving AP-I was unaffected by 16H5 and IL-2. 16H5 also attenuated CMO cell proliferation. Conclusions. 16H5 targets the STAT5 signaling pathway to attenuate IL-2 receptor signal transduction in human T cells. This observation provides a molecular explanation for the immunomodulatory actions of anti-CD4 antibodies. C1 Univ Kentucky, Med Ctr, Sect Pediat Nephrol, Dept Pediat,Kentucky Clin, Lexington, KY 40536 USA. NCI, Frederick Canc Res & Dev Ctr, Lab Leukocyte Biol, Frederick, MD 21702 USA. Univ Leipzig, Inst Clin Immunol & Transfus Med, D-04103 Leipzig, Germany. Humboldt Univ, Inst Med Immunol, D-10098 Berlin, Germany. Univ S Alabama, Lab Immunol & Transplantat, Mobile, AL 36688 USA. RP Goebel, J (reprint author), Univ Kentucky, Med Ctr, Sect Pediat Nephrol, Dept Pediat,Kentucky Clin, Room J455, Lexington, KY 40536 USA. FU NIAID NIH HHS [AI 30732] NR 19 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD MAR 27 PY 2001 VL 71 IS 6 BP 792 EP 796 DI 10.1097/00007890-200103270-00018 PG 5 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 424QC UT WOS:000168242100018 PM 11330544 ER PT J AU Misra, RR Tangrea, JA Virtamo, J Ratnasinghe, D Andersen, MR Barrett, M Taylor, PR Albanes, D AF Misra, RR Tangrea, JA Virtamo, J Ratnasinghe, D Andersen, MR Barrett, M Taylor, PR Albanes, D TI Variation in the promoter region of the myeloperoxidase gene is not directly related to lung cancer risk among male smokers in Finland SO CANCER LETTERS LA English DT Article DE alpha-tocopherol beta-carotene study; lung cancer; myeloperoxidase; smoking ID POLYMORPHISMS; ASSOCIATION; ACTIVATION; ADDUCTS; DISEASE; LAVAGE; NASAL; GSTM1 AB In order to examine whether a polymorphism in the promoter region of the myeloperoxidase (MPO) gene is associated with lung cancer among male smokers, we conducted a case-control study nested within a Finnish clinical trial cohort. Although we found no evidence of an overall association between lung cancer risk and MPO genotype, the variant MPO genotype was associated with an increased risk of lung cancer among a subset of older men. These findings contrast with those from previous studies that report decreased lung cancer risk among MPO variant individuals. (C) 2001 Published by Elsevier Science Ireland Ltd. C1 NCI, Canc Prevent Studies Branch, Div Clin Sci, Bethesda, MD 20892 USA. Natl Publ Hlth Inst, SF-00300 Helsinki, Finland. New Chem Ent Inc, Thetagen Div, Bothell, WA 98011 USA. Informat Management Serv Inc, Silver Spring, MD 20904 USA. RP Misra, RR (reprint author), NCI, Canc Prevent Studies Branch, Div Clin Sci, 6006 Execut Blvd,Suite 321, Bethesda, MD 20892 USA. RI Albanes, Demetrius/B-9749-2015 FU NCI NIH HHS [N01 CN45165] NR 25 TC 51 Z9 53 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD MAR 26 PY 2001 VL 164 IS 2 BP 161 EP 167 DI 10.1016/S0304-3835(01)00384-6 PG 7 WC Oncology SC Oncology GA 428BG UT WOS:000168440800008 PM 11179831 ER PT J AU Barry, C AF Barry, C TI Being a chemist SO CHEMICAL & ENGINEERING NEWS LA English DT Article C1 NIAID, Bethesda, MD 20892 USA. RP Barry, C (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0009-2347 J9 CHEM ENG NEWS JI Chem. Eng. News PD MAR 26 PY 2001 VL 79 IS 13 BP 94 EP 94 PG 1 WC Chemistry, Multidisciplinary; Engineering, Chemical SC Chemistry; Engineering GA 415JD UT WOS:000167717100063 ER PT J AU Barchi, J AF Barchi, J TI Chemistry benefits premature babies SO CHEMICAL & ENGINEERING NEWS LA English DT Article C1 NCI, Med Chem Lab, Div Basic Sci, Bethesda, MD 20892 USA. RP Barchi, J (reprint author), NCI, Med Chem Lab, Div Basic Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0009-2347 J9 CHEM ENG NEWS JI Chem. Eng. News PD MAR 26 PY 2001 VL 79 IS 13 BP 220 EP 220 PG 1 WC Chemistry, Multidisciplinary; Engineering, Chemical SC Chemistry; Engineering GA 415JD UT WOS:000167717100140 ER PT J AU Bosetti, F Solaini, G Tendi, EA Chikhale, EG Chandrasekaran, K Rapoport, SI AF Bosetti, F Solaini, G Tendi, EA Chikhale, EG Chandrasekaran, K Rapoport, SI TI Mitochondrial cytochrome c oxidase subunit III is selectively down-regulated by aluminum exposure in PC12S cells SO NEUROREPORT LA English DT Article DE aluminum; Alzheimer's disease; cytochrome c oxidase; dialysis dementia; gene expression; mitochondria; neurotoxicity; PC12S ID NERVE GROWTH-FACTOR; ALZHEIMERS-DISEASE; BRAIN ALUMINUM; RAT-BRAIN; NEUROBLASTOMA; TOXICITY; CALCIUM; EVENTS; SYSTEM; RNA AB Aluminum (Al) has been implicated in several neurological diseases including dialysis dementia and Alzheimer's disease (AD). One possible mechanism of Al neurotoxicity could involve alteration of mitochondrial gene expression. We exposed PC12 cells to 0.1-100 muM AlCl3 for 6 h at pH 7.4. Internalized Al, measured by atomic absorption spectrometry, was linearly proportional to the extracellular Al concentration. Northern blot analyses showed that cytochrome c oxidase subunit III (COX III) mRNA was significantly reduced by 70% after addition of 1 muM AlCl3. Higher concentrations of AlCl3 did not show a significant further effect. These results suggest that Al neurotoxicity involves a specific impairment of cytochrome c oxidase. NeuroReport 12:721-724 (C) 2001 Lippincott Williams & Wilkins. C1 NIA, Sect Brain Physiol & Metab, NIH, Bethesda, MD 20892 USA. Scuola Super Sant Anna, I-56127 Pisa, Italy. Univ Maryland, Sch Med, Dept Anesthesiol, Baltimore, MD 21201 USA. RP Bosetti, F (reprint author), NIA, Sect Brain Physiol & Metab, NIH, 9000 Rockville Pike,Bldg 10,Rm 6N 202, Bethesda, MD 20892 USA. OI SOLAINI, GIANCARLO/0000-0001-7825-0446 NR 25 TC 10 Z9 11 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 MAR 26 PY 2001 VL 12 IS 4 BP 721 EP 724 DI 10.1097/00001756-200103260-00021 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 411MW UT WOS:000167504700020 PM 11277571 ER PT J AU Dhanasekaran, N Gutkind, JS AF Dhanasekaran, N Gutkind, JS TI Signaling by G protein coupled receptors and G proteins: a perspective SO ONCOGENE LA English DT Editorial Material DE G proteins; signal transduction; oncogene; GTPases; kinases C1 Temple Univ, Sch Med, Fels Inst Canc Res & Mol Biol, Philadelphia, PA 19140 USA. NIH, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. RP Dhanasekaran, N (reprint author), Temple Univ, Sch Med, Fels Inst Canc Res & Mol Biol, Philadelphia, PA 19140 USA. RI Gutkind, J. Silvio/A-1053-2009 NR 0 TC 6 Z9 6 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAR 26 PY 2001 VL 20 IS 13 BP 1530 EP 1531 DI 10.1038/sj.onc.1204273 PG 2 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 421XX UT WOS:000168089800001 ER PT J AU Fukuhara, S Chikumi, H Gutkind, JS AF Fukuhara, S Chikumi, H Gutkind, JS TI RGS-containing RhoGEFs: the missing link between transforming G proteins and Rho? SO ONCOGENE LA English DT Article DE Rho; G proteins; Ras; signal transduction; G protein-coupled receptors ID GUANINE-NUCLEOTIDE EXCHANGE; VAV PROTOONCOGENE PRODUCT; HETEROTRIMERIC G-PROTEINS; CONSTITUTIVELY ACTIVATING MUTATION; SERUM RESPONSE ELEMENT; STRESS FIBER FORMATION; DBL ONCOGENE PRODUCT; GTP-BINDING PROTEIN; CELL-SHAPE CHANGES; COUPLED RECEPTORS C1 Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RI Gutkind, J. Silvio/A-1053-2009 NR 80 TC 142 Z9 144 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAR 26 PY 2001 VL 20 IS 13 BP 1661 EP 1668 DI 10.1038/sj.onc.1204182 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 421XX UT WOS:000168089800017 PM 11313914 ER PT J AU Liu, XC Sun, ZX Neiderhiser, JM Uchiyama, M Okawa, M AF Liu, XC Sun, ZX Neiderhiser, JM Uchiyama, M Okawa, M TI Low birth weight, developmental milestones, and behavioral problems in Chinese children and adolescents SO PSYCHIATRY RESEARCH LA English DT Article DE birth weight; child development; behavioral problems; emotional problems; aggressive problems ID GROSS MOTOR MILESTONES; AGE 6 YEARS; EMOTIONAL-PROBLEMS; PRETERM INFANTS; TEACHER REPORTS; SCHOOL-AGE; RISK; ASSOCIATION; METAANALYSIS; GROWTH AB This study examined the association of low birth weight (LBW) and developmental milestones with behavioral and emotional problems in a general population sample of 3344 Chinese children and adolescents aged 6-16 years in 1997, Parents completed a self-administrated questionnaire including information about birth weight and develop mental milestones (i.e. lifting the head up, tooth eruption, speech, walking and bedwetting cessation), and the Child Behavioral Checklist (CBCL). Teachers completed the Teacher's Report Form (TRF) to assess classroom behavior problems. Results indicated that LBW and delayed developmental milestones were significantly associated with an increased risk for almost all parent- and teacher-reported behavioral problems after controlling for the potential effects of child's gender, age and birth order, parental ages at birth, education, occupation, complications at birth and number of children in the family. LBW was significantly associated with delay in achieving all developmental milestones including lifting of the head, tooth eruption, sitting without support, walking without help, speech as saying words with meaning, and bedwetting cessation. It is concluded that LBW and delayed early childhood development may predict the occurrence of a wide range of behavioral and emotional problems in later childhood and adolescence. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Shandong Univ, Dept Psychiat, Shandong Mental Hlth Ctr, Jinan 250100, Peoples R China. Linyi Mental Hlth Ctr, Linyi, Peoples R China. George Washington Univ, Ctr Family Res, Washington, DC USA. NCNP, NIMH, Ichikawa, Japan. RP Liu, XC (reprint author), NIEHS, Epidemiol Branch, POB 12233,MD A3-05,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 41 TC 17 Z9 17 U1 1 U2 8 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD MAR 25 PY 2001 VL 101 IS 2 BP 115 EP 129 DI 10.1016/S0165-1781(00)00244-4 PG 15 WC Psychiatry SC Psychiatry GA 422GF UT WOS:000168109600003 PM 11286815 ER PT J AU Hoffmann, HJ Bjerke, T Karawajczyk, M Dahl, R Knepper, MA Nielsen, S AF Hoffmann, HJ Bjerke, T Karawajczyk, M Dahl, R Knepper, MA Nielsen, S TI SNARE proteins are critical for regulated exocytosis of ECP from human eosinophils SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE human; eosinophils; regulated exocytosis; allergy; cell activation; Fc receptors ID INTRACELLULAR VESICLES; GLUT4 TRANSLOCATION; MURINE MACROPHAGES; PITUITARY-CELLS; WATER CHANNELS; MEMBRANE; RECEPTORS; COMPARTMENTS; SECRETION; LEUKOCYTE AB The SNARE hypothesis, describing a protein assembly-disassembly pathway, was recently proposed for the sequential steps of synaptic vesicle docking, activation, and fusion. To determine if SNARE proteins are involved in regulated exocytosis in eosinophils, the presence and functional role of SNAREs was examined in human blood eosinophils. Immunoblotting, subcellular fractionation, and immunocytochemistry documented that vesicle-associated membrane protein-a (VAMP-S), a vesicle-SNARE, was expressed in human eosinophils. Syntaxin 4 and SNAP-25 were also detected. Sequencing of cloned RT-PCR products amplified from a domain conserved among VAMP isoforms revealed identity only to VAMP-S but not to VAMP-I or cellubrevin. Functional experiments revealed that tetanus toxin pretreatment, which cleaved VAMP-2 in eosinophils, significantly inhibited both IgE receptor- and phorbol ester-mediated exocytosis of eosinophil cationic protein (ECP) from streptolysin-O-permeabilized eosinophils. Thus, these results strongly suggest a critical role of SNAREs in regulated exocytosis in eosinophils. (C) 2001 Academic Press. C1 Aarhus Univ Hosp, Dept Resp Med, Allergy & Lung Res Lab, DK-8000 Aarhus C, Denmark. Aarhus Univ, Dept Cell Biol, DK-8000 Aarhus, Denmark. Univ Uppsala Hosp, Dept Med Sci, S-75185 Uppsala, Sweden. NHLBI, NIH, Bethesda, MD 20892 USA. RP Hoffmann, HJ (reprint author), Aarhus Univ Hosp, Dept Resp Med, Allergy & Lung Res Lab, Bldg 2B,Norrebrogade 44, DK-8000 Aarhus C, Denmark. FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 29 TC 20 Z9 21 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 23 PY 2001 VL 282 IS 1 BP 194 EP 199 DI 10.1006/bbrc.2001.4499 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 416UK UT WOS:000167798400031 PM 11263991 ER PT J AU Reilly, TP Bourdi, M Brady, JN Pise-Masison, CA Radonovich, MF George, JW Pohl, LR AF Reilly, TP Bourdi, M Brady, JN Pise-Masison, CA Radonovich, MF George, JW Pohl, LR TI Expression profiling of acetaminophen liver toxicity in mice using microarray technology SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE acetaminophen; hepatotoxicity; liver injury; adverse drug reactions; drug toxicity; oligonucleotide microarrays; gene expression; toxicogenomics ID PLASMINOGEN-ACTIVATOR INHIBITOR; HEAT-SHOCK-PROTEIN; NF-KAPPA-B; OXIDATIVE STRESS; INDUCED HEPATOTOXICITY; CELL-DEATH; TRANSCRIPTION FACTOR; PULMONARY FIBROSIS; STELLATE CELLS; POTENTIAL ROLE AB Drug-induced hepatotoxicity causes significant morbidity and mortality and is a major concern in drug development, This is due, in large part, to insufficient knowledge of the mechanism(s) of drug-induced liver injury. In order to address this problem, we have evaluated the modulation of gene expression within the livers of mice treated with a hepatotoxic dose of acetaminophen (APAP) using high-density oligonucleotide microarrays capable of determining the expression profile of >11,000 genes and expressed sequence tags (ESTs), Significant alterations in gene expression, both positive and negative, were noted within the livers of APAP-treated mice. APAP-induced toxicity affected numerous aspects of liver physiology causing, for instance, >twofold increased expression of genes that encode for growth arrest and cell cycle regulatory proteins, stress-induced proteins, the transcription factor LRG-21, suppressor of cytokine signaling (SOCS)-2-protein, and plasminogen activator inhibitor-1 (PAI-1), A number of these and other genes and ESTs were detectable within the liver only after APAP treatment suggesting their potential importance in propagating or preventing further toxicity. These data provide new directions for mechanistic studies that may lead to a better understanding of the molecular basis of drug-induced liver injury and, ultimately, to a more rational design of safer drugs. (C) 2001 Academic Press. C1 NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. NCI, Virus Tumor Biol Sect, NIH, Bethesda, MD 20892 USA. RP Reilly, TP (reprint author), NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, NIH, 9000 Rockville Pike,Bldg 10,Rm 8N110, Bethesda, MD 20892 USA. NR 49 TC 81 Z9 88 U1 2 U2 10 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 23 PY 2001 VL 282 IS 1 BP 321 EP 328 DI 10.1006/bbrc.2001.4576 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 416UK UT WOS:000167798400050 PM 11264010 ER PT J AU Zimmermann, C Ginis, I Furuya, K Klimanis, D Ruetzler, C Spatz, M Hallenbeck, JM AF Zimmermann, C Ginis, I Furuya, K Klimanis, D Ruetzler, C Spatz, M Hallenbeck, JM TI Lipopolysaccharide-induced ischemic tolerance is associated with increased levels of ceramide in brain and in plasma SO BRAIN RESEARCH LA English DT Article DE ceramide; lipopolysaccharide; ischemia; neuroprotection; tolerance; spontaneously hypertensive rat ID TUMOR-NECROSIS-FACTOR; CENTRAL-NERVOUS-SYSTEM; FACTOR-ALPHA; BACTERIAL LIPOPOLYSACCHARIDE; PARAVENTRICULAR NUCLEUS; PRETREATMENT PROTECTS; SIGNAL-TRANSDUCTION; FREE SPHINGOSINE; TNF-ALPHA; SPHINGOMYELIN AB Intravenous administration of lipopolysaccharide (LPS) (0.9 mg/kg) has been shown to induce ischemic tolerance in spontaneously hypertensive rats (SHR). TNF-alpha is believed to play a crucial role in preconditioning as its inhibition with TNF-alpha -binding protein abolished tolerance. Our recent studies (Liu et al., Am. J. Physiol. 278 C144, 2000) have demonstrated that ceramide, a downstream messenger in TNF-alpha signaling, is a mediator of hypoxia-induced tolerance in neuronal cells. To test the hypothesis that ceramide contributes to LPS-induced tolerance in vivo, SHR were injected intravenously with either LPS or saline and the levels of ceramide in brain and in plasma were determined by reversed phase HPLC. LPS injection resulted in a significant increase of ceramide in plasma with a maximum at 24 h (8.32 +/- 1.14 pmol/mul (LPS) vs. 2.65 +/- 0.62 pmol/mul (saline)). LPS also induced ceramide upregulation in brain cortex, which started between 6 and 12 h and remained elevated up to 48 h after LPS injection. Fluorescent NBD-C6 ceramide was able to cross blood-brain barrier and was found in brain vessels, perivascular cells and in brain parenchyma 30 min after intravenous injection. These findings demonstrate that LPS preconditioning leads to elevation of ceramide in brain and plasma and, in conjunction with previous work. suggests that ceramide plays a role in LPS-induced protection against brain ischemic injury in vivo. Published by Elsevier Science B.V. C1 Natl Inst Neurol Disorders & Stoke, NIH, Stroke Branch, Bethesda, MD 20892 USA. RP Zimmermann, C (reprint author), Natl Inst Neurol Disorders & Stoke, NIH, Stroke Branch, 36 Convent Dr,MSC4128,Bldg 36,Room 4A03, Bethesda, MD 20892 USA. NR 48 TC 54 Z9 60 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAR 23 PY 2001 VL 895 IS 1-2 BP 59 EP 65 DI 10.1016/S0006-8993(01)02028-5 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 415UR UT WOS:000167742400008 PM 11259760 ER PT J AU Moriuchi, M Moriuchi, H AF Moriuchi, M Moriuchi, H TI Octamer transcription factors up-regulate the expression of CCR5, a coreceptor for HIV-1 entry SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CELL-SPECIFIC COACTIVATOR; MACROPHAGE-TROPIC HIV-1; OCT-1 POU DOMAIN; FUNCTIONAL-CHARACTERIZATION; CHEMOKINE RECEPTORS; MOLECULAR-CLONING; PROMOTER ACTIVITY; OCA-B; INFECTION AB T cell activation can induce expression of CCR5, a major coreceptor for macrophage-tropic (R5) human immunodeficiency virus type 1 (HIV-1). Here we report that overexpression of the Oct-2 transcription factor and octamer coactivator BOB.1/OBF/OCA-B, both of which are induced in T cells following T cell receptor signaling, synergistically up-regulates CCR5 promoter activity via interaction with an octamer motif on the promoter. We also show that the octamer transcription factors can increase cell surface expression of CCR5 and fusogenicity of the cells with R5 HIV-1 Env. These results suggest that octamer transcription factors may play a critical role in the induction of CCR5 expression on, and thereby susceptibility to, R5 HIV-1 of T cells following antigenic stimulation. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Nagasaki Univ, Grad Sch Med Sci, Dept Mol Microbiol & Immunol, Div Med Virol, Nagasaki 8528523, Japan. RP Moriuchi, H (reprint author), Nagasaki Univ, Sch Med, Dept Pediat, 1-7-1 Sakamoto, Nagasaki 8528501, Japan. NR 39 TC 22 Z9 23 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 23 PY 2001 VL 276 IS 12 BP 8639 EP 8642 DI 10.1074/jbc.M008391200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 413HV UT WOS:000167607700005 PM 11071893 ER PT J AU Kerr, KM Sauna, ZE Ambudkar, SV AF Kerr, KM Sauna, ZE Ambudkar, SV TI Correlation between steady-state ATP hydrolysis and vanadate-induced ADP trapping in human P-glycoprotein - Evidence for ADP release as the rate-limiting step in the catalytic cycle and its modulation by substrates SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN MULTIDRUG TRANSPORTER; NUCLEOTIDE-BINDING DOMAINS; CYCLOSPORINE-A; TRANSITION-STATE; MAMMALIAN-CELLS; RESISTANCE CDNA; INSECT CELLS; SITE; PURIFICATION; EXPRESSION AB P-glycoprotein (Pgp) is a transmembrane protein conferring multidrug resistance to cells by extruding a variety of amphipathic cytotoxic agents using energy from ATP hydrolysis. The objective of this study was to understand how substrates affect the catalytic cycle of ATP hydrolysis by Pgp, The ATPase activity of purified and reconstituted recombinant human Pgp was measured using a continuous cycling assay. Pgp hydrolyzes ATP in the absence of drug at a basal rate of 0.5 mu mol.min.mg(-1) with a K-m for ATP of 0.33 mM. This basal rate can be either increased or decreased depending on the Pgp substrate used, without an effect on the K-m for ATP or 8-azidoATP and K-i for ADP, suggesting that substrates do not affect nucleotide binding to Pgp, Although inhibitors of Pgp activity, cyclosporin A, its analog PSC833, and rapamycin decrease the rate of ATP hydrolysis with respect to the basal rate, they do not completely inhibit the activity. Therefore, these drugs can be classified as substrates. Vanadate (Vi)-induced trapping of [alpha-P-32]8-azidoADP was used to probe the effect of substrates on the transition state of the ATP hydrolysis reaction. The K-m for [alpha-P-32]8-azidoATP (20 muM) is decreased in the presence of Vi; however, it is not changed by drugs such as verapamil or cyclosporin A. Strikingly, the extent of Vi-induced [alpha-P-32]8-azidoADP trapping correlates directly with the fold stimulation of ATPase activity at steady state, Furthermore, P-i exhibits very low affinity for Pgp (K(i)similar to 30 mM for Vi-induced 8-azidoADP trapping). In aggregate, these data demonstrate that the release of Vi trapped [alpha-P-32]8-azidoADP from Pgp is the rate-limiting step in the steady-state reaction. We suggest that substrates modulate the rate of ATPase activity of Pgp by controlling the rate of dissociation of ADP following ATP hydrolysis and that ADP release is the rate-limiting step in the normal catalytic cycle of Pgp. C1 NCI, Cell Biol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Ambudkar, SV (reprint author), NCI, Cell Biol Lab, Div Basic Sci, NIH, Bldg 37,Rm 1B-22,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. RI Ambudkar, Suresh/B-5964-2008 NR 55 TC 76 Z9 77 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 23 PY 2001 VL 276 IS 12 BP 8657 EP 8664 DI 10.1074/jbc.M010044200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 413HV UT WOS:000167607700008 PM 11121420 ER PT J AU El Kharroubi, A Piras, G Stewart, CL AF El Kharroubi, A Piras, G Stewart, CL TI DNA demethylation reactivates a subset of imprinted genes in uniparental mouse embryonic fibroblasts SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HISTONE DEACETYLASE COMPLEX; ALLELE-SPECIFIC METHYLATION; DEPENDENT KINASE INHIBITOR; GERM-LINE; SNRPN GENE; H19 GENE; EXPRESSION; IDENTIFICATION; MECHANISMS; ESTABLISHMENT AB Although most imprinted genes show allelic differences in DNA methylation, it is not clear whether methylation regulates the expression of some or all imprinted genes in somatic cells. To examine the mechanisms of silencing of imprinted alleles, we generated novel uniparental mouse embryonic fibroblasts exclusively containing either the paternal or the maternal genome. These fibroblasts retain parent-of-origin allele-specific expression of 12 imprinted genes,examined for more than 30 cell generations. We show that p57(Kip2) (cyclin-dependent kinase inhibitor protein 2) and Igf2 (insulinlike growth factor 2) are induced by inhibiting histone deacetylases; however, their activated state is reversed quickly by withdrawal of trichostatin A. In contrast, DNA demethylation results in the heritable expression of a subset of imprinted genes including H19 (H19 fetal liver mRNA), p57(Kip2), Peg3/Pw1 (paternally expressed gene 3), and Zac1 (zinc finger-binding protein regulating apoptosis and cell cycle arrest). Other imprinted genes such as Grb10 (growth factor receptor-bound protein 10), Peg1/Mest (paternally expressed gene 1/mesoderm-specific transcript), Sgce (epsilon-sarcoglycan), Snrpn (small nuclear ribonucleoprotein polypeptide N), and U2af1 (U2 small nuclear ribonucleoprotein auxiliary factor), remain inactive, despite their exposure to inhibitors of histone deacetylases and DNA methylation. These results demonstrate that changes in DNA methylation but not histone acetylation create a heritable epigenetic state at some imprinted loci in somatic cells. C1 NCI, Canc & Dev Biol Lab, Div Basic Sci, FCRDC,NIH, Frederick, MD 21702 USA. RP El Kharroubi, A (reprint author), NCI, Canc & Dev Biol Lab, Div Basic Sci, FCRDC,NIH, Bldg 539,Rm 135,1050 Boyles St,POB B, Frederick, MD 21702 USA. NR 48 TC 51 Z9 53 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 23 PY 2001 VL 276 IS 12 BP 8674 EP 8680 DI 10.1074/jbc.M009392200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 413HV UT WOS:000167607700010 PM 11124954 ER PT J AU Jones, PL Sachs, LM Rouse, N Wade, PA Shi, YB AF Jones, PL Sachs, LM Rouse, N Wade, PA Shi, YB TI Multiple N-CoR complexes contain distinct histone deacetylases SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID THYROID-HORMONE RECEPTOR; TRANSCRIPTIONAL REPRESSION; COREPRESSOR COMPLEX; MEDIATED REPRESSION; NUCLEAR RECEPTORS; PROTEIN; YEAST; SMRT; GENE; ACTIVATION AB N-CoR (nuclear receptor corepressor) is a corepressor for multiple transcription factors including unliganded thyroid hormone receptors (TRs). In vitro, N-CoR can interact with the Sin3 corepressor, which in turn binds to the histone deacetylase Rpd3 (HDAC1), predicting the existence of a corepressor complex containing N-CoR, Sin3, and histone deacetylase. However, previous biochemical studies of endogenous Sin3 complexes have failed to find an N CoR association. Xenopus laevis eggs and oocytes contain all of the necessary components for transcriptional repression by unliganded TRs. In this study, we report the biochemical fractionation of three novel macromolecular complexes containing N-CoR, two of which possess histone deacetylase activity, from Xenopus egg extract. One complex contains Sin3, Rpd3, and RbAp48; the second complex contains a Sin3-independent histone deacetylase; and the third complex lacks histone deacetylase activity. This study describes the first biochemical isolation of endogenous N-CoR-containing HDAC complexes and illustrates that N-CoR associates with distinct histone deacetylases that are both dependent and independent of Sin3. Immunoprecipitation studies show that N-CoR binds to unliganded TR expressed in the frog oocyte, confirming that N-CoR complexes are involved in repression by unliganded TR. These results suggest that N-CoR targets transcriptional repression of specific promoters through at least two distinct histone deacetylase pathways. C1 NICHD, UMM, LME, NIH, Bethesda, MD 20892 USA. Emory Univ, Dept Pathol, Atlanta, GA 30322 USA. RP Shi, YB (reprint author), NICHD, UMM, LME, NIH, Bldg 18T,Rm 106, Bethesda, MD 20892 USA. NR 34 TC 65 Z9 68 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 23 PY 2001 VL 276 IS 12 BP 8807 EP 8811 DI 10.1074/jbc.C000879200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 413HV UT WOS:000167607700027 PM 11254656 ER PT J AU Mantey, SA Coy, DH Pradhan, TK Igarashi, H Rizo, IM Shen, L Hou, W Hocart, SJ Jensen, RT AF Mantey, SA Coy, DH Pradhan, TK Igarashi, H Rizo, IM Shen, L Hou, W Hocart, SJ Jensen, RT TI Rational design of a peptide agonist that interacts selectively with the orphan receptor, bombesin receptor subtype 3 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GASTRIN-RELEASING PEPTIDE; GUINEA-PIG PANCREAS; HIGH-AFFINITY; DISPERSED ACINI; ENZYME-SECRETION; SIDE-CHAINS; CELLS; PHARMACOLOGY; CHOLECYSTOKININ; IDENTIFICATION AB The orphan receptor, bombesin (Bn) receptor subtype 3 (BRS-3), shares high homology with bombesin receptors (neuromedin B receptor (NMB-R) and gastrin-releasing peptide receptor (GRP-R)). This receptor is widely distributed in the central nervous system and gastrointestinal tract; target disruption leads to obesity, diabetes, and hypertension, however, its role in physiological and pathological processes remain unknown due to lack of selective ligands or identification of its natural ligand. We have recently discovered (Mantey, S. A., Weber, H. C., Saint, E., Akeson, M., Ryan, R. R. Pradhan, T. K., Searles, R. P., Spindel, E. R., Battey, J. F., Coy, D. H., and Jensen, R. T. (1997) J. Biol. Chem. 272, 26062-26071) that [D-Tyr(6),beta -Ala(11),Phe(13),Nle(14)]Bn-(6-14) has high affinity for BRS-3 and using this ligand showed BRS-3 has a unique pharmacology with high affinity for no known natural Bn peptides. However, use of this ligand is limited because it has high affinity for all known Bn receptors. In the present study we have attempted to identify BRS-3 selective ligands using a strategy of rational peptide design with the substitution of conformationally restricted amino acids into the prototype ligand [D-Tyr(6),beta -Ala(11),Phe(13),Nle(14)]Bn-(6-14) or its D-Phe(6) analogue. Each of the 22 peptides synthesized had binding affinities determined for hBRS-3, hGRPR, and hNMBR, and hBRS-3 selective ligands were tested for their ability to activate phospholipase C and increase inositol phosphates ([H-3]inositol phosphate). Using this approach we have identified a number of BRS-3 selective ligands. These ligands functioned as receptor agonists and their binding affinities were reflected in their potencies for altering [H-3]inositol phosphate. Two peptides with an (R)- or (S)-amino-3-phenylpropionic acid substitution for beta -Ala(11) in the prototype ligand had the highest selectivity for the hBRS-3 over the mammalian Bn receptors and did not interact with receptors for other gastrointestinal hormone s/neurotransmitters. Molecular modeling demonstrated these two selective BRS-3 ligands had a unique conformation of the position 11 beta -amino acid. This selectivity was of sufficient magnitude that these should be useful in explaining the role of hBRS-3 activation in obesity, glucose homeostasis, hypertension, and other physiological or pathological processes. C1 NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. Tulane Univ, Hlth Sci Ctr, Dept Med, New Orleans, LA 70112 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. NR 44 TC 54 Z9 54 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 23 PY 2001 VL 276 IS 12 BP 9219 EP 9229 DI 10.1074/jbc.M008737200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 413HV UT WOS:000167607700081 PM 11112777 ER PT J AU Dorowski, A Hofmann, A Steegborn, C Boicu, M Huber, R AF Dorowski, A Hofmann, A Steegborn, C Boicu, M Huber, R TI Crystal structure of paprika ferredoxin-NADP(+) reductase - Implications for the electron transfer pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHTHALATE DIOXYGENASE REDUCTASE; 1.7 ANGSTROM RESOLUTION; ANABAENA SP PCC-7119; AMINO-ACID-RESIDUES; X-RAY STRUCTURE; NADP+ REDUCTASE; FLAVOPROTEIN REDUCTASES; 3-DIMENSIONAL STRUCTURE; ESCHERICHIA-COLI; BINDING AB cDNA of Capsicum annuum Yolo Wonder (paprika) has been prepared from total cellular RNA, and the complete gene encoding paprika ferredoxin-NADP(+) reductase (pFNR) precursor was sequenced and cloned from this cDNA. Fusion to a T7 promoter allowed expression in Escherichia coli. Both native and recombinant pFNR were purified to homogeneity and crystallized. The crystal structure of pFNR has been solved by Patterson search techniques using the structure of spinach ferredoxin-NADP+ reductase as search model. The structure was refined at 2.5-Angstrom resolution to a crystallographic R-factor of 19.8% (R-free = 26.5%). The overall structure of pFNR is similar to other members of the ferredoxin-NADP(+) reductase family, the major differences concern a long loop (residues 167-177) that forms part of the FAD binding site and some of the variable loops in surface regions. The different orientation of the FAD binding loop leads to a tighter interaction between pFNR and the adenine moiety of FAD. The physiological redox partners [2Fe-2S]-ferredoxin I and NADP(+) were modeled into the native structure of pFNR. The complexes reveal a protein-protein interaction site that is consistent with existing biochemical data and imply possible orientations for the side chain of tyrosine 362, which has to be displaced by the nicotinamide moiety of NADP(+) upon binding. A reasonable electron transfer pathway could be deduced from the modeled structures of the complexes. C1 Max Planck Inst Biochem, Abt Struktforsch, D-82152 Planegg Martinsried, Germany. Max Planck Inst Biochem, Abt Mol Strukturbiol, D-82152 Planegg Martinsried, Germany. NCI, Macromol Struct Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Dorowski, A (reprint author), Max Planck Inst Biochem, Abt Struktforsch, Klopferspitz 18A, D-82152 Planegg Martinsried, Germany. RI Hofmann, Andreas/B-9515-2008 OI Hofmann, Andreas/0000-0003-4408-5467 NR 57 TC 33 Z9 34 U1 2 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 23 PY 2001 VL 276 IS 12 BP 9253 EP 9263 DI 10.1074/jbc.M004576200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 413HV UT WOS:000167607700085 PM 11053431 ER PT J AU Sinha, D Wyatt, MK Sarra, R Jaworski, C Slingsby, C Thaung, C Pannell, L Robison, WG Favor, J Lyon, M Wistow, G AF Sinha, D Wyatt, MK Sarra, R Jaworski, C Slingsby, C Thaung, C Pannell, L Robison, WG Favor, J Lyon, M Wistow, G TI A temperature-sensitive mutation of Crygs in the murine Opj cataract SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GAMMA-CRYSTALLIN SUPERFAMILY; EYE LENS; DOMINANT CATARACT; S-CRYSTALLIN; DELETION MUTATION; ALPHA-CRYSTALLIN; JUVENILE-ONSET; BETA-S; GENE; MOUSE AB In Opj, an inherited cataract in mice, opacity is associated with a mutation in Crygs, the gene for gammaS-crystallin, the first mutation to be associated with this gene. A single base change causes replacement of Phe-9, a key hydrophobic residue in the core of the N-terminal domain, by serine. Despite this highly non-conservative change, mutant protein folds normally at low temperature. However, it exhibits a marked, concentration-dependent decrease in solubility, associated with loss of secondary structure, at close to physiological temperatures. This is reminiscent of processes thought to occur in human senile cataracts in which normal proteins become altered and aggregate. The Opj cataract is progressive and more severe in Opj/Opj than in Opj/+. Lens histology shows that whereas fiber cell morphology in Opj/+ mice is essentially normal, in Opj/Opj, cortical fiber cell morphology and the loss of maturing fiber cell nuclei are both severely disrupted from early stages. This may indicate a loss of function of gammaS-crystallin which would be consistent with ideas that members of the beta gamma -crystallin superfamily may have roles associated with maintenance of cytoarchitecture. C1 NEI, Sect Mol Struct & Funct, NIH, Bethesda, MD 20892 USA. NIDDK, NIH, Bethesda, MD 20892 USA. Birkbeck Coll, Dept Crystallog, London, England. MRC, Didcot OX11 0RD, Oxon, England. MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. GSF, Natl Res Ctr Environm & Hlth, Inst Mammalian Genet, D-85764 Neuherberg, Germany. RP Wistow, G (reprint author), NEI, Sect Mol Struct & Funct, NIH, Bldg 6,Rm 331, Bethesda, MD 20892 USA. RI Thaung, Caroline/C-2180-2008 OI Thaung, Caroline/0000-0002-8318-046X NR 53 TC 44 Z9 46 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 23 PY 2001 VL 276 IS 12 BP 9308 EP 9315 DI 10.1074/jbc.M010583200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 413HV UT WOS:000167607700092 PM 11121426 ER PT J AU Perrotti, N He, RA Phillips, SA Haft, CR Taylor, SI AF Perrotti, N He, RA Phillips, SA Haft, CR Taylor, SI TI Activation of serum- and glucocorticoid-induced protein kinase (Sgk) by cyclic AMP and insulin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SIGNALING PATHWAY; INDUCIBLE KINASE; SODIUM-TRANSPORT; GRANULOSA-CELLS; RAT; VASOPRESSIN; PHOSPHORYLATION; PHOSPHATASES; SPECIFICITY; EXPRESSION AB Sgk (serum- and glucocorticoid-induced protein kinase) is a serine/threonine-specific protein kinase that is transcriptionally regulated by serum, glucorticoids, and mineralocorticoids, Sgk regulates the amiloride-sensitive sodium channel in kidney principal cells. Insulin and insulin-like growth factor-1 stimulate activity of Sgk by a mechanism mediated by phosphoinositide-dependent kinases (PDK)-1 and -2. In this study, we demonstrate that incubation of transfected cells with 8-(4-chlorophenylthio)-cAMP (8CPT-cAMP; 0.2 mM) led to a 2-fold activation of recombinant Sgk expressed in COS7 cells. Furthermore, the combination of insulin plus 8CPT-cAMP elicited a larger response than either agent alone. The effect of insulin was inhibited by wortmannin (100 nM), but not by the eyelid AMP-dependent protein kinase (PKA) inhibitor, H89 (10 muM). As expected, the effect of 8CPT-cAMP was completely blocked by H89, Surprisingly, the effect of 8CPT-cAMP was also inhibited by wortmannin, suggesting that phosphorylation of Sgk by PDK-1 and/or -2 is required for activation by 8CPT-cAMP. Mutational analysis led to similar conclusions. The Thr(369) --> Ala mutant, lacking the PKA phosphorylation site, was activated by insulin but not 8CPT-cAMP, In contrast, the Ser(422) --> Ala mutant, lacking a PDK-2 phosphorylation site, was inactive and resistant to activation by either insulin or 8CPT-cAMP. In summary, Sgk is subject to complex regulatory mechanisms. In addition to regulation at the level of gene expression, the enzymatic activity of Sgk is regulated by multiple protein kinases, including PKA, PDK-1, and PDK-2. Cross-talk among these signaling pathways may play an important role in the pathogenesis of the hypertension associated with hyperinsulinemia, obesity, and insulin resistance. C1 NIDDK, Diabet Branch, Div Intramural Res, Bethesda, MD 20892 USA. Univ Catanzaro, Dipartimento Med Sperimentale & Clin Gaetano Salv, I-88100 Catanzaro, Italy. RP Taylor, SI (reprint author), Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Mail Drop 424,355 E Merrill St, Indianapolis, IN 46285 USA. NR 17 TC 89 Z9 92 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 23 PY 2001 VL 276 IS 12 BP 9406 EP 9412 DI 10.1074/jbc.M007052200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 413HV UT WOS:000167607700105 PM 11096081 ER PT J AU Fabisiewicz, A Worth, L AF Fabisiewicz, A Worth, L TI Escherichia coli MutS,L modulate RuvAB-dependent branch migration between diverged DNA SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DIRECTED MISMATCH REPAIR; HOMEOLOGOUS RECOMBINATION; SALMONELLA-TYPHIMURIUM; RECA-PROTEIN; SACCHAROMYCES-CEREVISIAE; HOLLIDAY JUNCTIONS; STRAND EXCHANGE; GENETIC-RECOMBINATION; INTERSPECIES RECOMBINATION; MEIOTIC RECOMBINATION AB This study examines the interaction between Escherichia coli MutS,L and E. coli RuvAB during E. coli Reck-promoted strand exchange. RuvAB is a branch migration complex that stimulates heterologous strand exchange, Previous studies indicate that RuvAB increases the rate at which heteroduplex products are formed by RecA, that RuvA and RuvB are required for this stimulation, and that RuvAB does not stimulate homologous strand exchange. This study indicates that MutS,L inhibit the formation of full-length heteroduplex DNA between M13-fd DNA in the presence of RuvAB, such that less than 2% of the linear substrate is converted to product. Inhibition depends on the time at which MutS,L are added to the reaction and is strongest when MutS,L are added during initiation. The kinetics of the strand exchange reaction suggest that MutS,L directly inhibit RuvAB-dependent branch migration in the absence of Reck The inhibition requires the formation of base-base mismatches and ATP utilization; no effect on RuvAB-promoted strand exchange is seen if an ATP-deficient mutant of MutS (MutS501) is included in the reaction instead of wild-type MutS. These results are consistent with a role for MutS,L in maintaining genomic stability and replication fidelity. C1 NIEHS, Genet Mol Lab, NIH, Res Triangle Pk, NC 27709 USA. Polish Acad Sci, Inst Biochem & Biophys, PL-02106 Warsaw, Poland. RP Worth, L (reprint author), NIEHS, Genet Mol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 49 TC 17 Z9 18 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 23 PY 2001 VL 276 IS 12 BP 9413 EP 9420 DI 10.1074/jbc.M005176200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 413HV UT WOS:000167607700106 PM 11106642 ER PT J AU Smith, GD Dai, LX Miura, RM Sherman, A AF Smith, GD Dai, LX Miura, RM Sherman, A TI Asymptotic analysis of buffered calcium diffusion near a point source SO SIAM JOURNAL ON APPLIED MATHEMATICS LA English DT Article DE calcium domain; calcium buffer; reaction-diffusion equation; rapid, excess and immobile buffer approximations ID CA2+ DIFFUSION; CHANNEL; APPROXIMATION; MICRODOMAINS; ELEMENTARY; INDICATORS; RELEASE; MUSCLE AB The domain calcium (Ca2+) concentration near an open Ca2+ channel can be modeled as buffered diffusion from a point source. The concentration pro les can be well approximated by hemispherically symmetric steady-state solutions to a system of reaction-diffusion equations. After nondimensionalizing these equations and scaling space so that both reaction terms and the source amplitude are O(1), we identify two dimensionless parameters, epsilon (c) and epsilon (b) that correspond to the diffusion coefficients of dimensionless Ca2+ and buffer, respectively. Using perturbation methods, we derive approximations for the Ca2+ and buffer pro les in three asymptotic limits: (1) an "excess buffer approximation" (EBA), where the mobility of buffer exceeds that of Ca2+ (epsilon (b) >> epsilon (c)) and the fast diffusion of buffer toward the Ca2+ channel prevents buffer saturation (cf. Neher [ Calcium Electrogenesis and Neuronal Functioning Exp. Brain Res. 14, Springer-Verlag, Berlin, 1986, pp. 80-96]); (2) a rapid buffer approximation (RBA), where the diffusive time-scale for Ca2+ and buffer are comparable, but slow compared to reaction (epsilon (c) << 1, epsilon (b) << 1, and epsilon (c)/epsilon b = O(1)), resulting in saturation of buffer near the Ca2+ channel (cf. Wagner and Keizer [ Biophys. J. 67 (1994), pp. 447-456] and Smith [ Biophys. J. 71 (1996), pp. 3064-3072]); and (3) a new immobile buffer approximation ( IBA) where the diffusion of buffer is slow compared to that of Ca2+ (epsilon (b) <39 reproductive years [highest quartile] compared with <34 reproductive years [lowest quartile], 1.78; 95 % confidence interval [CI], 1.12-2.84), The adjusted RR per year of increase was 1.04 (95 % CI, 1.01-1.08), For risk of AD, the adjusted RRs were 1.51 (95% CI, 0.91-2.50) and 1.03 (95% CI, 1.00-1.07), respectively. Risk of dementia associated with a longer reproductive period was most pronounced in APOE 4 carriers (adjusted RR for >39 reproductive years compared with <34 reproductive years, 4.20 [95% CI, 1.97-8.92] for dementia and 3.42 [95% CI, 1.51-7.75] for AD), whereas in noncarriers, no clear association with dementia or AD was observed. Conclusion Our findings do not support the hypothesis that a longer reproductive period reduces risk of dementia in women who have natural menopause. C1 Erasmus Univ, Med Ctr, Dept Epidemiol & Biostat, NL-3000 DR Rotterdam, Netherlands. Erasmus Univ, Med Ctr, Dept Neurol, NL-3000 DR Rotterdam, Netherlands. NIA, NIH, Bethesda, MD 20892 USA. RP Geerlings, MI (reprint author), Erasmus Univ, Med Ctr, Dept Epidemiol & Biostat, POB 1738, NL-3000 DR Rotterdam, Netherlands. RI Breteler, Monique /J-5058-2014 NR 49 TC 49 Z9 51 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 MAR 21 PY 2001 VL 285 IS 11 BP 1475 EP 1481 DI 10.1001/jama.285.11.1475 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 410VQ UT WOS:000167462100030 PM 11255424 ER PT J AU Stoler, MH Schiffman, M AF Stoler, MH Schiffman, M CA Atypical Squamous Cells Undetermin TI Interobserver reproducibility of cervical cytologic and histologic interpretations - Realistic estimates from the ASCUS-LSIL triage study SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ATYPICAL GLANDULAR CELLS; HISTOPATHOLOGICAL DIAGNOSIS; UNDETERMINED SIGNIFICANCE; OBSERVER VARIATION; BIOPSY SPECIMENS; VARIABILITY; AGREEMENT; ABNORMALITIES; DYSPLASIA; CRITERIA AB Context Despite a critical presumption of reliability, standards of interpathologist agreement have not been well defined for interpretation of cervical pathology specimens. Objective To determine the reproducibility of cytologic, colposcopic histologic, and loop electrosurgical excision procedure (LEEP) histologic cervical specimen interpretations among multiple well-trained observers. Design and Setting The Atypical Squamous Cells of Undetermined Significance-Low-grade Squamous Intraepithelial Lesion (ASCUS-LSIL) Triage Study (ALTS), an ongoing US multicenter clinical trial. Subjects From women enrolled in ALTS during 1996-1998, 4948 monolayer cytologic slides, 2237 colposcopic biopsies, and 535 LEEP specimens were interpreted by 7 clinical center and 4 Pathology Quality Control Group (QC) pathologists. Main Outcome Measures kappa Values calculated for comparison of the original clinical center interpretation and the first QC reviewer's masked interpretation of specimens. Results For all 3 specimen types, the clinical center pathologists rendered significantly more severe interpretations than did reviewing QC pathologists. The reproducibility of monolayer cytologic interpretations was moderate (kappa =0.46; 95% confidence interval [CI], 0.44-0.48) and equivalent to the reproducibility of punch biopsy histopathologic interpretations (kappa =0.46; 95% CI, 0.43-0.49) and LEEP histopathologic interpretations (kappa =0.49; 95% CI, 0.44-0.55), The lack of reproducibility of histopathology was most evident for less severe interpretations. Conclusions Interpretive variability is substantial for all types of cervical specimens. Histopathology of cervical biopsies is not more reproducible than monolayer cytology, and even the interpretation of LEEP results is variable. Given the degree of irreproducibility that exists among well-trained pathologists, realistic performance expectations should guide use of their interpretations. C1 Univ Virginia Hlth Syst, Div Surg Pathol & Cytopathol, Charlottesville, VA 22908 USA. NCI, Bethesda, MD 20892 USA. RP Stoler, MH (reprint author), Univ Virginia Hlth Syst, Div Surg Pathol & Cytopathol, Box 800214, Charlottesville, VA 22908 USA. FU NCI NIH HHS [CN55157, CN15518, CN55105, CN55153, CN55154, CN55155, CN55156, CN55159] NR 32 TC 588 Z9 618 U1 0 U2 6 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 MAR 21 PY 2001 VL 285 IS 11 BP 1500 EP 1505 DI 10.1001/jama.285.11.1500 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 410VQ UT WOS:000167462100033 PM 11255427 ER PT J AU Kubo, A Kaye, FJ AF Kubo, A Kaye, FJ TI Searching for selective cyclin-dependent kinase inhibitors to target the retinoblastoma/p16 cancer gene pathway SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID PROTEIN; PHOSPHORYLATION; RB; APOPTOSIS; CLEAVAGE; MOLECULE; THERAPY; MOTIF; LINES; CDK4 C1 Natl Naval Med Ctr, Bethesda, MD 20889 USA. NCI, Med Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kaye, FJ (reprint author), Natl Naval Med Ctr, Bldg 8,Rm 5101, Bethesda, MD 20889 USA. RI kaye, frederic/E-2437-2011 NR 23 TC 7 Z9 8 U1 0 U2 1 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAR 21 PY 2001 VL 93 IS 6 BP 415 EP 417 DI 10.1093/jnci/93.6.415 PG 3 WC Oncology SC Oncology GA 411TA UT WOS:000167514300002 PM 11259459 ER PT J AU Barlow, WE Taplin, SH Yoshida, CK Buist, DS Seger, D Brown, M AF Barlow, WE Taplin, SH Yoshida, CK Buist, DS Seger, D Brown, M TI Cost comparison of mastectomy versus breast-conserving therapy for early-stage breast cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID RADIATION-THERAPY; LUMPECTOMY; SURGERY; WOMEN; CARE; AGE AB Background: Choice of treatment for early-stage breast cancer depends on many factors, including the size and stage of the cancer, the woman's age, comorbid conditions, and perhaps the costs of treatment. We compared the costs of all medical care for women with early-stage breast cancer cases treated by breast conserving therapy (BCT) or mastectomy. Methods: A total of 1675 women 35 years old or older with incident early-stage breast cancer were identified in a large regional nonprofit health maintenance organization in the period 1990 through 1997. The women were treated with mastectomy only (n = 183), mastectomy with adjuvant hormonal therapy or chemotherapy (n = 417), BCT with radiation therapy (n = 405), or BCT with radiation therapy and adjuvant hormonal therapy or chemotherapy (n = 670). The costs of all medical care for the period 1990 through 1998 were computed for each woman, and monthly costs were analyzed by treatment, adjusting for age and cancer stage. All statistical tests were two-sided. Results: At 6 months after diagnosis, the mean total medical care costs for the four groups differed statistically significantly (P<.001), with BCT being more expensive than mastectomy. The adjusted mean costs were $12 987, $14 309, $14 963, and $15 779 for mastectomy alone, mastectomy with adjuvant therapy, BCT plus radiation therapy, and BCT plus radiation therapy with adjuvant therapy, respectively. At 1 year, the difference in costs was still statistically significant (P<.001), but costs were influenced more by the use of adjuvant therapy than by type of surgery. The 1-year adjusted mean costs were $16 704, $18 856, $17 344, and $19 081, respectively, for the four groups. By 5 years, BCT was less expensive than mastectomy (P<.001), with 5-year adjusted mean costs of $41 930, $45 670, $35 787, and $39 926, respectively, Costs also varied by age, with women under 65 years having higher treatment costs than older women, Conclusions: BCT may have higher short-term costs but lower long-term costs than mastectomy. C1 Grp Hlth Cooperat, Ctr Hlth Studies, Seattle, WA 98101 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Univ Washington, Dept Family Med, Seattle, WA 98195 USA. NCI, Hlth Serv & Econ Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Barlow, WE (reprint author), Grp Hlth Cooperat, Ctr Hlth Studies, 1730 Minor Ave,Suite 1600, Seattle, WA 98101 USA. NR 26 TC 61 Z9 63 U1 0 U2 3 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAR 21 PY 2001 VL 93 IS 6 BP 447 EP + DI 10.1093/jnci/93.6.447 PG 10 WC Oncology SC Oncology GA 411TA UT WOS:000167514300011 PM 11259470 ER PT J AU Lodmell, DL Ewalt, LC AF Lodmell, DL Ewalt, LC TI Post-exposure DNA vaccination protects mice against rabies virus SO VACCINE LA English DT Article; Proceedings Paper CT 2nd World Congress on Vaccines and Immunisation CY AUG 29-SEP 03, 2000 CL LIEGE, BELGIUM DE rabies virus; DNA vaccine; HDCV vaccine; neutralizing antibody; survival; booster; post-exposures ID ANTIBODY-RESPONSES; IMMUNE-RESPONSES; DENDRITIC CELLS; EAR PINNA; IMMUNIZATION; VACCINES; SUPERIORITY; RESISTANCE; CYTOKINES; INFECTION AB Post-exposure anti-rabies vaccination for individuals who have not previously been immunized against rabies includes a cell culture-derived vaccine and a one time injection of rabies immune globulin. Recent studies have shown DNA vaccinations to be highly effective in rabies pre-exposure experiments, but post-exposure protection has not been achieved. This failure is likely due to the slow onset of DNA vaccine induced antibody production. In an attempt to accelerate the onset of the antibody response, we manipulated variables, such as the route of vaccination and booster frequency. Anti-rabies virus antibody was detected 5 days after the initial DNA vaccination. Using this vaccination protocol and a single non-protective dose of anti-rabies immune serum, we questioned whether mice injected 6 h previously with rabies virus would be protected if a DNA vaccine was substituted for the cell culture-derived human diploid cell vaccine (HDCV). The DNA vaccine protected 87% of the mice (P = 0.00005. compared with unvaccinated control mice). Some 75% of mice receiving HDCV were protected (P = 0.00097. compared with unvaccinated control mice). Mice receiving only anti-rabies immune serum were not protected (P > 0.05 compared to unvaccinated control mice). Thus, post-exposure therapy, substituting a DNA vaccine for HDCV, did not compromise protection against rabies virus. published by Elsevier Science Ltd. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. RP Lodmell, DL (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, 903 S 4th St, Hamilton, MT 59840 USA. NR 30 TC 25 Z9 26 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD MAR 21 PY 2001 VL 19 IS 17-19 SI SI BP 2468 EP 2473 DI 10.1016/S0264-410X(00)00475-8 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 412DH UT WOS:000167538400049 PM 11257379 ER PT J AU Wilson, PWF Kauppila, LI O'Donnell, CJ Kiel, DP Hannan, M Polak, JM Cupples, LA AF Wilson, PWF Kauppila, LI O'Donnell, CJ Kiel, DP Hannan, M Polak, JM Cupples, LA TI Abdominal aortic calcific deposits are an important predictor of vascular morbidity and mortality SO CIRCULATION LA English DT Article DE coronary disease; calcium; risk factors ID RISK-FACTORS; CORONARY CALCIUM; ATHEROSCLEROTIC PLAQUES; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; NATURAL-HISTORY; FOLLOW-UP; OSTEOPONTIN; ASSOCIATION; LESIONS AB Background-The impact of abdominal arterial calcific deposits on the prediction of cardiovascular disease (CVD) over a long follow-up interval deserves greater scrutiny. Methods and Results-Lateral lumbar radiographs were studied as a predictor of incident coronary heart disease (CHD), CVD, and CVD mortality in 1049 men and 1466 women (mean age, 61 years) who were followed from 1967 to 1989. Anterior and posterior wall calcific deposits in the aorta at the level of the first through fourth lumbar vertebrae were graded according to increasing severity using a previously validated rating scale for abdominal aortic calcium (AAC) that ranges from 0 to 24 points. There were 454 cases of CHD, 709 cases of CVD, and 365 CVD deaths. Proportional hazards logistic regression was used to test for associations between AAC and later events after adjustment for age, cigarette use, diabetes mellitus, systolic blood pressure, left ventricular hypertrophy, body mass index, cholesterol, and HDL cholesterol. In comparisons with the lowest AAC tertile, the multivariate age-adjusted relative risks (RR) for CVD were increased in tertile 2 (men: RR, 1.33; 95% confidence interval [CI], 1.02 to 1.74; women: RR, 1.25; 95% CI, 0.95 to 1.65) and tertile 3 (men: RR, 1.68; 95% CI, 1.25 to 2.27; women: RR, 1.78; 95% CI, 1.33 to 2.38). Similar results were obtained with CHD and CVD mortality. Conclusions-AAC deposits, detected by lateral lumbar radiograms, are a marker of subdinical atherosclerotic disease and an independent predictor of subsequent vascular morbidity and mortality. C1 Boston Univ, Sch Publ Hlth, Dept Biostat & Epidemiol, Boston, MA USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA USA. Harvard Univ, Sch Med, Div Aging, Hebrew Rehabil Ctr Aged, Boston, MA USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Boston, MA USA. Boston Univ, Sch Med, Framingham Heart Study, NHLBI, Framingham, MA 01702 USA. RP Wilson, PWF (reprint author), Boston Univ, Sch Med, Framingham Heart Study, NHLBI, 5 Thurber St, Framingham, MA 01702 USA. OI Kiel, Douglas/0000-0001-8474-0310 FU NHLBI NIH HHS [N01-HC-38038]; NIAMS NIH HHS [AR/AG 41398] NR 34 TC 320 Z9 337 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 20 PY 2001 VL 103 IS 11 BP 1529 EP 1534 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 413XL UT WOS:000167636800009 PM 11257080 ER PT J AU Pauly, DF Fraites, TJ Toma, C Bayes, HS Huie, ML Hirschhorn, R Plotz, PH Raben, N Kessler, PD Byrne, BJ AF Pauly, DF Fraites, TJ Toma, C Bayes, HS Huie, ML Hirschhorn, R Plotz, PH Raben, N Kessler, PD Byrne, BJ TI Intercellular transfer of the virally derived precursor form of acid alpha-glucosidase corrects the enzyme deficiency in inherited cardioskeletal myopathy Pompe disease SO HUMAN GENE THERAPY LA English DT Article; Proceedings Paper CT 70th Scientific Session of the American-Heart-Association CY NOV 09-13, 1997 CL ORLANDO, FLORIDA SP Amer Heart Assoc ID GLYCOGENOSIS TYPE-II; REPLICATION-DEFECTIVE ADENOVIRUS; HIGH-LEVEL PRODUCTION; SKELETAL-MUSCLE; CULTURED FIBROBLASTS; LYSOSOMAL GLYCOGEN; STORAGE; EXPRESSION; GENE; MICE AB Pompe disease is a lethal cardioskeletal myopathy in infants and results from genetic deficiency of the lysosomal enzyme acid alpha -glucosidase (GAA), Genetic replacement of the cDNA for human GAA (hGAA) is one potential therapeutic approach, Three months after a single intramuscular injection of 10(8) plaque-forming units (PFU) of E1-deleted adenovirus encoding human GAA (Ad-hGAA), the activity in whole muscle lysates of immunodeficient mice is increased to 20 times the native level, Direct transduction of a target muscle, however, may not correct all deficient cells, Therefore, the amount of enzyme that can be transferred to deficient cells from virally transduced cells was studied, Fibroblasts from an affected patient were transduced with Ad-hGAA, washed, and plated on transwell culture dishes to serve as donors of recombinant enzyme, Deficient fibroblasts were plated as acceptor cells, and were separated from the donor monolayer by a 22-mum pore size filter, Enzymatic and Western analyses demonstrate secretion of the 110-kDa precursor form of hGAA from the donor cells into the culture medium, This recombinant, 110-kDa species reaches the acceptor cells, where it can he taken up by mannose 6-phosphate receptor-mediated endocytosis. It then trafficks to lysosomes, where Western analysis shows proteolytic processing to the 76- and 70-kDa lysosomal forms of the enzyme, Patient fibroblasts receiving recombinant hGAA by this transfer mechanism reach levels of enzyme activity that are comparable to normal human fibroblasts. Skeletal muscle cell cultures from an affected patient were also transduced with Ad-hGAA, Recombinant hGAA is identified in a lysosomal location in these muscle cells by immunocytochemistry, and enzyme activity is transferred to deficient skeletal muscle cells grown in coculture, Transfer of the precursor protein between muscle cells again occurs via mannose 6-phosphate receptors, as evidenced by competitive inhibition with 5 mM mannose 6-phosphate. In vivo studies in GAA-knockout mice demonstrate that hepatic transduction with adenovirus encoding either murine or human GAA can provide a depot of recombinant enzyme that is available to heart and skeletal muscle through this mechanism, Taken together, these data show that the mannose 6-phosphate receptor pathway provides a useful strategy for cell-to-cell distribution of virally derived recombinant GAA. C1 Univ Florida, Ctr Gene Therapy, JHMHC, Gainesville, FL 32610 USA. GenVec Corp, Gaithersburg, MD 20878 USA. NIAMSD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. NYU, Med Ctr, Dept Internal Med, New York, NY 10016 USA. Univ Florida, Coll Med, Dept Med, Gainesville, FL 32610 USA. Univ Florida, Coll Med, Dept Pediat, Gainesville, FL 32610 USA. Univ Florida, Coll Med, Dept Mol Genet, Gainesville, FL 32610 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Peter Belfer Cardiac Lab, Baltimore, MD 21287 USA. RP Byrne, BJ (reprint author), Univ Florida, Ctr Gene Therapy, JHMHC, 1600 SW Archer Rd, Gainesville, FL 32610 USA. FU NHLBI NIH HHS [HL27867, HL7227]; NICHD NIH HHS [N01-HD-2-3144] NR 41 TC 34 Z9 35 U1 1 U2 2 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 MAR 20 PY 2001 VL 12 IS 5 BP 527 EP 538 DI 10.1089/104303401300042447 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 415PB UT WOS:000167730400006 PM 11268285 ER PT J AU Jero, J Mhatre, AN Tseng, CJ Stern, RE Coling, DE Goldstein, JA Hong, K Zheng, WW Hoque, ATMS Lalwani, AK AF Jero, J Mhatre, AN Tseng, CJ Stern, RE Coling, DE Goldstein, JA Hong, K Zheng, WW Hoque, ATMS Lalwani, AK TI Cochlear gene delivery through an intact round window membrane in mouse SO HUMAN GENE THERAPY LA English DT Article ID GUINEA-PIG COCHLEA; IN-VIVO; ADENOASSOCIATED VIRUS; TRANSGENE EXPRESSION; ADENOVIRUS RECEPTOR; NEUROTROPHIC FACTOR; HEARING IMPAIRMENT; DNA COMPLEXES; THERAPY; VECTOR AB Cochlear gene transfer studies in animal models have utilized mainly two delivery methods: direct injection through the round window membrane (RWM) or intracochlear infusion through a cochleostomy. However, the surgical trauma, inflammation, and hearing loss associated with these methods Lead us to investigate a less invasive delivery method. Herein, we studied the feasibility of a vector transgene-soaked gelatin sponge, Gelfoam, for transgene delivery into the mouse cochlea through an intact RWM, The Gelfoam absorbed with liposomes and adenovirus, but not with adeno-associated virus (AAV), was successful in mediating transgene expression across an intact RWM in a variety of cochlear tissues. The Gelfoam technique proved to be an easy, atraumatic, and effective, but vector-dependent, method of delivering transgenes through an intact RWM, Compared with the more invasive gene delivery methods, this technique represents a safer and a more clinically viable route of cochlear gene delivery in humans. C1 Univ Calif San Francisco, Dept Otolaryngol Head & Neck Surg, Lab Mol Otol, Epstein Labs, San Francisco, CA 94143 USA. Univ Helsinki, Cent Hosp, Dept Otolaryngol, FIN-00290 Helsinki, Finland. Calif Pacific Med Ctr, Res Inst, Liposome Res Lab, San Francisco, CA 94115 USA. Natl Inst Dent & Cranofacial Res, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Lalwani, AK (reprint author), Univ Calif San Francisco, Dept Otolaryngol Head & Neck Surg, Lab Mol Otol, Epstein Labs, 533 Parnassus Ave,U490A, San Francisco, CA 94143 USA. OI Coling, Donald/0000-0001-6285-5336 FU NIDCD NIH HHS [K23 DC 00112] NR 40 TC 72 Z9 82 U1 1 U2 5 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 MAR 20 PY 2001 VL 12 IS 5 BP 539 EP 548 DI 10.1089/104303401300042465 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 415PB UT WOS:000167730400007 PM 11268286 ER PT J AU Thameem, F Wolford, JK Bogardus, C Prochazka, M AF Thameem, F Wolford, JK Bogardus, C Prochazka, M TI Analysis of PBX1 as a candidate gene for type 2 diabetes mellitus in Pima Indians SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION LA English DT Article DE pre-B-cell leukemia factor-1; type 2 diabetes; single nucleotide polymorphism; candidate gene; association analysis; Pima Indian ID SOMATOSTATIN PROMOTER; INSULIN-RESISTANCE; HOMEODOMAIN; EXPRESSION; PROTEIN; TRANSCRIPTION; SEQUENCE; BINDING; MANNER; MOTIF AB The human proto-oncogene PBX1 codes for a homeodomain containing protein that modulates expression of several genes, including those contributing to regulation of insulin action and glucose metabolism. PBX1 is located on chromosome 1q22, a region linked with type 2 diabetes in Pima Indians. Caucasians. and an Old Order Amish population. We have investigated the PBX1 genomic sequence to identify polymorphisms that may contribute to diabetes susceptibility in the Pimas. PBX1 is composed of nine exons spanning approx. 117 kb and is located within 300 kb of microsatellite D1S1677, which marks the peak of linkage to diabetes susceptibility in the Pima Indians. We detected 16 single nucleotide polymorphisms in PBX1 including one causing a glycine to serine substitution at residue 21. Comparison of the frequencies of the polymorphisms between affected and unaffected Pima Indians did not detect any significant differences, indicating that mutations in PBX1 do not explain the linkage of Iq with type 2 diabetes in this population. The genomic structure of PBX1 provides a basis for similar systematic examinations of this candidate locus in other populations in relation to both type 2 diabetes and other metabolic disorders. (C) 2001 Elsevier Science B.V. All rights reserved. C1 NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. RP Prochazka, M (reprint author), NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, NIH, 4212 N 16th St, Phoenix, AZ 85016 USA. NR 26 TC 5 Z9 6 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4781 J9 BBA-GENE STRUCT EXPR JI Biochim. Biophys. Acta-Gene Struct. Expression PD MAR 19 PY 2001 VL 1518 IS 1-2 BP 215 EP 220 DI 10.1016/S0167-4781(01)00189-0 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 417EG UT WOS:000167822000031 PM 11267683 ER PT J AU Burkin, DJ Wallace, GQ Nicol, KJ Kaufman, DJ Kaufman, SJ AF Burkin, DJ Wallace, GQ Nicol, KJ Kaufman, DJ Kaufman, SJ TI Enhanced expression of the alpha 7 beta 1 integrin reduces muscular dystrophy and restores viability in dystrophic mice SO JOURNAL OF CELL BIOLOGY LA English DT Article DE alpha 7 beta 1 integrin; muscular dystrophy; dystrophin; utrophin; neuromuscular junction ID CREATINE-KINASE GENE; UTROPHIN-DEFICIENT MICE; SKELETAL-MUSCLE; MDX MICE; TRANSGENIC MICE; CARDIAC-MUSCLE; CYTOPLASMIC DOMAINS; LOCALIZATION; LAMININ; MOUSE AB Muscle fibers attach to laminin in the basal lamina using two distinct mechanisms: the dystrophin glycoprotein complex and the alpha7 beta1 integrin, Defects in these linkage systems result in Duchenne muscular dystrophy (DMD), alpha2 laminin congenital muscular dystrophy, sarcoglycan-related muscular dystrophy, and alpha7 integrin congenital muscular dystrophy. Therefore, the molecular continuity between the extracellular matrix and cell cytoskeleton is essential for the structural and functional integrity of skeletal muscle. To test whether the alpha7 beta1 integrin can compensate for the absence of dystrophin, we expressed the rat alpha7 chain in mdx/utr(-/-) mice that lack both dystrophin and utrophin. These mice develop a severe muscular dystrophy highly akin to that in DMD, and they also die prematurely, Using the muscle creatine kinase promoter, expression of the alpha 7BX2 integrin chain was increased 2.0-2.3-fold in mdx/utr(-/-) mice. Concomitant with the increase in the alpha7 chain, its heterodimeric partner, beta 1D was also increased in the transgenic animals. Transgenic expression of the alpha 7BX2 chain in the mdx/utr(-/-) mice extended their longevity by threefold, reduced kyphosis and the development of muscle disease, and maintained mobility and the structure of the neuromuscular junction. Thus, bolstering alpha7 beta1 integrin-mediated association of muscle cells with the extracellular matrix alleviates many of the symptoms of disease observed in mdx/utr(-/-) mice and compensates for the absence of the dystrophin- and utrophin-mediated linkage systems. This suggests that enhanced expression of the alpha7 beta1 integrin may provide a novel approach to treat DMD and other muscle diseases that arise due to defects in the dystrophin glycoprotein complex. A video that contrasts kyphosis gait, joint contractures, and mobility in mdx/utr(-/-) and alpha 7BX2-mdx/utr(-/-) mice can be accessed at http://www.jcb.org/cgi/content/full/152/6/1207. C1 Univ Illinois, Dept Cell & Struct Biol, Chem & Life Sci Lab B107, Urbana, IL 61801 USA. NCI, Bethesda, MD 20892 USA. RP Kaufman, SJ (reprint author), Univ Illinois, Dept Cell & Struct Biol, Chem & Life Sci Lab B107, Urbana, IL 61801 USA. NR 59 TC 179 Z9 179 U1 1 U2 7 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 MAR 19 PY 2001 VL 152 IS 6 BP 1207 EP 1218 DI 10.1083/jcb.152.6.1207 PG 12 WC Cell Biology SC Cell Biology GA 415HP UT WOS:000167715600009 PM 11257121 ER PT J AU Smyth, MJ Cretney, E Takeda, K Wiltrout, RH Sedger, LM Kayagaki, N Yagita, H Okumura, K AF Smyth, MJ Cretney, E Takeda, K Wiltrout, RH Sedger, LM Kayagaki, N Yagita, H Okumura, K TI Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) contributes to interferon gamma-dependent natural killer cell protection from tumor metastasis SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE rodent; tumor immunity; in vivo animal models; immunotherapy; interleukin 12 ID HUMAN T-CELLS; NKT CELLS; ALPHA-GALACTOSYLCERAMIDE; IN-VIVO; MEDIATED CYTOTOXICITY; RECEPTOR EXPRESSION; DENDRITIC CELLS; CUTTING EDGE; TUMORICIDAL ACTIVITY; IMMUNE-RESPONSES AB Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is expressed by in vitro activated natural killer (NK) cells, but the relevance of this observation to the biological function of NK cells has been unclear. Herein, we have demonstrated the in vivo induction of mouse TRAIL expression on various tissue NK cells and correlated NK cell activation with TRAIL-mediated antimetastatic function in vivo. Expression of TRAIL was only constitutive on a subset of liver NK cells, and innate NK cell control of Renca carcinoma hepatic metastases in the liver was partially TRAIL dependent. Administration of therapeutic doses of interleukin (IL)-12, a powerful inducer of interferon (IFN)-gamma production by NK cells and NKT cells, upregulated TRAIL expression on liver, spleen, and lung NK cells, and IL-12 suppressed metastases in both liver and lung in a TRAIL-dependent fashion. By contrast, alpha -galactosylceramide (alpha -GalCer), a powerful inducer of NKT cell IFN-gamma and IL-4 secretion, suppressed both liver and lung metastases but only stimulated NK cell TRAIL-mediated function in the liver. TRAIL. expression was not detected on NK cells from IFN-gamma -deficient mice and TRAIL-mediated antimetastatic effects of IL-12 and a-GalCer were strictly IFN-gamma dependent. These results indicated that TRAIL induction on NK cells plays a critical role in IFN-gamma -mediated antimetastatic effects of IL-12 and alpha -GalCer. C1 Juntendo Univ, Sch Med, Dept Immunol, Bunkyo Ku, Tokyo 1138421, Japan. Univ Sydney, Dept Pathol, Sydney, NSW 2006, Australia. NCI, Frederick Canc Res & Dev Ctr, Expt Immunol Lab, Div Basic Sci, Frederick, MD 21702 USA. Peter MacCallum Canc Inst, Sir Donald & Lady Trescowthick Labs, E Melbourne, Vic 3002, Australia. RP Smyth, MJ (reprint author), Peter MacCallum Canc Inst, Locked Bag 1,ABeckett St, Melbourne, Vic 8006, Australia. RI Smyth, Mark/H-8709-2014 OI Smyth, Mark/0000-0001-7098-7240 NR 52 TC 328 Z9 336 U1 1 U2 7 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 MAR 19 PY 2001 VL 193 IS 6 BP 661 EP 670 DI 10.1084/jem.193.6.661 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 413UZ UT WOS:000167631100002 PM 11257133 ER PT J AU Bashirova, AA Geijtenbeek, TBH van Duijnhoven, GCF van Vliet, SJ Eilering, JBG Martin, MP Wu, L Martin, TD Viebig, N Knolle, PA KewalRamani, VN van Kooyk, Y Carrington, M AF Bashirova, AA Geijtenbeek, TBH van Duijnhoven, GCF van Vliet, SJ Eilering, JBG Martin, MP Wu, L Martin, TD Viebig, N Knolle, PA KewalRamani, VN van Kooyk, Y Carrington, M TI A dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN)-related protein is highly expressed on human liver sinusoidal endothelial cells and promotes HIV-1 infection SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE L-SIGN; adhesion receptor; chromosome 19p13.2-3; ICAM-3; HIV-1 gp120 ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1; LECTIN; BINDING; RECEPTOR; INVITRO; ICAM-3; ALPHA; BLOOD; DNA AB The discovery of dendritic cell (DC)-specific intercellular adhesion molecule (ICAM)-3-grabbing nonintegrin (DC-SIGN) as a DC-specific ICAM-3 binding receptor that enhances HIV-1 infection of T cells in trans has indicated a potentially important role for adhesion molecules in AIDS pathogenesis. A related molecule called DC-SIGNR exhibits 77% amino acid sequence identity with DC-SIGN. The DC-SIGN and DC-SIGNR genes map within a 30-kb region on chromosome 19p13.2-3. Their strong homology and close physical location indicate a recent duplication of the original gene. Messenger RNA and protein expression patterns demonstrate that the DC-SIGN-related, molecule is highly expressed on Liver sinusoidal cells and in the lymph node but not on DCs, ill contrast to DC-SIGN. Therefore, we suggest that a more appropriate name for the DC-SIGN-related molecule is L-SIGN, liver/lymph node-specific ICAM-3-grabbing nonintegrin. We show that in the liver, L-SIGN is expressed by sinusoidal endothelial cells. Functional studies indicate that L-SIGN behaves similarly to DC-SIGN in that it has a high affinity for ICAM-3, captures HIV-1 through gp120 binding, and enhances HIV-1 infection of T cells in trans. We propose that L-SIGN may play an important role in the interaction between liver sinusoidal endothelium and trafficking lymphocytes, as well as function in the pathogenesis of HIV-1. C1 Zentrum Mol Biol Heidelberg, ZMBH, D-69120 Heidelberg, Germany. Univ Nijmegen, Med Ctr St Radbound, Tumor Immunol Dept, NL-6525 EX Nijmegen, Netherlands. NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. NCI, Lab Genomic Divers, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, Sci Applicat Int Corp, Frederick, MD 21702 USA. RP Carrington, M (reprint author), NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, Sci Applicat Int Corp, POB B, Frederick, MD 21702 USA. RI Geijtenbeek, Teunis/C-2229-2009; Wu, Li/E-4330-2011; OI Wu, Li/0000-0002-5468-2487; Knolle, Percy A./0000-0003-2983-0414 FU NCI NIH HHS [N01-CO-56000] NR 24 TC 251 Z9 269 U1 1 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 MAR 19 PY 2001 VL 193 IS 6 BP 671 EP 678 DI 10.1084/jem.193.6.671 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 413UZ UT WOS:000167631100003 PM 11257134 ER PT J AU Park, YG Park, S Lim, SO Lee, MS Ryu, CK Kim, I Cho-Chung, YS AF Park, YG Park, S Lim, SO Lee, MS Ryu, CK Kim, I Cho-Chung, YS TI Reduction in cyclin D1/Cdk4/retinoblastoma protein signaling by CRE-decoy oligonucleotide SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE CRE-decoy oligonucleotide; cyclin D1; retinoblastoma protein; G1 phase arrest; tumor growth inhibition ID BREAST-CANCER CELLS; REGULATED KINASE; BINDING PROTEIN; D1 PROMOTER; TRANSCRIPTION; GROWTH; ACTIVATION; INDUCTION; PATHWAY; ELEMENT AB We have previously demonstrated that the activation of p53 signaling may contribute to tumor growth inhibition by the CRE-decoy oligonucleotide containing CRE sequence (5'-TGACGTCA-3') (Lee et al., Biochemistry 39, 4863-4868, 2000). However, growth inhibition by CRE-decoy treatment was also observed in tumor cells containing a mutant p53 (Park et al., J. Biol. Chem. 274, 1573-1580, 1999), To understand additional mechanisms of the decoy oligonucleotide, we investigated the effect on cyclin D1 expression and a cyclin D1/Cdk4/retinoblastoma protein (pRB) signaling pathway. Here we show that in MCF7 breast cancer cells the CRE-decoy competed with cyclin D1-CRE (5'-T (A) under bar ACGTCA-3') for binding transcription factors and reduced cyclin D1 gene expression (in reporter gene assay, Northern blotting and Western blotting) to modulate cyclin D1/Cdk4/pRB signaling and G1-S progression in a steady state and/or under estrogen stimulation. Decrease of cyclin D1 protein level by CRE-decoy treatment was also observed in p53-mutated cancer cells. Cyclin D1 expression was also diminished in MCF7 cells stably expressing dominant negative mutant CREB indicating that the nonspecific effect of oligonucleotide or its degradation products could be excluded. These data suggest that inhibition of cyclin D1 expression contributes to the growth inhibition induced by the decoy oligonucleotide in MCF7 cells through a cyclin D1/Cdk4/pRB signaling pathway. Downregulation of cyclin D1 expression also provides a mechanism of CRE-decoy-induced growth inhibition in tumor cells having p53 mutation. (C) 2001 Academic Press. C1 Korea Univ, Coll Med, Dept Biochem, Seoul 136701, South Korea. Korea Univ, Coll Med, Dept Pathol, Seoul 136701, South Korea. NCI, Lab Tumor Immunol & Biol, Cellular Biochem Sect, Bethesda, MD 20892 USA. RP Park, YG (reprint author), Korea Univ, Coll Med, Dept Biochem, 126-1,5-Ga Anam Dong,Sungbuk Gu, Seoul 136701, South Korea. NR 29 TC 23 Z9 25 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 16 PY 2001 VL 281 IS 5 BP 1213 EP 1219 DI 10.1006/bbrc.2001.4521 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 414AA UT WOS:000167642700023 PM 11243864 ER PT J AU Berezhkovskii, AM Boguna, M Weiss, GH AF Berezhkovskii, AM Boguna, M Weiss, GH TI Evaluation of rate constants for conformational transitions using single-molecule fluorescence spectroscopy SO CHEMICAL PHYSICS LETTERS LA English DT Article ID DYNAMICS AB We develop formulae for translating single-molecule fluorescence spectroscopic data into estimates of the rate constants for slow conformational transitions between two states with different lifetimes of the fluorescent probe. These rate constants cannot be determined separately from the bulk experiment. (C) 2001 Published by Elsevier Science B.V. C1 NIH, Math & Stat Comp Lab, Div Comp Res & Technol, Ctr Informat Technol, Bethesda, MD 20892 USA. LY Karpov Phys Chem Res Inst, Moscow 103064, Russia. RP Weiss, GH (reprint author), NIH, Math & Stat Comp Lab, Div Comp Res & Technol, Ctr Informat Technol, Bldg 12 A,Room 2007, Bethesda, MD 20892 USA. RI Boguna, Marian/B-7795-2011 OI Boguna, Marian/0000-0001-7833-3487 NR 13 TC 7 Z9 9 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-2614 J9 CHEM PHYS LETT JI Chem. Phys. Lett. PD MAR 16 PY 2001 VL 336 IS 3-4 BP 321 EP 324 DI 10.1016/S0009-2614(01)00154-3 PG 4 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 413AM UT WOS:000167587800020 ER PT J AU Hoare, SRJ Gardella, TJ Usdin, TB AF Hoare, SRJ Gardella, TJ Usdin, TB TI Evaluating the signal transduction mechanism of the parathyroid hormone 1 receptor - Effect of receptor-G-protein interaction on the ligand binding mechanism and receptor conformation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID (PTH)/PTH-RELATED PEPTIDE RECEPTOR; FIRST EXTRACELLULAR LOOP; RADIOLIGAND BINDING; PTH/PTHRP RECEPTOR; CHIMERIC RECEPTORS; GUANINE-NUCLEOTIDE; TERMINAL REGION; KIDNEY-CELLS; AFFINITY; AGONIST AB Ligand binding to the PTH1 receptor is described by a "two-site" model, in which the C-terminal portion of the ligand interacts with the N-terminal domain of the receptor (N interaction), and the N-terminal region of the ligand binds the juxtamembrane domain of the receptor (J interaction). Previous studies have not considered the dynamic nature of receptor conformation in ligand binding and receptor activation. In this study the ligand binding mechanism was compared for the G-protein-coupled (RG) and uncoupled (R) PTH1 receptor conformations. The two site model was confirmed by demonstration of spatially distinct binding sites for PTH(3-34) and PTH(1-14): PTH(1-11), which binds predominantly to the J domain, only partially inhibited binding of I-125-PTH(3-34); and PTH(3-34), shown to bind predominantly to the N domain, only partially inhibited PTH(1-14)-stimulated cAMP accumulation. To assess the effect of R-G coupling, ligand binding to R was measured by displacement of I-125-PTH(3-34) with 30 muM guanosine 5'-3-O-(thio)triphosphate (GTP gammaS) present, and binding to RG was measured by displacement of I-125-[MAP]PTHrP(1-36) (where MAP is model amphipathic peptide), a new radioligand that binds selectively to RG. Agonists bound with higher affinity to RG than R, whereas antagonists bound similarly to these states. The J interaction was responsible for enhanced agonist binding to RG: residues 1 and 2 were required for increased PTB(1-34) affinity for RG; residue 5 of MAP-PTHrP(1-36) was a determinant of R/RG binding selectivity, and PTH(1-14) bound selectively to RG. The N interaction was insensitive to R-G coupling; PTH(3-34) binding was GTP gammaS-insensitive. Finally, several observations suggest the receptor conformation is more "closed" at RG than R. At the R state, an open conformation is suggested by the simultaneous binding of PTH(1-14) and PTH(3-34). At RG PTH(1-14) better occluded binding of I-125-PTH(3-34) and agonist ligands bound pseudo-irreversibly, suggesting a more closed conformation of this receptor state. The results extend the two-site model to take into account R and RG conformations and suggest a model for differences of receptor conformation between these states. C1 NIMH, Cell Biol Unit, Genet Lab, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Usdin, TB (reprint author), NIMH, Cell Biol Unit, Genet Lab, Rm 3D06,Bldg 36,36 Convent Dr, Bethesda, MD 20892 USA. NR 57 TC 58 Z9 58 U1 2 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 16 PY 2001 VL 276 IS 11 BP 7741 EP 7753 DI 10.1074/jbc.M009395200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 411AA UT WOS:000167474900012 PM 11108715 ER PT J AU Hiraiwa, H Pan, CJ Lin, BC Akiyama, TE Gonzalez, FJ Chou, JY AF Hiraiwa, H Pan, CJ Lin, BC Akiyama, TE Gonzalez, FJ Chou, JY TI A molecular link between the common phenotypes of type 1 glycogen storage disease and HNF1 alpha-null mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GLUCOSE-6-PHOSPHATASE GENE-TRANSCRIPTION; NUCLEAR FACTOR; MICROSOMAL GLUCOSE-6-PHOSPHATASE; INSULIN-SECRETION; CATALYTIC SUBUNIT; YOUNG MODY3; LIVER; MOUSE; EXPRESSION; PROTEINS AB The clinical manifestations of type 1 glycogen storage disease (GSD-1) in patients deficient in the glucose-6-phosphatase (G6Pase) system (e.g. growth retardation, hepatomegaly, hyperlipidemia, and renal dysfunction) are shared by Hnf1 alpha (-/-) mice deficient of a transcriptional activator, hepatocyte nuclear factor 1 alpha (HNF1 alpha). However, the molecular mechanism is unknown. The G6Pase system, essential for the maintenance of glucose homeostasis, is comprised of glucose 6-phosphate transporter (G6PT) and G6Pase. G6PT translocates G6P from the cytoplasm to the lumen of the endoplasmic reticulum where it is metabolized by G6Pase to glucose and phosphate, Deficiencies in G6Pase and G6PT cause GSD-1a and GSD-1b, respectively. Hnf1 alpha (-/-) mice also develop noninsulin-dependent diabetes mellitus caused by defective insulin secretion. In this study, we sought to determine whether there is a molecular link between HNF1 alpha deficiency and function of the G6Pase system. Transactivation studies revealed that HNF1 alpha is required for transcription of the G6PT gene. Hepatic G6PT mRNA levels and microsomal G6P transport activity are also markedly reduced in Hnf1 alpha (-/-) mice as compared with Hnf1 alpha (+/+) and Hnf1 alpha (+/-) littermates. On the other hand, hepatic G6Pase mRNA expression and activity are up-regulated in Hnf1 alpha (-/-) mice, consistent with observations that: G6Pase expression is increased in diabetic animals. Taken together, the results strongly suggest that metabolic abnormalities in HNF1 alpha -null mice are caused in part by G6PT deficiency and by perturbations of the G6Pase system. C1 NICHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Chou, JY (reprint author), NICHD, Heritable Disorders Branch, NIH, Bldg 10,Rm 9S241, Bethesda, MD 20892 USA. RI Lin, Baochuan/A-8390-2009 OI Lin, Baochuan/0000-0002-9484-0785 NR 41 TC 22 Z9 22 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 16 PY 2001 VL 276 IS 11 BP 7963 EP 7967 DI 10.1074/jbc.M010523200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 411AA UT WOS:000167474900042 PM 11121425 ER PT J AU Dass, B McMahon, KW Jenkins, NA Gilbert, DJ Copeland, NG MacDonald, CC AF Dass, B McMahon, KW Jenkins, NA Gilbert, DJ Copeland, NG MacDonald, CC TI The gene for a variant form of the polyadenylation protein CstF-64 is on chromosome 19 and is expressed in pachytene spermatocytes in mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RNA-POLYMERASE-II; CLEAVAGE STIMULATION FACTOR; PRE-MESSENGER-RNA; 3' UNTRANSLATED REGION; B-CELL DIFFERENTIATION; POLY(A) ADDITION SITE; BINDING DOMAIN; POINT MUTATIONS; MOUSE GENOME; TERMINATION AB Many mRNAs in male germ cells lack the canonical AAUAAA but are normally polyadenylated (Wallace, A. M., Dass, B., Ravnik, S. E., Tonk, V., Jenkins, N. A., Gilbert, D. J., Copeland, N. G., and MacDonald, C. C. (1999) Proc. Natl. Acad Sci. U. S. A. 96, 6763-6768). Previously, we demonstrated the presence of two distinct forms of the M-r 64,000 protein of the cleavage stimulation factor (CstF-64) in mouse male germ cells and in brain, a somatic M-r 64,000 form and a variant M-r 70,000 form. The variant form was specific to meiotic and postmeiotic germ cells. We localized the gene for the somatic CstF-64 to the X chromosome, which would be inactivated during male meiosis. This suggested that the variant CstF-64 was an autosomal homolog activated during that time. We have named the variant form "tau CstF-64," and we describe here the cloning and characterization of the mouse tau CstF-64 cDNA, which maps to chromosome 19. The mouse tau CstF-64 protein fits the criteria of the variant CstF-64, including antibody reactivity, size, germ cell expression, and a common proteolytic digest pattern with tau CstF-64 from testis. Features of m tau CstF-64 that might allow it to promote the germ cell pattern of polyadenylation include a Pro --> Ser substitution in the RNA-binding domain and significant changes in the region that interacts with CstF-77. C1 Texas Tech Univ, Hlth Sci Ctr, Dept Cell Biol & Biochem, Lubbock, TX 79430 USA. Texas Tech Univ, Hlth Sci Ctr, Med Ctr, SW Canc Ctr, Lubbock, TX 79430 USA. NCI, Mouse Canc Genet Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Texas Tech Univ, Hlth Sci Ctr, Dept Cell Biol & Biochem, 3601 4th St, Lubbock, TX 79430 USA. EM cbbccm2@ttuhsc.edu FU NICHD NIH HHS [1R01 HD37109-01A1] NR 61 TC 35 Z9 36 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 16 PY 2001 VL 276 IS 11 BP 8044 EP 8050 DI 10.1074/jbc.M009091200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 411AA UT WOS:000167474900053 PM 11113135 ER PT J AU Kristof, AS Marks-Konczalik, J Moss, J AF Kristof, AS Marks-Konczalik, J Moss, J TI Mitogen-activated protein kinases mediate activator protein-1-dependent human inducible nitric-oxide synthase promoter activation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NF-KAPPA-B; TRANSCRIPTION FACTOR AP-1; INDUCED LETHAL TOXICITY; TATA-BINDING PROTEIN; TOLL-LIKE RECEPTOR-2; ERK MAP KINASE; TYROSINE KINASE; SIGNAL-TRANSDUCTION; INTERFERON-GAMMA; GENE-EXPRESSION AB Inducible nitric-oxide synthase (iNOS) is an important signaling protein involved in the regulation of biological processes (e.g. vasodilation, inflammation) and is subject to transcriptional regulation by cytokines and lipopolysaccharide (LPS). Full activation of the human iNOS (hiNOS) promoter by cytokines (i.e., tumor necrosis factor-alpha, interleukin-1 alpha, interferon-gamma (IFN-gamma)) required downstream and upstream nuclear factor-KB (-115, -8283) and activator protein-1 (AP-1) (-5115, -5301) transcription factor binding sites. Human lung epithelial (A549) cells were transiently transfected with luciferase reporter plasmids containing an 8.3-kilobase human iNOS promoter to examine the molecular signaling events necessary for hiNOS transcriptional activation. The combination of LPS and IFN-gamma, but neither alone, increased hiNOS promoter activity 28-fold, in a reaction requiring two critical AP-1 (JunD.Fra-2) promoter binding sites. Mitogen-activated protein kinases (MAPKs) were assessed as potential activators of AP-1 and the hiNOS promoter. Both pharmacological and molecular inhibitors of the extracellular signal-related kinase (ERK) and p38 pathways reduced cytokine mixture (CM)- and LPS/IFN-gamma -induced promoter activation. By gel retardation analysis, the addition of MAP/ERK kinase-1 and p38 inhibitors significantly diminished AP-1 binding in both CM- and LPS/IFN-gamma -stimulated cells. Thus, p38- and ERK dependent pathways, through effects on the AP-1 complex, activate the hiNOS promoter in cells stimulated with CM or LPS/IFN-gamma. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Kristof, AS (reprint author), NHLBI, Pulm Crit Care Med Branch, NIH, Bldg 10,Rm 5N307,MSC 1434,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kristofa@nih.gov NR 61 TC 134 Z9 135 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 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 16 PY 2001 VL 276 IS 11 BP 8445 EP 8452 DI 10.1074/jbc.M009563200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 411AA UT WOS:000167474900104 PM 11112784 ER PT J AU Guo, SD Cichy, SB He, XW Yang, QY Ragland, M Ghosh, AK Johnson, PF Unterman, TG AF Guo, SD Cichy, SB He, XW Yang, QY Ragland, M Ghosh, AK Johnson, PF Unterman, TG TI Insulin suppresses transactivation by CAAT/enhancer-binding proteins beta (C/EBP beta) - Signaling to p300/CREB-binding protein by protein kinase B disrupts interaction with the major activation domain of C/EBP beta SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOSPHOENOLPYRUVATE CARBOXYKINASE GENE; FORKHEAD TRANSCRIPTION FACTOR; ADENOVIRUS E1A; GLUCOCORTICOID RESPONSE; CELL-PROLIFERATION; NUCLEAR-PROTEIN; COACTIVATOR CBP; LEUCINE-ZIPPER; FACTOR FKHR; P300 AB CAAT/enhancer-binding proteins (C/EBPs) play an important role in the regulation of gene expression in insulin-responsive tissues. We have found that a complex containing C/EBP beta interacts with an insulin response sequence in the insulin-like growth factor-binding protein-1 (IGFBP-1) gene and that a C/EBP-binding site can mediate effects of insulin on promoter activity. Here, we examined mechanisms mediating this effect of insulin. The ability of insulin to suppress promoter activity via a C/EBP-binding site is blocked by LY294002, a phosphatidylinositol 3-kinase inhibitor, but not by rapamycin, which blocks activation of p70(S6 kinase). Dominant negative phosphatidylinositol 3-kinase and protein kinase B (PKB) block the effect of insulin, while activated PKB suppresses promoter function via a C/EBP-binding site, mimicking the effect of insulin, Coexpression studies indicate that insulin and PKB suppress transactivation by C/EBP beta, but not C/EBP alpha, and that N-terminal transactivation domains in C/EBP beta are required. Studies with Gal4 fusion proteins reveal that insulin and PKB suppress transactivation by the major activation domain in C/EBP beta (AD II), located between amino acids 31 and 83, Studies with E1A protein indicate that interaction with p300/CBP is required for transactivation by AD II and the effect of insulin and PKB, Based on a consensus sequence, we identified a PKB phosphorylation site (Ser(1834)) within the region of p300/CBP known to bind C/EBP beta, Mammalian two-hybrid studies indicate that insulin and PKB disrupt interactions between this region of p300 and AD II and that Ser(1834) is critical for this effect. Signaling by PKB and phosphorylation of Ser(1834) may play an important role in modulating interactions between p300/CBP and transcription factors and mediate effects of insulin and related growth factors on gene expression. C1 Univ Illinois, Coll Med, Chicago, IL 60612 USA. Res Genet Inc, Huntsville, AL 35801 USA. NCI, Eukaryot Transcript Regulat Sect, Regulat Cell Growth Lab, Frederick Canc Res & Dev Ctr, Bethesda, MD 20892 USA. RP Unterman, TG (reprint author), Vet Affairs Chicago Hlth Care Syst W Side, Rm 5A122A Res MP 151,820 S Damen Ave, Chicago, IL 60612 USA. RI Johnson, Peter/A-1940-2012 OI Johnson, Peter/0000-0002-4145-4725 FU NIDDK NIH HHS [DK41430] NR 65 TC 77 Z9 77 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 16 PY 2001 VL 276 IS 11 BP 8516 EP 8523 DI 10.1074/jbc.M008542200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 411AA UT WOS:000167474900113 PM 11116148 ER PT J AU Blaszczyk, J Li, Y Yan, HG Ji, XH AF Blaszczyk, J Li, Y Yan, HG Ji, XH TI Crystal structure of unligated guanylate kinase from yeast reveals GMP-induced conformational changes SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE domain movement; N-terminal acetylation; guanylate kinase; multiwavelength anomalous diffraction; X-ray crystallography ID MULTIPLE ISOMORPHOUS REPLACEMENT; N-TERMINAL ACETYLATION; ADENYLATE KINASE; DIFFRACTION DATA; SUBSTRATE-SPECIFICITY; ESCHERICHIA-COLI; DOMAIN CLOSURE; PROTEINS; MONOPHOSPHATE; PHOSPHORYLATION AB The crystal structure of guanylate kinase (GK) from yeast (Saccharomyces cerevisiae) with a non-acetylated N terminus has been determined in its unligated form (apo-GK) as well as in complex with GMP (GK CMF). The structure of apo-GK was solved with multiwavelength anomalous diffraction data and refined to an X-factor of 0.164 (R-free = 0.199) at 2.3 Angstrom resolution. The structure of GK (.) GMP was determined using the crystal structure of GK with an acetylated N terminus as the search model and refined to an R-factor of 0.156 (R-free = 0.245) at 1.9 Angstrom. GK belongs to the family of nucleoside monophosphate (NMP) kinases and catalyzes the reversible phosphoryl transfer from ATP to GMP. Like other NMP kinases, GK consists of three dynamic domains: the CORE, LID, and NMP-binding domains. Dramatic movements of the GMP-binding domain and smaller but significant movements of the LID domain have been revealed by comparing the structures of apo-CK and GK (.) GMP. apo-GK has a much more open conformation than the GK GMP complex. Systematic analysis of the domain movements using the program DynDom shows that the large movements of the GMP-binding domain involve a rotation around an effective hinge axis approximately parallel with helix 3, which connects the GMP-binding and CORE domains. The C-terminal portion of helix 3, which connects to the CORE domain, has strikingly higher temperature factors in GK (.) GMP than in apo-CK, indicating that these residues become more mobile upon CMP binding. The results suggest that helix 3 plays an important role in domain movement. Unlike the GMP-binding domain, which moves toward the active center of the enzyme upon GMP binding, the LID domain moves away from the active center and makes the presumed ATP-binding site more open. Therefore, the LID domain movement may facilitate the binding of MgATP. The structure of the recombinant GK (.) CMP complex superimposes very well with that of the native GK (.) GMP complex, indicating that N-terminal acetylation does not have significant impact on the three-dimensional structure of GK. (C) 2001 Academic Press. C1 NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. Michigan State Univ, Dept Biochem, E Lansing, MI 48824 USA. RP Ji, XH (reprint author), NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. RI Ji, Xinhua/C-9664-2012 OI Ji, Xinhua/0000-0001-6942-1514 FU NIGMS NIH HHS [GM51901] NR 43 TC 55 Z9 56 U1 0 U2 0 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAR 16 PY 2001 VL 307 IS 1 BP 247 EP 257 DI 10.1006/jmbi.2001.4427 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 416DL UT WOS:000167764900021 PM 11243817 ER PT J AU Bebenek, K Tissier, A Frank, EG McDonald, JP Prasad, R Wilson, SH Woodgate, R Kunkel, TA AF Bebenek, K Tissier, A Frank, EG McDonald, JP Prasad, R Wilson, SH Woodgate, R Kunkel, TA TI 5 '-Deoxyribose phosphate lyase activity of human DNA polymerase iota in vitro SO SCIENCE LA English DT Article ID BASE EXCISION-REPAIR; ESCHERICHIA-COLI; BETA; SITE; FIDELITY; ENZYME; IDENTIFICATION; MUTAGENESIS; BYPASS AB DNA polymerase iota (pol iota) is one of several recently discovered DNA polymerases in mammalian cells whose function is unknown. We report here that human pol iota has an intrinsic 5'-deoxyribose phosphate (dRP) Lyase activity. In reactions reconstituted with uracil-DNA glycosylase (UDC), apurinic/apyrimidinic (AP) endonuclease and DNA Ligase I, pol iota can use its dRP Lyase and polymerase activities to repair G . U and A . U pairs in DNA, These data and three distinct catalytic properties of pol iota implicate it in specialized forms of base excision repair (BER). C1 NIEHS, Genet Mol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. NICHHD, Sect DNA Replicat Repair & Mutagenesis, NIH, Bethesda, MD 20892 USA. RP Kunkel, TA (reprint author), NIEHS, Genet Mol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 27 TC 134 Z9 144 U1 1 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD MAR 16 PY 2001 VL 291 IS 5511 BP 2156 EP 2159 DI 10.1126/science.1058386 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 412PP UT WOS:000167563800041 PM 11251121 ER PT J AU Domanski, MJ Sutton-Tyrrell, K Mitchell, GF Faxon, DP Pitt, B Sopko, G AF Domanski, MJ Sutton-Tyrrell, K Mitchell, GF Faxon, DP Pitt, B Sopko, G CA BARI Investigators TI Determinants and prognostic information provided by pulse pressure in patients with coronary artery disease undergoing revascularization (The Balloon Angioplasty Revascularization Investigation [BARI]) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID RISK; STIFFNESS; WOMEN AB Arterial stiffness, as evidenced by increased pulse pressure (PP), is associated with adverse cardiovascular events. However, the prognostic importance of PP in patients who have undergone revascularization is unknown. We examined the prognostic importance of PP and predictors of increased PP in patients entered into the Balloon Angioplasty Revascularization Investigation (BARI). Estimated correlation and standardized regression coefficients were reported, indicating the relative magnitude of independent effects of baseline characteristics on PP. The independent association of PP and outcome over 5 years was determined. Baseline characteristics independently associated with PP were higher mean arterial pressure, older age, female sex, noncoronary vascular disease, history of diabetes mellitus, and history of hypertension (p <0.001 for all). Cox regression covariates significantly associated with time to death were age, smoking, male gender, diabetes history, congestive heart failure, and baseline use of angiotensin-converting enzyme inhibitors, diuretic, or digitalis. When PP was added to the model, it was found to be an independent predictor of time to death (p = 0.008). When PP and mean arterial pressure were added to the model, PP remained significantly associated with time to death (p = 0.033). When renal disease and noncoronary vascular disease were added to the model, the relative risk declined from 1.07 to 1.04 and the association was no longer statistically significant. Thus, increased PP is directly and independently associated with mean arterial pressure, hypertension, age 65 years, diabetes mellitus, and the presence of noncoronary vascular disease, and inversely associated with a history of myocardial infarction. After coronary revascularization, PP, reflecting arterial stiffness, is independently associated with total mortality. (C) 2001 by Excerpta Medica, Inc. C1 NHLBI, Clin Trials Grp, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. NHLBI, Clin Med Grp, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. Cardiovasc Engn Inc, Dover, MA USA. Univ So Calif, Div Cardiol, Los Angeles, CA USA. Univ Michigan, Med Ctr, Div Cardiol, Ann Arbor, MI 48109 USA. RP Domanski, MJ (reprint author), NHLBI, Clin Trials Grp, Div Epidemiol & Clin Applicat, Bldg 10, Bethesda, MD 20892 USA. NR 17 TC 23 Z9 30 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 MAR 15 PY 2001 VL 87 IS 6 BP 675 EP 679 DI 10.1016/S0002-9149(00)01482-X PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 410KR UT WOS:000167439600001 PM 11249882 ER PT J AU Kleinerman, RA Linet, MS Tarone, RE Wacholder, S Kaune, WT Hatch, EE AF Kleinerman, RA Linet, MS Tarone, RE Wacholder, S Kaune, WT Hatch, EE TI Re: "Are children living near high-voltage power lines at increased risk of acute lymphoblastic leukemia?" - Six of the authors reply SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter ID MAGNETIC-FIELDS; EXPOSURE C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM Factors, Richland, WA 99352 USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA 02118 USA. RP Kleinerman, RA (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAR 15 PY 2001 VL 153 IS 6 BP 617 EP 617 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 411YB UT WOS:000167526300017 ER PT J AU Devan, BD McDonald, RJ AF Devan, BD McDonald, RJ TI A cautionary note on interpreting the effects of partial reinforcement on place learning performance in the water maze SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE alternative place/cue responses; aversive motivation; competitive contingencies of reinforcement; partial reinforcement effects; place learning; procedural considerations; thigmotaxis; water maze ID ON-DEMAND PLATFORM; DORSAL STRIATUM; SWIMMING POOL; NAVIGATION; HIPPOCAMPAL; TASK; MEMORY; CUES; RATS AB The effects of partial reinforcement on dry land and swimming pool place learning tasks have recently been;compared and it has been suggested that they differ fundamentally [8]. That is, partial reinforcement impairs performance in the water maze, but not on dry land. However, other evidence suggests that partial reinforcement may have the opposite effect in the water maze, strengthening the accuracy and persistence of spatial responses. We discuss how the discrepancy may depend on 'levels' of negative reinforcement (e.g. escaping to a submerged platform before complete removal from the pool) and how experimental procedures may set up competitive contingencies that reinforce alternative behaviors. Finally, we consider data from past lesion studies and suggest ways to improve the design of future water maze experiments. (C) 2001 Published by Elsevier Science B.V. All rights reserved. C1 George Mason Univ, Krasnow Inst Adv Study, Fairfax, VA 22030 USA. NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. Univ Toronto, Dept Psychol, Toronto, ON, Canada. RP Devan, BD (reprint author), Towson State Univ, Dept Psychol, Lab Comparat Neuropsychol, Towson, MD 21204 USA. NR 19 TC 9 Z9 9 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD MAR 15 PY 2001 VL 119 IS 2 BP 213 EP 216 DI 10.1016/S0166-4328(00)00342-9 PG 4 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 404VQ UT WOS:000167123100010 PM 11165337 ER PT J AU Ji, XD Kim, YC Ahern, DG Linden, J Jacobson, KA AF Ji, XD Kim, YC Ahern, DG Linden, J Jacobson, KA TI [H-3]MRS 1754, a selective antagonist radioligand for A(2B) adenosine receptors SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE G protein-coupled receptors; tritium purines; xanthines; adenosine analogues ID 1,3-DIALKYLXANTHINE DERIVATIVES; CARBOXYLIC CONGENER; HIGH POTENCY; CELLS; ACTIVATION; AGONISTS; ASTHMA AB MRS 1754 [N-(4-cyanophenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)-phenoxy]acetamide] is a selective antagonist ligand of A(2B) adenosine receptors. This is the least well-defined adenosine receptor subtype, and A(2B) antagonists have potential as antiasthmatic drugs. For use as a radioligand, MRS 1754, a p-cyanoanilide xanthine derivative, was tritiated on the propyl groups in a two-step reaction using a p-carboxamido precursor, which was dehydrated to the cyano species using trifluoroacetic anhydride. [H-3]MRS 1754 (150 Ci/mmol) bound to recombinant human A(2B) adenosine receptors in membranes of stably transfected HEK-293 cells. Specific binding was saturable, competitive, and followed a one-site model, with a K-D value of 1.13 +/- 0.12 nM and a B-max value of 10.9 +/- 0.6 pmol/mg protein. Specific binding utilizing 0.7 nM [H-3]MRS 1754 was > 70% of total binding. The affinity calculated from association and dissociation binding constants was 1.22 nM (N = 4). Binding to membranes expressing rat and human A(1) and A(3), adenosine receptors was not significant, and binding in membranes of HEK-293 cells expressing human A(2A) receptors was of low affinity (K-D > 50 nM). The effects of cations and chelators were explored. Specific binding was constant over a pH range of 4.5 to 6.5, with reduced binding at higher pH. The pharmacological profile in competition experiments with [H-3]MRS 1754 was consistent with the structure-activity relationship for agonists and antagonists at A(2B) receptors. The K-i values of XAC (xanthine amine congener) and CPX (8-cyclopentyl-1,3-diproplylxanthine) were 16 and 55 nM, respectively. NECA (5'-N-ethylcarboxamidoadenosine) competed for [H-3]MRS 1754 binding with a K-i of 570 nM, similar to its potency in functional assays. Thus, [H-3]MRS 1754 is suitable as a selective, high-affinity radioligand for A(2B) receptors. (C) 2001 Elsevier Science Inc. All rights reserved. C1 NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NEN Life Sci Prod, Boston, MA 02118 USA. Univ Virginia, Hlth Sci Ctr, Dept Internal Med & Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Room B1A-19, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 26 TC 65 Z9 66 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD MAR 15 PY 2001 VL 61 IS 6 BP 657 EP 663 DI 10.1016/S0006-2952(01)00531-7 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 416UN UT WOS:000167798700004 PM 11266650 ER PT J AU Long, L Moschel, RC Dolan, ME AF Long, L Moschel, RC Dolan, ME TI Debenzylation of O-6-benzyl-8-oxoguanine in human liver: implications for O-6-benzylguanine metabolism SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE O-6-benzyl-8-oxoguanine; O-6-benzylguanine; 8-oxoguanine; metabolism; alkyltransferase; CYP1A2 ID IN-VITRO METABOLISM; HUMAN TUMOR-CELLS; O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; PHENETHYL ISOTHIOCYANATE; ALKYLATING-AGENTS; MALIGNANT GLIOMA; INHIBITOR PROBES; CYTOCHROMES P450; CROSS-LINKS AB O-6-Benzylguanine (BG) effectively inactivates the DNA repair protein O-6-alklylguanine-DNA alkyltransferase, and enhances the effectiveness of 1,3-bis(2-chloroethyl)-1-nitrosourea in cells in culture and tumor-bearing animals. BG is presently in phase II clinical trials. In humans, BG is converted to O-6-benzyl-8-oxoguanine (8-oxoBG), a longer-lived, yet equally potent inactivator. We have isolated and identified the debenzylated product, 8-oxoguanine, in plasma and urine of patients following administration of BG. The purpose of this work was to determine the human liver enzymes responsible for the debenzylation of 8-oxoBG. Therefore, 8-oxoBG was incubated with human liver microsomes and cytosol, and the concentration of 8-oxoguanine was determined. No appreciable product was formed in the cytosol; however, increasing amounts of 8-oxoguanine were formed with increasing concentrations of pooled human liver microsomes. The amount of 8-oxoguanine formed increased with time and substrate concentration. Go-incubation of human liver microsomes with 8-oxoBG and various cytochrome P450 isoform-selective inhibitors suggested the possible involvement of CYP1A2, 2E1, and/or 2A6 in this reaction. Incubation of 8-oxoBG with baculovirus cDNA-overexpressed CYP1A2, 2E1, 2A6, and 3A4 demonstrated that formation of 8-oxoguanine was due mainly to CYP1A2. Debenzylation of 8-oxoBG complied with Michaelis-Menten kinetics with K-m and V-max values of 35.9 muM and 0.59 pmol/min/pmol of CYP1A2, respectively. CYP1A2 appears to be mainly responsible for the debenzylation of 8-oxoBG in human liver. (C) 2001 Elsevier Science Inc. All rights reserved. C1 Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA. Univ Chicago, Comm Clin Pharmacol, Canc Res Ctr, Chicago, IL 60637 USA. NCI, Frederick Canc Res & Dev Ctr, Chem Carcinogenesis Lab, Frederick, MD 21702 USA. RP Dolan, ME (reprint author), Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA. FU NCI NIH HHS [CA71627, CA57725] NR 40 TC 8 Z9 8 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD MAR 15 PY 2001 VL 61 IS 6 BP 721 EP 726 DI 10.1016/S0006-2952(01)00523-8 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 416UN UT WOS:000167798700011 PM 11266657 ER PT J AU Al-Amin, HA Weickert, CS Weinberger, DR Lipska, BK AF Al-Amin, HA Weickert, CS Weinberger, DR Lipska, BK TI Delayed onset of enhanced MK-801-induced motor hyperactivity after neonatal lesions of the rat ventral hippocampus SO BIOLOGICAL PSYCHIATRY LA English DT Review DE dizocilpine; hippocampus; animal model; schizophrenia; behavior; NMDA mRNA; binding ID MEDIAL PREFRONTAL CORTEX; EXTRACELLULAR DOPAMINE LEVELS; NMDA RECEPTOR ANTAGONISTS; AMINO-ACID RECEPTORS; H-3 MK-801 BINDING; NUCLEUS-ACCUMBENS; TEGMENTAL AREA; DIZOCILPINE MK-801; GLUTAMATERGIC NEUROTRANSMISSION; QUANTITATIVE AUTORADIOGRAPHY AB Background: Abnormalities in the glutamatergic system, glutamate/dopamine/gamma -aminobutyric acid interactions, and cortical development are implicated in schizophrenia. Moreover, patients with schizophrenia show symptom exacerbation in response to N-methyl-D-aspartate (NMDA) antagonist drugs, Using an animal model of schizophrenia, we compared the impact of neonatal and adult hippocampal lesions on behavioral responses to MK-801, a noncompetitive NMDA antagonist, Methods: Neonatal rats were lesioned on postnatal day 7, Their motor activity in response to MK-801 was tested at a juvenile age, in adolescence, and in adulthood. We also measured binding of [H-3]MK-801 and the expression of NR1 messenger RNA (mRNA) in the medial prefrontal cortex and nucleus accumbens, Adult mts received similar lesions and were tested 4 and 8 weeks after the lesion. Results: As juveniles, neonatally lesioned rats did not differ from control mts in responsiveness to MK-801, whereas in adolescence and adulthood they showed more pronounced hyperactivity than control rats. The adult lesion did not alter behaviors elicited by MK-801. Neonatally lesioned rats showed no apparent changes in [H-3]MK-801 binding or expression of the NRI mRNA. Conclusions: These results suggest that an early lesion of the ventral hippocampus affects development of neural systems involved in MK-801 action without changes at the NMDA receptor level, and they show that the behavioral changes manifest first in early adulthood. Biol Psychiatry 2001;49:528-539 (C) 2001 Society of Biological Psychiatry. C1 NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bldg 10,Room 4N306, Bethesda, MD 20892 USA. RI Shannon Weickert, Cynthia/G-3171-2011; Lipska, Barbara/E-4569-2017; OI Al-Amin, Hassen/0000-0001-6358-1541 NR 111 TC 53 Z9 55 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAR 15 PY 2001 VL 49 IS 6 BP 528 EP 539 DI 10.1016/S0006-3223(00)00968-9 PG 12 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 411TY UT WOS:000167516400006 PM 11257238 ER PT J AU Fry, TJ Christensen, BL Komschlies, KL Gress, RE Mackall, CL AF Fry, TJ Christensen, BL Komschlies, KL Gress, RE Mackall, CL TI Interleukin-7 restores immunity in athymic T-cell-depleted hosts SO BLOOD LA English DT Article ID BONE-MARROW TRANSPLANTATION; RECEPTOR-DEFICIENT MICE; HIV-INFECTED PERSONS; ANTIRETROVIRAL THERAPY; INCREASED SUSCEPTIBILITY; PERIPHERAL LYMPHOCYTES; LYMPH-NODES; NUDE RATS; APOPTOSIS; BCL-2 AB Thymic-deficient hosts rely primarily on antigen-driven expansion to restore the peripheral T-cell compartment following T-cell depletion (TCD), The degree to which this thymic-independent pathway can restore immune competence remains poorly understood but has important implications for a number of clinical conditions including stem cell transplantation and human immunodeficiency virus (HIV) infection. A model of MY-mediated skin graft rejection by athymic, TCD mice was used to show that restoration of naive and recall responses via peripheral expansion requires transfer of only 25 x 10(6) lymph node (LN) cells representing approximately 10% of the T-cell repertoire, Constitutive expression of bcl-2 in the expanding inocula restored recall responses to MY at a substantially lower LN cell dose (1 x 10(6)), which is normally insufficient to induce MY-mediated graft rejection in athymic hosts. Interestingly, bcl-2 had no effect on primary responses. Interleukin-7 (IL-7) potently enhanced thymic-independent peripheral expansion and led to MY graft rejection using an LN cell dose of 1 x 10(6) in both primary and recall models, The restoration of immune competence by IL-7 appeared to be mediated through a combination of programmed cell death inhibition, improved costimulation, and modulation of antigen-presenting cell (APC) function. These results show that immune competence for even stringent antigens such as HY can be restored in the absence of thymic function and identify IL-7 as a potent modulator of thymic-independent T-cell regeneration. (Blood. 2001;97:1525-1533) (C) 2001 by The American Society of Hematology. C1 NCI, Mol Oncol Sect, Pediat Branch, NIH, Bethesda, MD 20892 USA. NCI, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21701 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Fry, TJ (reprint author), Bldg 10,Rm 13N240,MSC 1928,10 Ctr Dr, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CO-56000] NR 64 TC 116 Z9 119 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 MAR 15 PY 2001 VL 97 IS 6 BP 1525 EP 1533 DI 10.1182/blood.V97.6.1525 PG 9 WC Hematology SC Hematology GA 409VR UT WOS:000167406800001 PM 11238086 ER PT J AU Otsu, M Sugamura, K Candotti, F AF Otsu, M Sugamura, K Candotti, F TI Lack of dominant-negative effects of a truncated gamma c on retroviral-mediated gene correction of immunodeficient mice SO BLOOD LA English DT Article ID HEMATOPOIETIC PROGENITOR CELLS; BONE-MARROW CELLS; LYMPHOID DEVELOPMENT; INTERLEUKIN-2 IL-2; CHAIN; RECEPTOR; THERAPY; EXPRESSION; DEFICIENT; MURINE AB A recent clinical trial of gene therapy for X-linked severe combined immunodeficiency (XSCID) has shown that retroviral-mediated gene correction of bone marrow stem cells can lead to the development of normal immune function. These exciting results have been preceded by successful immune reconstitution in several XSCID mouse models, all carrying null mutations of the common gamma chain (gammac). One question not formally addressed by these previous studies is that of possible dominant-negative effects of the endogenous mutant gammac protein on the activity of the wild-type transferred gene product. The present work was therefore undertaken to study whether corrective gene transfer was applicable to an XSCID murine model with preserved expression of a truncated gammac molecule (Delta gammac(+)-XSCID). Gene correction of Delta gammac(+)-XSCID mice resulted in the reconstitution of lymphoid development, and preferential repopulation of lymphoid organs by gene-corrected cells demonstrated the selective advantage of gammac-expressing cells in vivo. Newly developed B cells showed normalization of lipopolysaccharide-mediated proliferation and interleukin-4 (IL-4)-induced immunoglobulin G1 isotype switching. Splenic T cells and thymocytes of treated animals proliferated normally to mitogens and responded to the addition of IL-2, IL-4, and IL-7, indicating functional reconstitution of gammac-sharing receptors. Repopulated thymi showed a clear increase of CD4(-)/CD8(-) and CD8(+) fractions, both dramatically reduced in untreated Delta gammac(+)-XSCID mice. These improvements were associated with the restoration of Bcl-2 expression levels and enhanced cell survival. These data indicate that residual expression of the endogenous truncated ye did not lead to dominant-negative effects in this murine model and suggest that patient selection may not be strictly necessary for gene therapy of XSCID. (Blood, 2001;97:1618-1624). (C) 2001 by The American Society of Hematology. C1 NHGRI, Clin Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. Tohoku Univ, Sch Med, Dept Microbiol & Immunol, Sendai, Miyagi 980, Japan. RP Candotti, F (reprint author), NHGRI, Clin Gene Therapy Branch, NIH, 10 Ctr Dr,Bldg 10,Rm 10C103,MSC 1851, Bethesda, MD 20892 USA. OI Otsu, Makoto/0000-0002-9769-0217 NR 37 TC 18 Z9 18 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 MAR 15 PY 2001 VL 97 IS 6 BP 1618 EP 1624 DI 10.1182/blood.V97.6.1618 PG 7 WC Hematology SC Hematology GA 409VR UT WOS:000167406800018 PM 11238100 ER PT J AU Guedez, L Mansoor, A Birkedal-Hansen, B Lim, MS Fukushima, P Venzon, D Stetler-Stevenson, WG Stetler-Stevenson, M AF Guedez, L Mansoor, A Birkedal-Hansen, B Lim, MS Fukushima, P Venzon, D Stetler-Stevenson, WG Stetler-Stevenson, M TI Tissue inhibitor of metalloproteinases 1 regulation of interleukin-10 in B-cell differentiation and lymphomagenesis SO BLOOD LA English DT Article ID ERYTHROID-POTENTIATING ACTIVITY; FOLLICULAR DENDRITIC CELLS; GROWTH-PROMOTING ACTIVITY; NON-HODGKINS-LYMPHOMA; GERMINAL CENTER; IN-VITRO; APOPTOSIS; LYMPHOCYTES; DEATH; EXPRESSION AB Tissue inhibitors of metalloproteinases (TIMPs), first described as specific inhibitors of matrix metalloproteinases, have recently been shown to exert growth factor activities. It was previously demonstrated that TIMP-1 inhibits apoptosis in germinal center B cells and induces further differentiation. Interleukin-10 (IL-10) is reported as a vital factor for the differentiation and survival of germinal center B cells and is also a negative prognostic factor in non-Hodgkin lymphoma (NHL). However, the mechanism of IL-10 activity in B cells and the regulation of its expression are not well understood. IL-10 has been shown to up-regulate TIMP-1 in tissue macrophages, monocytes, and prostate cancer cell lines, but IL-10 modulation of TIMP-1 in B cells and the effect of TIMP-1 on IL-10 expression has not been previously studied. It was found that TIMP-1 expression regulates IL-10 levels in B cells and that TIMP-1 mediates specific B-cell differentiation steps. TIMP-1 inhibition of apoptosis is not IL-10 dependent. TIMP-1 expression in B-cell NHL correlates closely with IL-10 expression and with high histologic grade. Thus, TIMP-1 regulates IL-10 expression in B-cell NHL and, through the inhibition of apoptosis, appears responsible for the negative prognosis associated with IL-10 expression in these tumors. (Blood. 2001; 97:1796-1802) (C) 2001 by The American Society of Hematology. C1 NCI, Flow Cytometry Unit, Pathol Lab, Div Clin Sci,NIH, Bethesda, MD 20892 USA. NCI, Data Management Sect, Div Clin Sci, Bethesda, MD 20892 USA. NCI, Extracellular Matrix Pathol Sect, Pathol Lab, Bethesda, MD 20892 USA. RP Stetler-Stevenson, M (reprint author), NCI, Flow Cytometry Unit, Pathol Lab, Div Clin Sci,NIH, Bldg 10,Rm 2N-108, Bethesda, MD 20892 USA. RI Venzon, David/B-3078-2008; Stetler-Stevenson, William/H-6956-2012; Guedez, Liliana/H-4951-2012 OI Stetler-Stevenson, William/0000-0002-5500-5808; NR 42 TC 34 Z9 34 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 15 PY 2001 VL 97 IS 6 BP 1796 EP 1802 DI 10.1182/blood.V97.6.1796 PG 7 WC Hematology SC Hematology GA 409VR UT WOS:000167406800040 PM 11238122 ER PT J AU Sellers, SE Tisdale, JF Agricola, BA Metzger, ME Donahue, RE Dunbar, CE Sorrentino, BP AF Sellers, SE Tisdale, JF Agricola, BA Metzger, ME Donahue, RE Dunbar, CE Sorrentino, BP TI The effect of multidrug-resistance 1 gene versus neo transduction on ex vivo and in vivo expansion of rhesus macaque hematopoietic repopulating cells SO BLOOD LA English DT Article ID BONE-MARROW CELLS; NONHUMAN-PRIMATES; PERIPHERAL-BLOOD; PROGENITOR CELLS; STEM-CELLS; HUMAN MDR1; IN-VITRO; CHEMOTHERAPY; TRANSPLANTATION; ENGRAFTMENT AB Transduction of murine stem cells with a multidrug-resistance 1 gene (MDR1) retrovirus results in dramatic ex vivo and in vivo expansion of repopulating cells accompanied by a myeloproliferative disorder, Given the use of MDR1-containing vectors in human trials, investigations have been extended to nonhuman primates, Peripheral blood stem cells from 2 rhesus monkeys were collected, CD34-enriched, split into 2 portions, and transduced with either MDR1 vectors or neo vectors and continued in culture for a total of 10 days before reinfusion. At engraftment, the copy number in granulocytes was extremely high from both MDR vectors and neo vectors, but the copy number fell to 0.01 to 0.05 for both. There were no perturbations of the leukocyte count or differential noted. After 3 cycles of stem cell factor/granulocyte colony-stimulating factor, there were no changes in the levels of MDR1 vector- or neo vector-containing cells. There was no evidence for expansion of MDR1 vector-transduced cells. Longterm engraftment with MDR1 vector- and neo vector-transduced cells occurred de spite prolonged culture. (Blood. 2001;97: 1888-1891) (C) 2001 by The American Society of Hematology. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. St Jude Childrens Res Hosp, Dept Biochem, Memphis, TN 38105 USA. RP Dunbar, CE (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Rm 7C103,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 20 TC 39 Z9 45 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 MAR 15 PY 2001 VL 97 IS 6 BP 1888 EP 1891 DI 10.1182/blood.V97.6.1888 PG 4 WC Hematology SC Hematology GA 409VR UT WOS:000167406800054 PM 11238136 ER PT J AU Palmantier, R George, MD Akiyama, SK Wolber, FM Olden, K Roberts, JD AF Palmantier, R George, MD Akiyama, SK Wolber, FM Olden, K Roberts, JD TI cis-polyunsaturated fatty acids stimulate beta(1) integrin-mediated adhesion of human breast carcinoma cells to type IV collagen by activating protein kinases C-epsilon and -mu SO CANCER RESEARCH LA English DT Article ID MAMMARY ADENOCARCINOMA CELLS; EXTRACELLULAR-MATRIX PROTEINS; MURINE MELANOMA-CELLS; COLON-CANCER CELLS; EXPERIMENTAL METASTASIS; PHORBOL ESTER; ARACHIDONIC-ACID; TYROSINE PHOSPHORYLATION; LIPOXYGENASE METABOLITE; MEMBRANE FLUIDITY AB We have investigated the effects of various fatty acids (FAs) on integrin-mediated MDA-MB-435 breast carcinoma cell adhesion to type IV collagen (collagen IV) in vitro. Arachidonic acid (AA) and linoleic acid both induced a dose-dependent increase in cell adhesion to collagen IV with no significant increase in nonspecific adhesion to polylysine and BSA. Oleic acid (a monounsaturated FA), AA methyl ester, and linoelaidic acid (a trans-isomer of linoleic acid) failed to stimulate adhesion to collagen IV, suggesting that these effects required cis-polyunsaturation and a free carboxylic moiety and that they were not due to membrane perturbations. Calphostin C, a protein kinase C (PKC) inhibitor, blocked cis-polyunsaturated FA (cis-PUFA)-induced cell adhesion in a dose-dependent manner, suggesting a role for a calcium-dependent PKC in this signal transduction pathway. Immunoblotting revealed that cis-PUFAs induced the translocation of PKC epsilon and PKC mu, two of the novel PKC isozymes, from the cytosol to the membrane. In contrast, a conventional PKC isozyme, PKC alpha, as well as the atypical isozymes, PKC zeta and PKC iota, did not translocate after cis-PUFA treatment. Function-blocking antibodies specific for alpha (1), alpha (2), and beta (1) integrin subunits inhibited cell adhesion to collagen IV, whereas antibodies to alpha (3) and alpha (5) did not. No increase in the expression of these integrins on the cell surface was detected after the incubation of cells with cis-PUFAs, suggesting that there is an increase in the activity, but not in the amount, of these beta (1) integrins. Altogether, these data suggest that cis-PUFAs enhance human breast cancer cell adhesion to collagen IV by selectively activating specific PKC isozymes, which leads to the activation of beta (1) integrins. C1 NIEHS, Lab Mol Carcinogenesis, NIH, Res Triangle Pk, NC 27709 USA. RP Roberts, JD (reprint author), NIEHS, Lab Mol Carcinogenesis, NIH, POB 12233,Mail Drop C2-14, Res Triangle Pk, NC 27709 USA. NR 82 TC 43 Z9 45 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2001 VL 61 IS 6 BP 2445 EP 2452 PG 8 WC Oncology SC Oncology GA 415AC UT WOS:000167697500020 PM 11289113 ER PT J AU Tilbrook, PA Palmer, GA Bittorf, T McCarthy, DJ Wright, MJ Sarna, MK Linnekin, D Cull, VS Williams, JH Ingley, E Schneider-Mergener, J Krystal, G Klinken, SP AF Tilbrook, PA Palmer, GA Bittorf, T McCarthy, DJ Wright, MJ Sarna, MK Linnekin, D Cull, VS Williams, JH Ingley, E Schneider-Mergener, J Krystal, G Klinken, SP TI Maturation of erythroid cells and erythroleukemia development are affected by the kinase activity of Lyn SO CANCER RESEARCH LA English DT Article ID ERYTHROPOIETIN-INDUCED DIFFERENTIATION; P56/P53(LYN) TYROSINE KINASE; COLONY-STIMULATING FACTOR; J2E CELLS; PHOSPHATIDYLINOSITOL 3-KINASE; TERMINAL DIFFERENTIATION; TRANSCRIPTION FACTOR; IONIZING-RADIATION; PROGENITOR CELLS; BINDING PROTEIN AB This study examined the impact of the tyrosine kinase Lyn on erythropoietin-induced intracellular signaling in erythroid cells. In J2E erythroleukemic cells, Lyn coimmunoprecipitated with numerous proteins, including SHP-1, SHP-2, ras-GTPase-activating protein, signal transducers and activators of transcription (STAT) 5a, STAT5b, and mitogen-activated protein kinase; however, introduction of a dominant-negative Lyn (Y397F Lyn) inhibited the interaction of Lyn with all of these molecules except SHP-1. Cells containing the dominant-negative Lyn displayed altered intracellular phosphorylation patterns, including mitogen-activated protein kinase, but not erythropoietin receptor, Janus-activated kinase (JAK) 2, or STAT5. As a consequence, erythropoietin-initiated differentiation and basal proliferation were severely impaired. Y397F Lyn reduced the protein levels of erythroid transcription factors erythroid Kruppel-like factor and GATA-1 up to 90%, which accounts for the inability of J2E cells expressing Y397F Lyn to synthesize hemoglobin. Although Lyn was shown to bind several sites on the cytoplasmic domain of the erythropoietin receptor, it was not activated when a receptor mutated at the JAK2 binding site was ectopically expressed in J2E cells, indicating that JAK2 is the primary kinase in erythropoietin signaling and that Lyn is a secondary kinase. In normal erythroid progenitors, erythropoietin enhanced phosphorylation of Lyn; moreover, exogenous Lyn increased colony forming unit-erythroid, but not burst forming unit-erythroid, colonies from normal progenitors, demonstrating a stage-specific effect of the kinase. Significantly, altering Lyn activity in J2E cells had a profound effect on the development of erythroleukemias in vivo: the mortality rate was markedly reduced and latent period extended when either wild-type Lyn or Y397F Lyn was introduced into these cells. Taken together, these data show that Lyn plays an important role in intracellular signaling in nontransformed and leukemic erythroid cells. C1 Royal Perth Hosp, Western Australian Inst Med Res, Lab Canc Med, Perth, WA 6000, Australia. Univ Western Australia, Dept Biochem, Perth, WA 6000, Australia. British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada. Humboldt Univ, Charite, Inst Med Immunol, Berlin, Germany. NCI, Frederick Canc Res & Dev Ctr, Basic Res Lab, Div Basic Sci, Frederick, MD 21702 USA. Univ Rostock, Inst Med Biochem, Rostock, Germany. RP Klinken, SP (reprint author), Western Australian Inst Med Res, 6th Floor,MRF Bldg,Rear,50 Murray St, Perth, WA 6000, Australia. RI Fear, Vanessa/A-6876-2013; Ingley, Evan/C-2401-2013; Sarna, Mohinder/Q-7834-2016 OI Ingley, Evan/0000-0002-8112-9134; Sarna, Mohinder/0000-0002-2448-1588 NR 57 TC 43 Z9 44 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2001 VL 61 IS 6 BP 2453 EP 2458 PG 6 WC Oncology SC Oncology GA 415AC UT WOS:000167697500021 PM 11289114 ER PT J AU Izzotti, A Balansky, RM D'Agostini, F Bennicelli, C Myers, SR Grubbs, CJ Lubet, RA Kelloff, GJ De Flora, S AF Izzotti, A Balansky, RM D'Agostini, F Bennicelli, C Myers, SR Grubbs, CJ Lubet, RA Kelloff, GJ De Flora, S TI Modulation of biomarkers by chemopreventive agents in smoke-exposed rats SO CANCER RESEARCH LA English DT Article ID CHRONIC DEGENERATIVE DISEASES; ENVIRONMENTAL TOBACCO-SMOKE; CARCINOGEN-DNA ADDUCTS; N-ACETYLCYSTEINE; CIGARETTE-SMOKE; HEMOGLOBIN ADDUCTS; LUNG; 4-AMINOBIPHENYL; ISOTHIOCYANATES; INDUCTION AB Chemoprevention opens new perspectives in the prevention of cancer and other chronic degenerative diseases associated with tobacco smoking, exploitable in current smokers and, even more, in exsmokers and passive smokers. Evaluation of biomarkers in animal models is an essential step for the preclinical assessment of efficacy and safety of potential chemopreventive agents. Groups of Sprague Dawley rats were exposed whole body to a mixture of mainstream and sidestream cigarette smoke for 28 consecutive days. Five chemopreventive agents were given either with drinking water (N-acetyl-L-cysteine, 1 g/kg body weight/day) or with the diet (1,2-dithiole-3-thione, 400 mg; Oltipraz, 400 mg; phenethyl isothiocyanate, 500 mg; and 5,6-benzoflavone, 500 mg/kg diet). The monitored biomarkers included: DNA adducts in bronchoalveolar lavage cells, tracheal epithelium, lung and heart; oxidative damage to pulmonary DNA; hemoglobin adducts of 4-aminobiphenyl and benzo(a)pyrene-7,8-diol-9,10-epoxide; micronucleated and polynucleated alveolar macrophages and micronucleated polychromatic erythrocytes in bone marrow. Exposure of rats to smoke resulted in dramatic alterations of all investigated parameters. N-Acetyl-L-cysteine, phenylethyl isothiocyanate, and 5,6- benzoflavone exerted a significant protective effect on all alterations. 1,2-Dithiole-3-thione was a less effective inhibitor and exhibited both a systemic toxicity and genotoxicity in alveolar macrophages, whereas its substituted analogue Oltipraz showed limited protective effects in this model. Interestingly, combination of N-acetyl-L-cysteine with Oltipraz was the most potent treatment, resulting in an additive or more than additive inhibition of smoke-related DNA adducts in the lung and hemoglobin adducts. These results provide evidence for the differential ability of test agents to modulate smoke-related biomarkers in the respiratory tract and other body compartments and highlight the potential advantages in combining chemopreventive agents working with distinctive mechanisms. C1 Univ Genoa, Dept Hlth Sci, I-16132 Genoa, Italy. NCI, Bethesda, MD 20892 USA. Univ Alabama, Chemoprevent Ctr, Birmingham, AL 35294 USA. Univ Louisville, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. RP De Flora, S (reprint author), Univ Genoa, Dept Hlth Sci, Via A Pastore 1, I-16132 Genoa, Italy. OI izzotti, alberto/0000-0002-8588-0347 FU NCI NIH HHS [N01-CN-75008] NR 43 TC 65 Z9 66 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2001 VL 61 IS 6 BP 2472 EP 2479 PG 8 WC Oncology SC Oncology GA 415AC UT WOS:000167697500024 PM 11289117 ER PT J AU Hollander, MC Kovalsky, O Salvador, JM Kim, KE Patterson, AD Raines, DC Fornace, AJ AF Hollander, MC Kovalsky, O Salvador, JM Kim, KE Patterson, AD Raines, DC Fornace, AJ TI Dimethylbenzanthracene carcinogenesis in Gadd45a-null mice is associated with decreased DNA repair and increased mutation frequency SO CANCER RESEARCH LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; P53-REGULATED PROTEIN GADD45; MESSENGER-RNA CONTENT; XERODERMA-PIGMENTOSUM; FILTER HYBRIDIZATION; GENE XPA; UV-LIGHT; CHROMATIN; LACKING; BINDING AB Mice lacking the Gadd45a gene are susceptible to ionizing radiation-induced tumors. Increased levels of Gadd45a transcript and protein are seen after treatment of cells with ionizing radiation as well as many other agents and treatments that damage DNA, Because cells deficient in Gadd45a were shown to have a partial defect in the global genomic repair component of the nucleotide excision repair pathway of UV-induced photoproducts, dimethylbenzanthracene (DMBA) carcinogenesis was investigated because this agent produces bulky adducts in DNA that are also repaired by nucleotide excision repair. Wild-type mice and mice deficient for Gadd45a were injected with a single i.p. dose of DMBA at 10-14 days of age. The latency for spontaneous deaths was slightly decreased for Gadd45a-null mice compared with wild-type mice. At 17 months, all surviving animals were killed, and similar percentages of each genotype were found to have tumors. However, nearly twice as many Gadd45a-null than wild-type mice had multiple tumors, and three times as many had multiple malignant tumors, The predominant tumor types in wild-type mice were lymphoma and tumors of the intestines and liver. In Gadd45a-null mice, there was a dramatic increase in female ovarian tumors, male hepatocellular tumors, and in vascular tumors in both sexes. In wild-type mice, this dose of DMBA induced a >5-fold increase in Gadd45a transcript in the spleen and ovary, whereas the increase in liver was >20-fold. Nucleotide excision repair, which repairs both UV- and DMBA-induced DNA lesions, was substantially reduced in Gadd45a-null lymphoblasts, Mutation frequency after DMBA treatment was threefold higher in Gadd45a-null liver compared with mild-type liver, Therefore, lack of basal and DMBA-induced Gadd45a may result in enhanced tumorigenesis because of decreased DNA repair and increased mutation frequency. Genomic instability, decreased cell cycle checkpoints, and partial loss of normal growth control in cells from Gadd45a-null mice may also contribute to this process. C1 NCI, NIH, Div Basic Sci, Bethesda, MD 20892 USA. NCI, Sci Applicat Int Corp, Frederick, MD 21702 USA. RP Hollander, MC (reprint author), NCI, NIH, Div Basic Sci, Bldg 37,Room 6144, Bethesda, MD 20892 USA. RI Fornace, Albert/A-7407-2008; Patterson, Andrew/G-3852-2012 OI Fornace, Albert/0000-0001-9695-085X; Patterson, Andrew/0000-0003-2073-0070 NR 22 TC 79 Z9 86 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2001 VL 61 IS 6 BP 2487 EP 2491 PG 5 WC Oncology SC Oncology GA 415AC UT WOS:000167697500026 PM 11289119 ER PT J AU Guadagni, F Kantor, J Aloe, S Carone, MD Spila, A D'Alessandro, R Abbolito, MR Cosimelli, M Graziano, F Carboni, F Carlini, S Perri, P Sciarretta, F Greiner, JW Kashmiri, SVS Steinberg, SM Roselli, M Schlom, J AF Guadagni, F Kantor, J Aloe, S Carone, MD Spila, A D'Alessandro, R Abbolito, MR Cosimelli, M Graziano, F Carboni, F Carlini, S Perri, P Sciarretta, F Greiner, JW Kashmiri, SVS Steinberg, SM Roselli, M Schlom, J TI Detection of blood-borne cells in colorectal cancer patients by nested reverse transcription-polymerase chain reaction for carcinoembryonic antigen messenger RNA: Longitudinal analyses and demonstration of its potential importance as an adjunct to multiple serum markers SO CANCER RESEARCH LA English DT Article ID PERIPHERAL-BLOOD; BREAST-CANCER; TUMOR-CELLS; CARCINOMA PATIENTS; MOLECULAR-DETECTION; GASTRIC-CARCINOMA; BONE-MARROW; LYMPH-NODES; EXPRESSION; GENE AB The use of reverse transcription-PCR (RT-PCR) to analyze cells in the blood of cancer patients for the detection of mRNA expressed in tumor cells has implications for both the prognosis and the monitoring of cancer patients for the efficacy of established or experimental therapies. Carcinoembryonic antigen (CEA) is expressed on similar to 95% of colorectal, gastric, and pancreatic tumors, and on the majority of breast, non-small cell lung, and head and neck carcinomas. CEA shed in serum is useful as a marker in only similar to 50% of colorectal cancer patients and rarely is shed by some other carcinoma types, RT-PCR has been used previously to detect CEA mRNA in cells in the blood and lymph nodes of cancer patients, Under the assay conditions validated in the studies reported here, 34 of 51 (67%) patients with different stages of colorectal cancer had blood cells that were positive by RT-PCR for CEA mRNA, whereas none of 18 patients with colonic polyps were positive; 2 of 60 apparently healthy individuals (who were age and sex matched with the carcinoma patients and were part of a colon cancer screening program as controls) were marginally positive. The results of CEA PCR in the blood of the carcinoma patients and the other groups showed strong statistical correlation with the disease (P2 < 0.0001). Analyses were carried out to detect both serum CEA protein levels and CEA mRNA in blood cells of colorectal carcinoma patients by RT-PCR, For all stages of disease, 18 of 51 patients (35%) were positive for serum CEA, whereas 35 of 51 (69%) were positive by RT-PCR. More importantly, only 5 of 23 (20%) of stage B and C colorectal cancer patients were positive for serum CEA, whereas 16 of 23 (70%) were positive by RT-PCR, The use of two other serum markers (CA19.9 and CA72-4) for colorectal cancer in combination with serum CEA scored two additional patients as positive; both were positive by RT-PCR for CEA mRNA. Pilot long-term longitudinal studies conducted before and after surgery identified some patients with CEA mRNA in blood cells that were negative for all serum markers, who eventually developed clinical metastatic disease, The studies reported here are the first to correlate RT-PCR results for CFA mRNA in blood cells with one or more serum markers for patients with different stages of colorectal cancer, and are the first long-term longitudinal studies to use RT-PCR to detect CEA mRNA in blood cells of cancer patients, Larger cohorts will be required in future studies to define the impact, if any, of this technology on prognosis and/or disease monitoring, C1 NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. Regina Elena Canc Inst, Clin Pathol Lab, I-00144 Rome, Italy. Regina Elena Canc Inst, Div Surg Oncol 2, I-00144 Rome, Italy. Regina Elena Canc Inst, Div Surg Oncol 3, I-00144 Rome, Italy. Regina Elena Canc Inst, Dept Pathol, I-00144 Rome, Italy. Univ Roma Tor Vergata, Dept Surg, I-00144 Rome, Italy. RP Kantor, J (reprint author), NCI, Tumor Immunol & Biol Lab, NIH, 10 Ctr Dr,Bldg 10,Room 8B09, Bethesda, MD 20892 USA. RI Guadagni, Fiorella/J-4432-2013 OI Guadagni, Fiorella/0000-0003-3652-0457 NR 29 TC 66 Z9 74 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2001 VL 61 IS 6 BP 2523 EP 2532 PG 10 WC Oncology SC Oncology GA 415AC UT WOS:000167697500032 PM 11289125 ER PT J AU Montaner, S Sodhi, A Pece, S Mesri, EA Gutkind, JS AF Montaner, S Sodhi, A Pece, S Mesri, EA Gutkind, JS TI The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor promotes endothelial cell survival through the activation of Akt/protein kinase B SO CANCER RESEARCH LA English DT Article ID MIDDLE-T-ANTIGEN; NF-KAPPA-B; PHOSPHATIDYLINOSITOL 3-KINASE ACTIVATION; GROWTH-FACTOR; AKT; KSHV; APOPTOSIS; HUMAN-HERPESVIRUS-8; ANGIOGENESIS; EXPRESSION AB The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor (KSHV-GPCR) is a key molecule in the pathogenesis of Kaposi's sarcoma, playing a central role in the promotion of vascular endothelial growth factor (VEGF)-driven angiogenesis and spindle cell proliferation. We previously have shown that KSHV-GPCR has oncogenic potential when overexpressed in fibroblasts and is responsible for the expression and secretion of VEGF through the regulation of different intracellular signaling pathways (A, Sodhi ed nl., Cancer Res., 60: 4873-4880, 2000; C, Bais et al., Nature, 391: 86-89, 1998). Here, we describe that this constitutively active G protein-coupled receptor is able to promote cell survival in primary human umbilical vein endothelial cells and that this effect is independent of its ability to secrete VEGF because it is not prevented by the expression of antisense constructs for VEGF or the addition of VEGF-blocking antibodies. Instead we found that ectopic expression of KSHV-GPCR potently induces the kinase activity of Akt/protein kinase E in a dose-dependent manner and triggers its translocation to the plasma membrane, This signaling pathway requires the function of phosphatidylinositol 3 ' -kinase and is dependent on beta gamma subunits released from both pertussis toxin-sensitive and -insensitive G proteins. Furthermore, we found that KSHV-GPCR is able to protect human umbilical vein endothelial cells from the apoptosis induced by serum deprivation and that both wortmannin and the expression of a kinase-deficient Akt K179M mutant are able to block this effect. Finally, we observed that the AktK179M protein also inhibits the activation of nuclear factor-kappaB induced by KSHV-GPCR, suggesting that this transcription factor may represent one of the putative downstream targets for Akt in the survival-signaling pathway. These results provide further knowledge in the elucidation of the signal transduction pathways activated by KSHV-GPCR and support its key role in promoting the survival of viral-infected cells. Moreover, the present findings also emphasize the importance of this G protein-coupled receptor in the development of KSHV-related neoplasias. C1 Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. Cornell Univ, Coll Med, Howard Hughes Med Inst, Res Scholars Program,NIH, New York, NY 10021 USA. Cornell Univ, Coll Med, Lab Viral Oncogenesis, Div Hematol Oncol,Dept Med, New York, NY 10021 USA. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Bldg 30,Room 211, Bethesda, MD 20892 USA. RI Gutkind, J. Silvio/A-1053-2009; Pece, Salvatore/B-9609-2013 OI Pece, Salvatore/0000-0003-1764-3929 FU NIAID NIH HHS [AI-39192] NR 63 TC 146 Z9 151 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2001 VL 61 IS 6 BP 2641 EP 2648 PG 8 WC Oncology SC Oncology GA 415AC UT WOS:000167697500049 PM 11289142 ER PT J AU Mitsiades, N Poulaki, V Mitsiades, C Tsokos, M AF Mitsiades, N Poulaki, V Mitsiades, C Tsokos, M TI Ewing's sarcoma family tumors are sensitive to tumor necrosis factor-related apoptosis-inducing ligand and express death receptor 4 and death receptor 5 SO CANCER RESEARCH LA English DT Article ID TRAIL-INDUCED APOPTOSIS; NF-KAPPA-B; FADD-DEPENDENT APOPTOSIS; FAS LIGAND; MEDIATED APOPTOSIS; IN-VIVO; MONOCLONAL-ANTIBODY; ANTITUMOR-ACTIVITY; MELANOMA-CELLS; P53 MUTATIONS AB In this study, we investigated the sensitivity of Ewing's sarcoma family tumors (ESFTs) of children and adolescents to the tumor necrosis factor related apoptosis-inducing Ligand (TRAIL). TRAIL binds to death receptors (DRs) DR4, DR5, DcR1, and DcR2. Either DR4 or DRS can induce apoptosis, whereas DcR1 and DcR2 are considered inhibitory receptors. Nine of 10 ESFT cell lines, including several that were Fas resistant, underwent apoptosis with TRAIL through activation of caspase-10, capase-8 (FLICE), caspase-3, and caspase-9. In contrast to the Las signaling pathway, caspase-10, but not caspase-8 or the Fas-associated death domain-containing molecule, was recruited to the TRAIL receptor-associated signaling complex. We found that 9 of 10 ESFT cell lines expressed both DR4 and DR5 by Western blotting, whereas the TRAIL-resistant line expressed only DR4. However, DR4 was absent from the cell surface In the resistant and two additional lines (three of five tested lines), suggesting that it may have been nonfunctional. On the contrary, DR5 was located on the cell surface in all four sensitive lines tested, being absent only from the cell surface of the resistant line that was also DRS-negative by Western blotting. In agreement with these findings, the resistance of the line was overcome by restoration of DR5 levels by transfection. Levels of DcR1 and DcR2 or levels of the FLICE-inhibitory protein (FLIP) did not correlate with TRAIL resistance, and protein synthesis inhibition did not sensitize the TRAIL-resistant line to TRAIL. Because these data suggested that sensitivity of ESFTs to TRAIL was mainly based on the presence of DR4/DR5, we investigated the presence of these receptors in 32 ESFT tissue sections by immunohistochemistry. We found that 23 of 32 tumor tissues (72%) expressed both receptors, 8 of 32 (25%) expressed one receptor only, and 1 was negative for both. Our finding of wide expression of DR4/DR5 in ESFT in vivo, in combination with their high sensitivity to TRAIL in vitro and the reported lack of toxicity of TRAIL in mice and monkeys, suggests that TRAIL may be a novel effective agent in the treatment of ESFTs. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Tsokos, M (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Room 2A-10, Bethesda, MD 20892 USA. NR 65 TC 96 Z9 100 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2001 VL 61 IS 6 BP 2704 EP 2712 PG 9 WC Oncology SC Oncology GA 415AC UT WOS:000167697500058 PM 11289151 ER PT J AU Chrobak, P Gress, RE AF Chrobak, P Gress, RE TI Veto activity of activated bone marrow does not require perforin and Fas ligand SO CELLULAR IMMUNOLOGY LA English DT Article DE mouse; CD8(+) T lymphocyte; peripheral tolerance; bone marrow; veto cell; IL-2; clonal deletion; perforin/granzyme; Fas/Fas ligand ID CYTOTOXIC LYMPHOCYTES-T; CYTO-TOXIC RESPONSES; CELL-DEATH; KILLER-CELLS; PERIPHERAL TOLERANCE; CLONAL DELETION; SUPPRESSION; EXPRESSION; MECHANISMS; INHIBITION AB Veto cells suppress generation of CD8(+) T cell immune responses in an antigen-specific manner, with specificity dictated by antigens on the veto cell surface. Activated bone marrow (ABM) veto cells belong to the NK cell type lineage and veto by clonally deleting antigen-specific precursor cytotoxic T cell lymphocyte (CTL), In vitro cytotoxicity of ABM depends largely on the perforin/granzyme and Fas/Fas ligand pathways. Utilizing perforin-deficient and functional Fas ligand-deficient gld mice as a source of ABM and functional Fas-deficient lpr mice as a source of precursor CTL, we demonstrate in this study that ABM cells utilize a perforin- and Fas-independent pathway to veto allogeneic cell-mediated cytotoxic responses. We also show that ABM cells mediate perforin- and Fas-independent veto activity even in an g-h clonal deletion assay. We conclude that ABM veto activity does not require the two primary pathways of cell-mediated death. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Inst Rech Clin Montreal, Montreal, PQ H2W 1R7, Canada. RP Chrobak, P (reprint author), NCI, Expt Immunol Branch, NIH, Room 4B-36,Bldg 10, Bethesda, MD 20892 USA. NR 40 TC 15 Z9 16 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0008-8749 J9 CELL IMMUNOL JI Cell. Immunol. PD MAR 15 PY 2001 VL 208 IS 2 BP 80 EP 87 DI 10.1006/cimm.2001.1771 PG 8 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 431RK UT WOS:000168644200002 PM 11333140 ER PT J AU Ito, A Lai, CH Zhao, X Saito, S Hamilton, MH Appella, E Yao, TP AF Ito, A Lai, CH Zhao, X Saito, S Hamilton, MH Appella, E Yao, TP TI p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2 SO EMBO JOURNAL LA English DT Article DE acetylation; CBP; MDM2; p300; p53 ID DAMAGE-INDUCED PHOSPHORYLATION; DNA-DAMAGE; TUMOR-SUPPRESSOR; STABILIZES P53; ACTIVATES P53; DEGRADATION; P19(ARF); P300; CBP; TRANSCRIPTION AB The tumor suppressor p53 is activated in response to many types of cellular and environmental insults via mechanisms involving post-translational modification, Here we demonstrate that, unlike phosphorylation, p53 invariably undergoes acetylation in cells exposed to a variety of stress-inducing agents including hypoxia, anti-metabolites, nuclear export inhibitor and actinomycin D treatment. lie vivo, p53 acetylation is mediated by the p300 and CBP acetyltransferases. Overexpression of either p300 or CBP, but not an acetyltransferase-deficient mutant, efficiently induces specific p53 acetylation, In contrast, MDM2, a negative regulator of p53, actively suppresses p300/CBP-mediated p53 acetylation in vivo and in vitro. This inhibitory activity of MDM2 on p53 acetylation is in turn abrogated by tumor suppressor p19(ARF), indicating that regulation of acetylation is a central target of the p53-MDM2-p19(ARF) feedback loop. Functionally, inhibition of deacetylation promotes p53 stability, suggesting that acetylation plays a positive role in the accumulation of p53 protein in stress response. Our results provide evidence that p300/CBP-mediated acetylation may be a universal and critical modification for p53 function. C1 Duke Univ, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Yao, TP (reprint author), Duke Univ, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. RI Ito, Akihiro/A-6100-2015 FU NCI NIH HHS [CA85676-01A1, R01 CA085676]; NIDDK NIH HHS [DK50494, R01 DK050494] NR 46 TC 338 Z9 342 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD MAR 15 PY 2001 VL 20 IS 6 BP 1331 EP 1340 DI 10.1093/emboj/20.6.1331 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 416HT UT WOS:000167774800012 PM 11250899 ER PT J AU Sarafianos, SG Das, K Tantillo, C Clark, AD Ding, J Whitcomb, JM Boyer, PL Hughes, SH Arnold, E AF Sarafianos, SG Das, K Tantillo, C Clark, AD Ding, J Whitcomb, JM Boyer, PL Hughes, SH Arnold, E TI Crystal structure of HIV-1 reverse transcriptase in complex with a polypurine tract RNA : DNA SO EMBO JOURNAL LA English DT Article DE HIV-1; polypurine tract; reverse transcriptase; RNase H; RNA : DNA ID MURINE LEUKEMIA-VIRUS; DOUBLE-STRANDED DNA; SEQUENCE FEATURES IMPORTANT; PYRIMIDINE-RICH STRANDS; ANTIBODY FAB FRAGMENT; AMINO-ACID-RESIDUES; RIBONUCLEASE-H; HYBRID DUPLEX; ANGSTROM RESOLUTION; MOLECULAR-STRUCTURE AB We have determined the 3.0 Angstrom resolution structure of wild-type HIV-1 reverse transcriptase in complex with an RNA:DNA oligonucleotide whose sequence includes a purine-rich segment from the HIV-1 genome called the polypurine tract (PPT). The PPT is resistant to ribonuclease H (RNase H) cleavage and is used as a primer for second DNA strand synthesis. The 'RNase H primer grip', consisting of amino acids that interact with the DNA primer strand, may contribute to PNase H catalysis and cleavage specificity. Cleavage specificity is also controlled by the width of the minor groove and the trajectory of the RNA:DNA, both of which are sequence dependent, An unusual 'unzipping' of 7 bp occurs in the adenine stretch of the PPT: an unpaired base on the template strand takes the base pairing out of register and then, following two offset base pairs, an unpaired base on the primer strand re-establishes the normal register. The structural aberration extends to the RNase H active site and may play a role in the resistance of PPT to RNase H cleavage. C1 Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. Rutgers State Univ, Dept Chem, Piscataway, NJ 08854 USA. ViroLog Inc, S San Francisco, CA 94080 USA. NCI, Frederick Canc Res & Dev Ctr, HIV D Resistance Program, Frederick, MD 21702 USA. RP Arnold, E (reprint author), Ctr Adv Biotechnol & Med, 679 Hoes Lane, Piscataway, NJ 08854 USA. OI Sarafianos, Stefan G/0000-0002-5840-154X FU NIAID NIH HHS [AI 09578, AI 27690, F32 AI009578, R37 AI027690] NR 77 TC 295 Z9 299 U1 2 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD MAR 15 PY 2001 VL 20 IS 6 BP 1449 EP 1461 DI 10.1093/emboj/20.6.1449 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 416HT UT WOS:000167774800023 PM 11250910 ER PT J AU Podlutsky, AJ Dianova, II Podust, VN Bohr, VA Dianov, GL AF Podlutsky, AJ Dianova, II Podust, VN Bohr, VA Dianov, GL TI Human DNA polymerase beta initiates DNA synthesis during long-patch repair of reduced AP sites in DNA SO EMBO JOURNAL LA English DT Article DE AP sites; base excision repair; DNA polymerase beta; human cell extracts ID BASE-EXCISION-REPAIR; GLYCOSYLASE; PATHWAY; EPSILON; DELTA; RECONSTITUTION; REQUIREMENT; RESIDUES; PROTEINS; CELLS AB Simple base damages are repaired through a short-patch base excision pathway where a single damaged nucleotide is removed and replaced. DNA polymerase beta (Pol beta) is responsible for the repair synthesis in this pathway and also removes a 5'-sugar phosphate residue by catalyzing a beta -eliminatlon reaction. However, some DNA lesions that render deoxyribose resistant to beta -elimination are removed through a long-patch repair pathway that involves strand displacement synthesis and removal of the generated flap by specific endonuclease, Three human DNA polymerases (Pol beta, pol delta and pol epsilon) have been proposed to play a role in this pathway, however the identity of the polymerase involved and the polymerase selection mechanism are not clear. In repair reactions catalyzed by cell extracts we have used a substrate containing a reduced apurinic/apyrimidinic (AP) site resistant to p-elimination and inhibitors that selectively affect different DNA polymerases, Using this approach we find that in human cell extracts Pol beta is the major DNA polymerase incorporating the first nucleotide during repair of reduced AP sites, thus initiating long-patch base excision repair synthesis. C1 NIA, Genet Mol Lab, NIH, Baltimore, MD 21224 USA. Vanderbilt Univ, Dept Biol Mol, Nashville, TN 37232 USA. MRC, Radiat & Genome Stabil Unit, Didcot OX11 0RD, Oxon, England. RP Dianov, GL (reprint author), NIA, Genet Mol Lab, NIH, Baltimore, MD 21224 USA. RI Podlutsky, Andrej/F-5421-2015 FU NIGMS NIH HHS [R01 GM052948, GM52948] NR 27 TC 112 Z9 119 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD MAR 15 PY 2001 VL 20 IS 6 BP 1477 EP 1482 DI 10.1093/emboj/20.6.1477 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 416HT UT WOS:000167774800026 PM 11250913 ER PT J AU Wassif, CA Zhu, PJ Kratz, L Krakowiak, PA Battaile, KP Weight, FF Grinberg, A Steiner, RD Nwokoro, NA Kelley, RI Stewart, RR Porter, FD AF Wassif, CA Zhu, PJ Kratz, L Krakowiak, PA Battaile, KP Weight, FF Grinberg, A Steiner, RD Nwokoro, NA Kelley, RI Stewart, RR Porter, FD TI Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith-Lemli-Opitz syndrome SO HUMAN MOLECULAR GENETICS LA English DT Article ID DEFECTIVE CHOLESTEROL-BIOSYNTHESIS; CULTURED SKIN FIBROBLASTS; 3-BETA-HYDROXYSTEROID DEHYDROGENASE; CHONDRODYSPLASIA PUNCTATA; DELTA-7-STEROL REDUCTASE; EMBRYONIC LETHALITY; LIVER-MICROSOMES; CHILD SYNDROME; MUTATIONS; MICE AB The RSH/Smith-Lemli-Opitz syndrome (RSH/SLOS) is a human autosomal recessive syndrome characterized by multiple malformations, a distinct behavioral phenotype with autistic features and mental retardation. RSH/SLOS is due to an inborn error of cholesterol biosynthesis caused by mutation of the 3 beta -hydroxysterol Delta (7)-reductase gene, To further our understanding of the developmental and neurological processes that underlie the pathophysiology of this disorder, we have developed a mouse model of RSH/SLOS by disruption of the BP-hydroxysterol Delta (7)\reductase gene. Here we provide the biochemical, phenotypic and neurophysiological characterization of this genetic mouse model. As in human patients, the RSH/SLOS mouse has a marked reduction of serum and tissue cholesterol levels and a marked increase of serum and tissue 7-dehydrocholesterol levels. Phenotypic similarities between this mouse model and the human syndrome include intra-uterine growth retardation, variable craniofacial anomalies including cleft palate, poor feeding with an uncoordinated suck, hypotonia and decreased movement. Neurophysiological studies showed that although the response of frontal cortex neurons to the neurotransmitter gamma -amino-eta -butyric acid was normal, the response of these same neurons to glutamate was significantly impaired. This finding provides insight into potential mechanisms underlying the neurological dysfunction seen in this human mental retardation syndrome and suggests that this mouse model will allow the testing of potential therapeutic interventions. C1 NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. NIAAA, Mol & Cellular Neurobiol Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Kennedy Krieger Inst, Baltimore, MD 21205 USA. Oregon Hlth Sci Univ, Doernbecher Mem Hosp Children, Child Dev & Rehabil Ctr, Dept Pediat, Portland, OR USA. Oregon Hlth Sci Univ, Doernbecher Mem Hosp Children, Child Dev & Rehabil Ctr, Dept Med & Mol Genet, Portland, OR USA. NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Porter, FD (reprint author), NICHHD, Heritable Disorders Branch, NIH, Bldg 10,Room 9S241,10 Ctr Dr, Bethesda, MD 20892 USA. OI Battaile, Kevin/0000-0003-0833-3259; Steiner, Robert/0000-0003-4177-4590; Wassif, Christopher/0000-0002-2524-1420 FU NCRR NIH HHS [RR00334-33S3]; NICHD NIH HHS [5P30-HD33703-04] NR 48 TC 110 Z9 115 U1 0 U2 5 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 MAR 15 PY 2001 VL 10 IS 6 BP 555 EP 564 DI 10.1093/hmg/10.6.555 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 412BH UT WOS:000167533800001 PM 11230174 ER PT J AU Sunyaev, S Ramensky, V Koch, I Lathe, W Kondrashov, AS Bork, P AF Sunyaev, S Ramensky, V Koch, I Lathe, W Kondrashov, AS Bork, P TI Prediction of deleterious human alleles SO HUMAN MOLECULAR GENETICS LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISMS; HUMAN GENES; CANDIDATE GENES; SEQUENCE; HEMOCHROMATOSIS; ALIGNMENTS; DIVERSITY; SELECTION; DATABASE; MUTATION AB Single nucleotide polymorphisms (SNPs) constitute the bulk of human genetic variation, occurring with an average density of similar to1/1000 nucleotides of a genotype, SNPs are either neutral allelic variants or are under selection of various strengths, and the impact of SNPs on fitness remains unknown. Identification of SNPs affecting human phenotype, especially leading to risks of complex disorders, is one of the key problems of medical genetics. SNPs in protein-coding regions that cause amino acid variants (nonsynonymous cSNPs) are most likely to affect phenotypes. We have developed a straightforward and reliable method based on physical and comparative considerations that estimates the impact of an amino acid replacement on the three-dimensional structure and function of the protein, We estimate that similar to 20% of common human non-synonymous SNPs damage the protein. The average minor allele frequency of such SNPs in our data set was two times lower than that of benign non-synonymous SNPs, The average human genotype carries approximately 10(3) damaging nonsynonymous SNPs that together cause a substantial reduction in fitness. C1 European Mol Biol Lab, D-69117 Heidelberg, Germany. Max Delbruck Ctr Mol Med, D-13122 Berlin, Germany. VA Engelhardt Mol Biol Inst, Moscow 117984, Russia. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. RP Bork, P (reprint author), European Mol Biol Lab, Meyerhofstr 1, D-69117 Heidelberg, Germany. RI Koch, Ina/D-8899-2011; Bork, Peer/F-1813-2013 OI Bork, Peer/0000-0002-2627-833X NR 36 TC 784 Z9 808 U1 7 U2 31 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 MAR 15 PY 2001 VL 10 IS 6 BP 591 EP 597 DI 10.1093/hmg/10.6.591 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 412BH UT WOS:000167533800005 PM 11230178 ER PT J AU Ahmed, FA Tomarev, SI AF Ahmed, FA Tomarev, SI TI Rat Myoc/Tigr mRNA levels in the eye after experimentally-induced neuronal degeneration. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, NIH, Mol & Dev Biol Lab, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 3014 BP S562 EP S562 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392102980 ER PT J AU Alam, S Sakurai, S Tsai, JY Sato, S AF Alam, S Sakurai, S Tsai, JY Sato, S TI Establishment of human retinal pericytes cell lines by oncogene transfection. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1099 BP S205 EP S205 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101090 ER PT J AU Alexandridou, A Elliot, S Espinosa, D Hernandez, E Csaky, KG Cousins, SW AF Alexandridou, A Elliot, S Espinosa, D Hernandez, E Csaky, KG Cousins, SW TI Gender differences in susceptibility of mice to sub-RPE deposit formation. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Bascom Palmer Eye Inst, Miami, FL 33136 USA. NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1200 BP S223 EP S223 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101191 ER PT J AU Astuto, LM Orten, DJ Weston, MD Fields, RR Askew, JW Bork, JM Morrell, RJ Kremer, H Cremers, CWRJ Kimberling, WJ AF Astuto, LM Orten, DJ Weston, MD Fields, RR Askew, JW Bork, JM Morrell, RJ Kremer, H Cremers, CWRJ Kimberling, WJ TI Identification of Novel CDH23 mutations in Usher 1D and DFNB12 patients. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Boys Town Natl Res Hosp, Gene Marker Lab, Omaha, NE 68131 USA. Univ Nijmegen Hosp, Dept Otorhinolaryngol, NL-6500 HB Nijmegen, Netherlands. NIH, Genet Mol Lab, Rockville, MD USA. RI Kremer, Hannie/F-5126-2010; Cremers, C.W.R.J./L-4254-2015 OI Kremer, Hannie/0000-0002-0841-8693; NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 3463 BP S644 EP S644 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392103427 ER PT J AU Augustin, WG Buggage, RR Smith, JA Roy, C Levy-Clarke, GA Chan, CC Nussenblatt, RB AF Augustin, WG Buggage, RR Smith, JA Roy, C Levy-Clarke, GA Chan, CC Nussenblatt, RB TI Fluorescein angiogram interpretation in the diagnosis of primary intraocular lymphoma. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NIH, NEI, Immunol Lab, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 2489 BP S462 EP S462 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392102458 ER PT J AU Avichezer, D Kennedy, MC Gery, I Chan, CC Lewis, GM Caspi, RR AF Avichezer, D Kennedy, MC Gery, I Chan, CC Lewis, GM Caspi, RR TI Peripheral induction of immunologic tolerance and protection from ocular autoimmunity by adoptive transfer of lymphoid cells expressing endogenous IRBP. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract 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 BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 4914 BP S914 EP S914 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392104877 ER PT J AU Baffi, J Byrnes, G Cousins, SW Csaky, K AF Baffi, J Byrnes, G Cousins, SW Csaky, K TI The recruitment of inflammatory cells into vascular endothelial growth factor (VEGF) induced choroidal neovascularization (CNV) in the rat. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NIH, NEI, Ocular Gene Therapy Sect, Immunol Lab, Bethesda, MD USA. Natl Naval Med Ctr, Bethesda, MD USA. Bascom Palmer Eye Inst, Miami, FL 33136 USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1221 BP S227 EP S227 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101212 ER PT J AU Barr, JT Gordon, MO Wilson, BS Zadnik, K Edrington, TB McMahon, TT Everett, DF AF Barr, JT Gordon, MO Wilson, BS Zadnik, K Edrington, TB McMahon, TT Everett, DF TI Factors associated with incident corneal scarring in the collaborative longitudinal evaluation of keratoconus (CLEK) Study. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Ohio State Univ, Coll Optometry, CLEK Study Grp, Columbus, OH 43210 USA. Univ Washington, Sch Med, Seattle, WA 98195 USA. So Calif Coll Optometry, Fullerton, CA 92634 USA. Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL 60612 USA. NEI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 4737 BP S883 EP S883 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392104700 ER PT J AU Becerra, SP Wu, YQ Montuenga, L Wong, P Pfeffer, B AF Becerra, SP Wu, YQ Montuenga, L Wong, P Pfeffer, B TI Pigment epithelium-derived factor (PEDF) in the monkey eye: Apical secretion from the retinal pigment epithelium. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NIH, NEI, Retinal Cell & Mol Biol Lab, Bethesda, MD 20892 USA. NIH, NCI, DCS, Bethesda, MD USA. Univ Navarra, Dept Histol, E-31080 Pamplona, Spain. Univ Alberta, Dept Sci Biol, Edmonton, AB, Canada. Bausch & Lomb Inc, Valley Cottage, NY USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 4134 BP S772 EP S772 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392104097 ER PT J AU Becker, KG AF Becker, KG TI Comparative genomics of autoimmune disease and susceptibility/resistance to infectious diseases. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NIA, NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 24 BP S4 EP S4 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392100014 ER PT J AU Bettelheim, FA Lizak, MJ Zigler, JS AF Bettelheim, FA Lizak, MJ Zigler, JS TI Proton magnetic resonance imaging and relaxation study of human lenses under pressure. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Adelphi Univ, Garden City, NY 11530 USA. NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1530 BP S283 EP S283 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101520 ER PT J AU Buggage, RR Shen, DF Suedekum, B Tuaillon, N Chan, CC AF Buggage, RR Shen, DF Suedekum, B Tuaillon, N Chan, CC TI Role of apoptosis in a murine model of acquired toxoplasmosis. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. Univ Missouri, Sch Med, Kansas City, MO 64108 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 3125 BP S582 EP S582 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392103090 ER PT J AU Caruso, RC Ayres, LM Hertle, RW Kaiser-Kupfer, MI AF Caruso, RC Ayres, LM Hertle, RW Kaiser-Kupfer, MI TI Diagnosis of optic chiasm decussation anomalies with steady-state flash visual evoked potentials. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 365 BP S66 EP S66 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392100355 ER PT J AU Chadid, S Yuan, P Lutz, RJ King, BA Csaky, KG Robinson, MR AF Chadid, S Yuan, P Lutz, RJ King, BA Csaky, KG Robinson, MR TI Doxycycline intravitreal implants for choroidal neovascularization. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NIH, ORS, Div Bioengn & Phys Sci Program, Bethesda, MD USA. NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. NIH, NEI, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 927 BP S173 EP S173 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392100918 ER PT J AU Chan, CC Koch, CA Kaiser-Kupfer, MI Parry, DM Zhuang, ZP Vortmeyer, AO AF Chan, CC Koch, CA Kaiser-Kupfer, MI Parry, DM Zhuang, ZP Vortmeyer, AO TI Loss of heterozygosity for the NF2 gene in retinal but not iris lesions of patients with neurofibromatosis 2. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, Bethesda, MD 20892 USA. NINDS, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. RI Koch, Christian/A-4699-2008 OI Koch, Christian/0000-0003-3127-5739 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1810 BP S335 EP S335 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101780 ER PT J AU Cheng, QF Zigler, JS AF Cheng, QF Zigler, JS TI Lovastatin-induced cataract can be prevented by geranylgeranyl pyrophosphate. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, Lab Mechanisms Ocular Dis, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 2887 BP S538 EP S538 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392102854 ER PT J AU Chew, EY SanGiovanni, JP Klebanoff, M Remaley, NA Reed, G Sugimoto, T Bateman, JB AF Chew, EY SanGiovanni, JP Klebanoff, M Remaley, NA Reed, G Sugimoto, T Bateman, JB TI Risk factors for and prevalence of infantile cataract. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, Bethesda, MD 20892 USA. NICHHD, Bethesda, MD 20892 USA. Univ Colorado, Denver, CO 80202 USA. RI SanGiovanni, John Paul/A-7605-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 2870 BP S535 EP S535 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392102837 ER PT J AU Ciulla, TA Criswell, MH Robinson, MR King, BA Hill, TE Yuan, P Csaky, CG AF Ciulla, TA Criswell, MH Robinson, MR King, BA Hill, TE Yuan, P Csaky, CG TI Choroidal neovascular membrane (cnvm) inhibition in rat with intraocular sustained-release triamcinolone acetonide micro-implants. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Indiana Univ, Sch Med, Dept Ophthalmol, Indianapolis, IN 46202 USA. NEI, NIH, Bethesda, MD 20892 USA. NIH, Bioengn & Phys Sci Program, OD, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 2804 BP S521 EP S521 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392102771 ER PT J AU Cohen, CS Hertle, RW Schiffmann, R Maybodi, M FitzGibbon, EJ Yang, D AF Cohen, CS Hertle, RW Schiffmann, R Maybodi, M FitzGibbon, EJ Yang, D TI Vertical saccade main sequence in type 3 Gaucher's disease. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Washington Hosp Ctr, Washington Natl Eye Ctr, Washington, DC 20010 USA. NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 3350 BP S623 EP S623 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392103314 ER PT J AU Colvis, CM Garland, DL AF Colvis, CM Garland, DL TI Identification of cleaved intermediates of lens beta B2-crsyatllin. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NIH, NEI, Lab Mechanisms Ocular Dis, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1581 BP S292 EP S292 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101571 ER PT J AU Coyle, BM Papagiotas, SS Choi, G Piatigorsky, J West-Mays, JA AF Coyle, BM Papagiotas, SS Choi, G Piatigorsky, J West-Mays, JA TI AP-2 alpha transcription factor controls cell migration in the developing lens. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 New England Med Ctr, Boston, MA 02111 USA. NIH, NEI, LMDB, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 4951 BP S922 EP S922 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392104914 ER PT J AU Crouch, RK Moiseyev, G Goletz, P Bealle, G Redmond, TM Ma, JX AF Crouch, RK Moiseyev, G Goletz, P Bealle, G Redmond, TM Ma, JX TI RPE65 is essential but not sufficient for production of 11-cis retinal. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Med Univ S Carolina, Dept Ophthalmol, Charleston, SC 29425 USA. NEI, Bethesda, MD 20892 USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 3525 BP S655 EP S655 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392103489 ER PT J AU Csaky, K Baffi, J Byrnes, G Cousins, SW AF Csaky, K Baffi, J Byrnes, G Cousins, SW TI Strain specific phenotypic variation in vascular endothelial growth factor (VEGF) induced choroidal neovascularization (CNV) in the rat. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NIH, NEI, Immunol Lab, Ocular Gene Therapy Sect, Bethesda, MD USA. Natl Naval Med Ctr, Bethesda, MD 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 BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1220 BP S227 EP S227 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101211 ER PT J AU Cui, W Tomarev, SI Swain, PK Swaroop, A Duncan, MK AF Cui, W Tomarev, SI Swain, PK Swaroop, A Duncan, MK TI c-Maf is coexpressed with NRL and Prox1 in lens fiber cells and able to activate chicken beta B1 crystallin gene expression. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Univ Delaware, Dept Biol Sci, Newark, DE USA. NEI, LMDB, Bethesda, MD USA. Univ Michigan, WK Kellogg Eye Ctr, Dept Human Genet, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 2878 BP S536 EP S536 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392102845 ER PT J AU Curcio, CA Bailey, T Kruth, HS AF Curcio, CA Bailey, T Kruth, HS TI Cholesterol in basel deposits and drusen of eyes with age-related maculopathy (ARM): filipin histochemistry. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Univ Alabama, Dept Ophthalmol, Birmingham, AL 35294 USA. NHLBI, Sect Expt Atherosclerosis, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 5054 BP S944 EP S944 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392105017 ER PT J AU Cusick, M Chew, EY SanGiovanni, JP Dabas, KH Csaky, KG Reed, GF Ferris, FL AF Cusick, M Chew, EY SanGiovanni, JP Dabas, KH Csaky, KG Reed, GF Ferris, FL TI Results of the National Eye Institute-Visual Function Questionnaire-25 (NEI-VFQ 25) in patients with diabetic retinopathy. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Georgetown Univ, Sch Med, Washington, DC USA. NEI, Bethesda, MD 20892 USA. RI SanGiovanni, John Paul/A-7605-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 3758 BP S698 EP S698 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392103721 ER PT J AU D'Amato, RJ Rohan, R Joussen, A Fernandez, A Poulaki, V Ma, J Liu, S Redmond, TM Adamis, A Schwesinger, C AF D'Amato, RJ Rohan, R Joussen, A Fernandez, A Poulaki, V Ma, J Liu, S Redmond, TM Adamis, A Schwesinger, C TI Intrachoroidal neovascularization in transgenic mice overexpressing vascular endothelial growth factor in the retinal pigment epithelium. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Childrens Hosp, Surg Res Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Freiburg, Freiburg, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 2806 BP S522 EP S522 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392102773 ER PT J AU Dias, L Manny, R Hyman, L Fera, K AF Dias, L Manny, R Hyman, L Fera, K CA COMET Grp TI Ocular factors and self-perceptions in myopic children SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, NIH, Bethesda, MD USA. Univ Alabama, Sch Optometry, Birmingham, AL 35294 USA. Penn Coll Optometry, Philadelphia, PA 19141 USA. New England Coll Optometry, Boston, MA USA. Univ Houston, Coll Optometry, Houston, TX USA. Univ Med Ctr, Stony Brook, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 2101 BP S390 EP S390 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392102071 ER PT J AU Djalilian, AR Nagineni, CN Smith, JA Nussenblatt, RB Hooks, JJ AF Djalilian, AR Nagineni, CN Smith, JA Nussenblatt, RB Hooks, JJ TI Effects of dexamethasone and cyclosporin A on the production of cytokines by human corneal epithelial cells and fibroblasts. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract 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 BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 3086 BP S575 EP S575 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392103051 ER PT J AU Espinosa, D Hernandez, E Csaky, KG Cousins, SW AF Espinosa, D Hernandez, E Csaky, KG Cousins, SW TI Age may be an independent risk factor for severity of experimental choroidal neovascularization (CNV). SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NIH, NEI, Bethesda, MD 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 BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1326 BP S245 EP S245 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101316 ER PT J AU Fan, J Hollowell, GP Chepelinsky, AB AF Fan, J Hollowell, GP Chepelinsky, AB TI Identification of AP2 alpha-binding proteins using two human cDNA phage display libraries. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 3554 BP S660 EP S660 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392103518 ER PT J AU Fine, HF Shen, DF Suedekum, BK Buggage, RR Nussenblatt, RB Chan, CC AF Fine, HF Shen, DF Suedekum, BK Buggage, RR Nussenblatt, RB Chan, CC TI Kinetics of vascular endothelial growth factor expression in experimental autoimmune uveitis. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Jamaica Plain, MA USA. NEI, Immunol Lab, Bethesda, MD 20892 USA. Univ Missouri, Sch Med, Kansas City, MO 64108 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 4923 BP S916 EP S916 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392104886 ER PT J AU Gabison, EE Hoang-Xuan, T Kure, T Ye, HQ Ang, RT Kato, T Chang, JH Shapiro, SD Azar, DT AF Gabison, EE Hoang-Xuan, T Kure, T Ye, HQ Ang, RT Kato, T Chang, JH Shapiro, SD Azar, DT TI Enhanced expression of human metalloelastase in ocular surface disorders. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. Univ Paris 07, Dept Ophthalmol, Bichat Hosp, Paris, France. Univ Paris 07, Fdn A De Rothschild, Paris, France. NEI, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Barnes Jewish Hosp, Dept Internal Med & Cell Biol & Physiol, St Louis, MO USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 2616 BP S485 EP S485 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392102585 ER PT J AU Gouras, P Kong, J Salchow, DJ Ekesten, B Tsang, SH Redmond, M AF Gouras, P Kong, J Salchow, DJ Ekesten, B Tsang, SH Redmond, M TI Retinal degeneration and RPE transplantation in Rpe65-/- mice. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Columbia Univ, Dept Ophthalmol, New York, NY 10027 USA. SUAS, Unit Ophthalmol, Uppsala, Sweden. Univ Calif Los Angeles, Jules Stein Eye Inst, Los Angeles, CA 90024 USA. NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 4167 BP S778 EP S778 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392104130 ER PT J AU Guerami, AH Yang, D Maybodi, M Hertle, RW Fitzgibbon, EJ AF Guerami, AH Yang, D Maybodi, M Hertle, RW Fitzgibbon, EJ TI Latency of gaze dependent optotype recognition in patients with congenital nystagmus (CN) versus control subjects. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NIH, NEI, Sensorimotor Res Lab, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1719 BP S318 EP S318 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101694 ER PT J AU Haque, R Chong, NW Klein, DC Iuvone, PM AF Haque, R Chong, NW Klein, DC Iuvone, PM TI Melatonin biosynthesis in chick retinal photoreceptor cells: Developmental and cAMP-stimulated expression of serotonin N-acetyltransferase promoter constructs. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Emory Univ, Atlanta, GA 30322 USA. NICHD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1914 BP S354 EP S354 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101884 ER PT J AU Hatton, MP Chen, PW Wistow, G Perez, VL Ksander, BR AF Hatton, MP Chen, PW Wistow, G Perez, VL Ksander, BR TI Melastatin-2 gene transcription in normal and malignant uveal melanocytes. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. Schepens Eye Res Inst, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. NEI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 598 BP S110 EP S110 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392100588 ER PT J AU Hertle, RW Dell'Osso, LF FitzGibbon, EJ Thompson, DJ Yang, D Mellow, SD AF Hertle, RW Dell'Osso, LF FitzGibbon, EJ Thompson, DJ Yang, D Mellow, SD TI Horizontal rectus tenotomy in the treatment of congenital nystagmus (CN): Results of a study in ten adult patients (phase 1). SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NIH, NEI, Sensorimotor Res Lab, Bethesda, MD USA. Case Western Reserve Univ, Dept Neurol, Cleveland, OH 44106 USA. Case Western Reserve Univ, Dept Biomed Engn, Cleveland, OH 44106 USA. VA Med Ctr, Cleveland, OH USA. EMMES Corp, Potomac, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1720 BP S319 EP S319 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101695 ER PT J AU Hollyfield, JG Foletta, VC Nishiyama, K Rayborn, ME Shadrach, KG Young, WS AF Hollyfield, JG Foletta, VC Nishiyama, K Rayborn, ME Shadrach, KG Young, WS TI Spatial and temporal patterns of SPACRCAN gene expression and protein synthesis during development of the retina and pineal gland of the rat. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Cleveland Clin Fdn, Cole Eye Inst, Cleveland, OH USA. NIH, NIMH, Bethesda, MD USA. RI Young, W Scott/A-9333-2009 OI Young, W Scott/0000-0001-6614-5112 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1977 BP S366 EP S366 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101947 ER PT J AU Hough, RB Piatigorsky, J AF Hough, RB Piatigorsky, J TI The characterization of a corneal enzyme in the rabbit: ALDH1. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 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 BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 3158 BP S588 EP S588 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392103122 ER PT J AU Jinks, RN Dabdoub, A Payne, R AF Jinks, RN Dabdoub, A Payne, R TI Protein kinase C-induced internalization of photosensitive membrane in Limulus ventral photoreceptors. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Franklin & Marshall Coll, Dept Biol, Lancaster, PA 17604 USA. NIDCD, NIH, Rockville, MD USA. Univ Maryland, Dept Biol, College Pk, MD 20742 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 4123 BP S769 EP S769 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392104086 ER PT J AU John, M Carper, DA Wang, RR Ma, W Spector, A AF John, M Carper, DA Wang, RR Ma, W Spector, A TI Microarray analysis of rat lenses exposed to oxidative stress. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NIH, NEI, Lab Mechanisms Ocular Dis, Bethesda, MD 20892 USA. Columbia Univ, Dept Ophthalmol, New York, NY 10027 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 546 BP S100 EP S100 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392100536 ER PT J AU Kador, PF Takahashi, Y Akagi, Y Sato, S Wyman, M AF Kador, PF Takahashi, Y Akagi, Y Sato, S Wyman, M TI Inhibition of cataract formation indicates inhibition of retinal capillary pericyte degeneration in galactose-fed dogs. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, Lab Ocular Therapeut, NIH, Bethesda, MD 20892 USA. Fukui Med Sch, Fukui 91011, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1119 BP S208 EP S208 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101110 ER PT J AU Kannan, R Ouyang, B Wawrousek, EF Kaplowitz, N Song, Z Andley, UP AF Kannan, R Ouyang, B Wawrousek, EF Kaplowitz, N Song, Z Andley, UP TI Mechanisms of GSH regulation by alpha A-crystallin in alpha A expressing human lens epithelial cells (HLE-B3) and alpha A- knockout mouse lenses. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Univ So Calif, Sch Med, Los Angeles, CA USA. NEI, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Ophthalmol & Visual Sci, Cataract Res Ctr, St Louis, MO 63110 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1570 BP S290 EP S290 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101560 ER PT J AU Kanungo, J Piatigorsky, J AF Kanungo, J Piatigorsky, J TI Gelsolin, the major cytoplasmic corneal protein in zebrafish is expressed early in development. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 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 BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 2564 BP S475 EP S475 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392102533 ER PT J AU Kim, SJ Shen, DF Zhang, MF Wawrousek, EF Gery, I Chan, CC AF Kim, SJ Shen, DF Zhang, MF Wawrousek, EF Gery, I Chan, CC TI Immune-mediated ocular inflammation: Detection of cytokines by microdissection. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, Bethesda, MD 20892 USA. Howard Hughes Med Inst, NIH, Res Scholars Program, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 4919 BP S915 EP S915 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392104882 ER PT J AU King, BA Chadid, S Lutz, RJ Nussenblatt, RB Wilson, WH Yuan, P Rosenberg, J Dedrick, RL Chan, CC Robinson, MR AF King, BA Chadid, S Lutz, RJ Nussenblatt, RB Wilson, WH Yuan, P Rosenberg, J Dedrick, RL Chan, CC Robinson, MR TI Pharmacokinetics and ocular toxicity of intravitreal Rituxan injections SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 ORS, Div Bioengn & Phys Sci, NIH, Bethesda, MD USA. NEI, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. Idec Pharmaceut Corp, San Diego, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 941 BP S176 EP S176 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392100932 ER PT J AU Ledee, DR Zelenka, PS AF Ledee, DR Zelenka, PS TI The Cdk5 activating protein, p39, is expressed in lens but not in cornea. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1558 BP S288 EP S288 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101548 ER PT J AU Levinson, RD Smith, JR Holland, GN Jabs, DA Robinson, MR Whitcup, SM Rosenbaum, JT AF Levinson, RD Smith, JR Holland, GN Jabs, DA Robinson, MR Whitcup, SM Rosenbaum, JT TI Differential efficacy of tumor necrosis factor inhibition in the management of ocular inflammatory disease and associated rheumatic disease SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Univ Calif Los Angeles, Jules Stein Eye Inst, Los Angeles, CA 90024 USA. Oregon Hlth Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. NIH, NEI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 3815 BP S708 EP S708 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392103778 ER PT J AU Levy-Clarke, GA Buggage, RR Smith, JA AF Levy-Clarke, GA Buggage, RR Smith, JA TI The spectrum of corneal and external disease findings in a cohort of patients, of African descent with, human T-cell lymphotrophic virus type-1(HTLV-1) induced adult T-cell leukemia/lymphoma. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract 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 BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 2483 BP S461 EP S461 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392102452 ER PT J AU Lewis, KG Robinson, MR Levy-Clark, G Chan, CC Smith, JA AF Lewis, KG Robinson, MR Levy-Clark, G Chan, CC Smith, JA TI Corneal stem cell deficiency following therapy for primary intraocular lymphoma. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1801 BP S333 EP S333 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101771 ER PT J AU Lizak, MJ Kador, PF AF Lizak, MJ Kador, PF TI In vivo measurement of aldose reductase inhibitor activity in the rabbit lenses by MRI. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, Lab Ocular Therapeut, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1534 BP S283 EP S283 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101524 ER PT J AU Lopez, P Caruso, RC Kaiser-Kupfer, MI AF Lopez, P Caruso, RC Kaiser-Kupfer, MI TI The normal range of fast oscillations of the human electro-oculogram. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NIH, NEI, Ophthalm Genet & Visual Funct Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 396 BP S72 EP S72 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392100386 ER PT J AU Magone, MT Gelderman, MP Schuck, P Whitcup, SM Chan, CC AF Magone, MT Gelderman, MP Schuck, P Whitcup, SM Chan, CC TI Allergic conjunctivitis in CD40 ligand deficient mice after treatment with anti B7-1 monoclonal antibody (mAb). SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Georgetown Univ, Med Ctr, Ctr Sight, Washington, DC 20007 USA. NEI, NIH, Bethesda, MD 20892 USA. NIH, Div Bioengn & Phys Sci, OD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 3100 BP S577 EP S577 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392103065 ER PT J AU Mahdi, RM Zhang, MF Gery, I Egwuagu, CE AF Mahdi, RM Zhang, MF Gery, I Egwuagu, CE TI Suppressors of cytokine signaling transcription factors (SOCS) are differentially expressed in Th1 and Th2 cells. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 4989 BP S930 EP S930 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392104952 ER PT J AU Maldonado, VK Hertle, RW AF Maldonado, VK Hertle, RW TI Clinical and ocular motor analysis of congenital nystagmus in the first six months of life. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Washington Hosp Ctr, Dept Ophthalmol, Washington, DC 20010 USA. NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 879 BP S164 EP S164 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392100870 ER PT J AU Mao, Y Xiang, H Wang, J Li, DW Reddan, J Piatigorsky, J Horvitz, J AF Mao, Y Xiang, H Wang, J Li, DW Reddan, J Piatigorsky, J Horvitz, J TI Human Bcl-2 gene down-regulates expression of alpha crystallin genes in rabbit lens epithelial cells, N/N1003A. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Univ Med & Dent New Jersey, Sch Osteopath Med, Dept Mol Biol, Stratford, NJ 08084 USA. Oakland Univ, Dept Biol Sci, Rochester, MI 48309 USA. NEI, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Sch Med, Jules Stein Eye Inst, Los Angeles, CA 90024 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 4730 BP S881 EP S881 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392104693 ER PT J AU Marin-Castano, ME Striker, LJ Striker, GE Elliot, SJ Karl, M Csaky, KG Cousins, SW AF Marin-Castano, ME Striker, LJ Striker, GE Elliot, SJ Karl, M Csaky, KG Cousins, SW TI 17 beta-estradiol regulates expression of both estrogen receptor subtypes and matrix metalloproteinase (MMP-2) in human retinal pigment epithelium (RPE). SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Univ Miami, Sch Med, Bascom Palmer Eye Inst, Miami, FL USA. Univ Miami, Sch Med, Vasc Biol Inst, Miami, FL USA. NEI, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1921 BP S355 EP S355 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101891 ER PT J AU Miles, FA AF Miles, FA TI Context dependent modulation of short-latency visually driven eye movements. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 602 BP S111 EP S111 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392100593 ER PT J AU Monroy, D Marin-Castafio, ME Striker, LJ Striker, GE Elliot, SJ Csaky, KG Cousins, SW AF Monroy, D Marin-Castafio, ME Striker, LJ Striker, GE Elliot, SJ Csaky, KG Cousins, SW TI RPE expression of matrix metalloproteinase (MMP-2) and MCP-1 after different kinds of injury. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Univ Miami, Sch Med, Bascom Palmer Eye Inst, Miami, FL USA. Univ Miami, Sch Med, Vasc Biol Inst, Miami, FL USA. NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 4060 BP S758 EP S758 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392104023 ER PT J AU Morgan, GA Gao, J Smith, JA Whitcup, SM Russell, DL Tieu, D Ngo, M Stern, ME AF Morgan, GA Gao, J Smith, JA Whitcup, SM Russell, DL Tieu, D Ngo, M Stern, ME TI The role of ICAM-1 in the pathophysiology of keratoconjunctivitis sicca (KCS). SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Allergan Pharmaceut Inc, Irvine, CA 92715 USA. NEI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1413 BP S261 EP S261 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101403 ER PT J AU Nagineni, CN Pardhasaradhi, K Detrick, B Hooks, JJ AF Nagineni, CN Pardhasaradhi, K Detrick, B Hooks, JJ TI Expression of VEGF, MMP-9 and TIMP-1 by human retinal pigment epithelial cells: Role of TGF-BETA. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NIH, NEI, Immunol Lab, Bethesda, MD USA. Walter Reed Army Med Inst, Washington, DC 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 BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 512 BP S93 EP S93 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392100502 ER PT J AU Neal, RE Zigler, JS Bettelheim, FA AF Neal, RE Zigler, JS Bettelheim, FA TI Examination of the equilibrium between denatured alpha-lactalbumin and the alpha-crystallin/alpha-lactalbumin chaperone complex. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NIH, NEI, Lab Mecan Ocular Dis, Bethesda, MD 20892 USA. Adelphi Univ, Dept Chem, Garden City, NY 11530 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1588 BP S293 EP S293 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101578 ER PT J AU Nees, D Piatigorsky, J AF Nees, D Piatigorsky, J TI A highly expressed 68 kD protein in mouse cornea SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 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 BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 3157 BP S588 EP S588 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392103121 ER PT J AU Negash, S Wang, HS Gao, C Zelenka, PS AF Negash, S Wang, HS Gao, C Zelenka, PS TI Cdk5 promotes lens epithelial cell adhesion. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. Natl Yang Ming Univ, Dept Anat, Taipei 112, Taiwan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1557 BP S288 EP S288 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101547 ER PT J AU Nelson, RF Bender, AM Connaughton, VP AF Nelson, RF Bender, AM Connaughton, VP TI Na plus /K plus ATPase adds long-term hyperpolarizing components to glutamate responses of zebrafish retinal neurons. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. American Univ, Dept Biol, Washington, DC 20016 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 3596 BP S668 EP S668 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392103559 ER PT J AU Nussbaum, R AF Nussbaum, R TI Why mice are superior to humans: Studies on mice deficient in the enzyme that causes Lowe syndrome in humans. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NHGRI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 23 BP S4 EP S4 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392100013 ER PT J AU Rait, VK Kador, PF AF Rait, VK Kador, PF TI Rapid method for the isolation of Aldose Reductase ligand with immobilized enzyme SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, Lab Ocular Therapeut, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1531 BP S283 EP S283 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101521 ER PT J AU Redmond, TM Bhatti, R Yu, S Fariss, RN Cunningham, FX Gentleman, S AF Redmond, TM Bhatti, R Yu, S Fariss, RN Cunningham, FX Gentleman, S TI Expression of beta-carotene 15, 15 ' dioxygenase in retina and RPE. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, LRCMB, NIH, Bethesda, MD 20892 USA. Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. NEI, LMOD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 4146 BP S774 EP S774 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392104109 ER PT J AU Reed, GF AF Reed, GF TI Combining correlations for both eyes. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, Biometry Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 4631 BP S862 EP S862 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392104594 ER PT J AU Rhee, DJ Russell, P AF Rhee, DJ Russell, P TI Prostaglandin receptor and transporter exist in trabecular meshwork endothelial cells. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 753 BP S141 EP S141 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392100744 ER PT J AU Roberts, AB AF Roberts, AB TI Signal transduction and the fibrotic response. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 8 BP S1 EP S1 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392100004 ER PT J AU Roberts, JE Kukielczak, B Bielski, P Sik, R Chignell, CF Hu, DN AF Roberts, JE Kukielczak, B Bielski, P Sik, R Chignell, CF Hu, DN TI The role of A2E in the protection of and light damage to human retinal pigment epithelial cells. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Fordham Univ, New York, NY 10023 USA. NIEHS, LPC, Res Triangle Pk, NC 27709 USA. New York Eye & Ear Infirm, Tissue Culture Ctr, New York, NY 10003 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 5049 BP S943 EP S943 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392105012 ER PT J AU Robinson, MR Yuan, P Baffi, J Chadid, S Dedrick, RL Byrnes, G King, BA Csaky, KG AF Robinson, MR Yuan, P Baffi, J Chadid, S Dedrick, RL Byrnes, G King, BA Csaky, KG TI The efficacy of 2-methoxyestradiol intravitreal micro-implants in a rat model of choroidal neovascularization SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NIH, NEI, Bethesda, MD USA. NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. NIH, ORS, Bioengn & Phys Sci Program, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 926 BP S173 EP S173 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392100917 ER PT J AU Russell, P Rhee, DJ AF Russell, P Rhee, DJ TI Osteonectin is expressed in human trabecular meshwork and cultured meshwork cells. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 752 BP S141 EP S141 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392100743 ER PT J AU Sakurai, S Alam, S Tsai, JY Sato, S AF Sakurai, S Alam, S Tsai, JY Sato, S TI The effects of prostaglandins on the cell variability of human retinal capillary pericytes. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NIH, NEI, Lab Ocular Therapeut, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1097 BP S204 EP S204 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101088 ER PT J AU Seddon, JM Rosner, B Sperduto, RD Yannuzzi, L Haller, JA Blair, NP Willett, W AF Seddon, JM Rosner, B Sperduto, RD Yannuzzi, L Haller, JA Blair, NP Willett, W TI Dietary fat and risk of advanced age-related macular degeneration. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. NEI, Bethesda, MD 20892 USA. Manhattan Eye Ear & Throat Hosp, New York, NY 10021 USA. Wilmer Eye Inst, Baltimore, MD USA. Univ Illinois, Chicago, IL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 2419 BP S448 EP S448 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392102389 ER PT J AU Seko, Y Yu, X Ragheb, J AF Seko, Y Yu, X Ragheb, J TI Analysis of the mouse IL-2 mRNA transcriptional initiation site. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract 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 BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1030 BP S191 EP S191 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101021 ER PT J AU Self, CA Chruysberg, L Sanders, J Kohn, EC Yuan, P Franklin, AJ Edelhauser, HF AF Self, CA Chruysberg, L Sanders, J Kohn, EC Yuan, P Franklin, AJ Edelhauser, HF TI Scleral permeability of carboxyamido-triazole (CAI). SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Univ Tennessee, COM, Chattanooga Unit, Dept Ophthalmol, Chattanooga, TN USA. Emory Univ, Dept Ophthalmol, Atlanta, GA 30322 USA. NEI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 4963 BP S925 EP S925 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392104926 ER PT J AU Sergeev, YV Wingfield, PT Hejtmancik, JF AF Sergeev, YV Wingfield, PT Hejtmancik, JF TI The role of domain structure in association of beta-crystallins. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NIH, NEI, OGVFB, Bethesda, MD USA. NIH, NIAMSD, PEL, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1583 BP S293 EP S293 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101573 ER PT J AU Shen, DF Tuaillon, N Buggage, RR Chan, CC AF Shen, DF Tuaillon, N Buggage, RR Chan, CC TI IFN-gamma plays major role in MCP-1 deficient mice infected with Toxoplasma gondii (T-gondii). SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 3128 BP S582 EP S582 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392103093 ER PT J AU Silk, W Cousins, SW Csaky, K AF Silk, W Cousins, SW Csaky, K TI A pilot study examining gene expression patterns in circulating monocytes and dermal fibroblasts in patients with age-related macular degeneration. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, NIH, 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 BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 4292 BP S800 EP S800 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392104255 ER PT J AU Skolik, SA AF Skolik, SA TI Severe arthritic diseases may offer protection against the development of diabetic retinopathy in some patients with IDDM & NIDDM and importantly, this "protective factor" effect seems to occurs even in patients not taking anti-inflammatory medications SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Huntington Retina Ctr, Huntington, WV USA. NIH, NEI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 4319 BP S805 EP S805 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392104282 ER PT J AU Smith, JA Reed, GF Grieshaber, SA Vanderhoof, VA Nelson, LN AF Smith, JA Reed, GF Grieshaber, SA Vanderhoof, VA Nelson, LN TI Keratoconjunctivitis sicca in patients with premature ovarian failure. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. NICHHD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 220 BP S39 EP S39 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392100210 ER PT J AU Sosne, G Szliter, EA Barrett, R Kernacki, KA Kleinman, HK Hazlett, LD AF Sosne, G Szliter, EA Barrett, R Kernacki, KA Kleinman, HK Hazlett, LD TI Thymosin beta 4 promotes corneal wound healing and decreases inflammation in vivo following alkali burn. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Henry Ford Hosp, Eye Care Serv, Detroit, MI USA. Wayne State Univ, Dept Anat & Cell Biol, Detroit, MI USA. NIH, Natl Inst Dent & Craniofacial Res, Dev Biol Lab, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 4758 BP S887 EP S887 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392104721 ER PT J AU Stiemer, RH Fischer-Lamprecht, C Wiggert, B Zoeller, M Guenthert, U Zierhut, M AF Stiemer, RH Fischer-Lamprecht, C Wiggert, B Zoeller, M Guenthert, U Zierhut, M TI Kinetics of c-erbB2 oncoprotein and CD44 isoform expression in the IRBP induced experimental autoimmune uveitis (EAU). SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Univ Tubingen, Eye Clin, Tubingen, Germany. NEI, Bethesda, MD 20892 USA. German Canc Res Ctr, D-6900 Heidelberg, Germany. Inst Immunol, Basel, Switzerland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 4915 BP S915 EP S915 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392104878 ER PT J AU Sun, G Ma, Y Gao, X Kador, PF AF Sun, G Ma, Y Gao, X Kador, PF TI Method for isolating tight-binding inhibitors of rat lens aldose reductase with minimal contamination SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, Lab Ocular Therapeut, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1532 BP S283 EP S283 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101522 ER PT J AU Tamm, ER Flugel-Koch, C Piatigorsky, J AF Tamm, ER Flugel-Koch, C Piatigorsky, J TI Overexpression of TGF-beta 1 during development prevents differentiation of the cornea in transgenic mice. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Univ Erlangen Nurnberg, Dept Anat 2, Erlangen, Germany. NEI, NIH, LMDB, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 2579 BP S477 EP S477 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392102548 ER PT J AU Tomarev, SI Zinovieva, RD Torrado, M Wistow, GJ Ahmed, F AF Tomarev, SI Zinovieva, RD Torrado, M Wistow, GJ Ahmed, F TI Characterization of gene expression in the tissues of the rat eye angle: Optimedin, a new olfactomedin-related gene highly expressed in the eye. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NIH, NEI, LMDB, Bethesda, MD USA. NIH, NEI, MSF, Bethesda, MD USA. RI Torrado, Mario/A-4889-2010 OI Torrado, Mario/0000-0001-9762-7018 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 724 BP S137 EP S137 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392100715 ER PT J AU Torrado, M Tanemoto, K Tomarev, SI AF Torrado, M Tanemoto, K Tomarev, SI TI The mouse Myoc/Tigr promoter directs protein expression to the tissues of the eye angle in adult transgenic mice. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, Mol & Dev Biol Lab, Bethesda, MD 20892 USA. NIH, NEI, Bethesda, MD USA. RI Torrado, Mario/A-4889-2010 OI Torrado, Mario/0000-0001-9762-7018 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 3035 BP S565 EP S565 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392103001 ER PT J AU Tsai, JY Yu, ZX Wawrousek, EF Pagan-Mercado, G AF Tsai, JY Yu, ZX Wawrousek, EF Pagan-Mercado, G TI Generation and characterization of SMAA-GFP mice. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, Lab Ocular Therapeut, Bethesda, MD USA. NEI, Cent Transgen Facil, Bethesda, MD USA. NHLBI, Pathol Sect, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 2734 BP S507 EP S507 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392102703 ER PT J AU Tsang, SH Jiang, M Kong, J Salchow, D Lin, CC Jahromi, S Redmond, M Goff, SP Gouras, P Farber, DB AF Tsang, SH Jiang, M Kong, J Salchow, D Lin, CC Jahromi, S Redmond, M Goff, SP Gouras, P Farber, DB TI Toward repair of retinal degenerations with differentiated and embryonic stem (ES) cells. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Univ Calif Los Angeles, Los Angeles, CA USA. Columbia Univ, Harkness Eye Inst, New York, NY USA. NIH, NEI, Bethesda, MD USA. Columbia Univ, Howard Hughes Med Inst, New York, NY 10032 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 2836 BP S528 EP S528 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392102803 ER PT J AU Tsilou, E Rubin, BI Reed, GF Iwata, F Gahl, W Kaiser-Kupfer, MI AF Tsilou, E Rubin, BI Reed, GF Iwata, F Gahl, W Kaiser-Kupfer, MI TI Late-onset anterior-segment manifestations of infantile nephropathic cystinosis. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. NEI, Div Biometry & Epidemiol, NIH, Bethesda, MD 20892 USA. NICHD, Sect Human Biomed Genet, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 375 BP S68 EP S68 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392100365 ER PT J AU Valentin, FE Brown, J Folk, JC Oh, KT Oh, DM Whitcup, SM Nussenblatt, RB AF Valentin, FE Brown, J Folk, JC Oh, KT Oh, DM Whitcup, SM Nussenblatt, RB TI The association of HLA DQ3 and A2 with multifocal choroiditis. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 Brooke Army Med Ctr, San Antonio, TX USA. Walter Reed Army Inst Res, Brooks AFB, TX USA. Univ Iowa, Dept Ophthalmol & Visual Sci, Iowa City, IA USA. NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 3060 BP S570 EP S570 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392103026 ER PT J AU Vistica, BP Zhang, MF Hung, L Kim, SJ Wawrousek, EF Gery, I AF Vistica, BP Zhang, MF Hung, L Kim, SJ Wawrousek, EF Gery, I TI Shedding new light on the pathogenesis of lens-associated uveitis. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 4918 BP S915 EP S915 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392104881 ER PT J AU Wheelock, RH Russell, P AF Wheelock, RH Russell, P TI Differential subcellular distribution of modified forms of alpha B-crystallin in U373MG glioma cells. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NIH, NEI, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1578 BP S292 EP S292 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101568 ER PT J AU Wiggert, B Duncan, T Darrow, RM Organisciak, DT AF Wiggert, B Duncan, T Darrow, RM Organisciak, DT TI Effects of light duration, genetics and dimethylthiourea on retinoid content and distribution following light induced retinal damage. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, NIH, Bethesda, MD 20892 USA. Wright State Univ, Dayton, OH 45435 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 1048 BP S195 EP S195 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392101039 ER PT J AU Xu, Z Piatigorsky, J AF Xu, Z Piatigorsky, J TI A novel corneal LIM-domain and zinc-finger protein expressed in newborn mice. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 2565 BP S475 EP S475 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392102534 ER PT J AU Yang, D Maybodi, M Hertle, RW Guerami, AH FitzGibbon, EJ AF Yang, D Maybodi, M Hertle, RW Guerami, AH FitzGibbon, EJ TI Latency of dynamic optotype recognition in patients with congenital nystagmus (CN) versus control subjects. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 883 BP S165 EP S165 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392100874 ER PT J AU Zelenka, PS Gao, CY Stepp, MA AF Zelenka, PS Gao, CY Stepp, MA TI Overexpression of Cdk5 in corneal epithelium of transgenic mice inhibits corneal wound healing. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 George Washington Univ, Washington, DC USA. NIH, NEI, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 568 BP S104 EP S104 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392100558 ER PT J AU Zhang, MF Byrnes, G Hung, L Vistica, BP Kim, SJ Wawrousek, EF Chan, CC Gery, I AF Zhang, MF Byrnes, G Hung, L Vistica, BP Kim, SJ Wawrousek, EF Chan, CC Gery, I TI Antigen induced uveitis mediated by Th1 or Th2 cells. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, NIH, Bethesda, MD 20892 USA. Natl Naval Med Ctr, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 4917 BP S915 EP S915 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392104880 ER PT J AU Zigler, JS Cheng, QF AF Zigler, JS Cheng, QF TI Effect of lovastatin on isoprenylation in the organ-cultured rat lens. SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Meeting Abstract C1 NEI, Lab Mechanisms Ocu Dis, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR 15 PY 2001 VL 42 IS 4 SU S MA 2886 BP S538 EP S538 PG 1 WC Ophthalmology SC Ophthalmology GA 427EP UT WOS:000168392102853 ER PT J AU Shotland, LI Ondrey, FG Mayo, KA Viner, JL AF Shotland, LI Ondrey, FG Mayo, KA Viner, JL TI Recommendations for cancer prevention trials using potentially ototoxic test agents SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ALPHA-DIFLUOROMETHYLORNITHINE DFMO; SENSORINEURAL HEARING-LOSS; NASOPHARYNGEAL CARCINOMA; PHASE-I; CHEMOPREVENTION; RADIATION; IRRADIATION; THRESHOLD; PROGRESS; THERAPY AB Purpose: Preventive oncology applies pharmacologic agents to reverse, retard, or halt progression of neoplastic cells to invasive malignancy, a process that may require administration of agents over long periods of rime. Although ototoxicity may be a tolerable side effect of anticancer or antimicrobial therapy, even modest ototoxicity may not be acceptable in agents developed for preventive oncology that are routinely administered to subjects who neither are, nor necessarily will become, clinically ill. Materials and Methods: Age-related shifts in hearing may occur over the course of longterm or open-ended therapy; consequently, age-adjusted norms enable researchers to better distinguish hearing loss caused by drugs from that caused by aging. Norms for hearing sensitivity are derived from the Baltimore Longitudinal Study of Aging and are the basis for the proposed audiologic monitoring recommendations. Results: Audiologic monitoring recommendations are presented that standardize patient selection, adverse event reporting, posttreatment follow up, and audiologic testing for potentially ototoxic investigational agents. Conclusion: These recommendations are applicable to trials of investigational agents as well as various classes of drugs used in routine clinical care, (C) 2001 by American Society of Clinical Oncology. C1 Natl Inst Deafness & Other Commun Disorders, Neuro Otol Branch, Hearing Sect, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, Tumor Biol Sect, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Dept Otolaryngol, Minneapolis, MN USA. CCS Associates Inc, Mt View, CA USA. RP Shotland, LI (reprint author), Natl Inst Deafness & Other Commun Disorders, Neuro Otol Branch, Hearing Sect, NIH, 9000 Rockville Pike,Bldg 10,Rm 5C-306, Bethesda, MD 20892 USA. FU NIDCD NIH HHS [DC-00016] NR 50 TC 7 Z9 7 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 15 PY 2001 VL 19 IS 6 BP 1658 EP 1663 PG 6 WC Oncology SC Oncology GA 414EG UT WOS:000167652500009 PM 11250994 ER PT J AU Breathnach, OS Freidlin, B Conley, B Green, MR Johnson, DH Gandara, DR O'Connell, M Shepherd, FA Johnson, BE AF Breathnach, OS Freidlin, B Conley, B Green, MR Johnson, DH Gandara, DR O'Connell, M Shepherd, FA Johnson, BE TI Twenty-two years of phase III trials for patients with advanced non-small-cell lung cancer: Sobering results SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SOUTHWEST-ONCOLOGY-GROUP; VINDESINE PLUS CISPLATIN; RANDOMIZED TRIAL; COMBINATION CHEMOTHERAPY; BRONCHOGENIC-CARCINOMA; SINGLE-AGENT; MITOMYCIN-C; DOXORUBICIN; CYCLOPHOSPHAMIDE; REGIMENS AB Purpose: To determine the changes in clinical trials and outcomes of patients with advanced-stage nonsmall-cell lung cancer (NSCLC) treated on phase III randomized trials initiated in North America from 1973 to 1994, Patients and Methods: Phase III trials for patients with advanced-stage NSCLC were identified through a search of the National Cancer Institute's Cancer Therapy Evaluation Program database from 1973 to 1994, contact with Cooperative Groups, and by literature search of MEDLINE. Patients with advanced NSCLC treated during a similar time interval were also examined in the SEER database. Trends were tested in the number of trials, in the number and sex of patients entered on the trials, and in survival over time, Results: Thirty-three phase III trials were initiated between 1973 and 1994. Twenty-four trials (73%) were initiated within the first half of this period (1973 to 1983) and accounted for 5,359 (64%) of the 8,434 eligible patients. The median number of patients treated per arm of the trials rose from 77 (1973 to 1983) to 121 (1984 to 1994) (P < .001). five trials (15%) showed a statistically significant difference in survival between treatment arms, with a median prolongation of the median survival of 2 months (range, 0.7 to 2.7 months). Conclusion: Analysis of past trials in North America shows that the prolongation in median survival between two arms of a randomized study was rarely in excess of 2 months. Techniques for improved use of patient resources and appropriate trial design for phase III randomized therapeutic trials with patients with advanced NSCLC need to be developed. <(c)> 2001 by American Society of Clinical Oncology. C1 Dana Farber Canc Inst, Thorac Oncol Program, Lowe Ctr Thorac Oncol, Dept Adult Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. NCI, Div Canc Treatment & Diag, Canc Therapy Evaluat Program, Biometr Res Branch,Clin Invest Branch, Bethesda, MD 20892 USA. Canc & Leukemia Grp B, Chicago, IL USA. Eastern Cooperat Oncol Grp, Pittsburgh, PA USA. SW Oncol Grp, San Antonio, TX USA. N Cent Canc Treatment Grp Philadelphia, Philadelphia, PA USA. Natl Canc Inst, Canada Clin Trials Grp, Kingston, ON, Canada. RP Breathnach, OS (reprint author), Dana Farber Canc Inst, Thorac Oncol Program, Lowe Ctr Thorac Oncol, Dept Adult Oncol, Ste 1234,44 Binney St, Boston, MA 02115 USA. RI Johnson, David/A-7437-2009 NR 50 TC 249 Z9 259 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 15 PY 2001 VL 19 IS 6 BP 1734 EP 1742 PG 9 WC Oncology SC Oncology GA 414EG UT WOS:000167652500019 PM 11251004 ER PT J AU Simon, RM Steinberg, SM Hamilton, M Hildesheim, A Khleif, S Kwak, LW Mackall, CL Schlom, J Topalian, SL Berzofsky, JA AF Simon, RM Steinberg, SM Hamilton, M Hildesheim, A Khleif, S Kwak, LW Mackall, CL Schlom, J Topalian, SL Berzofsky, JA TI Clinical trial designs for the early clinical development of therapeutic cancer vaccines SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PHASE-II; SAMPLE-SIZE; PILOT TRIALS; MELANOMA; PEPTIDE; SERIES; AGENTS AB There are major differences between therapeutic tumor vaccines and chemotherapeutic agents that have important implications for the design of early clinical trials. Many vaccines are inherently safe and do not require phase I dose finding trials. patients with advanced cancers and compromised immune systems are not good candidates for assessing either the toxicity or efficacy of therapeutic cancer vaccines. The rapid pace of development of new vaccine candidates and the variety of possible adjuvants and modifications in method of administration makes it important to use efficient designs for clinical screening and evaluation of vaccine regimens. We review the potential advantages of a wide range of clinical trial designs for the development of tumor vaccines. We address the role of immunological endpoints in early clinical trials of tumor vaccines, investigate the design implications of attempting to use disease stabilization as an end point and discuss the difficulties of reliably utilizing historical control data. Several conclusions for expediting the clinical development of effective cancer vaccines are proposed. (C) 2001 by American Society of Clinical Oncology. C1 NCI, Biometr Res Branch, Bethesda, MD 20892 USA. NCI, Environm Epidemiol Branch, Bethesda, MD 20892 USA. NCI, Med Branch, Bethesda, MD 20892 USA. NCI, Branch Pediat Oncol, Bethesda, MD 20892 USA. NCI, Surg Branch, Bethesda, MD 20892 USA. NCI, Metab Branch, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. NCI, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. RP Simon, RM (reprint author), NCI, Biometr Res Branch, Bldg EPN,Room 8134, Bethesda, MD 20892 USA. NR 15 TC 80 Z9 81 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 15 PY 2001 VL 19 IS 6 BP 1848 EP 1854 PG 7 WC Oncology SC Oncology GA 414EG UT WOS:000167652500032 PM 11251017 ER PT J AU Anderson, CC Carroll, JM Gallucci, S Ridge, JP Cheever, AW Matzinger, P AF Anderson, CC Carroll, JM Gallucci, S Ridge, JP Cheever, AW Matzinger, P TI Testing time-, ignorance-, and danger-based models of tolerance SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RESTRICTED CROSS-PRESENTATION; T-CELL TOLERANCE; DENDRITIC CELLS; SELF-ANTIGENS; ALLOGRAFT-REJECTION; NEONATAL TOLERANCE; AUTOIMMUNE-DISEASE; B-CELLS; INDUCTION; MICE AB In this study, we present data showing that tolerance to Ags in the periphery is not determined by the time at which the Ag appears, or by special properties of tissues in newborn mice or newly developing immune systems. We placed male grafts onto immunoincompetent female mice, allowed the grafts to heal for up to 5 mo, and then repopulated the recipients with fetal liver stem cells, We found that the newly arising T cells were neither tolerant nor ignorant of the grafts, but promptly rejected them, though they did not reject female grafts, nor show any signs of autoimmunity, We also found that the H-Y Ag was continuously cross-presented on host APCs, that this presentation was immunogenic, not tolerogenic, and that it depended on the continuous presence of the graft. In searching for the stimulus that might activate the host APCs, we analyzed mRNA expression with a highly sensitive real-time quantitative PCR assay, By using two different "housekeeping" molecules for comparison, we analyzed the message levels for several stress and/or inflammatory molecules in the healed grafts. We found that the long-healed grafts were not equivalent to "normal" skin because the healed grafts expressed lower levels of GAPDH. Altogether, these data suggest that acceptance vs rejection of peripheral tissues is not attributable to ignorance, timing-based tolerance, or special circulation properties of naive T cells in neonatal tissues. It is more likely attributable to an aspect of the context of Ag presentation that remains to be identified. C1 NIAID, Cellular & Mol Immunol Lab, Ghost Lab, Sect T Cell Tolarance & Mem,NIH, Bethesda, MD 20892 USA. Genet Inst, Andover, MA 01810 USA. Biomed Res Inst, Rockville, MD 20852 USA. RP Anderson, CC (reprint author), NIAID, Cellular & Mol Immunol Lab, Ghost Lab, Sect T Cell Tolarance & Mem,NIH, Bldg 4,Room 111,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 60 TC 51 Z9 54 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 15 PY 2001 VL 166 IS 6 BP 3663 EP 3671 PG 9 WC Immunology SC Immunology GA 410JW UT WOS:000167437700008 PM 11238605 ER PT J AU Cheng, PC Brown, BK Song, WX Pierce, SK AF Cheng, PC Brown, BK Song, WX Pierce, SK TI Translocation of the B cell antigen receptor into lipid rafts reveals a novel step in signaling SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PROTEIN-TYROSINE KINASES; FC-EPSILON-RI; IG-ALPHA; ACTIVATION; DOMAINS; IMMUNOGLOBULIN; SYK; AUTOPHOSPHORYLATION; TRANSMEMBRANE; TRANSDUCTION AB The cross-linking of the B cell Ag receptor (BCR) leads to the initiation of a signal transduction cascade in which the earliest events involve the phosphorylation of the immunoreceptor tyrosine-based activation motifs of Ig alpha and Ig beta by the Src family kinase Lyn and association of the BCR with the actin cytoskeleton, However, the mechanism by which BCR cross-linking initiates the cascade remains obscure. In this study, using various A20-transfected cell lines, biochemical and genetic evidence is provided that BCR cross-linking leads to the translocation of the BCR into cholesterol- and sphingolipid-rich lipid rafts in a process that is independent of the initiation of BCR signaling and does not require the actin cytoskeleton. Translocation of the BCR into lipid rafts did not require the Ig alpha /Ig beta signaling complex, was not dependent on engagement of the FcR, and was not blocked by the Src family kinase inhibitor PP2 or the actin-depolymerizing agents cytochalasin D or latrunculin. Thus, cross-linking or oligomerization of the BCR induces the BCR translocation into lipid rafts, defining an event in B cell activation that precedes receptor phosphorylation and association with the actin cytoskeleton. C1 NIAID, Immunol Lab, NIH, Rockville, MD 20852 USA. Northwestern Univ, Dept Biochem Mol Biol & Cell Biol, Evanston, IL 60208 USA. Univ Maryland, Dept Mol Genet & Cell Biol, College Pk, MD 20742 USA. RP Pierce, SK (reprint author), NIAID, Immunol Lab, NIH, Twinbrook 2,12441 Parklawn Dr,Room 200B,MSC 8180, Rockville, MD 20852 USA. FU NIAID NIH HHS [AI 40309, AI 18939, AI 27957, AI42093]; NIGMS NIH HHS [GM08152] NR 39 TC 98 Z9 101 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 15 PY 2001 VL 166 IS 6 BP 3693 EP 3701 PG 9 WC Immunology SC Immunology GA 410JW UT WOS:000167437700012 PM 11238609 ER PT J AU Park, JW Gruys, ME McCormick, K Lee, JK Subleski, J Wigginton, JM Fenton, RG Wang, JM Wiltrout, RH AF Park, JW Gruys, ME McCormick, K Lee, JK Subleski, J Wigginton, JM Fenton, RG Wang, JM Wiltrout, RH TI Primary hepatocytes from mice treated with IL-2/IL-12 produce T cell chemoattractant activity that is dependent on monokine induced by IFN-gamma (Mig) and chemokine responsive to gamma-2 (Crg-2) SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTERFERON-INDUCIBLE PROTEIN-10; IN-VIVO; CXC CHEMOKINES; SPONTANEOUS METASTASES; INTERLEUKIN-12; EXPRESSION; IP-10; TUMOR; IL-12; ANGIOGENESIS AB The IFN-gamma -inducible proteins monokine induced by IFN-y (Mig) and chemokine responsive to gamma -2 (Crg-2) can contribute to IL-12-induced antiangiogenic and leukocyte-recruiting activities, but the extent to which leukocytes vs parenchymal cells in different organs contribute to the production of these molecules remains unclear. The results presented herein show that IFN-gamma -dependent induction of Mig and Crg-2 gene expression can occur in many nonlymphoid organs, and these genes are rapidly induced in purified hepatocytes isolated from mice treated with IL-2 plus IL-12, or from Hepa 1-6 hepatoma cells treated in vitro with IFN-y, In addition to depending on IFN-y, the ability of IL-12 or IL-2/IL-12 to induce Mig and Crg-2 gene expression in purified hepatocytes also is accompanied by the coordinate up-regulation of the IFN-y R alpha and beta -chains, in the absence of IL-12R components. Supernatants of primary hepatocytes obtained from mice treated in vivo with IL-2/IL-12 or from hepatocytes treated in vitro with IFN-y contain increased chemotactic activity for enriched human and mouse CD3(+) T cells, as well as mouse DX5(+) NK cells. The hepatocyte-derived chemotactic activity for mouse T cells but not NK cells was ablated by Abs specific for Mig and Crg-2, These results suggest that parenchymal cells in some organs may contribute substantially to initiation and/or amplification of inflammatory or antitumor responses. C1 NCI, Frederick Canc Res & Dev Ctr, Expt Immunol Lab, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, IRSP, Sci Aplicant Int Corp, Frederick, MD 21702 USA. NIH, Pediat Oncol Branch, Bethesda, MD USA. Univ Maryland, Sch Med, Greenbaum Canc Ctr, Baltimore, MD 21201 USA. NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Frederick, MD 21702 USA. RP Wiltrout, RH (reprint author), NCI, Frederick Canc Res & Dev Ctr, Expt Immunol Lab, Bldg 560,Room31-93, Frederick, MD 21702 USA. FU PHS HHS [N0-56000] NR 33 TC 29 Z9 31 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 MAR 15 PY 2001 VL 166 IS 6 BP 3763 EP 3770 PG 8 WC Immunology SC Immunology GA 410JW UT WOS:000167437700021 PM 11238618 ER PT J AU Yang, D Chen, Q Le, YY Wang, JM Oppenheim, JJ AF Yang, D Chen, Q Le, YY Wang, JM Oppenheim, JJ TI Differential regulation of formyl peptide receptor-like 1 expression during the differentiation of monocytes to dendritic cells and macrophages SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LIPOXIN A(4) RECEPTOR; SERUM AMYLOID-A; PROTEIN-COUPLED RECEPTOR; NECROSIS-FACTOR-ALPHA; INFLAMMATORY RESPONSE; SCAVENGER RECEPTORS; CUTTING EDGE; IN-VIVO; CHEMOATTRACTANT; CHEMOKINES AB Monocytes are the common precursors for myeloid dendritic cells (DC) and macrophages. Identification of chemotactic receptors expressed by myeloid DC, macrophages, and their precursors in the course of differentiation and maturation is important not only for elucidation of their in vivo trafficking, but also for understanding of the functional distinction between DC and macrophages. We chose to study formyl peptide receptor like-i (FPRL1), a chemotactic receptor known to interact with several endogenous agonists that are involved in inflammatory and host defense responses. Here we show that FPRL1 is down-regulated as monocytes differentiate into DC. This down-regulation occurs at both mRNA and functional levels. Therefore, the interaction of FPRL1 with its agonists is more likely to regulate the in vivo trafficking of DC precursors than DC. In contrast, FPRL1 expression is maintained at both mRNA and functional levels as monocytes differentiate into macrophages. Thus, our results demonstrate further distinctions between myeloid DC and macrophages, albeit they share a common precursor. The fact that macrophages rather than myeloid DC express functional FPRL1 suggests that this chemotactic receptor may be more involved in inflammatory reactions and innate host defense than in adaptive immune responses. C1 NCI, Mol Immunoregulat Lab, Div Basic Sci, NIH, Frederick, MD 21702 USA. RP Oppenheim, JJ (reprint author), NCI, Mol Immunoregulat Lab, Div Basic Sci, NIH, Bldg 560,Room 21-89, Frederick, MD 21702 USA. NR 53 TC 56 Z9 57 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 MAR 15 PY 2001 VL 166 IS 6 BP 4092 EP 4098 PG 7 WC Immunology SC Immunology GA 410JW UT WOS:000167437700061 PM 11238658 ER PT J AU Thomas, JB Herault, XM Rothman, RB Atkinson, RN Burgess, JP Mascarella, SW Dersch, CM Xu, H Flippen-Anderson, JL George, CF Carroll, FI AF Thomas, JB Herault, XM Rothman, RB Atkinson, RN Burgess, JP Mascarella, SW Dersch, CM Xu, H Flippen-Anderson, JL George, CF Carroll, FI TI Factors influencing agonist potency and selectivity for the opioid delta receptor are revealed in structure-activity relationship studies of the 4-[(N-substituted-4-piperidinyl) arylamino]-N,N-diethylbenzamides SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MESSAGE-ADDRESS CONCEPT; MEDIATED PHENOMENA; HIGH-AFFINITY; ANTAGONISTS; ANALOGS; BINDING; SNC-80; PROBES; DESIGN; BW373U86 AB A study of the effect of transposition of the internal nitrogen atom for the adjacent benzylic carbon atom in delta -selective agonists such as BW373U86 (1) and SNC-80 (2) has been undertaken. It was shown that high-affinity, fully efficacious, and delta opioid receptor-selective compounds can be obtained from this transposition. In addition to the N,N-diethylamido group needed as the delta address, the structural features identified to promote delta receptor affinity in the set of compounds studied included a cis relative stereochemistry between the 3- and 4-substituents in the piperidine ring, a trans-crotyl or allyl substituent on the basic nitrogen, the lack of a 2-methyl group in the piperidine ring, and either no substitution or hydroxyl substitution in the aryl ring not substituted with the N,N-diethylamido group. Structural features found to be important for mu affinity include hydroxyl substitution in the aryl ring, the presence of a 2-methyl group in a cis relative relationship to the 4-amino group as well as N-substituents such as cyclopropylmethyl. It was also determined that mu receptor affinity could be increased while maintaining delta receptor affinity, especially when hydroxyl-substituted compounds are considered. Additionally, it was discovered that the somewhat lower mu/delta selectivities observed for the piperidine compounds relative to the piperazine-based ligands appear to arise as a consequence of the carbon-nitrogen transposition which imparts an overall lower delta and higher mu affinity to the piperidine-based ligands. This higher affinity for the mu receptor, apparently intrinsic to the piperidine-based compounds, suggests that ligands of this class will more easily be converted to mu/delta combination agonists compared to the piperazine ligands such as 1. This is particularly important since analogues of 1, which show both mu- and delta -type activity, are now recognized as important for their strong analgesia and cross-canceling of many of the side effects found in agonists operating exclusively from either the delta or mu opioid receptor. C1 Res Triangle Inst, Res Triangle Pk, NC 27709 USA. NIDA, Clin Psychopharmacol Sect, Addict Res Sect, Baltimore, MD 21224 USA. USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. RP Carroll, FI (reprint author), Res Triangle Inst, POB 12194,3040 Cornwallis, Res Triangle Pk, NC 27709 USA. FU NIDA NIH HHS [DA09045] NR 38 TC 13 Z9 13 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAR 15 PY 2001 VL 44 IS 6 BP 972 EP 987 DI 10.1021/jm000427g PG 16 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 413ZK UT WOS:000167641300014 PM 11300879 ER PT J AU Frolenkov, GI Mammano, F Kachar, B AF Frolenkov, GI Mammano, F Kachar, B TI Action of 2,3-butanedione monoxime on capacitance and electromotility of guinea-pig cochlear outer hair cells SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID RAT VENTRICULAR MYOCYTES; MEMBRANE CAPACITANCE; CALCIUM CHANNELS; PROTEIN-PHOSPHORYLATION; VOLTAGE-DEPENDENCE; GATING CHARGE; MOTILITY; SALICYLATE; CALMODULIN; INHIBITION AB 1. Whole-cell patch-clamp recordings were obtained from isolated cochlear outer hair cells (OHCs) while applying 2,3-butanedione monoxime (BDM) by pressure. BDM (5 mM) shifted the range of voltage sensitivity of membrane capacitance and cell length in the hyperpolarised direction by -49.6 +/- 4.0 mV (n = 12; mean +/- S.E.M.), without appreciable effects on membrane conductance. The shift was completely reversible and dose dependent, with a Hill coefficient of 1.8 +/- 0.4 and a half-maximal dose of 3.0 +/- 0.8 mM (values +/- S.D). 2. The shift of the capacitance curve was also reproducible in cells whose natural turgor had been removed. BDM had no detectable effect on the capacitance of Deiters' cells, a non-sensory cell type of the organ of Corti. 3. The effect of BDM on membrane capacitance was faster than that of salicylate. At similar saturating concentrations (20 mM), the time constant of the capacitance changes was 1.8 +/- 0.3 s (n = 3) for salicylate and 0.75 +/- 0.06 s (n = 3) for BDM. The recovery periods were 13 +/- 1 s and 1.7 +/- 0.4 s, respectively (means +/- S.E.M.). 4. The effect of BDM, a known inorganic phosphatase, was compared to the effects of okadaic acid, trifluoperazine and W-7, which are commonly used in studies of protein phosphorylation. Incubation of OHCs with okadaic acid (1 muM, 30-60 min) shifted the voltage sensitivity of the membrane capacitance in the hyperpolarised direction. Incubation with trifluoperazine (30 muM) and W-7 (150 muM) shifted it in the opposite, depolarised direction. BDM induced hyperpolarising shifts even in the presence of W-7. 5. Simultaneous measurement of membrane capacitance and intracellular free Ca2+ concentration ([Ca2+](i)) showed that BDM action on OHC voltage-dependent capacitance and electromotility is not mediated by changes of [Ca2+](i). 6. Our results suggest that: (a) the effects of BDM are unrelated to its inorganic phosphatase properties, cell turgor conditions or Ca2+ release from intracellular stores; and (b) BDM may target directly the voltage sensor of the OHC membrane motor protein. C1 NIDCD, Sect Struct Cell Biol, Lab Cellular Biol, NIH, Bethesda, MD 20892 USA. Int Sch Adv Studies, Biophys Lab, Trieste, Italy. Int Sch Adv Studies, INFM Unit, Trieste, Italy. RP Frolenkov, GI (reprint author), NIDCD, Sect Struct Cell Biol, Lab Cellular Biol, NIH, 9000 Rockville Pike,Bldg 36-5D15, Bethesda, MD 20892 USA. RI Mammano, Fabio/I-5064-2012 OI Mammano, Fabio/0000-0003-3751-1691 FU NIDCD NIH HHS [Z01 DC 00002-11, Z01 DC000002] NR 50 TC 8 Z9 8 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI PORT CHESTER PA 110 MIDLAND AVE, PORT CHESTER, NY 10573-4930 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD MAR 15 PY 2001 VL 531 IS 3 BP 667 EP 676 DI 10.1111/j.1469-7793.2001.0667h.x PG 10 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 418YJ UT WOS:000167922400011 PM 11251049 ER PT J AU Lagostena, L Ashmore, JF Kachar, B Mammano, F AF Lagostena, L Ashmore, JF Kachar, B Mammano, F TI Purinergic control of intercellular communication between Hensen's cells of the guinea-pig cochlea SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID EXTRACELLULAR ATP; SUPPORTING CELLS; SENSORINEURAL DEAFNESS; DOMINANT DEAFNESS; GAP-JUNCTIONS; CA2+ RELEASE; RAT COCHLEA; CL-CURRENTS; MUTATIONS; CALCIUM AB 1. Hensen's cells in the isolated cochlea were stimulated by extracellular adenosine 5 ' -triphosphate (XTP) applied to their endolymphatic surface while changes in membrane current and intracellular calcium concentration ([Ca(2+)](i)) were measured simultaneously. The response consisted of (i) an initial rapid inward current accompanied by elevation of the [Ca(2+)](i), (ii) a more slowly rising inward current accompanied by a rise of the [Ca(2+)](i) and (iii) a slowly developing reduction of input conductance. 2. The slower responses were maintained in the absence of extracellular Ca(2+). Similar responses were produced by increasing the [Ca(2+)](i) via UV flash photolysis of intracellular D-myo-inositol 1,4,5-triphosphate, P4(5)-(1 -(2-nitrophenyl)ethyl) ester (caged InsP(3)) loaded at pipette concentrations of 8-16 muM. 3. The slow inward current, reversing around 0 mV, was blocked by 4-4 ' -diisothiocyanato-stilbene-2-2 ' -disulfonic acid (DIDS). 4. Bath application of U-73122 (1 muM), a phospholipase C inhibitor, eliminated the slow Ca(2+)-release component of the response to ATP. It is proposed that the effects of ATP are mediated by the co-activation of ionotropic P2X and metabotropic P2Y receptors. 5. Immunohistochemistry using light and electron microscopy revealed that inositol 1,4,5-trisphosphate (InsP(3)) receptors delineate a network within the cells. 6. The coupling ratio (CR) between cell pairs measured in dual patch-clamp recordings was 0.356 +/- 0.024. The coupling reversibly decreased to 51% of the control within 2 min of applying 100 muM ATP. Flash photolysis of 32 muM intracellular caged InsP(3) and 1 mM caged Ca(2+) reduced CR to 42 and 62 % of the control, respectively. 7. We propose that endolymphatic ATP via P2X and P2Y receptors can control intercellular communication amongst Hensen's cells by reducing gap junction conductance in a Ca(2+) and InsP(3)-dependent manner. C1 SISSA, Settore Biofis, I-34014 Trieste, Italy. SISSA, INFM, I-34014 Trieste, Italy. UCL, Dept Physiol, London WC1E 6BT, England. NIDCD, Sect Struct Cell Biol, NIH, Bethesda, MD USA. RP Mammano, F (reprint author), Scuola Int Super Studi Avanzati, Via Beirut 2-4, I-34014 Trieste, Italy. EM mammano@sissa.it RI Mammano, Fabio/I-5064-2012 OI Mammano, Fabio/0000-0003-3751-1691 NR 43 TC 35 Z9 38 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD MAR 15 PY 2001 VL 531 IS 3 BP 693 EP 706 DI 10.1111/j.1469-7793.2001.0693h.x PG 14 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 418YJ UT WOS:000167922400013 PM 11251051 ER PT J AU Nielsen, JN Derave, W Kristiansen, S Ralston, E Ploug, T Richter, EA AF Nielsen, JN Derave, W Kristiansen, S Ralston, E Ploug, T Richter, EA TI Glycogen synthase localization and activity in rat skeletal muscle is strongly dependent on glycogen content SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article AB 1. The influence of muscle glycogen content on glycogen synthase (GS) localization and GS activity was investigated in skeletal muscle from male Wistar rats. 2. Two groups of rats were obtained, preconditioned with a combination of exercise and diet to obtain either high (HG) or low (LG) muscle glycogen content. The cellular distribution of GS was studied using subcellular fractionation and confocal microscopy of immunostained single muscle fibres. Stimulation of GS activity in HG and LG muscle was obtained with insulin or contractions in the perfused rat hindlimb model. 3. We demonstrate that GS translocates from a glycogen-enriched membrane fraction to a cytoskeleton fraction when glycogen levels are decreased. Confocal microscopy supports the biochemical observations that the subcellular localization of GS is influenced by muscle glycogen content. GS was not found in the nucleus. 4. Investigation of the effect of glycogen content on GS activity in basal and insulin- and contraction-stimulated muscle shows that glycogen has a strong inhibitory effect on GS activity. Our data demonstrate that glycogen is a more potent regulator of glycogen synthase activity than insulin. Furthermore we show that the contraction-induced increase in GS activity is merely a result of a decrease in muscle glycogen content. 5. In conclusion, the present study shows that GS localization is influenced by muscle glycogen content and that not only basal but also insulin- and contraction-stimulated GS activity is strongly regulated hy glycogen content in skeletal muscle. C1 Univ Copenhagen, Copenhagen Muscle Res Ctr, Dept Human Physiol, DK-2100 Copenhagen, Denmark. State Univ Ghent, Dept Movement & Sports Sci, B-9000 Ghent, Belgium. NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. Univ Copenhagen, Dept Med Physiol, Panum Inst, DK-1168 Copenhagen, Denmark. RP Richter, EA (reprint author), Univ Copenhagen, Copenhagen Muscle Res Ctr, Dept Human Physiol, 13 Univ Parken, DK-2100 Copenhagen, Denmark. RI Derave, Wim/B-2554-2014 OI Derave, Wim/0000-0002-2225-5587 NR 1 TC 91 Z9 95 U1 1 U2 8 PU CAMBRIDGE UNIV PRESS PI PORT CHESTER PA 110 MIDLAND AVE, PORT CHESTER, NY 10573-4930 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD MAR 15 PY 2001 VL 531 IS 3 BP 757 EP 769 DI 10.1111/j.1469-7793.2001.0757h.x PG 13 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 418YJ UT WOS:000167922400018 PM 11251056 ER PT J AU Chandross, KJ Champagne, B Auble, K Hudson, LD AF Chandross, KJ Champagne, B Auble, K Hudson, LD TI Tracking oligodendrocytes during development and regeneration SO MICROSCOPY RESEARCH AND TECHNIQUE LA English DT Article DE myelinating glial cells; transgenic models; gliogenesis; transplantation; viral vectors ID CENTRAL-NERVOUS-SYSTEM; STEM-CELL TRANSPLANTATION; SPINAL-CORD; TRANSGENIC MICE; BONE-MARROW; PROGENITOR CELLS; SCHWANN-CELLS; MOUSE-BRAIN; MONOCLONAL-ANTIBODIES; EXTENSIVE MYELINATION AB Over the past decade, advances in strategies to tag cells have opened new avenues for examining the development of myelin-forming glial cells and for monitoring transplanted cells in animal models of myelin insufficiency. The strategies for labelling glial cells have encompassed a range of genetic modifications as well as methods for directly attaching labels to cells. Genetically modified oligodendrocytes have been engineered to express enzymatic (e.g., beta -galactosidase, alkaline phosphatase), naturally fluorescent (e.g., green fluorescent protein), and antibiotic resistance (e.g., neomycin, zeomycin) reporters. Genes have been introduced in vivo and in vitro with viral or plasmid vectors to somatically label glial cells. To generate germ-line transmission of tagged oligodendrocytes, transgenic mice have been created both by direct injection into mouse fertilized eggs and. by "knock-in" of reporters targetted to myelin gene loci in embryonic stem cells. Each experimental approach has advantages and limitations that need to be considered for individual applications. The availability of tagged glial cells has expanded our basic understanding of how oligodendrocytes are specified from stem cells and should continue to fill in the gaps in our understanding of how oligodendrocytes differentiate, myelinate, and maintain their myelin sheaths. Moreover, the ability to select oligodendrocytes by virtue of their acquired antibiotic resistance has provided an important new tool for isolating and purifying oligodendrocytes. Tagged glial cells have also been invaluable in evaluating cell transplant therapies in the nervous system. The tracking technologies that have driven these advances in glia cell biology are continuing to evolve and present new opportunities for examining oligodendrocytes in living systems. Published 2001 Wiley-Liss, Inc.dagger C1 NINDS, Lab Dev Neurogenet, NIH, Bethesda, MD 20892 USA. RP Hudson, LD (reprint author), Bldg 36,Room 5D02,36 Convent Dr,MSC 4160, Bethesda, MD 20892 USA. NR 83 TC 2 Z9 2 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 1059-910X J9 MICROSC RES TECHNIQ JI Microsc. Res. Tech. PD MAR 15 PY 2001 VL 52 IS 6 BP 766 EP 777 DI 10.1002/jemt.1061 PG 12 WC Anatomy & Morphology; Biology; Microscopy SC Anatomy & Morphology; Life Sciences & Biomedicine - Other Topics; Microscopy GA 412HF UT WOS:000167548400016 PM 11276129 ER PT J AU Noskov, VN Koriabine, M Solomon, G Randolph, M Barrett, JC Leem, SH Stubbs, L Kouprina, N Larionov, V AF Noskov, V. N. Koriabine, M. Solomon, G. Randolph, M. Barrett, J. C. Leem, S. -H. Stubbs, L. Kouprina, N. Larionov, V. TI Defining the minimal length of sequence homology required for selective gene isolation by TAR cloning SO NUCLEIC ACIDS RESEARCH LA English DT Article AB The transformation-associated recombination (TAR) cloning technique allows selective and accurate isolation of chromosomal regions and genes from complex genomes. The technique is based on in vivo recombination between genomic DNA and a linearized vector containing homologous sequences, or hooks, to the gene of interest. The recombination occurs during transformation of yeast spheroplasts that results in the generation of a yeast artificial chromosome (YAC) containing the gene of interest. To further enhance and refine the TAR cloning technology, we determined the minimal size of a specific hook required for gene isolation utilizing the Tg.AC mouse transgene as a targeted region. For this purpose a set of vectors containing a B1 repeat hook and a Tg.AC-specific hook of variable sizes (from 20 to 800 bp) was constructed and checked for efficiency of transgene isolation by a radial TAR cloning. When vectors with a specific hook that was >= 60 bp were utilized, similar to 2% of transformants contained circular YACs with the Tg.AC transgene sequences. Efficiency of cloning dramatically decreased when the TAR vector contained a hook of 40 bp or less. Thus, the minimal length of a unique sequence required for gene isolation by TAR is similar to 60 bp. No transgene-positive YAC clones were detected when an ARS element was incorporated into a vector, demonstrating that the absence of a yeast origin of replication in a vector is a prerequisite for efficient gene isolation by TAR cloning. C1 [Noskov, V. N.; Koriabine, M.; Kouprina, N.; Larionov, V.] Natl Inst Environm Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. [Solomon, G.; Randolph, M.; Barrett, J. C.] Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. [Leem, S. -H.] Dong A Univ, Fac Nat Sci, Dept Biol, Pusan 604714, South Korea. [Stubbs, L.] Lawrence Livermore Natl Lab, Genome Div, Livermore, CA 94550 USA. [Noskov, V. N.] St Petersburg State Univ, St Petersburg, Russia. RP Larionov, V (reprint author), NCI, Lab Biosyst & Canc, NIH, Bldg 49,Room 4-A56,49 Convent Dr, Bethesda, MD 20892 USA. EM larionov@mail.nih.gov NR 17 TC 11 Z9 11 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR 15 PY 2001 VL 29 IS 6 AR e32 DI 10.1093/nar/29.6.e32 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA V17WP UT WOS:000207967600003 PM 11239009 ER PT J AU Maeda, R Mood, K Jones, TL Aruga, J Buchberg, AM Daar, IO AF Maeda, R Mood, K Jones, TL Aruga, J Buchberg, AM Daar, IO TI Xmeis1, a protooncogene involved in specifying neural crest cell fate in Xenopus embryos SO ONCOGENE LA English DT Article DE Xmeis1; neural crest; homeodomain; Xenopus ID HEDGEHOG SIGNALING PATHWAY; COOPERATIVE DNA-BINDING; SONIC HEDGEHOG; HOMEOBOX GENES; FLOOR PLATE; TRANSCRIPTION FACTOR; MESSENGER-RNA; GLI PROTEINS; PBX PROTEINS; HOX PROTEINS AB Meis1 (Myeloid Ecotropic viral Integration Site 1) is a homeobox gene that was originally isolated as a common site of viral integration in myeloid tumors of the BXH-2 recombinant inbred mice strain. We previously isolated a Xenopus homolog of Meis1 (Xmeis1), Here we show that Xmeis1 may play a significant role in neural crest development. In developing Xenopus embryos, Xmeis1 displays a broad expression pattern, but strong expression is observed in tissue of neural cell fate, such as midbrain, hindbrain, the dorsal portion of the neural tube, and neural crest derived branchial arches. In animal cap explants, overexpression of Xmeis1b, an alternatively spliced form of Ymeis1, induces expression of neural crest marker genes in the absence of mesoderm, Moreover, Xmeis1b induces XGli-3 and XZic3, pre-pattern genes involved at the earliest stages of neural crest development, and like these two genes, can induce ectopic pigmented cell masses when overexpressed in developing embryos. Misexpression of Ymeis1b also induces ectopic expression of neural crest markers along the antero-posterior axis of the neural tube in developing Xenopus embryos. In contrast, Xmeis1a, another splice variant, is much less effective at inducing these effects. These data suggest that Xmeis1b is involved in neural crest cell fate specification during embryogenesis, and can functionally intersect with the Gli/Zic signal transduction pathway. C1 NCI, Regulat Cell Growth Lab, Frederick, MD 21702 USA. RIKEN, Brain Sci Inst, Dev Neurobiol Lab, Wako, Saitama 3510198, Japan. Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. RP Daar, IO (reprint author), NCI, Regulat Cell Growth Lab, Bldg 560 Room 22-3, Frederick, MD 21702 USA. RI Aruga, Jun/H-5837-2011; OI Buchberg, Arthur/0000-0002-0543-5631; Daar, Ira/0000-0003-2657-526X FU NCI NIH HHS [N01-CO-5600] NR 81 TC 47 Z9 48 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAR 15 PY 2001 VL 20 IS 11 BP 1329 EP 1342 DI 10.1038/sj.onc.1204250 PG 14 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 411JM UT WOS:000167495000007 PM 11313877 ER PT J AU Hayashi, T Hirata, H Asanuma, M Ladenheim, B Tsao, L Cadet, JL Su, TP AF Hayashi, T Hirata, H Asanuma, M Ladenheim, B Tsao, L Cadet, JL Su, TP TI Delta opioid peptide [D-Ala(2), D-Leu(5)]enkephalin causes a near complete blockade of the neuronal damage induced by a single high dose of methamphetamine: Examining the role of p53 SO SYNAPSE LA English DT Article DE methamphetamine; delta opioid; DADLE; apoptosis; neurotoxicity; neuroprotection; dopamine transporter; dopamine; 5-hydroxytryptamine; tyrosine hydroxylase; p53 ID TUMOR-SUPPRESSOR GENE; DOPAMINE TRANSPORTERS; OXIDATIVE STRESS; CELL-DEATH; ENKEPHALIN; NEUROTOXICITY; PRESERVATION; INVOLVEMENT; BRAIN; MICE AB The delta opioid peptide [D-Ala(2), D-Leu(5)]enkephalin (DADLE) has been reported to block the neurotoxicity induced by multiple administrations of a moderate dose of methamphetamine (METH). We examined in this study if DADLE might block the neurotoxicity caused by a single high dose of METH in CD-1 mice, The levels of dopamine transporter (DAT), tyrosine hydroxylase (TH), major biogenic amines including DA, 5-hydroxytryptamine (5-HT), and their metabolites were examined. In addition, since the tumor suppressor p53 has been implicated in the neurotoxicity of METH, this study also examined the levels of p53 mRNA and protein affected by METH and DADLE. METH (25 mg/kg, i.p.) caused significant losses of DAT, TH, DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-HT in the striatum within 72 h. The administration of a single dose of DADLE (20 mg/kg, i.p., 30 min before METH) caused a complete blockade of all losses induced by METH except for that of the DA content (a similar to 50% blockade). DADLE did not affect the changes of rectal temperature induced by the administration of the high dose of METH, METH increased p53 mRNA in the striatum and the hippocampus of CD-1 mouse. DADLE abolished the p53 mRNA increase caused by METH. METH tended to increase the p53 protein level at earlier time points. However, METH significantly decreased the p53 protein level by about 30% at the 72-h time point. DADLE blocked both the increase of p53 mRNA and the decrease of p53 protein caused by METH. These results demonstrate a neuroprotective effect of DADLE against the neuronal damage and the alteration of p53 gene expression caused by a single high dose of METH. The results also indicate an apparent discordance between the protein level of p53 and the neurotoxicity caused by a high dose of METH. Synapse 39:305-312, 2001, Published 2001 Wiley-Liss, Inc.dagger. C1 NIDA, Cellular Pathobiol Unit, Mol Neuropsychiat Sect, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Su, TP (reprint author), NIDA, Cellular Pathobiol Unit, Mol Neuropsychiat Sect, Intramural Res Program,NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Hayashi, Teruo/A-9690-2008 NR 27 TC 15 Z9 16 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD MAR 15 PY 2001 VL 39 IS 4 BP 305 EP 312 DI 10.1002/1098-2396(20010315)39:4<305::AID-SYN1013>3.0.CO;2-E PG 8 WC Neurosciences SC Neurosciences & Neurology GA 396YR UT WOS:000166666300004 PM 11169780 ER PT J AU Acri, JB Thompson, AC Shippenberg, T AF Acri, JB Thompson, AC Shippenberg, T TI Modulation of pre- and postsynaptic dopamine D2 receptor function by the selective kappa-opioid receptor agonist U69593 SO SYNAPSE LA English DT Article DE kappa-opioid; D2 receptors; autoreceptors; microdialysis; dopamine; dorsal striatum ID FREELY MOVING RATS; NUCLEUS-ACCUMBENS; BEHAVIORAL SENSITIZATION; QUANTITATIVE MICRODIALYSIS; EXTRACELLULAR DOPAMINE; INVIVO MICRODIALYSIS; LOCOMOTOR-ACTIVITY; RHESUS-MONKEYS; KNOCK-OUT; IN-VITRO AB The repeated administration of selective kappa-opioid receptor agonists prevents the locomotor activation produced by acute cocaine administration and the development of cocaine-induced behavioral sensitization. Previous studies have shown that dopamine (DA) D2 autoreceptors modulate the synthesis and release of DA in the striatum. Evidence that; kappa agonist treatment downregulates DA D2 receptors in this same brain region has recently been obtained. Accordingly, the present studies were undertaken to examine the influence of repeated kappa-opioid receptor agonist administration on pre- and postsynaptic DA D2 receptor function in the dorsal striatum using pre- and postsynaptic receptor-selective doses of quinpirole. Rats were injected once daily with the selective kappa-opioid receptor agonist U69593 (0.16-0.32 mg/kg s.c.) or vehicle for 3 days. Microdialysis studies assessing basal and quinpirole-evoked (0.05 mg/kg s.c.) DA levels were conducted 2 days later. Basal and quinpirole-stimulated locomotor activity were assessed in a parallel group of animals. The no-net flux method of quantitative microdialysis revealed no effect of U69593 on basal DA dynamics, in that extracellular DA concentration and extraction fraction did not differ in control and U69593-treated animals. Acute administration of quinpirole significantly decreased striatal DA levels in control animals, but in animals treated with U69593, the inhibitory effects of quinpirole were significantly reduced. Quinpirole produced a dose-related increase in locomotor activity in control animals, and this effect was significantly attenuated in U69593-treated animals. These data reveal that prior repeated administration of a selective kappa-opioid receptor agonist attenuates quinpirole-induced alterations in DA neurotransmission and locomotor activity. These results suggest that both pre- and postsynaptic striatal DA D2 receptors may be downregulated following repeated kappa-opioid receptor agonist administration. Synapse 39:343-350, 2001, Published 2001 Wiley-Liss. Inc.dagger. C1 NIDA, Div Treatment Res & Dev, Integrat Neurosci Unit, Behav Neurosci Branch,IRP, Bethesda, MD 20892 USA. RP Acri, JB (reprint author), NIDA, Div Treatment Res & Dev, Integrat Neurosci Unit, Behav Neurosci Branch,IRP, 6001 Execut Blvd,Room 4123,MSC 9551, Bethesda, MD 20892 USA. NR 55 TC 33 Z9 33 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 0887-4476 J9 SYNAPSE JI Synapse PD MAR 15 PY 2001 VL 39 IS 4 BP 343 EP 350 DI 10.1002/1098-2396(20010315)39:4<343::AID-SYN1018>3.0.CO;2-Q PG 8 WC Neurosciences SC Neurosciences & Neurology GA 396YR UT WOS:000166666300009 PM 11169785 ER PT J AU Malkevitch, N McDermott, DH Yi, YJ Grivel, JC Schols, D De Clercq, E Murphy, PM Glushakova, S Collman, RG Margolis, L AF Malkevitch, N McDermott, DH Yi, YJ Grivel, JC Schols, D De Clercq, E Murphy, PM Glushakova, S Collman, RG Margolis, L TI Coreceptor choice and T cell depletion by R5, X4, and R5X4 HIV-1 variants in CCR5-deficient (CCR5 Delta 32) and normal human lymphoid tissue SO VIROLOGY LA English DT Article DE HIV; chemokine receptor; CCR5; CXCR4; T lymphocytes; pathogenesis; RANTES; AMD3100 ID IMMUNODEFICIENCY-VIRUS TYPE-1; CHEMOKINE RECEPTORS; DISEASE PROGRESSION; CC-CHEMOKINES; TROPIC HIV-1; INFECTION; ENTRY; REPLICATION; MACROPHAGES; PHENOTYPE AB Coreceptor utilization by HIV-1 is an important determinant of pathogenesis. However, coreceptor selectivity is defined in vitro, while in vivo critical pathogenic events occur in lymphoid tissues. Using pharmacological inhibitors, we recently provided evidence that coreceptor selectivity by the R5X4 dual-tropic isolate 89.6 was more restricted in ex vivo infected lymphoid tissue than in vitro [S. Glushakova, Y. Yi, J. C. Grivel, A. Singh, D. Schols E. De Clercq, R. G. Collman, and L Margolis (1999). J. Clin. Invest 104, R7-R11]. Here we extend those observations using CCR5-deficient (CCR5 Delta 32) lymphoid tissue as well as additional primary isolates. We definitively show that neither CCR5 nor Secondary coreceptors used in vitro mediate 89.6 infection in lymphoid tissue. We also demonstrate that restricted coreceptor use in lymphoid tissue ex vivo compared with in vitro utilization occurs with other dual-tropic primary isolates and is not unique to 89.6. For all strains tested that are dual tropic in vitro, severe CD4 T cell depletion in lymphoid tissue correlated with preferential CXCR4 use in this ex vivo system. (C) 2001 Academic Press. C1 Univ Penn, Sch Med, Philadelphia, PA 19104 USA. NICHHD, Lab Mol & Cellular Biophys, NIH, Bethesda, MD 20892 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Katholieke Univ Leuven, Rega Inst Med Res, B-3000 Louvain, Belgium. RP Margolis, L (reprint author), Univ Penn, Sch Med, 807 Abramson Bldg,34th & Civ Ctr Blvd, Philadelphia, PA 19104 USA. OI McDermott, David/0000-0001-6978-0867 FU NIAID NIH HHS [AI-35502]; NIMH NIH HHS [MH-61139] NR 41 TC 18 Z9 18 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR 15 PY 2001 VL 281 IS 2 BP 239 EP 247 DI 10.1006/viro.2000.0807 PG 9 WC Virology SC Virology GA 416VC UT WOS:000167800000009 PM 11277696 ER PT J AU Sinha, N Nussinov, R AF Sinha, N Nussinov, R TI Point mutations and sequence variability in proteins. Redistributions of preexisting populations SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE population shifts; energy landscape; crystal packing; mutant structures ID HIV-1 PROTEASE; 3-DIMENSIONAL STRUCTURE; TRANSITION-STATE; RETROVIRAL PROTEASES; ASPARTYL PROTEASE; INHIBITOR BINDING; RESOLUTION; LYSOZYME; DOMAIN; FLEXIBILITY AB Here we study the effect of point mutations in proteins on the redistributions of the conformational substates. We show that regardless of the location of a mutation in the protein structure and of its type, the observed movements of the backbone recur largely at the same positions in the structures. Despite the different interactions that are disrupted and formed by the residue substitution, not only are the conformations very similar, but the regions that move are also the same, regardless of their sequential or spatial distance from the mutation. This observation leads us to conclude that, apart from some extreme cases, the details of the interactions are not critically important in determining the protein conformation or in specifying which parts of the protein would be more prone to take on different local conformations in response to changes in the sequence. This finding further illustrates why proteins manifest a robustness toward many mutational events. This nonuniform distribution of the conformer population is consistently observed in a variety of protein structural types. Topology is critically important in determining folding pathways, kinetics, building block cutting, and anatomy trees. Here we show that topology is also very important in determining which regions of the protein structure will respond to sequence changes, regardless of the sequential or spatial location of the mutation. C1 NCI, Intramural Res Support Program, Sci Applicat Int Corp, Lab Expt & Computat Biol, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Fac Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Intramural Res Support Program, Sci Applicat Int Corp, Lab Expt & Computat Biol, Bldg 469,Room 151, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 38 TC 74 Z9 74 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 13 PY 2001 VL 98 IS 6 BP 3139 EP 3144 DI 10.1073/pnas.051399098 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 411WB UT WOS:000167521300039 PM 11248045 ER PT J AU Rivas, G Fernandez, JA Minton, AP AF Rivas, G Fernandez, JA Minton, AP TI Direct observation of the enhancement of noncooperative protein self-assembly by macromolecular crowding: Indefinite linear self-association of bacterial cell division protein FtsZ SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE excluded volume; analytical ultracentrifugation; sedimentation equilibrium ID CONCENTRATED HEMOGLOBIN-SOLUTIONS; BOVINE SERUM-ALBUMIN; SEDIMENTATION EQUILIBRIUM; EXCLUDED-VOLUME; ARBITRARY CONCENTRATION; GLOBULAR-PROTEINS; MOLECULAR-WEIGHT; LIGHT-SCATTERING; MODEL; CONSEQUENCES AB Recent measurements of sedimentation equilibrium and sedimentation velocity have shown that the bacterial cell division protein FtsZ self-associates to form indefinitely long rod-like linear aggregates in the presence of GDP and Mg2+. In the present study, the newly developed technique of non-ideal tracer sedimentation equilibrium was used to measure the effect of high concentrations-up to 150 g/liter-of each of two inert "crowder" proteins, cyanmethemoglobin or BSA, on the thermodynamic activity and state of association of dilute FtsZ under conditions inhibiting (-Mg2+) and promoting (+Mg2+) FtsZ self-association. Analysis of equilibrium gradients of both FtsZ and crowder proteins indicates that, under the conditions of the present experiment, FtsZ interacts with each of the two crowder proteins essentially entirely via steric repulsion, which may be accounted for quantitatively by a simple model in which hemoglobin, albumin, and monomeric FtsZ are modeled as effective spherical hard particles, and each oligomeric species of FtsZ is modeled as an effective hard spherocylinder. The functional dependence of the sedimentation of FtsZ on the concentrations of FtsZ and either crowder indicates that, in the presence of high concentrations of crowder, both the weight-average degree of FtsZ self-association and the range of FtsZ oligomer sizes present in significant abundance are increased substantially. C1 CSIC, Ctr Invest Biol, E-28006 Madrid, Spain. RP Minton, AP (reprint author), NIDDKD, Sect Phys Biochem, Lab Biochem & Genet, NIH, Bldg 8,Room 226, Bethesda, MD 20892 USA. OI Rivas, German/0000-0003-3450-7478 NR 43 TC 109 Z9 110 U1 0 U2 14 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 MAR 13 PY 2001 VL 98 IS 6 BP 3150 EP 3155 DI 10.1073/pnas.051634398 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 411WB UT WOS:000167521300041 PM 11248047 ER PT J AU Sekiguchi, J Ferguson, DO Chen, HT Yang, EM Earle, J Frank, K Whitlow, S Gu, YS Xu, Y Nussenzweig, A Alt, FW AF Sekiguchi, J Ferguson, DO Chen, HT Yang, EM Earle, J Frank, K Whitlow, S Gu, YS Xu, Y Nussenzweig, A Alt, FW TI Genetic interactions between ATM and the nonhomologous end-joining factors in genomic stability and development SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DNA-LIGASE-IV; STRAND BREAK REPAIR; CENTRAL-NERVOUS-SYSTEM; V(D)J RECOMBINATION; ATAXIA-TELANGIECTASIA; DEPENDENT PHOSPHORYLATION; CHROMOSOMAL-ABERRATIONS; DEFECTIVE NEUROGENESIS; TARGETED DISRUPTION; EMBRYONIC LETHALITY AB DNA ligase IV (Lig4) and the DNA-dependent protein kinase (DNA-PK) function in nonhomologous end joining (NHEJ). However, although Lig4 deficiency causes late embryonic lethality, deficiency in DNA-PK subunits (Ku70, Ku80, and DNA-PKcs) does not. Here we demonstrate that, similar to p53 deficiency, ataxia-telangiectasia-mutated (ATM) gene deficiency rescues the embryonic lethality and neuronal apoptosis, but not impaired lymphocyte development, associated with Lig4 deficiency. However, in contrast to p53 deficiency, ATM deficiency enhances deleterious effects of Lig4 deficiency on growth potential of embryonic fibroblasts (MEFs) and genomic instability in both MEFs and cultured progenitor lymphocytes, demonstrating significant differences in the interplay of p53 vs. ATM with respect to NHEJ. Finally, in dramatic contrast to effects on Lig4 deficiency, ATM deficiency causes early embryonic lethality in Ku- or DNA-PKcs-deficient mice, providing evidence for an NHEJ-independent role for the DNA-PK holoenzyme. C1 Childrens Hosp, Harvard Med Sch, Boston, MA 02115 USA. Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Univ Calif San Diego, Dept Biol, La Jolla, CA 92093 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Alt, FW (reprint author), Childrens Hosp, Harvard Med Sch, 300 Longwood Ave,Enders 861, Boston, MA 02115 USA. OI Sekiguchi, JoAnn/0000-0002-7178-4258 FU NCI NIH HHS [R01 CA077563, CA77563]; NIAID NIH HHS [R01 AI020047, AI35714, AI01428, AI20047, P01 AI035714, R37 AI020047] NR 39 TC 107 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 MAR 13 PY 2001 VL 98 IS 6 BP 3243 EP 3248 DI 10.1073/pnas.051632098 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 411WB UT WOS:000167521300057 PM 11248063 ER PT J AU Chang, YC Penoyer, LA Kwon-Chung, KJ AF Chang, YC Penoyer, LA Kwon-Chung, KJ TI The second STE12 homologue of Cryptococcus neoformans is MATa-specific and plays an important role in virulence SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CAPSULE-ASSOCIATED GENE; DNA-BINDING DOMAIN; TRANSCRIPTION FACTOR; MATING-TYPE; KINASE CASCADE; HOMEO DOMAIN; PROTEIN; ELEMENTS; FUNGI; ALPHA AB Cryptococcus neoformans STE12 alpha, a homologue of Saccharomyces cerevisiae STE12, exists only in MAT alpha strains. We identified another STE12 homologue, STE12a, which is MATa specific. As in the case with Delta ste12 alpha, the mating efficiency for Delta ste12a was reduced significantly. The Delta ste12a strains surprisingly still mated with Delta ste12 alpha strains. In MAT alpha strains, STE12a functionally complemented STE12 alpha for mating efficacy, haploid fruiting, and regulation of capsule size in the mouse brain. Furthermore, when STE12a was replaced with two copies of STE12 alpha, the resulting MATa strain produced hyphae on filament agar, STE12a regulates mRNA levels of several genes that are important for virulence including CNLAC1 and CAP genes. STE12a also modulates enzyme activities of phospholipase and superoxide dismutase. Importantly, deletion of STE12a markedly reduced the virulence in mice, as is the case with STE12 alpha. Brain smears of mice infected with the Delta ste12a strain showed yeast cells with a considerable reduction in capsule size compared with those infected with STE12a strains. When the disrupted locus of ste12a was replaced with a wild-type STE12a gene, both in vivo and in vitro mutant phenotypes were reversed. These results suggest that STE12a and STE12 alpha have similar functions, and that the mating type of the cells influences the alleles to exert their biological effects. C. neoformans, thus, is the first fungal species that contains a mating-type-specific STE12 homologue in each mating type. Our results demonstrate that mating-type-specific genes are not only important for saprobic reproduction but also play an important role for survival of the organism in host tissue. C1 NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Kwon-Chung, KJ (reprint author), NIAID, Clin Invest Lab, NIH, Bldg 10,Room 11C304, Bethesda, MD 20892 USA. NR 35 TC 63 Z9 67 U1 1 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 13 PY 2001 VL 98 IS 6 BP 3258 EP 3263 DI 10.1073/pnas.061031998 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 411WB UT WOS:000167521300060 PM 11248066 ER PT J AU Qin, GJ Takenaka, T Telsch, K Kelley, L Howard, T Levade, T Deans, R Howard, BH Malech, HL Brady, RO Medin, JA AF Qin, GJ Takenaka, T Telsch, K Kelley, L Howard, T Levade, T Deans, R Howard, BH Malech, HL Brady, RO Medin, JA TI Preselective gene therapy for Fabry disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ALPHA-GALACTOSIDASE-A; BONE-MARROW CELLS; HEAT-STABLE ANTIGEN; HEMATOPOIETIC-CELLS; RETROVIRAL VECTOR; GAUCHER-DISEASE; SELECTION; MICE; EXPRESSION; PROGENITOR AB Fabry disease is a lipid storage disorder resulting from mutations in the gene encoding the enzyme cy-galactosidase A (alpha -gal A; EC 3.2.1.22), We previously have demonstrated long-term alpha -gal A enzyme correction and lipid reduction mediated by therapeutic ex vivo transduction and transplantation of hematopoietic cells in a mouse model of Fabry disease, We now report marked improvement in the efficiency of this gene-therapy approach. For this study we used a novel bicistronic retroviral vector that engineers expression of both the therapeutic alpha -gal A gene and the human IL-2R alpha chain (huCD25) gene as a selectable marker. Coexpression of huCD25 allowed selective immunoenrichment (preselection) of a variety of transduced human and murine cells, resulting in enhanced intracellular and secreted alpha -gal A enzyme activities. Of particular significance for clinical applicability, mobilized CD34(+) peripheral blood hematopoietic stem/progenitor cells from Fabry patients have low-background huCD25 expression and could be enriched effectively after ex vivo transduction, resulting in increased alpha -gal A activity. We evaluated effects of preselection in the mouse model of Fabry disease. Preselection of transduced Fabry mouse bone marrow cells elevated the level of multilineage gene-corrected hematopoietic cells in the circulation of transplanted animals and improved in vivo enzymatic activity levels in plasma and organs for more than 6 months after both primary and secondary transplantation. These studies demonstrate the potential of using a huCD25-based preselection strategy to enhance the clinical utility of ex vivo hematopoietic stem/progenitor cell gene therapy of Fabry disease and other disorders. C1 Univ Illinois, Hematol Oncol Sect, Dept Med, Chicago, IL 60607 USA. Natl Inst Neurol Disorders & Stroke, Dev & Metab Neurol Branch, Bethesda, MD 20892 USA. NICHHD, Lab Mol Growth Regulat, Bethesda, MD 20892 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Inst Louis Bugnard, Biochim Lab, F-31403 Toulouse, France. Osiris Therapeut, Baltimore, MD 21231 USA. Univ Illinois, Dept Biochem & Mol Biol, Chicago, IL 60612 USA. RP Medin, JA (reprint author), Univ Illinois, Hematol Oncol Sect, Dept Med, MBRB Room 3150,M-C 734,900 S Ashland Ave, Chicago, IL 60607 USA. RI Levade, Thierry/O-8948-2014 NR 32 TC 54 Z9 57 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 MAR 13 PY 2001 VL 98 IS 6 BP 3428 EP 3433 DI 10.1073/pnas.061020598 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 411WB UT WOS:000167521300089 PM 11248095 ER PT J AU Lee, HC Bernstein, HD AF Lee, HC Bernstein, HD TI The targeting pathway of Escherichia coli presecretory and integral membrane proteins is specified by the hydrophobicity of the targeting signal SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ENDOPLASMIC-RETICULUM MEMBRANE; MALTOSE-BINDING PROTEIN; RECOGNITION PARTICLE; SEQUENCE RECOGNITION; 4.5S RNA; NASCENT PREPROLACTIN; SECRETORY PROTEIN; DOCKING PROTEIN; TRIGGER FACTOR; GTP-BINDING AB Previous studies have demonstrated that presecretory proteins such as maltose binding protein (MBP) and outer membrane protein A (OmpA) are targeted to the Escherichia coli inner membrane by the molecular chaperone SecB, but that integral membrane proteins are targeted by the signal recognition particle (SRP). In vitro studies have suggested that trigger factor binds to a sequence near the N terminus of the mature region of OmpA and shunts the protein into the SecB pathway by blocking an interaction between SRP and the signal peptide. By contrast, we have found that the targeting pathway of a protein under physiological conditions is dictated by the composition of its targeting signal. Replacement of the MBP or OmpA signal peptide with the first transmembrane segment of AcrB abolished the dependence on SecB for transport and rerouted both proteins into the SRP targeting pathway. More modest alterations of the MBP signal peptide that simply increase its hydrophobicity also promoted SRP binding. Furthermore, we obtained evidence that SRP has a low affinity for typical signal peptides in vivo. These results imply that different classes of E. coli proteins are targeted by distinct pathways because bacterial SRP binds to a more restricted range of targeting signals than its eukaryotic counterpart. C1 NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Bernstein, HD (reprint author), NIDDKD, Genet & Biochem Branch, NIH, Bldg 10,Room 9D-20, Bethesda, MD 20892 USA. EM harris_bernstein@nih.gov NR 36 TC 123 Z9 124 U1 1 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 13 PY 2001 VL 98 IS 6 BP 3471 EP 3476 DI 10.1073/pnas.051484198 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 411WB UT WOS:000167521300096 PM 11248102 ER PT J AU Hernandez-Sanchez, C Basile, AS Fedorova, I Arima, H Stannard, B Fernandez, AM Ito, Y LeRoith, D AF Hernandez-Sanchez, C Basile, AS Fedorova, I Arima, H Stannard, B Fernandez, AM Ito, Y LeRoith, D TI Mice transgenically overexpressing sulfonylurea receptor 1 in forebrain resist seizure induction and excitotoxic neuron death SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SENSITIVE K+ CHANNELS; HIPPOCAMPAL CA1 NEURONS; HEAT-SHOCK PROTEIN; RAT HIPPOCAMPUS; KAINIC ACID; POTASSIUM CHANNELS; GENE-EXPRESSION; GLOBAL-ISCHEMIA; ATP CHANNELS; OPENERS AB The ability of the sulfonylurea receptor (SUR) 1 to suppress seizures and excitotoxic neuron damage was assessed in mice transgenically overexpressing this receptor. Fertilized eggs from FVB mice were injected with a construct containing SUR cDNA and a calcium-calmodulin kinase II alpha promoter. The resulting mice showed normal gross anatomy, brain morphology and histology, and locomotor and cognitive behavior. However, they overexpressed the SUR1 transgene, yielding a 9- to 12-fold increase in the density of [H-3]glibenclamide binding to the cortex, hippocampus, and striatum. These mice resisted kainic acid-induced seizures, showing a 36% decrease in average maximum seizure intensity and a 75% survival rate at a dose that killed 53% of the wild-type mice. Kainic acid-treated transgenic mice showed no significant loss of hippocampal pyramidal neurons or expression of heat shock protein 70, whereas wild-type mice lost 68-79% of pyramidal neurons in the CA1-3 subfields and expressed high levels of heat shock protein 70 after kainate administration. These results indicate that the transgenic overexpression of SUR1 alone in forebrain structures significantly protects mice from seizures and neuronal damage without interfering with locomotor or cognitive function. C1 NIDDKD, Sect Mol & Cellular Physiol, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP LeRoith, D (reprint author), NIDDKD, Sect Mol & Cellular Physiol, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RI Hernandez Sanchez, Catalina/N-1737-2014; Arima, Hiroshi/I-7383-2014 OI Hernandez Sanchez, Catalina/0000-0002-0846-5019; Arima, Hiroshi/0000-0003-3746-1997 NR 40 TC 73 Z9 73 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 13 PY 2001 VL 98 IS 6 BP 3549 EP 3554 DI 10.1073/pnas.051012898 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 411WB UT WOS:000167521300109 PM 11248115 ER PT J AU Runyon, SP Savage, JE Taroua, M Roth, BL Glennon, RA Westkaemper, RB AF Runyon, SP Savage, JE Taroua, M Roth, BL Glennon, RA Westkaemper, RB TI Influence of chain length and N-alkylation on the selective serotonin receptor ligand 9-(aminomethyl)-9,10-dihydroanthracene SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID 5-HT2A RECEPTOR; AGENTS; MODEL AB Comparison of the serotonin 5-HT2A receptor affinities of chain lengthened and N-alkylated analogues of the novel ligand 9-aminomethyl-9,10-dihydroanthracene (AMDA) and a structurally similar prototypical tricyclic amine imipramine suggests that the two agents bind to the receptor in different fashions. The demonstration that AMDA is highly selective for serotonin receptors (5-HT2A, K-i = 20 nM; 5-HT2c, K-i = 43 nM) versus the dopamine D-2 receptor (K-i >10,000 nM), as well as the serotonin and norepinephrine transporters (Ki >10,000 nM) further suggests that AMDA and the nonselective ligand imipramine interact with these target macromolecules in different ways. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Virginia Commonwealth Univ, Sch Pharm, Dept Med Chem, Richmond, VA 23298 USA. Case Western Reserve Univ, Sch Med, Dept Biochem, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Psychiat, Cleveland, OH 44106 USA. NIMH, Psychoact Drug Screening Program, Bethesda, MD 20892 USA. RP Westkaemper, RB (reprint author), Virginia Commonwealth Univ, Sch Pharm, Dept Med Chem, RB Smith Bldg,410 N 12th St,POB 980540, Richmond, VA 23298 USA. RI Roth, Bryan/F-3928-2010 FU NIMH NIH HHS [MH57969, MH01366, MH57635] NR 19 TC 12 Z9 12 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD MAR 12 PY 2001 VL 11 IS 5 BP 655 EP 658 DI 10.1016/S0960-894X(01)00023-3 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 409GG UT WOS:000167375700011 PM 11266163 ER PT J AU Woods, DB Vousden, KH AF Woods, DB Vousden, KH TI Regulation of p53 function SO EXPERIMENTAL CELL RESEARCH LA English DT Review ID TUMOR-SUPPRESSOR P53; UBIQUITIN LIGASE ACTIVITY; DNA-BINDING FUNCTION; RING-FINGER DOMAIN; MDM2 ONCOPROTEIN; NUCLEAR EXPORT; NUCLEOLAR-LOCALIZATION; SUMO-1 MODIFICATION; CELL-CYCLE; IN-VITRO C1 NCI, Regulat Cell Growth Lab, Frederick, MD 21702 USA. RP Vousden, KH (reprint author), NCI, Regulat Cell Growth Lab, 1050 Boyles St, Frederick, MD 21702 USA. NR 136 TC 251 Z9 261 U1 0 U2 6 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD MAR 10 PY 2001 VL 264 IS 1 BP 56 EP 66 DI 10.1006/excr.2000.5141 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 413QQ UT WOS:000167623600006 PM 11237523 ER PT J AU Srivastava, DK Tendler, CL Milani, D English, MA Licht, JD Wilson, SH AF Srivastava, DK Tendler, CL Milani, D English, MA Licht, JD Wilson, SH TI The HIV-1 transactivator protein Tat is a potent inducer of the human DNA repair enzyme beta-polymerase SO AIDS LA English DT Article DE lymphoma; AIDS; HIV-1; Tat; Rev; base excision repair; DNA rearrangement; DNA recombination; Sp1 ID HUMAN-IMMUNODEFICIENCY-VIRUS; CELL LYMPHOTROPIC VIRUS; EPSTEIN-BARR VIRUS; SP1-MEDIATED TRANSCRIPTIONAL ACTIVATION; HUMAN LYMPHOCYTES-B; KINETIC-ANALYSIS; GENE-EXPRESSION; UP-REGULATION; INFECTION; PROMOTER AB Objective: This study examines the effects of the HIV-1 regulatory proteins, Tat and Rev, on the expression of the DNA polymerase beta (beta -pol) gene, which encodes a key protein in the DNA base-excision repair pathway. The rationale for these experiments is to examine the potential involvement of base-excision repair protein deregulation in HIV-1-related lymphomas. Design: Expression of beta -pol mRNA was examined in AIDS-related lymphomas and non-AIDS-related lymphomas and as a function of HIV-1 infection of B cells in culture. The effect of Tat or Rev over-expression on beta -pol promoter expression was tested by transient co-transfection assays with a beta -pol promoter reporter plasmid and a Tar or Rev over-expression plasmid. Methods: Northern blot analysis was used to quantitate beta -pol expression in lymphoma and cells. Raji cells were co-transfected with a chloramphenicol acetyltransferase (CAT) reporter plasmid and a plasmid over-expressing Tat or Rev. CAT activity was measured in transfected cells. Results: beta -Pol mRNA was >10-fold higher in AIDS-related than in non-AIDS B-lineage lymphomas. beta -Pol expression was up-regulated in a B-cell line upon infection with HIV-1, and increased in Raji cells upon recombinant expression of the Tar gene. The beta -pol promoter was transactivated (fourfold induction) by Tat, but not by Rev. Tat-dependent transactivation required a binding site for the transcription factor Sp1 in the beta -pol promoter. Conclusion: These results suggest that HIV-1 Tat can interact with cellular transcription factors to increase the steady-state level of beta -pol in B cells. Tat-mediated induction of beta -pol may alter DNA stability in AIDS-related lymphomas. (C) 2001 Lippincott Williams & Wilkins. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. Schering Plough Res Inst, Kenilworth, NJ 07033 USA. Mt Sinai Sch Med, Div Pediat Hematol Oncol, New York, NY USA. Mt Sinai Sch Med, Div Mol Med, New York, NY USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. FU NICHD NIH HHS [HD28583] NR 46 TC 10 Z9 10 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAR 9 PY 2001 VL 15 IS 4 BP 433 EP 440 DI 10.1097/00002030-200103090-00001 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 409UL UT WOS:000167404000001 PM 11242139 ER PT J AU Kim, JS Lee, SM Lee, T Lee, YW Trepel, JB AF Kim, JS Lee, SM Lee, T Lee, YW Trepel, JB TI Transcriptional activation of p21(WAF1/C1P1) by apicidin, a novel histone deacetylase inhibitor SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE apicidin; p21(WAF1/C1P1); transcription; histone; acetylation ID TRANSFORMED-CELL DIFFERENTIATION; P53-MEDIATED G(1) ARREST; CHROMATIN STRUCTURE; GENE; SP1; ACETYLATION; WAF1/CIP1; PROMOTER; INDUCERS; PROLIFERATION AB Apicidin [cyclo(N-O-methyl-L-tryptophanyl-L-isoleucinyl-D-pipecolinyl-L-2-amino-8-oxodecanoyl)], a novel histone deacetylase inhibitor, has been identified as an antiprotozoal and antiproliferative agent. In this study, we show apicidin induces transcriptional activation of p21(WAF1/CIP1) (p21) in human prostate carcinoma cells. Apicidin induces expression of p21 protein and mRNA and activation of p21 promoter-luciferase reporter constructs, Apicidin causes an accumulation of acetylated histones H3 and H4 in total cellular chromatin. Chromatin immunoprecipitation shows p21 promoter DNA is associated with hyperacetylated histones H3 and H4 after treatment with apicidin. Therefore, the data here demonstrate that apicidin activates p21 transcription associated with the acetylation of histones H3 and H4. (C) 2001 Academic Press. C1 NCI, Med Branch, NIH, Bethesda, MD 20892 USA. Seoul Natl Univ, Sch Agr Biotechnol, Suwon 441744, South Korea. RP Kim, JS (reprint author), Georgetown Univ, Sch Med, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. NR 35 TC 46 Z9 49 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 9 PY 2001 VL 281 IS 4 BP 866 EP 871 DI 10.1006/bbrc.2001.4434 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 413QX UT WOS:000167624300005 PM 11237739 ER EF